Virtual Library

Background:
To assess the utility of four-dimensional (4D) ventilation/perfusion (V/Q) PET/CT lung imaging to facilitate mid-radiotherapy treatment adaption with volumetric modulated arc radiotherapy (VMAT).

Method:
In a prospective clinical trial, patients with non-small cell lung cancer (NSCLC) underwent [68]Ga-4D-V/Q PET/CT scanning before and during a six-week (60Gy) course of definitive chemoradiation. Functional lung volumes were delineated on both datasets as ‘highly perfused’ (HPLung) and ‘highly ventilated’ (HVLung), using a 70[th] centile SUV threshold. Three VMAT plans were created on the mid-treatment datatsets: optimised to anatomical lung, HPLung, and HVLung volumes, respectively. Functional dose volumetrics were assessed using the parameters of mean lung dose (MLD), and lung volume receiving 5, 20 or 30Gy, (V5, V20, and V30). Plan quality was assessed for consistency with respect to conformity indices, and doses to critical structures.

Result:
The study cohort consisted of 10 patients resulting in a total of 30 VMAT plans. PTV volumes reduced by a mean of 5.5% between scans. HVLung volume increased between scans by a median value of 39.2%. Subsequent volumetric and spatial changes were reflected in varying DICE similarity coefficients, or DSC (ranging from 0.336-0.923). HPLung decreased by a median value of 4.5% with spatial discrepancy represented by DSC of 0.568-0.805. Increase in ventilated function was most prevalent adjacent to the target, limiting the benefit of adaptive planning (Fig 1). Plan quality was consistent with the median PTV D95 ranging from 60.6-61.3Gy, and mean conformity index ranging from 1.23-1.25. Functional MLD of HPLung decreased by a mean of 7.3%, p=0.02. Plans optimised to HPLung resulted in a reduction of perfused lung V5 by a mean of 13.2%, p<0.01, with HVlung plans yielding a decrease in ventilated lung V5 of 9.6%, p=0.02. Fig 1 Figure 1



Conclusion:
To achieve reduced irradiation of functional lung, radiotherapy adaptation is more effectively facilitated by perfusion rather than ventilation imaging.

Background:
Recent randomized and observational studies suggested that pre-existing cardiac disease and higher radiation heart doses were associated with more cardiac events and worse overall survival (OS) in locally-advanced non-small cell lung cancer (NSCLC) treated with definitive chemoradiation. Post-operative thoracic radiotherapy (PORT) delivered via non-modern radiation techniques had also been shown to increase cardiac mortality. Hence we performed this study to determine the impact of pre-existing ischaemic heart disease and radiation heart dose on OS in NSCLC patients treated with PORT using contemporary radiation techniques.

Method:
Study eligibility criteria included stage I to III NSCLC treated with PORT at two institutions from 2007 to 2014. Clinical data and dosimetric parameters affecting overall survival were collected from the institutional electronic medical records as well as the national death and acute myocardial infarction registries. Univariate cox regression was performed using Stata version 13.

Result:
Twenty eligible patients were identified. Median follow-up duration was 30.4 months (2.3- 81.9). Median age was 59 years. Median prescription dose was 57 Gy. Median mean heart dose was 12Gy. 10% had pre-existing ischaemic heart disease. 75% underwent lobectomy. 60% had pathological stage III disease. 40% had left-sided disease. 70% received chemotherapy. The 1- and 2-year OS were 75% and 60% respectively. Univariate analysis showed that pre-existing ischaemic heart disease was significantly associated with worse OS (hazard ratio 7.13, 95% confidence interval 1.17-43.47, P value < 0.03). Mean heart dose and the other cardiac dosimetric parameters (volume of heart receiving ≥ 5, 25, 30, 40, 50Gy, and dose to ≥ 30% of heart volume) were not associated with OS.

Conclusion:
Pre-existing ischaemic heart disease was a significant predictor for worse OS in NSCLC patients treated with modern PORT. We plan to expand the cohort to confirm these findings. Patients should be screened for ischaemic heart disease and cardiac function optimised prior to PORT and on follow-up.

Background:
Stereotactic body radiation therapy (SBRT) has emerged as a treatment option for patients with early-stage lung cancer, especially in the medically inoperable population. As most reported data are from developed countries, the purpose of this study was to report clinical outcomes and toxicity for SBRT in these patients from a single academic institution from Brazil.

Method:
Between January 2007 and September 2015, 102 consecutives lung lesions at Hospital Sírio–Libanês, São Paulo, were treated with SBRT, of which 59 primary non-small cell lung cancer (NSCLC) (biopsy-proven) lesions from 54 inoperable patients were reviewed from a specific registry (43 lesions were excluded: metastatic or with no biopsy). For patient immobilization, semi-rigid (vaclok based) system was used. The CTV was delineated based on CT data from 3 phases superimposed on 3-dimensional radiation treatment planning systems to obtain an internal target volume (ITV). A median dose of 54Gy (45-60Gy) was prescribed in 3 – 5 fractions per lesion and image guidance was mandatory. Treatment outcomes for in-field local control (LC) per lesions, progression free survival (PFS) and overall survival (OS) were assessed with Kaplan-Meier estimates. Toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.0

Result:
Of the 54 patients analyzed, the majority were elderly (average age 75.7 years; SD ±8.8 years). More than 90% were PET/CT staged with Stage IA 40 (68%) and adenocarcinoma 46 (78,0%) representing the most common stage and histology, respectively. Median follow-up was 21,3 months (4 -55 months) for LC, 22.3 months (4 -55,8 months) for PFS, and 18.7 months (4.2 - 56,4 months) for OS. The 2-year rates of LC, PFS and OS were 89.1%, 79%, and 80.3%. Median LC, PFS, OS was 48.5 months, not reached, 41,8 months, respectively. Histology, size and stage of the primary were not a significant predictor for LC (P = 0.58; P = 0.26; P= 0.64, respectively), PFS (P = 0.81; P = 0.86; P = 0.64, respectively), or OS (P=0.21; P = 0.62; P = 0.94, respectively). Grade 3+ toxicities were observed in 2 patients (3.7%), of which 1 was grade 3 pneumonitis and one was grade 4 skin toxicity.

Conclusion:
Our data also show that SBRT is effective and feasible in a predominantly elderly and medically inoperable patient population in Brazil.

Background:
The optimal radiation schedule for small cell lung cancer (SCLC) has not yet fully established. This study was designed to compare the clinical outcomes between twice- and once-daily radiotherapy in the treatment of SCLC.

Method:
One hundred and twenty-four consecutive patients diagnosed with extensive stage SCLC and treated with chemoradiotherapy were retrospectively reviewed. Either twice-daily hyper-fractionated irradiation (45 Gy/30 fractions/BID), or alternative schedules, including hypo-fractionated (45 Gy/15 fractions/QD) or conventionally fractionated (50 Gy/25 fractions/QD or 60 Gy/30 fractions/QD) radiation was delivered, with etoposide and platinum prescribed concurrently or sequentially. Local controls and overall survivals were calculated and compared between twice- and once-daily schedules based on Kaplan-Meier method. Toxicities were record according to Common Terminology Criteria Adverse Events.

Result:
There were 67 and 57 patients received twice- and once-daily chest radiotherapy, respectively. With a median follow-up of 27 and 24 months, the local control rates were reported 64.2% and 63.2%. The 2-year estimated local progression-free survival rates were similar (61.6% vs 61.0%, p=0.90). Progressive disease identified three months after radiotherapy was correlated to increased local failure (p=0.026). There was no difference between the incidences of grade 3-4 toxicities between twice- and once-daily schedules (23.9% vs 12.3%, p=0.16).

Conclusion:
Either twice- (45 Gy/30 fractions/BID) or once-daily (45 Gy/15 fractions/QD, 50 Gy/25 fractions/QD, 60 Gy/30 fractions/QD) radiation schedule could be considered in the treatment of SCLC, resulting in comparable local control and toxicities.

Background:
[18]F-Fluorodeoxyglucose positron emission tomography-computed tomography ([18]F-FDG-PET-CT) has the potential to increase the precision in contouring of gross tumour volume (GTV). However, detection of tumour edge in the halo around the tumour has been a problem. A surgical histopathological examination is the current gold standard for tumour size estimation in NSCLC. The aim of this study was to determine an optimal cut-off of standardized uptake value (SUV) on FDG-PET-CT images that correlates best with tumour size on surgical histopathology examination.

Method:
From January 2013- July 2014, 25 consecutive patients with diagnosed early NSCLC (pT1-pT3,N0M0) who underwent surgical resection (either a lobectomy or pneumonectomy) were accrued. GTVs were delineated on a preoperative FDG-PET-CT scan (acquired within 8 weeks before surgery) by automatic delineation using % threshold SUV at 20%, 30%, 40%, 50% of maximal uptake and threshold as absolute SUV 2, 2.5, 3, 3.5 and 4. The maximum tumour size was recorded from the surgical histopathology reports. First order linear regression was used to obtain values of optimal cut off SUV for each patient at which maximum size of GTV on FDG-PET-CT matched with maximum tumor size on histopathology. Different SUV thresholds of GTV delineation were compared with histopathology with respect to the estimation of maximum tumour size using Bland-Altman plots. The above methodology was carried out in 25 patients in test set. 12 additional patients were used to validate the results of the test set.

Result:
On analysis of 25 patients in the test set using first order linear approximation, the mean optimal cut-off values for GTV delineation on FDG-PET-CT images were 35.6 % ± 18.6 for % threshold SUV and a 4.35 ± 1.7 for absolute SUV. On analysis of 12 more patients in the validation set, the mean optimal cut-off values for GTV delineation on FDG-PET-CT images were 36.9 ± 16.9 % threshold SUV and a 4.1 ± 1.6 absolute SUV. After combined analysis of all 37 patients, the mean optimal cut-off values for GTV delineation on FDG-PET-CT images were 36 ± 17.9 % threshold SUV and a 4.27 ± 1.7 absolute SUV. On comparing various methods of delineation by Bland-Altman plots, auto-contouring with percentage threshold of 40% and absolute SUV 4 were in greater agreement with the histopathological tumour size.

Conclusion:
Auto-contouring of GTV in NSCLC with the help of optimal cut-off SUV in FDG-PET-CT will improve precision in delineation, reduce inter-observer variability and importantly will save time.

Background:
We report the results of a randomized, placebo-controlled pilot study for measuring the effect of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, on pulmonary distress in patients receiving thoracic radiotherapy (TRT) with or without chemotherapy. We aimed to evaluate the practicality for developing a larger-scale, randomized phase III study in the future.

Method:
Twenty-three (23) eligible patients receiving TRT (≥45 Gy) for predominantly non-small cell lung cancers were enrolled; an ECOG performance of 2 or better was required. The patients were randomized to receive either 20 mg of lisinopril or placebo once daily during and up to 3 months post-RT. The trial stopped early due to lower accrual than anticipated. The baseline and weekly during RT patient-reported outcome (PRO) results for Symptom Experience Questionnaire (SEQ), Lung Cancer Symptom Scale (LCSS), the EORTC for Lung Cancer Questionnaire (EORTC-QLQ-LC13), and Function Assessment of Cancer Treatment were analyzed. Adverse events (AE) were measured according to CTCAE v4.0. Our primary endpoint was safety and AE profile of lisinopril, followed by PRO comparisons; multiple comparisons for secondary analyses were not adjusted.

Result:
There were 11 and 12 eligible patients on the placebo and lisinopril arms, respectively. Mean age was 63.5 years; 13 (62%) were male. Eighteen (86%) were either former or current smokers. All baseline characteristics were balanced. All baseline PRO results were balanced except for more shortness of breath by SEQ/LCSS which were slightly worse in the placebo arm. The placebo patients reported more dyspnea on climbing stairs at baseline on EORTC-QLQ-LC13. The incidences of grade 2 hypotension were 2 vs. 4 patients for placebo and lisinopril, respectively (P=0.26). One (1) patient taking lisinopril had grade 2 acute kidney injury (P=0.20). One (1) patient developed grade 4 dyspnea on placebo arm. No patients experienced grade 5 toxicities. Patients taking lisinopril did not have more cough or allergic reaction. Acute respiratory distress as measured by worst dyspnea score was poorer in placebo vs. lisinopril patients (42.0 vs. 77.5 respectively, P=0.006). The rest of the PRO indices were with no clinically meaningful differences between arms.

Conclusion:
Although this novel trial was underpowered which was not intended, the results provided a strong signal for safety and perhaps even efficacy, by PRO, in concurrently administering lisinopril, an ACE inhibitor, for advanced lung cancer patients who require RT-based therapies. Using lisinopril for mitigating or preventing radiation-induced pulmonary distress or pneumonitis will require future trial testing. Support: UG1CA189823.

Background:
[Background] Chemoradiotherapy is the standard treatment for locally advanced non-small cell lung cancer. Histological difference has not been taken into account in the chemoradiotherapy unlike in chemotherapy for metastatic disease. The purpose of this study is to evaluate the results and relapse pattern difference between squamous cell carcinoma (Sq) and adenocarcinoma (Ad) histology.

Method:
[Methods] We retrospectively analyzed the outcomes and relapse pattern in patients who received definitive chemoradiotherapy for locally advanced non-small cell lung cancer in our institute between 2003 and 2012

Result:
[Results] There were 74 Sq patients and 36 Ad patients. Sq patients had more advanced T Stage, and less female ratio. Other factors were well balanced. Median follow-up time in all patients and surviving patients were 21.3 and 79.6 month, respectively. Median survival time was not significantly different between Sq and Ad patients (P=0.61; 20.8 and 26.7 month, respectively). Relapse pattern was different between the two histologies (P=0.0149). Locoregional, distant, and simultaneous relapse of locoregional and distant sites were observed in 32 (55.2 %), 23 (39.8 %) and 3 (5.2 %) for Sq patients; and 7(22.6 %), 20(64.5 %) and 4(12.9 %) for Ad patients, respectively. The time from relapse to death in Sq patients were shorter than Ad patients (median, 8.9 months and 14.9 months; P=0.046). Numbers of patients surviving without any relapse for 5 years or more were 9 (12.2 %) in Sq and 1 (2.8 %) in Ad. Figure 1



Conclusion:
[Conclusion] More than 10% of Sq patients could achieve relapse-free survival longer than 5 years. However, in relapsed patients, prognosis was poorer in Sq patients compared to Ad patients. Dominant pattern of relapse was locoregional in the Sq patients. More aggressive local treatment such as combination with surgery or dose escalation of radiotherapy may improve survival in Sq patients.

Background:
Three dimensional conformal radiation therapy (3DCRT) with 10-15 static fields is the most common technique used to create the desired conformal dose distribution for SBRT. The main drawback of 3DCRT planning is the lengthy treatment time relating to patient setup and radiation delivery resulted from many fields needed to create an acceptable treatment plan. The capability of VMAT to increase the sparing of organs at risk (OARs) without compromising conformal dose distributions in a shorter treatment time compared to IMRT and 3DCRT has been demonstrated for both conventional fractional radiotherapy and SBRT in the treatment of lung cancer. The purpose of this study is to investigate the feasibility of partial arc volumetric modulated arc therapy (VMAT) in lung cancer stereotactic body radiotherapy (SBRT), as well as the volumetric and dosimetric effects of different internal target volume (ITV) definitions with 4D CT.

Method:
Fourteen patients with primary and metastatic lung cancer underwent SBRT were enrolled in this study. Full and partial VMAT plans were generated with four different ITVs: ITVall, ITV~MIP~, ITV~AIP~ and ITV~2phases~, representing ITVs generated from all 10 respiratory phases, maximum intensity projection (MIP), average intensity projection (AIP), and 2 extreme respiratory phases. Volumetric and dosimetric differences, as well as MU and delivery time were investigated.

Result:
Full arc VMAT irradiated less dose 2 cm away from the PTV compared with partial arc VMAT (P=0.002), other than this, there was no significant difference on target coverage between partial and full arc VMAT plans. However, partial arc VMAT irradiated less MLD and V5 compared with full arc VMAT. Partial arc VMAT also achieved better protection on spinal cord, heart and esophagus compared with full arc VMAT. The average MU and delivery time of full arc VMAT plans were 240 and 1.6 min more than those of partial arc VMAT. No other significant difference was observed between these two planning schemes. There were no significant differences on target coverage and organ at risks (OARs) sparing among four ITVs. The average percent volume differences of ITV~MIP~, ITV~AIP~ and ITV~2phases~ to ITV~all~ were 8.6%, 13.4%, and 25.2%, respectively.

Conclusion:
Partial arc VMAT was feasible and more efficient for lung SBRT. Although ITV~MIP~, ITV~AIP~ and ITV~2phases~ were smaller than ITVall, no significant dosimetric differences resulted due to a relative small target volume of lung SBRT.

Background:
As the use of radiotherapy (RT) in lung cancer patients in the ICU is poorly described; we evaluated characteristics, outcomes, RT utilization and costs in a population-based cohort of ICU lung cancer patients in Ontario, Canada.

Method:
Eligible patients between April 1, 2007 and March 31, 2014 were identified through provincial administrative healthcare databases. Given that a patient could receive multiple RT deliveries, each ICU stay was analyzed separately as an episode of care. Significant differences in patient, treatment, institution and tumor characteristics between RT and non-RT groups were compared with t-tests and chi-square tests, as appropriate. Pre-ICU disposition was by ER admission, same institution admission or different institution transfer. The Kaplan-Meier method was used to estimate overall survival (OS), measured from index ICU admission to death, censoring at the end of the observation period. Differences in OS between the RT and non-RT groups were compared using the log-rank test. Univariable and multivariable Cox proportional hazard modeling were performed to assess the effect of RT on OS. Daily costs were calculated in 2015 Canadian dollars (converted using consumer price indices) for RT patients only, based on acute hospitalizations, ER visits, cancer clinic visits, same-day surgeries, and physician billings. For all analyses, a p-value threshold of <0.05 was used to define statistical significance.

Result:
In 13,739 unique lung cancer ICU patients, RT was delivered in 133 episodes to 1.0% (n=131) of patients. The RT group tended to be younger (median age 65 vs. 68, p<0.001), on some form of ventilation (79.8% vs. 38.2%, p<0.001) and with longer ventilation durations ((median [IQR]) 6 [1-11] vs. 0 [0-2] days, p<0.001). RT patients were more likely to present from the ER (28.2% vs. 21.9%, p=0.002) or via transfer (35.3% vs. 9.7%, p<0.001). While ICU discharge was common in both RT (56.4%) and non-RT (71.4%) cohorts, 1-year OS was poor with both groups, but most notably in the RT group (11.3% vs. 42.4%). RT was associated with inferior 1-year OS on unadjusted modeling (HR=1.99, 95% CI:1.65-2.38, p<0.001), with ventilation status and pre-ICU disposition adjusting this finding towards the null on multivariable modeling (HR=1.17, 95% CI:0.97-1.40, p=0.095). The median daily cost of medical care in RT patients was $2771 (IQR $1757-$3753), with acute hospitalization accounting for more than half (median $1723) of calculated costs.

Conclusion:
The use of RT needs to be considered judiciously for lung cancer patients in the ICU, given the poor prognosis and increased costs incurred.

Background:
Stereotactic Body Radio Therapy (SBRT) is a curative treatment option for patients diagnosed with primary lung cancer, who are deemed unsuitable for surgical resection. Currently, the most commonly used contouring method utilises 4D-CT delineated Internal Target Volumes (ITVs). This takes into account the tumour positions throughout all phases of the respiratory cycle but can result in unnecessarily large Planning Target Volumes (PTVs). The time-weighted mid-ventilation (TWMV) method is an alternative contouring method in which the gross tumour volume (GTV) is contoured on a single 3D-CT structure from the 4D dataset at the phase closest to its time-weighted average position. We hypothesise that the TWMV method will result in significantly smaller PTV and treated lung volumes when compared with the ITV method

Method:
5 consecutive lung SBRT patients who participated in a Phase 2 Clinical Trial were contoured with the ITV method using Velocity Advanced Imaging software (v.3.2.0). The PTVs and irradiated lung volumes were recorded. The GTVs were then re-contoured both manually on each phase of the 4D-CT and automatically using deformable image registration (DIR). The time-weighted average tumour position was determined and PTV volumes generated from the phase closest to this position using patient-specific margins described by Wolthaus et al. Finally, PTVs and treated lung volumes were recorded and compared with those from the ITV plans.

Result:
There was close agreement in both manual and automatic contouring methodologies for the time-weighted average position, with a three-dimensional vector error between the GTV centroids of 1.6mm ± 0.8 mm (1 SD). The manual contouring methods resulted in the same phase from the 4DCT being used for the mid-ventilation approach for all 5 patients. Using the mid-ventilation approach, the PTV volumes decreased by an average of 24.5% (range 19.8% - 33.7%), corresponding to an average decrease in irradiated healthy lung of 17.1cc ± 6.5cc. The decrease in PTV volume was greater for patients with a larger cranio-caudal tumour motion, with a linear relationship found between the two (R[2] = 0.995).

Conclusion:
For patients undergoing lung SBRT, contouring using the TWMV method resulted in a significant decrease in both PTVs and irradiated lung volumes compared with the ITV method. DIR for implementation of the mid-ventilation technique was feasible and reproducible. Application of this technique may improve the therapeutic ratio, and enable dose escalation for treatment of patients with unfavourable lung function to reduce lung toxicities.

Background:
Recombinant human endostatin (Endostar) is an angiogentic medicine with mild toxicity and strong efficacy in systematic treatment of NSCLC. Recently, several studies proved that Endostar combined with radiotherapy could enhance NSCLC treatment efficiency according to mechanism of microenvironment normalization. However, this combination therapy has not tested in elderly population up to now. In this trial, we observed the efficacy and safety of Endostar combined with concurrent intensity modulated radiation therapy (IMRT) for inoperable elderly local advanced NSCLC.

Method:
This trial was perspective, open‐labeled study. A total of 40 inoperable elderly local advanced NSCLC were randomly assigned into two arms. Twenty patients received IMRT alone in control arm, the dosage of primary tumor and mediastinal lymph node metastasis was DT 60 66 G/30 33/6‐ 7w. Intravenous infusion of Endostar concurrently inducted with IMRT in experimental arm. Endostar is administrated in 15mg once daily for two weeks followed by one week interval, repeated twice. The efficacy was evaluated according to RECIST 1.1 criteria and recorded ORR, DCR, mDFS and mOS. Safety and efficacy evaluation were performed based on NCI CTC v4.0 criteria.

Result:
In the experimental arm, 15 cases were PR and 5 cases were SD. Although a superiority of patient number showed comparing to the control group, there is no statistical difference between two arms either ORR (75.0% vs. 80.0%, p=0.326) or DCR (100% vs. 90.0%, p = 0.031). The mDFS (9.4M vs. 6.8M, p=0.286) and mOS (17.5M vs. 14.1M, p=0.052) in the two groups were not significantly different. One year survival rate were 79.4% vs 61.1%, and 2 year survival rate was 9.0% vs 0% in experimental arm and control arm, respectively. In the experimental arm, risk of disease progression decreased by 35% by using Endostar plus IMRT, HR = 0.649 (95% CI, 0.288 to 1.464), meanwhile the risk of death decreased by 66%, HR = 0.435 (95% CI, 0.184 to 1.030) . Most toxicities occured in two arms were grade 1/2, there is no grade 3/4 adverse events occured. In contrast to the control arm, no difference in safety events was found in the Endostar plus IMRT group.

Conclusion:
Endostar combined with concurrent IMRT for inoperable elderly local advanced NSCLC had a good safety and activity profile. One and two year survival rates were all increased, with a tendency of prolonging median survival time. Therefore the conclusion is worth to further confirmed in similar clinical study but with larger sample size.

Background:
SABR is a definitive treatment option in patients diagnosed with an early stage lung cancer. It is a suitable alternative for patients of poor performance status who may be medically inoperable. The Cyberknife (CK) machine delivers high dose, hypofractionated regimes using extensive non-coplanar beams of radiation. This enables lesions to be treated with radiobiologically higher doses, maximising local tumour control. University Hospital Birmingham has delivered the most CK-based lung SABR for any stage lung cancer in the UK. Limited data exists for outcomes following CK treated lung cancers. At our institute we reviewed a cohort of patients with early stage lung cancer treated with CK over a 30 month period looking at overall survival and local control rates to ensure this was comparable to accepted SABR outcome statistics.

Method:
A retrospective analysis was performed on 88 patients with primary lung cancer treated with CK from June 2014 to December 2016.

Result:
From the 88 patients reviewed, 1 was excluded due to lack of follow-up data. Demographic data is presented in table 1. Median follow-up was 14 months (range 0.5 to 36). Local control (LC) was achieved in 93% of patients. The median progression free survival (PFS) interval was 15 months. Overall survival (OS) at 1 year was 90% and at 3 years 72%. The median overall survival was 14 months (range 0.5 to 36). During follow-up, 14 patients progressed. However, only 6 of these progressed within the treated lesion. There were no treatment-related deaths, nor grade 3 or 4 adverse toxicities documented. Table 1 Demographics

SEX	Male 52 (59%) Female 36 (41%)
AGE	Mean: 72 Years Range : 55- 87
ECOG PERFORMANCE STATUS	1 : 21 2: 33 3: 2 Not available: 32
TNM STAGING	T1aN0M0 : 4 T1bN0M0 : 32 T2aN0M0 : 46 T2bN0M0 : 6
HISTOLOGY	Adenocarcinoma : 8 Squamous: 9 NSCLC not differentiated: 2 Radiological diagnosis: 69
DOSE FRACTIONATION	50Gy/ 5# : 2 51Gy/ 3# : 1 54Gy/ 3# : 15 54Gy/ 5# : 1 55Gy/ 5# : 58 60Gy/ 8# : 11

Conclusion:
These results have proven Cyberknife radiotherapy to be a safe and effective treatment for acquiring local disease control in early lung cancers. LC rates are in line with previously published outcomes for lung SABR. OS appears better at 3 years, but this does warrant further follow up.

Background:
Surgical resection is generally accepted as the gold standard for managing early stage lung cancer. There remains, however, a subset of patients who do not proceed to surgery. Many of these patients are ‘medically inoperable’ due to comorbidities. Others may decline surgery or their tumour is deemed inoperable due to technical difficulties. In this subset, SABR has been shown to be an effective alternative treatment option. SABR involves multiple beams, which together deliver an ablative dose of radiation to a precise area. There is rapid dose fall-off which ensures sparing of nearby structures. Evidence suggests that SABR is not associated with a clinically relevant deterioration in quality of life (QoL). The negative impact on pulmonary function is also minimal. This audit aims to assess the effect of SABR on both pulmonary function and QoL of a cohort of patients undergoing treatment in the West Midlands.

Method:
The Queen Elizabeth Hospital, Birmingham delivers SABR to patients across the West Midlands. We followed a cohort of 45 patients who received SABR between September 2016 and April 2017 for early stage lung cancer. If patients had baseline PFTs, these were repeated between 3-13 weeks post treatment. Patients had their QoL assessed using the EORTC Quality of Life Questionnaire (QLQ-C30 version 3). This was recorded at baseline, early and late follow up (defined as 13-28 days and 30-75 days post treatment respectively).

Result:
To date, twenty patients have had baseline FEV1 and FVC which was repeated post treatment. Median baseline FEV1 was 1.52 (range 0.56-2.92) and median baseline FVC was 2.63 (range 1.25-4.89). Post treatment median FEV1 was 1.34 (range 0.60-2.61) and median FVC was 2.42 (range 1.40- 3.95). Using a Wilcoxon Signed Ranks test, there was no significant difference between pre and post treatment FEV1 or FVC (Z=-0.78,p=0.43 and Z=-1.0,p=0.31 respectively). Similarly, there was no difference in DLCO pre and post treatment (Z= -0.27,p=0.79) Thirty nine patients had their baseline QoL assessed. Of these, 36 had this repeated at early follow-up and 31 at late follow up. Median QoL score at baseline, early and late follow up was 66/100, 54/100 and 50/100 respectively. There was no significant difference in either early or late QoL compared to baseline (Z=-0.49,p=0.63 and Z=-0.15,p=0.88).

Conclusion:
Overall this study shows no significant difference in either PFTs or QoL in this cohort of patients undergoing SABR in Birmingham. These results compare favourably with other published data and are reassuring for our practice

Background:
The majority of patients offered lung SABR have a radiological diagnosis of primary lung cancer only. This is commonly due to poor performance status, multiple co-morbidities, poor lung function or medical inoperability rendering them unsuitable for lung biopsy. Local control rates (LCR) for SABR-treated lung lesions are in the order of > 90% at 12 months. Little data exists on whether histological subtype affects this or overall survival (OS).

Method:
We retrospectively analysed local control and survival data on all patients treated for primary lung cancer with SABR (using volumetric modulated arc therapy (VMAT) technique) at our tertiary centre over a 4-year period from May 2013 until February 2017.

Result:
153 patients in total were treated, with follow-up data available for 135 patients. Baseline demographic data and analysis are presented in table 1. Median follow-up was 13 months (range 0.5 to 45). The LCR in treated lesions for all patients was 95.2%. Squamous cell carcinomas (SCC) had a better LCR when compared to adenocarcinomas (100% vs 92.8%). Median OS for all patients was 13 months (range 0.5 to 45). By histological subtype, SCC had better OS when compared to adenocarcinomas (15.5 months vs 12.5 months). 35.7% of adenocarcinomas progressed either within the thorax or at distant sites compared to only 12.5% of SCC. However, in 93% of adenocarcinomas and 100% of SCC the original treated lesion did not progress. Those with no histology had LCR of 95% with a median OS of 12 months respectively.

Table 1

SEX Male – 82 (53.6%) Female – 71 (46.4%) AGE Mean – 73 Range – 48-92 PERFORMANCE STATUS (PS) PS 0 – 4 (2.6%) PS 1 – 66 (43.1%) PS 2 – 60 (39.2%) PS 3 – 6 (3.9%) Not recorded – 17 (11.1%) DISEASE T-STAGE T1a – 100 (63.4%) T1b – 29 (18.9%) T2a – 24 (15.7%) HISTOLOGY Adenocarinoma – 15 (9.8%) Squamous cell – 8 (5.2%) NSCLC not specified – 2 (1.3%) Large cell – 1 (0.7%) Carcinoid – 1 (0.7%) No histology – 126 (82.3%) DOSE/FRACTIONATION 54Gy/3 – 38 (24.9%) 55Gy/5 – 103 (67.3%) 60Gy/8 – 12 (7.8%) MEDIAN OVERALL SURVIVAL BY HISTOLOGY Adenocarcinoma – 12.5 months (range 3 to 38) Squamous cell – 15.5 months (range 1 to 43) NSCLC not specified – no follow-up data available Large cell – 18 months (1 patient only) Carcinoid – 14 months (1 patient only) No histology – 12 months (range 0.5 to 45) LOCAL CONTROL RATE BY HISTOLOGY Adenocarcinoma – 92.8% Squamous cell – 100% NSCLC not specified – no follow-up data available Large cell – 100% Carcinoid – 100% No histology – 95.0%

Conclusion:
Our data suggests a trend towards slightly better OS and LCR with SCC over adenocarcinomas. More adenocarcinomas progressed both locally and at distant sites than SCC did. This information may be useful prognostically and it suggests adenocarcinomas may need closer follow-up post-SABR. Overall, our LCR is in line with published data.

Background:
SABR has become a commonly used treatment for early stage lung cancers, particularly in patients not suitable for radical surgery. It provides excellent local tumour control and is well-tolerated. At our institute, we have two platforms to deliver SABR; Linac-based volumetric modulated arc therapy (VMAT) and Cyberknife (CK). Little data exists directly comparing these two in terms of local control (LC) and overall survival (OS), thus, we performed an analysis to ascertain whether one platform outperforms the other. We have conducted lung SABR using VMAT since June 2013 and CK since June 2014.

Method:
We retrospectively analysed data on all early stage primary lung cancer patients treated with lung SABR from June 2013 to February 2017. Demographic and survival data was collected.

Result:
241 patients were treated in total, 153 using VMAT and 88 using CK. 19 patients were excluded from analysis due to lack of follow-up data (18 VMAT, 1 CK). Median follow-up for all patients was 13 months (range 0.5 to 45). Age, sex and histological breakdown were similar for the two groups. The majority in both groups were treated based on a radiological diagnosis. In terms of staging, there were more T1 tumours treated with VMAT than CK due to our local departmental policy excluding tumours less than 2cm being considered for CK. LC was 95.2% for VMAT compared to 93% for CK at median follow-up. Median OS was 13 months for VMAT compared to 14 months for CK. We saw a higher proportion of disease progression (local or distant) in the VMAT group (25.8% versus 17.0%). Lung cancer related deaths were equal in both groups (8.9% VMAT versus 8.0% CK). Neither platform had any grade 3 or higher toxicities reported.

Conclusion:
We demonstrated both treatment modalities were well tolerated by patients and produced similar LC and OS outcomes. In those where the disease progressed, within the CK group a higher proportion of them progressed within the treated lesion, whereas in the VMAT group it was at other sites (ie new lung nodules or distant metastases). This could be due to staging and the fact the CK group featured significantly more T2 tumours. Overall, both treatment modalities gave comparable outcomes to surgery when looking at LC.

Background:
In this study, we aimed to investigate the validity and clinical outcomes of lung resection after curative intent chemoradiation for locally advanced NSCLC.

Method:
The retrospective review of the prospectively recorded data of patients with NSCLC that was treated with curative intent induction chemoradiation followed by surgery between 1996 and 2016 was carried out. The patients undergoing segmentectomy or bigger resection with lymph node dissection after chemoradiotherapy were included into study. Patients received 2-6 cycles of chemotherapy and 45-70 Gy radiotherapy and were divided into two groups; Group 1: patients who received 60 Gy radiotherapy or less; Group 2: patients who received 61 Gy radiotherapy or more. We compared the chemotherapy drugs, doses, cycles, body mass index and performance status, type of lung resection, 90-day postoperative complications, mortality and long term survival between the two groups.

Result:
One hundred and forty two patients were included into study (group 1 n=88, group 2 n=54). All but 17 patients were male with a mean age of 56.5y (31-85y). Twenty patients underwent pneumonectomy and 122 patients received lobectomy (55 patients with extended resection, chest wall resection and sleeve etc). Complete pathological response was observed in 44(31%) patients (group 1= 29.5% (26/88), group 2= 33.3% (18/54), p=0.63. Postoperative morbidity rate was 42.2% (group 1=47.7% (42/88), group 2=33.3% (18/54), p=0.09. In addition, 90-day mortality rate was 6.3% (group 1=5.6%, group 2=7.4%, p=0.68). The overall survival 5-year survival rate was 54.1% that was 61% in Group 1 and 43.6% in Group 2, respectively (p=0.14). We found no relationships between the radiotherapy dose and the complete response rate, mortality, morbidity and survival.

Conclusion:
These findings reveal that lobectomy or pneumonectomy can be safely performed following high-dose chemoradiotherapy without affecting surgical outcomes. However, the positive or negative effect of high-dose radiotherapy on complete response and survival has not been proven.

Background:
Use of postoperative radiotherapy (PORT) in completely resected (R0) pathologic stage IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial. To assess the impact of PORT, we analyzed on the patterns of failure and survival difference in these patients.

Method:
Consecutive 50 patients with pathologic stage ⅢA-N2 NSCLC who underwent surgery with complete resection (R0) between Apr. 2004 and Dec. 2013 were retrospectively reviewed. Thirty-five(70%) patients were male and median age was 63 years (range, 35 - 82 years). Thirty-nine(78%) patients underwent lobectomy, 7(14%) bilobectomy, and 4(8%) pneumonectomy. Postoperative adjuvant therapy consisted of chemotherapy (ChT) alone in 26(52%) patients, ChT + PORT in 10(20%), PORT alone in 4(8%), and none in 10(20%). Radiation dose was ranged from 34 to 60 Gy with the median 55 Gy. Follow-up period was ranged from 4 to 132 months with median 42 months. Survival was calculated from the date of surgery. Kaplan-Meier method was used for survival calculation and their comparison was done using log-rank test.

Result:
The 3 and 5-year overall survival (OS) rate of all 50 patients was 70% and 58%, respectively and the median survival time was not yet reached. Both univariate and multivariate analysis showed age (> 70 yrs old) and ratio of node positive (LNR > 17%) were correlated with the poor OS. The locoregional recurrence was appeared in 19(38%) patients and distant metastasis in 27(54%). The median time to recurrence was 16 months (range, 1 - 87 months) in locoregional failure and that of distant metastasis was 20 months (range, 6 - 60 months). Lymphovascular space invasion (LVSI) was the only statistically significant factor correlating to the locoregional recurrence-free survival (LRFS) both in univariate and multivariate analysis. PORT did not improve both OS and LRFS. Three and 5-years OS in patients with PORT were 56% and 40%, in a while 76% and 68% in patients without PORT (P=0.166), respectively. Three and 5-years LRFS in patients with or without PORT was 80% and 80% versus 54% and 50% (P=0.105), respectively. We could find that the LNR over 17% (p=0.003), tumor extension (p=0.006), and LVSI (p=0.01) were more prevalent in patients group with PORT.

Conclusion:
In this analysis, the most important prognostic factor in the pathologic stage IIIA-N2 (R0) NSCLC patients was the age and positive lymph node ratio. Risk of locoregional recurrence was decreased with the use of PORT. However, this benefit was not leaded to the overall survival benefit.

Background:
Volumetric-modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time and less MU compared to conventional intensity-modulated fixed-field treatment (IMRT) in the treatment of inoperable non–small-cell lung cancer (NSCLC). However, published data on clinical outcome and lung toxicities of VMAT in the treatment of NSCLC are scarce. The purpose of the present retrospective cohort study was to evaluate clinical outcome, acute and late pulmonary toxicities using VMAT (sequential/concurrent chemo) radiotherapy in inoperable NSCLC.

Method:
The clinical outcome, acute and late pulmonary toxicities of 134 consecutive inoperable NSCLC patients treated by VMAT with or without concurrent chemotherapy were retrospectively reviewed. Univariate and multivariate analysis on the dosimetric and characteristic factors associated with acute radiation pnuemonitis (RP) and pulmonary fibrosis were evaluated.

Result:
The average prescriptions dose to these patients were 5736.38±649.11 cGy (range from 5200 to 6400 cGy) with a median follow-up of 18.6 months (range, 2–45 months) for the enrolled 134 patients. The two-year progression-free survival (PFS) and overall survival (OS) for all patients was 18.2% and 38.4% with a median PFS and OS of 7.6 months and 18.6 months, respectively. There were 14 and 12 out of 134 patients experienced grade III/higher RP (10.45%) and pulmonary fibrosis (8.95%), respectively. Age, chemotherapy exposure, dose prescription, V10, V13, V20 and V30 were significantly associated with acute RP. Dose prescription was related to pulmonary fibrosis. Only V13 (p=0.02) and age (p=0.02) were independently associated with acute RP according to multivariate analysis. Based on regression analysis, the threshold for lung dosimetric metrics V10,V13,V20 andV30 were 50%,40%,28% and 18% in VMAT treatment of NSCLC to limit the RP rate <10%.

Conclusion:
VMAT can be delivered safely with acceptable acute and late toxicities for NSCLC. Lung dosimetric metrics were valuable in predicting acute RP. A threshold of 40% of Lung V13 in VMAT treatment of NSCLC was helpful to limit the RP rate <10%.

Background:
Stereotactic ablative radiotherapy (SABR) can result in high local control rates for adrenal metastases when biological doses of at least 100 Gy~BED10~ are delivered [Chance WW, 2017]. SABR is technically challenging due to respiration-induced displacements of the adrenals and adjacent organs at risk (OAR), both of which are poorly visualised using imaging techniques currently available at linear accelerators. MR imaging enables superior anatomical imaging of both the adrenals and OAR’s. We implemented stereotactic MR-guided adaptive radiotherapy (SMART) using daily on-table re-optimization of pretreatment SABR plans using the anatomy-of-the-day. We studied the impact such daily plan re-optimization for adrenal metastases.

Method:
Since mid-2016, 13 patients with adrenal metastases from lung cancer have undergone video-assisted, respiratory-gated SMART delivery on the MRIdian system (ViewRay Inc.). This entails using visual feedback involving projection of both target volume and safety margins onto a monitor visible to patients. The radiotherapy system automatically shuts-off delivery when the target is outside pre-specified safety margins (3mm). The commonest fractionation scheme delivered was 5-fractions of 10 Gy (in 9 patients). Prior to each fraction, a 17-second MR scan in shallow breath-hold was performed with patient in treatment position, in which the GTV was rigidly registered to that on the baseline MR scan. Setup was performed on the gross tumor volume (GTV), and contour deformation was used to automatically generate OAR’s according to the anatomy-of-the-day. Baseline SABR plans were recalculated on the anatomy-of-the-day (defined as ‘predicted plans’), before being routinely re-optimized.

Result:
The median planning target volume (PTV = GTV + 3mm) was 35.1 cc (range 6.5 – 69.8 cc). Online plan adaptation improved PTV coverage in 78% of all fractions. Re-optimized plans exhibited significantly better sparing of OAR and achieved a reduction in volumes of stomach, bowel and duodenum receiving 33Gy, with respect to predicted plans. All patients completed the planned treatments using repeated breath-holds. The total on-table duration was approximately 50 minutes for each fraction.

Conclusion:
Breath-hold SABR delivery under MR-guidance is advantageous for adrenal tumors. Substantial variations in OAR’s positions were observed at imaging prior to delivery of each fraction, leading to improved target coverage and OAR sparing when on-table plan re-optimization was performed.

Background:
Concurrent chemoradiation (CCRT) is the preferred treatment approach in inoperable non-small cell lung cancer (NSCLC) patients. However, CCRT increases the risk of acute esophagus toxicity (AET) compared to radiotherapy alone or sequential chemoradiation. To minimize the risk of AET, an international RT-dose constraint of either V50Gy or V60Gy <50% is used. However, clinical applicability of those models is not evident since assessment of the model accuracy and validity should be performed before generalizing to other populations. Therefore, the aim of this study was to clinically validate the two NTCP-models to predict acute esophagus toxicity in NSCLC patients treated with CCRT.

Method:
To validate the NTCP-models, clinical data of 274 inoperable NSCLC patients receiving CCRT using IMRT was used. The planned V50Gy and V60Gy and the prospectively scored grade ≥2 AET (CTC-AE) were retrieved and independently reviewed. The grade ≥2 AET probability for the V50Gy and V60Gy was calculated as; [1/1+[exp][[-0.515 + (0.027*V][50]] and [1/1+[exp][[-0.701 + (0.029*V6][0]]]. Validity of the model was assessed with the ability to predict the number of grade ≥2 AET events (calibration) and the ability to distinguish between those who develop grade ≥2 AET from those who do not (discrimination, area under the curve (AUC)). Furthermore, sensitivity and specificity for different cut-off points were determined.

Result:
From the 274 NSCLC patients, 125 (45.6%) patients developed grade ≥2 AET (93.8% grade 2, 6.2% grade 3), median V50Gy 23% (interquartile range 10.1-35.6%), median V60Gy 4.3% (interquartile range 0-20.5%). Calibration showed that the V50 overestimated the risk of developing grade ≥2 AET in low-risk patients while the V60 underestimated the risk of developing grade ≥2 AET in high-risk patients. Discrimination of both algorithms demonstrated a similar moderate fit (AUC 0.70 95%CI 0.64 to 0.76 and AUC 0.69 95%CI 0.63 to 0.76 for the V50Gy and V60Gy, respectively). For V50Gy, a cut-off point of more than 40% probability of developing grade ≥2 AET resulted in the most favorable sensitivity of 95.8% for grade ≥2 and 100% for grade 3, with specificity scores of 54.6% and 40.7% respectively. For V60Gy, a cut-off point of more than 60% resulted in the most favorable sensitivity of 95.1% for grade ≥2 and 100% for grade 3, with remarkably low specificity scores of 9.1% and 18.8%, respectively.

Conclusion:
The NTCP-models to predict acute esophagus toxicity in NSCLC patients both showed good predictive accuracy. For clinical practice, the V50Gy seems to be the most sensitive without compromising safety and efficacy.

Abstract not provided

Background:
Despite recent advances in combined chemoradiotherapy for the management of locally advanced, unresectable, stage III non-small cell lung cancer, the majority of patients treated ultimately relapse from their disease. Identifying prognostic factors that predict outcome may improve patient selection for definitive therapy and provide relevant clinical information for their future care.

Method:
This retrospective analysis assessed survival data for a consecutive series of patients with stage III non-small cell lung cancer treated with 6 weeks of curative-intent carboplatin (AUC 2) - paclitaxel (45mg/m[2]) plus radiotherapy at the Princess Alexandra Hospital, Brisbane, between January 2009 and December 2015. Kaplan-Meier analysis on an intention-to-treat basis was used to assess survival data, with attention to a number of clinicopathologic subgroups. Cox proportional hazards regression was performed on continuous and discrete patient covariates to identify those with an independent association with survival.

Result:
The study included 171 patients, with a median follow-up time of 30.5 months. Median overall survival (mOS) was 27.3 months (95% CI = 22.6 - 33.0) for the entire cohort. An improved mOS was seen in stage IIIA (34.3mo) vs IIIB (13.1mo, p<0.001) patients, and with non-squamous compared to squamous histologic subtype (35.5mo vs 22.7mo, p = 0.022). A longer mOS in females compared to males did not meet statistical significance (27.7mo vs 23.2mo, p = 0.21). Multivariate analysis revealed four factors most strongly and independently associated with poor survival: serum neutrophil:lymphocyte ratio (HR 1.15 for each unit increase, p <0.001), lactate dehydrogenase (HR 1.28 for each 50 U/L increase, p = 0.005), alkaline phosphatase (HR 1.1 for each 20 IU/L increase, p = 0.045), and albumin (inverse relationship, HR 0.76 for each 5 g/L increase, p = 0.047).

Conclusion:
This analysis confirms that outcomes for our cohort of stage III non-small cell cancer patients are consistent with international best practice. Our subgroup analyses were also in keeping with recognised clinical factors asociated with improved survival including earlier stage tumours and non-squamous histopathology. A number of pre-treament blood parameters, less well established as prognostic factors, independently influenced survival including the neutrophil:lymphocyte ratio, and lactate dehydrogenase, alkaline phosphatase and albumin levels. Analysis of oncogenic driver mutation status, PD-L1 expression and degree of tumor-infiltrating lymphocytes in available tumor samples is planned, with the goal of establishing a prognostic model to stratify and direct treatment options in this cohort of potentially curable patients.

Background:
Small molecule inhibitors targeting bromodomain and extraterminal domain (BET) protein is promising for cancer therapy. According to our previous study, BRD4 was highly expressed in small cell lung cancer (72%) and correlated with poor prognosis.

Method:
Series small molecular compound NHWD which design and modify by ourselves is a potent and selective BET family bromodomain inhibitor and only binds bromodomains of BRD2/3/4/T. We use the MTT in small cell lines to evaluate the activity and selected the best. And then potential pathway was demonstrated with Western blot and low cytometry. Finally, the activity of small compounds was conducted by xenograft and Patient Derived Xenograft (PDX).

Result:
Compare with JQ1 and other molecular compounds, NHWD-870 has the best effectiveness and powerful anti-cancer, and the IC50 was 1.579nM (figure 1). NHWD-870 exhibited robust single agent activity in cell viability assay across cell lines in vitro and xenografts of small cell lung cancer in vitro by downregulating the PDGFRβ, MEK1/2 and STAT1/MYC pathway (figure 1). Consistent with its broad spectrum of activities in invo, NHWD-870 has potent tumor suppressive efficacies in PDX model of small cell lung cancer (figure 2).Figure 1Figure 2





Conclusion:
Further research will be conducted about series small molecular compounds from bench to beside.

Background:
Neuroendocrine tumors of lung are classified into four histological types (WHO-2015): typical carcinoid, atypical carcinoid, small-cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC). The Pulmonary LCNEC is considered as an orphan disease due to its low incidence. Our aim was to evaluate the clinical presentation and outcome of standard chemotherapy for LCNEC. All India Institute of Medical Sciences, Bhubaneswar, is an institute of national importnace situated in eastern India. No case of LCNEC has been reported from this part of India till date.

Method:
We retrospectively analysed data of patients from June 2014 June to May 2017 with special focus on pulmonary neuroendocrine tumors. We examined incidence of different histological types of pulmonary neuroendocrine tumors. We also analysed clinical characteristics of patients with pulmonary LCNEC and their treatment outcomes.

Result:
In this new Institution 263 Lung Cancer patients were diagnosed by bronchoscopic and transthoracic biopsies. There were 26 (10%) patients with pulmonary neuroendocrine tumors(NEC). Seven(2.7%) of them were LCNEC, 3(1%) carcinoid and 17 (7%) were SCLC. Median age of pulmonary LCNEC was 60 years with M:F ratio 5:2. Four of them were smokers. Median performance status (ECOG) was 2.5. Three patients presented with superior vena cava obstruction and 5 patients had central mass lesions. All the elligible patients with LCNEC were offered chemotherapy with Cisplatin 60 mg/m [2] IV on day-1 plus etoposide 120 mg/m [2] IV on days 1 to 3 in every 21days for initial 4 cycles as a standard treatment in addition to other supportive care. Two patients could not complete initial 4 cycles of chemotherapy due to progression of the diseases and drug intolerance. Four (57%) of the patients had partial response in initial chemotherapy and subsequent progression of disease. Two patients were offered Topotecan as second line chemotherapy but no significant response was observed. Overall survival of patients of LCNEC was 7 months (4-11).

Conclusion:
Incidence of pulmonary LCNEC is low but is increasingly encountered. Most of the patients were diagnosed at advanced stages. Overall survival was poor despite chemotherapy. There is no definite second line regimen recommended for LCNEC. There is a need for clinical trial with alternative modalities including targeted and immunological treatment for these types of lung cancer.

Background:
Small cell lung cancer (SCLC), which accounts for approximately 15% of lung cancer, is one of the most malignant diseases world-wide, with a high mortality. Despite progress in treatment of small cell lung cancer (SCLC), the biology of the tumor still remains poorly understood. Recently, we globally investigated the contributions of lncRNA in SCLC with a special focus on sponge regulatory network. Here we report lncRNA HOTTIP, which is specifically amplified in SCLC, is associated with SCLC proliferation and poor prognosis of patients.

Method:
RT-qPCR was used to investigate the expression of HOTTIP in SCLC tissues and cell lines. The role of HOTTIP in SCLC cell proliferation was demonstrated by CCK8 assay, colony formation assay, flow cytometry analysis and in vivo models of transplant tumor in mice through HOTTIP loss- and gain-of function effects. Western blot assay was used to evaluated gene expression in cell lines at protein level. RNA pull-down, Mass spectrometry and RNA binding protein immunoprecipitation (RIP) were performed to confirm the molecular mechanism of HOTTIP involved in SCLC progression.

Result:
We found that HOTTIP was overexpressed in SCLC tissues, and its expression was correlated with the clinical stage and the shorter survival time of SCLC patients. Moreover, HOTTIP knockdown could impair cell proliferation, affect the cell cycle and inhibit tumor growth of mice, while HOTTIP overexpression might enhance cell proliferation and cell cycle in vitro and in vivo. Mechanistic investigations showed that HOTTIP functions as an oncogene in SCLC progression by sponging miR-574-5p and affecting the expression of several protein-coding cancer driver genes, such as polycomb group protein EZH1 and EZH2. By in-depth study of mechanism, we identified Ago2 as an RNA-binding protein that binds to HOTTIP, which confirmed miRNAs interact with HOTTIP by the RNA-induced silencing complex (RISC).


Conclusion:
Our findings not only illuminate how HOTTIP confers an oncogenic function in SCLC pathogenesis, but also underscore a novel gene expression governing hallmarks in the disease.

Background:
Since December 2013, we initiated a phase II/III trial [Japan Clinical Oncology Group (JCOG) 1201/Thoracic Oncology Research Group (TORG) 1528: UMIN000012605] for elderly patients with extensive-disease small-cell lung cancer (ED-SCLC). Aim of the study is to demonstrate that a carboplatin plus irinotecan regimen is superior to carboplatin plus etoposide in elderly patients with ED-SCLC. However, the patient accrual rate did not satisfactorily match our expectations a year from the time of initiation of our study. To define factors related to low accrual, we searched institutional records and analyzed.

Method:
We collected data of elderly patients with ED-SCLC from each institution and investigated the total number of elderly patients with ED-SCLC, number of patients eligible/ineligible for the study, numbers of patients registered for the study, and the reasons for non-registration of even eligible patients. Doctor-reported questionnaires concerning elderly (≥71 years old) ED-SCLC patients diagnosed in their institutions were sent to chief or coordinate doctors at each institution in December 2014.

Result:
We received a response from 32 (84%) of 38 institutions. Approximately 260 patients were diagnosed as elderly patients with ED-SCLC in the last year. Only 100 patients (38%) were eligible for the JCOG 1201/TORG1528 trial. Reasons for ineligibility primarily included poor performance status (PS) (25%), low organ functions (25%), interstitial pneumonitis (19%) and double cancer (18%). Only 23 patients among the 100 eligible candidates accrued to the study. The primary reasons for non-accrual were delayed approval from the Institutional Review Board (IRB) of the individual institution (24%), physician preferences (23%), patient refusal (18%), and registration for other trials (12%).

Conclusion:
Our data demonstrated that 62% of ED-SCLC patients were ineligible for the protocol due to frailty with the most frequent reason being comorbidities such as poor PS and low organ functions. However, inactive institutions need to increase their efforts to register a greater number of eligible patients in addition to obtaining quicker IRB approval of protocol. Based on responses to questionnaires sent out as part of our investigation, in January 2016, the protocol was revised in terms of eligibility criteria to enhance patient accrual. Eligibility criteria for participation of elderly patients with ED-SCLC need to be formulated prudently so that patients are benefitted in routine clinical practice.

Background:
The benefits of second-line chemotherapy on the overall survival (OS) of small-cell lung cancer (SCLC) patients might be confounded by subsequent therapies. In this study, we aimed to determine the influence of progression-free survival (PFS) and of post-progression survival (PPS) on OS after second-line chemotherapy in patients with refractory SCLC treated with amrubicin monotherapy.

Method:
We analyzed the data of 35 patients with refractory SCLC who were treated with amrubicin monotherapy as second-line chemotherapy between July 2005 and December 2015. The correlations of PFS and PPS with OS were statistically analyzed at the individual level using Spearman rank correlation and linear regression analyses.

Result:
The correlation between PPS and OS was strong (r = 0.88, p < 0.05, R[2 ]= 0.87), while that between PFS and OS was weak (r = 0.60, p < 0.05, R[2] = 0.15). The number of regimens administered after disease progression post-second-line chemotherapy was significantly associated with PPS (p = 0.003).

Conclusion:
OS is more strongly linked to PPS than to PFS in refractory SCLC patients who undergo amrubicin monotherapy as a second-line treatment. Moreover, receiving additional regimens after second-line treatment is a significant independent prognostic factor for PPS. Taken together, our results indicate that additional treatments administered after second-line chemotherapy favorably affect the OS of refractory SCLC patients treated with amrubicin monotherapy.

Background:
Small cell lung cancer (SCLC) accounts for about 15% of all lung cancer cases. SCLC is characterized by frequent relapse, and current treatments lack tumor specificity. Arginase is an important enzyme in human, but it is deficient in some tumors. Arginine deprivation has become a potential therapeutic option in selected tumors. BCT-100 is a pegylated arginase which has demonstrated anticancer activity in arginine auxotrophic tumors, such as melanoma, hepatocellular carcinoma and acute myeloid leukemia. One of resistance mechanisms to arginase is overexpression of argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC). The aim of this study is to determine the effects of BCT-100 on SCLC in vitro and in vivo.

Method:
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect cell viability of different SCLC cell lines after BCT-100 treatment. Western blotting was employed to evaluate the protein expression. Knockdown of OTC was performed using specific siRNA. Xenograft models were established in nude mice for testing the anticancer effect of BCT-100.

Result:
The IC~50~ values of BCT-100 in H69, DMS79, H187, H209, H446, H510A, H526, H841 and SW1271 cells were 462.9±112.2, >1000, 24.9±6.4, 8.6±0.8, 18.0±0.7, 18.2±4.0, 10.1±0.7, >1000 and 49.2±7.4 mU/mL respectively. Knockdown of OTC increased sensitivity to BCT-100 in H841 cells, partially mediated via apoptosis. Mitochondrial membrane depolarization was observed in BCT-100 treatment and cytochrome c and SMAC were released from mitochondria to cytosol. N-acetylcysteine (NAC), the reactive oxygen species (ROS) scavenger, could reverse the apoptosis induced by BCT-100 significantly. Besides, cell cycle specific proteins, cyclin A2, cyclin B1 and CDK4, were downregulated in a time-dependent manner. The tumor growth was inhibited and median survival of mice was prolonged in BCT-100 group in H446 and H510A xenograft models. Serum and intratumoral arginine level was sharply decreased, associated with G1 arrest and apoptosis in H446 and H510A xenografts.

Conclusion:
The SCLC cell lines with low expression of ASS1 and OTC were susceptible to BCT-100 treatment. ROS was involved in BCT-100 induced-apoptosis. BCT-100 showed potential anticancer activity in SCLC xenograft models.

Background:
Survival outcomes for extensive stage small cell lung cancer (ES-SCLC) remain poor. The standard management of ES-SCLC is chemotherapy. For those achieving a good response consolidation thoracic radiotherapy and prophylactic cranial irradiation (PCI) is considered. This retrospective audit analysed patterns of care and survival for all patients with ES-SCLC treated at Prince of Wales Hospital (POWH) over 15 years. Factors correlating with survival were also analysed. A literature review was performed to benchmark our results.

Method:
We identified ­­187 patients diagnosed with SCLC at Prince of Wales Hospital between 2000 and 2014 from the departmental electronic patient information system (MOSAIQ, Elekta). Eligibility criteria were: age >18 years, histopathologically confirmed diagnosis of SCLC, extensive stage according to the two-stage Veterans’ Affairs Lung Study Group staging criteria, and treatment at POWH. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and log-rank test (IBM SPSS version ­24).

Result:
Eighty-three patients fulfilled the eligibility criteria. Median age was 70 years. 42% of patients were female and 63.9% had an Eastern Cooperative Oncology Group performance status (PS) of 0-1. Median PFS and OS were 5.0 and 8.2 months respectively, comparable with published literature. There was correlation between PS (0-1 versus >2) and OS (p=0.025) but not PFS (p=0.16). 79.5% of patients received initial chemotherapy, 48.5% of these patients received 6 cycles, of which 89.4% was carboplatin and etoposide. Median time from date of diagnosis to start of chemotherapy was 12 days, with correlation between time to chemotherapy and OS (p=0.006) and PFS (p=0.003). 75.9% patients received radiotherapy of any kind, but only radiotherapy directed at the thorax was associated with improved OS (p=0.01) but not PFS (p=0.5). Five (6%) patients underwent consolidation thoracic radiotherapy, while 32.5% underwent palliative thoracic radiotherapy. Palliative whole brain radiotherapy was given to 11 (13.3%) patients and only 2 patients received PCI. 78.3% of patients had documented progression after treatment, with simultaneous loco-regional and distant progression the most common pattern. 66.2% of patients had treatment at progression, with most (86%) receiving palliative radiotherapy.

Conclusion:
Our current analysis demonstrates an association between survival outcomes and baseline PS, time to initiation of chemotherapy and receipt of thoracic radiotherapy for patients with ES-SCLC. The survival outcomes are comparable to the reported literature. This highlights the importance of early referral and treatment commencement for improved outcomes in ES-SCLC.

Background:
Pulmonary neuroendocrine carcinoma, including small cell lung cancer (SCLC), large cell neuroendocrine carcinoma (LCNEC), and carcinoid tumor, is a highly malignant cancer with poor prognosis. Because of its rarity, the molecular information available to investigate suitable therapeutic targets is insufficient, and little advancement has been made in the development of molecular-targeted therapies for these patients. This study aimed to determine a molecular signature of pulmonary neuroendocrine carcinoma by genomic analysis to explore therapeutic targets.

Method:
Surgically resected primary tumor specimens obtained between January 2014 and June 2016 from 15 patients with neuroendocrine carcinoma [SCLC, 8; LCNEC, 6; typical carcinoid (TC), 1; categorized based on WHO classification] were subjected to whole-exome sequencing (WES) and gene-expression profiling (GEP). Corresponding peripheral blood samples were collected as controls to identify tumor-specific genetic alterations in WES. Written informed consent was obtained from all patients. WES was performed on an Ion Proton system. An Agilent SurePrint G3 Human Gene Expression 8×60K v2 Microarray was used to detect tumor-specific gene expression. Oncogenic fusions were detected by targeted RNA sequencing. Copy number alterations were detected by integrating copy numbers resulting from WES and GEP. Promising oncogenic genetic alterations were selected using the OncodriveFML and Cancer Genome Interpreter.

Result:
Patient characteristics were: median age, 67 years; men, 67% (10/15); smokers, 93% (14/15); ratio of stage I/II/III/IV (%), 40/47/13/0. The median tumor mutational burden (TMB) in SCLC and LCNEC was 7.6 mutations (mt)/Mb (1.1–11.3) and 8.0 mt/Mb (3.5–12.6), respectively, which were significantly higher than that in lung adenocarcinoma (1.6 mt/Mb; p = 0.0025, p = 0.009), but not in lung squamous cell carcinoma (5.6 mt/Mb). One patient with TC showed low TMB (0.7 mt/Mb) and harbored a truncating mutation in MEN1, indicating a typical molecular signature of carcinoid tumor. The commonly altered genes (≥ 20%) were TP53 [60%, mut, 8; downregulation (down), 1], RB1 (53%, mut, 6; down, 2), CCNE1 [27%, amplification (amp), 4], APC (27%, mut, 3; down, 1), and BCL2 (20%, amp, 3). All genetic alterations detected in TP53, RB1, and APC were putative loss-of-functions. We observed no significant differences in frequency of alterations in the commonly altered genes between SCLC and LCNEC. One patient with LCNEC harbored EGFR-activating mutation, indicating possibility that this tumor was combined LCNEC with adenocarcinoma.

Conclusion:
This study revealed a molecular signature in Japanese patients with pulmonary neuroendocrine carcinoma, which could contribute to the development of novel molecular-targeted therapies.

Background:
Small cell lung cancer (SCLC) that constitutes of 15-18% of all lung cancers is a highly lethal malignancy. The functional effects of long noncoding RNAs(lncRNAs) in cancer have been widely recognized. Long intergenic non-protein coding RNA 173(Linc00173) was first identified in SCLC, and was found to be involved in chemoresistance. We aimed to explore the regulatory mechanisms of Linc00173 using drug-resistant cell lines and human tissues.

Method:
We used microarrays to compare expression profiles of lncRNAs in SCLC cell line and the drug-resistant subline and Linc00173 was identified. Linc00173 was examined in 60 SCLC patient samples by qRT-PCR assay. The functional roles of Linc00173 in SCLC were studied by overexpression and RNA interference approaches in vitro and in vivo. The localization of the genes were involved in competitive endogenous RNAs(ceRNAs) regulatory network was studied by separating cytoplasmic and nuclear RNA fractions from SCLC. Bioinformatic analysis, luciferase assays, RNA immunoprecipitation and pull-down assays were performed to elucidate the role of Linc00173 in mechanism of ceRNA. The positive Linc00173/Etk correlation was further verified by qRT-PCR assay and bivariate correlation analysis in clinical tissues and blood samples.

Result:
We found that Linc00173 expression was significantly associated with chemoresistance and the shorter survival time in SCLC patients. Downregulation of Linc00173 expression could impair cell proliferation and increased cell sensitivity to anticancer drugs, while upregulation of Linc00173 promoted the proliferation and induced multidrug resistance both in vitro and in vivo. Linc00173 overexpression enhanced the expression of Etk through competitively ‘spongeing’ miRNA-218 resulting in the activation of STAT3. Particularly, the ceRNA regulatory network of above genes was occurred in nucleus. Finally, the positive Linc00173/Etk correlation was found in SCLC tissues and blood samples.

Conclusion:
Figure 1Linc00173 was first identified to promote proliferation and chemoresistance of SCLC. It regulates levels of Etk by acting as ‘sponger ’of miR-218. These genes may be novel indices for clinical diagnosis of tumor growth and chemoresistance in SCLC.

Background:
Epithelial and endothelial tyrosine kinase(Etk), also known as Bone marrow X kinase (Bmx), was found to be critical in modulating chemoresistance of small cell lung cancer(SCLC) in our preliminary study. However, the molecular mechanisms of Etk leading to chemoresistance in SCLC remain obscure.

Method:
Knockdown of Etk by siRNAs was performed to evaluate autophagy change in SCLC. Subsequently, a microarray analysis identified PFKFB4 as a downstream molecule of Etk, and CoIP and GST-pull down was used to test protein interaction. We then explored whether PFKFB4 affected autophagy of SCLC. Gain or loss-of-function in vitro or in vivo was used to evaluate the effects PFKFB4 on chemotherapy sensitivity. The expression of PFKFB4 in SCLC tissues were measured by immunohistochemistry(IHC). Besides, luciferase assays, Western blot and CCK8 assay were performed to confirmed whether miR-218 regulates Etk and its effect on chemoresistance. As Etk shares conserved domains with Btk(Bruton’s tyrosine kinase) family, we also explored whether ibrutinib, a Btk inhibitor used in leukemia, affected chemotherapy sensitivity of SCLC.

Result:
Etk affected autophagy in SCLC, and directly inhibition of autophagy sensitized cells to chemotherapy. PFKFB4 was found as a downstream molecule of Etk and they interacted with each other in protein level directly. Moreover, knockdown of PFKFB4 suppressed autophagy of SCLC. PFKFB4 affected chemoresistance of SCLC in vitro and in vivo, and high level of PFKFB4 was associated with poor therapeutic response and prognosis. Furthermore, miR-218 directly modulated Etk expression as a novel regulator and it affected chemoresistance in SCLC. We demonstrated that ibrutinib exhibited a synergistic effect with chemotherapy in SCLC.

Conclusion:
Figure 1 Our results demonstrated for the first time that Etk interacts with PFKFB4 to modulate the chemoresistance of SCLC by autophagy and Etk is a direct target of miR-218. These genes may be predictive factors for the chemotherapy response as well as potential therapeutic targets in SCLC.

Background:
Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung are highly malignant tumors and classified as variants of endocrine carcinoma and subdivided into pure or combined type. Clinical benefit of this stratification and strategy for target therapy has not been established in these tumors.

Method:
This study aimed to compare genetic and clinicopathological features between SCLC and LCNEC or pure and combined types, evaluate the usefulness of classification methodology, and explore the possibility of target therapy using next-generation sequencing (NGS). NGS custom panel was designed to cover 36 genes with median coverage percentage of 99.57% (80.89-100). As clinicopathological features, patients’ characteristics and immunohistochemistry using 8 antibodies were evaluated.

Result:
In 13 SCLC and 22 LCNEC cases, 72 point mutations, 19 deletions, and 3 insertions were detected. As therapeutically targetable variants, mutations in EGFR (L858R), KRAS (G12D, G12A, G12V), and PIK3CA (E545K) were detected in 5 cases. One combined LCNEC cases harboring EGFR mutation (L858R) showed response to EGFR-tyrosine kinase inhibitor. However, these therapeutically targetable cases were not accompanied by specific features in immunohistochemistry or histology. And there was no significant genetic feature between SCLC and LCNEC or pure and combined types.

Conclusion:
Although even SCLC and LCNEC cases harbored therapeutically targetable mutations and potentially include the benefit for target therapy, they were not identifiable by clinicopathologic background. And there was not significant genetic difference between SCLC and LCNEC, including between pure and combined types. Classifying SCLC and LCNEC in same category is reasonable. However, distinguishing the pure type from combined type was not validated. Comprehensive genetic analysis should be performed to detect targetable variants in any type of SCLC and LCNEC.

Background:
Section not applicable

Method:
The clinical data of 15 patients with small cell lung cancer(SCLC) combined with paraneoplastic limbic encephalitis(PLE) from 1980 to 2017 were collected from Peking Union medical college hospital. Their symptoms and laboratory data were analyzed and the prognosis of the patients was followed.

Result:
1. PLE is a rare disease, the incidence rate in small cell lung cancer is about 0.842%.The data may be underestimated because of misdiagnose or missed diagnosis. 2. High incidence crowd of the disease is the middle-aged male smoker, The TNM stages of them are later than others. 3. Typical neurological symptoms include varying degrees of short-term memory loss, seizures and varying degrees of mental disorders; neurological symptoms usually occur before the onset of cancer or respiratory symptoms appear, an average of about 2 months be taken from onset to diagnosis. 4. Serum antibody (anti-Hu, GABA-R-Ab), cerebrospinal fluid, head MRI and EEG of the patients has abnormalities; Videography, especially CT is a good means of screening the primary tumor, pathology diagnosis mainly rely on bronchoscopy. 5. The treatment of primary tumors can be more effective in alleviating the nervous system symptoms than immunotherapy.

Conclusion:
Paraneoplastic limbic encephalitis is a rare paraneoplastic syndrome in nervous system caused by malignant neoplasms often characterized by facial neurological symptoms. The disease are usually associated with lung cancer (especially small cell lung cancer) .Its nervous system symptoms occur earlier than the tumor diagnosis. Early diagnosis and treatment for primary tumors will increase the benefit.

Background:
Relapsed or refractory small cell lung cancer (SCLC) has a poor prognosis, with no good therapeutic options. Topotecan, a topoisomerase I inhibitor, and doxorubicin, a topoisomerase II inhibitor, are both active drugs in SCLC. We evaluated the safety and efficacy of a novel combination of oral topotecan and weekly doxorubicin, providing sequential topoisomerase I and II inhibition, in this setting.

Method:
Adult patients (>19 years) with relapsed or refractory SCLC who had received at least one prior chemotherapy regimen were included in the study. Patients received escalating doses of oral topotecan for five days (Days 1-5 of each cycle) every three weeks for a maximum of 5 cycles. The dosing cohorts were: DL1: 0.85 mg/m[2], DL2: 1.05 mg/m[2], DL3: 1.35 mg/m[2], DL4: 1.65 mg/m[2] and DL5: 2.30 mg/m[2]. All patients received weekly doxorubicin 20 mg/m[2] intravenously starting Day 6 of the first cycle and continued weekly for the duration of the study (maximum 15 weeks). The study design involved a standard 3+3 approach. In the absence of pre-specified criteria for dose limiting toxicities (DLT), patients were enrolled serially to escalated dose level cohorts. Patients received therapy until disease progression, undue toxicity or completion of the study. Primary objectives were safety and efficacy, dose limiting toxicity and response rate.

Result:
A total of 22 patients were enrolled in the study, of which 18 were evaluable for toxicity. Median age was 60.5 years, 72% were male and 95% were Caucasian. Most common adverse events observed were hematological toxicities. Grade 3/4 adverse events included: anemia (44%), thrombocytopenia (50%), neutropenia (44%), lymphopenia (33%), leucopenia (39%), transaminitis (17%), hypokalemia (11%), hypotension (5%) and dehydration (5%). There were no therapy-related Grade 5 toxicities. Incidence of DLT based on cohorts were: DL1: 0/3, DL2: 1/6 (Grade 4 Thrombocytopenia), DL3: 1/6 (AST Elevation) and DL4: 2/4 (Grade 4 Thrombocytopenia). Response rate was 16.6% (3/18) and disease control rate (SD + PR) was 33%. The median progression free and overall survival were 3.4 months and 5.8 months, respectively.

Conclusion:
The novel combination of oral topotecan and weekly doxorubicin was safe and showed promising efficacy in relapsed/refractory SCLC. The maximum tolerated dose of oral topotecan was 1.35 mg/m[2] when given concurrently with weekly doxorubicin. A phase 2 trial using this regimen is being developed.

Background:
Currently the chemotherapy protocol for extensive stage small cell lung cancer at Auckland Regional Cancer and Blood Service does not include a recommendation for the use of growth colony stimulating factor (G-CSF) support as either primary prophylaxis or in the secondary setting. The protocol does provide guidelines for treatment delay and dose reduction in the setting of haematological toxicity. Access to publicly funded pegfilgrastim (Neulasta) became available in New Zealand in May 2013. Individual physicians may choose to prescribe G-CSF prophylaxis for any patient they believe fits the funding criteria. We therefore reviewed current clinical practice and outcomes in this patient population.

Method:
A retrospective audit of patients 18 years and over with a histologically confirmed diagnosis of extensive stage small cell lung cancer who were schedule to receive carboplatin with or without etoposide chemotherapy, from 1 January 2015 to 31 December 2015 was undertaken. Primary end point was rate of febrile neutropenia (FN) with secondary end points of G-CSF use, patient related risk factors for FN and dose reductions / delays.

Result:
32 patients met the inclusion criteria, 29 of these received chemotherapy. The rate of FN in the entire population was 14% (4 episodes in 29 patients). One patient had 2 episodes of FN. The rate of FN in patients not receiving primary G-CSF was 13% (3 episodes in 23 patients). Six patients were administered G-CSF in the primary setting (20%, 6/29). One patient treated with primary G-CSF had FN (20%, 1/6). Two patients received G-CSF in the secondary setting. Risk factors for FN were commonly seen, including age >65 years (63%) chronic obstructive respiratory disease (41%) and multiple co-morbid conditions (22%). Treatment delays were experienced by 14 patients (48%) at some stage throughout their chemotherapy primarily due to haematological toxicity. Dose reductions occurred in 17 patients (58%).

Conclusion:
This retrospective audit confirms an overall rate of FN of 14%, in keeping with published data of moderate risk of neutropenia with carboplatin etoposide chemotherapy. In this retrospective study, primary G-CSF did not decrease this risk, but numbers are small. This population of patients commonly have risk factors for FN and many patients experience treatment delays. Given this and the importance of dose intensity in the treatment of small cell lung cancer, consideration for primary G-CSF support is warranted.

Background:
The biological and clinical significance of thyroid transcription factor 1 (TTF-1) remains unclear in small cell lung cancer (SCLC). The purpose of this study was to clarify the clinicopathological characteristics of TTF-1-negative SCLC.

Method:
We retrospectively studied the associations between survival and the expression of TTF-1, and examined the association between the expression of TTF-1 and neuroendocrine markers (Synaptophysin, Chromogranin, and CD56), neuroendocrine cell-specific transcription factor (ASCL1, BRN2), and NF1B, which is an oncogene for SCLC. Formalin fixing and paraffin embedding (FFPE) and clinical data in SCLC patients were collected and used. The study was approved by the institutional review board.

Result:
Thirty-five patients were examined. Eleven patients were negative for TTF-1, and twenty-four patients were positive for TTF-1. The analysis demonstrated that overall survival was not statistically significant between patients with TTF-1-negative and those with TTF-1-positive SCLC. However, frequency of negativity of Synaptophysin and Chromogranin was greater in patients with TTF-1-negative SCLC than in those with TTF-1-positive SCLC based on immunohistochemical expression, and the difference was statistically significant. mRNA expression of ASCL1, NF1B, and serum ProGRP were significantly lower in patients with TTF-1-negative SCLC than in those with TTF-1-positive SCLC. We showed that TTF-1-negative SCLC showed less neuroendocrine differentiation. It is suspected that TTF-1-positive and -negative SCLC have different biological characteristics.

Conclusion:
TTF-1-negative SCLC was different in terms of aspects of neuroendocrine differentiation (negativity of Synaptophysin and Chromogranin, lower expression of ASCL1 and NF1B) compared to TTF-1-positive SCLC.

Background:
Amrubicin (AMR) monotherapy is one of treatment options in patients with relapsed high grade neuroendocrine carcinoma (HGNEC) of the lung. Although topoisomerase-II (Topo-II), a target of AMR, has been reported to be a predictive or prognostic marker for chemosensitivity and clinical outcomes in various types of malignancies, its role remains unknown in this population.

Method:
Eighty-four patients with relapsed HGNEC (consisting of small cell lung cancer [SCLC] and large cell neuroendocrine carcinoma [LCNEC]) who received AMR monotherapy between 2003 and 2015 were enrolled into this study. We retrospectively collected clinical data including histological type, anti-tumor effect, and survival data from medical records. The expression levels of Topo-II were examined by immunohistochemical staining in tumor specimens obtained from surgical resection or biopsy.

Result:
The majority of enrolled patients were men (89%) and had a histological type of SCLC (92%) with a median age of 70 years (range, 49-83 years). Twenty-three percent of patients had poor performance status of 2 to 4. Sixteen percent of patients exhibited Topo-II overexpression in the tumors. The overall response rates in patients with high and low expression of Topo-II were 38.5% and 25.7%, respectively (p = 0.34). In multivariate analysis, patients with high expression of Topo-II had significantly longer progression-free survival (Hazard Ratio [HR] 0.39, p < 0.01) and overall survival (HR 0.48, p = 0.04).

Conclusion:
Our findings suggest that Topo-II expression is associated with clinical outcomes in patients with relapsed HGNEC receiving AMR monotherapy.

Abstract not provided

Background:
Intercostal nerve blocks with a liposomal Marcaine formulation (Exparel) was reported to provide pain relief equivalent to an epidural in the immediate post operative period following a thoracotomy. We compared pain relief of thoracotomies that received an Exparel block to minimally invasive procedures in the immediate and extended post-operative period.

Method:
We reviewed the records of 166 patients who underwent thoracic surgery procedures with a thoracotomy or a video-assisted thoracoscopic surgery (VATS) and who received multilevel paravertebral nerve blocks with either Exparel or 1 % Marcaine with epinephrine. Pain scores and opiate use were routinely recorded by nurses for the first 48 hours as well as opiate use in the postoperative days (POD) 5 to 13 (by patients). Clinical variables, atrial fibrillation, pulmonary complications, and hospital length of stay (LOS) were also examined. Statistics included t-test for means, and Fisher exact for proportions.

Result:
Fifty patients underwent a VATS wedge resection with a paravertebral block with Exparel (VATS-E) and 53 patients underwent a VATS wedge resection with a paravertebral block with Marcaine (VATS-M). The pain score were lower for the VATS-E vs. the VATS-M patients (p< 0.001). 32 patients underwent a thoracotomy with an Exparel block (Thor-E) (30 lobectomies) and 15 patients had a VATS lobectomy with a Marcaine block (VATS-lobe-M). Thor-E patients expressed lower pain scores compared to VATS-M and VATS-lobe-M in the first 48 hours after surgery (p<0.001). Opiate use was also lower in the Thor-E patients compared to VATS-lobe-M patients, with 25% of the Thor-E patients not taking opiates by POD 5. Opiate use was not significantly different between Thor-E and VATS-E patients from POD5 to POD 13. The LOS was 3.2 days for Thor-E and 5.7 days for historic control thoracotomy lobectomy patients who received a Marcaine nerve block.

Conclusion:
Our study suggests that the pain relief provided by an Exparel block in thoracotomy patients compares favorably to that of VATS procedures in the immediate and extended postoperative period, and that Exparel paravertebral nerve blocks may also improve hospital length of stay.

Background:
Current practice guidelines by the National Comprehensive Cancer Network (NCCN) recommend the complete dissection of at least three mediastinal nodal stations during lobectomy for lung cancer. Controversy exists concerning the adequacy of lymph node sampling (LNS) achieved by video assisted thoracic surgery (VATS) lobectomy for lung cancer and furthermore whether or not small volume centers could compare to the national benchmarks. Several large studies have shown conflicting evidence concerning the LNS yield in VATS vs thoracotomy. For thoracic surgeons in a rural community setting there may be warranted concern about the adequacy of lymph node dissection during VATS. This study aimed to assess the adequacy of lymph node sampling by VATS at our institution, a rural 300 bed community teaching hospital in western Massachusetts.

Method:
Retrospective review of clinical and pathological data were reviewed for 103 hospital admissions in patients undergoing lung Lobectomy performed from 2010-2016. Variables included age, sex, number of mediastinal nodes and node stations dissected.

Result:
103 patients with 103 VATs Lobectomies, 49 males (ave age 64.6 yrs) and 55 females (ave age 67.5), had a mean number of mediastinal lymph nodes (MLD) of 10.98 and the mean number of dissected N1+N2 stations was 3.47. The mean N2 station yield averaged 2.93 stations. S1 was resected in 2/103cases (2%); S2, 10/103 (10%); S3, 0/103 (0%); S4, 62/103 (64%); S5, 29/103 (30%); S6, 25/103 (25%); S7, 79/103 (81%); S8, 7/103 (7%); S9, 37/103 (38%); S10, 51/103 (53%); S11, 33/103 (34%); S12, 22/103 (23%); S13, 1/103 (1%).

Conclusion:
Recent data presented at Annual Meeting of the American Association for Thoracic Surgery (AATS) suggests VATS lymphadenectomy is inadequate 60% of the time. It was postulated that small volume centers and/or inexperienced general surgeons are contributing to this high percentage. This study agrees with previous data affirming the lymph node yield is adequate with VATs lobectomy. When compared to the current NCCN recommendations our institutions mean number of MLN and MLN stations dissected is similar or better to that of many larger volume centers across the nation and supports the adequacy of VATs Lobectomy in rural community hospitals.

Background:
For tissue diagnosis of an indeterminate lung tumor with a strong suspicion of lung cancer, wedge resection is sometimes difficult because of tumor size or location. Intra-operative needle aspiration biopsy can be considered when tumor biopsy via flexible bronchoscopy (FB), or using transthoracic needle aspiration biopsy (TTNA), fails to prove malignancy in tumors with a high rate of false negatives. There are numerous lesions where an easy wedge resection or TTNA cannot be carried out, and lobectomy followed by thorough pathological examination is required.

Method:
From April in 2010 through December in 2015, 30 patients with indeterminate lung tumors who underwent lobectomy (including 2 upper segmentectomy in the left upper lobe) followed by thorough pathological examination were reviewed. Right middle lobe lesion was excluded in this study.

Result:
Sixteen were men and 14 were women. The median age of the patients was 67 years with a range of 24 to 85 years). According to the size and location of the lesion, each case was classified in two patterns: deep nodule (18 patients, locates centrally, inner two thirds from the lung surface) or mass (12 patients, greater than 30mm in diameter). Tumor located in the right upper lobe/ right lower lobe/ left upper lobe/ left lower lobe in 13 (deep nodule/mass: 8/5) / 4 (deep nodule/mass: 3/1) / 7 (deep nodule/mass: 4/3) / 6(deep nodule/mass: 3/3) patients, respectively. Preoperative examination was chest computed-tomography/F-18 FDG PET/transbronchial biopsy through bronchofiberscopy in 30/24/19 patients, respectively. Pathological diagnosis were as followings: 25 primary lung cancer (13 adenocarcinoma, 1 adenosquamous cell carcinoma, 1 mucoepidermoid carcinoma, 4 bronchiolo-alveolar varcinoma, 1 pleomorphic carcinoma, 1 small cell carcinoma, 4 squamous cell carcinoma) / 1 inflammatory myoblastic tumor/ 1 metastatic carcinoma/ 1 organizing pneumonia/ 1 caseous granuloma/ 1 Non Tuberculous Mycobacteriosis(Mycobacterium xenopi). Pathological stages of primary lung cancer were stage IA/IB/IIB/IIIA/IV in 6/1/3/2/1/3 patients, respectively. Operative time was 110~304 minutes (median: 182.5 min), and intra-operative blood loss was 0~530ml (median: 60 ml). Post-operative drainage were 2~18 days (median: 3 days) and post-operative hospital stay was 5~23 days (median: 10 days). Post-operative complications of Clavien-Dindo grade grater than or equal to II occurred in 6 patients (II/III: 3:3), all of them resolved conservative therapy.

Conclusion:
Diagnostic lobectomy followed by thorough pathological examination were carried out safely with acceptable range of postoperative complications.

Background:
Pulmonary lymph flows are predominantly regarded to run along bronchi. In addition, limited resections such as segmentectomy are increasing recently. However there are some cases suggesting alternative lymph pathways, such as the skip metastases. We herein observed pleural lymph flows by the indocyanine green (ICG) fluorescence method with a near-infrared camera device in patients who underwent lung resections.

Method:
After thoracotomy, we injected ICG to subpleural spaces of the lung lobe that planned to resect in 100 cases. Intraoperative fluorescence images were observed in real time using a near-infrared camera. Patients with pleural involvement were excluded.

Result:
In 58 out of 100 cases, ICG movements were observed in subpleural space. In 18 cases, ICG flowed into adjacent lobes over the interlobular line. In 5 cases, ICG flowed into the mediastinum directly. Subpreural lymph flow detection rates were significantly lower in patients with smoking pack-year >40 than those with pack-years <40.

Conclusion:
In our study, in more than half of the cases, pleural lymph flows were observed and there were lymph flows that flowed into the mediastinum directly. In addition, the reduction of subpleural lymph flows in smokers with >40 pack-year suggests that smoking might modify lymph flow patterns. In the future, these findings may help us to select appropriate procedures for patients with possible skip metastasis.

Background:
Preoperative trans-bronchial biopsy and/or computed tomography (CT)–guided biopsy inevitably disrupt lung structure and might disseminate tumour cells into airway, vessels or the pleural cavity. Because preoperative diagnostic intervention may potentially disperse tumour cells, it may affect relapse and/or prognosis.

Method:
The data from the consecutive patients with cTanyN0M0 lung cancer who underwent surgery between January 2006 and December 2012 at our institute were extracted by chart review and analysed retrospectively. Prognostic factors of overall and recurrence-free survival were compared among the groups (the trans-bronchial biopsy group, the CT-guided biopsy group and the intra- or postoperative-diagnosis group) by using the univariate and multivariate Cox proportional hazard model. A stepwise backward elimination method with a probability level of 0.15 was used to select the most powerful sets of outcome predictors. A p-value <0.05 was considered statistically significant.

Result:
Data from 397 patients were available for analysis (the trans-bronchial biopsy group: 221, the CT-guided biopsy group: 71 and the intra- or postoperative-diagnosis group: 105). Solid tumour size was larger in the trans-bronchial biopsy and/or the CT–guided biopsy than the intra- or postoperative-diagnosis group (p = 0.0001). In the crude analysis, the trans-bronchial biopsy group and the CT-guided biopsy group showed higher probability of pleural dissemination (p = 0.048) and showed worse prognosis than the intra- or postoperative-diagnosis group (overall survival: p = 0.0458, recurrence-free survival: p = 0.0101). However, the method of diagnosis was not identified as an independent risk factor for pleural dissemination and overall and recurrence-free survivals by multivariate analyses. Figure 1



Conclusion:
Preoperative diagnostic intervention did not affect relapse and/or prognosis in this study cohort. Preoperative diagnostic intervention is recommended if necessary.

Background:
Locking of scapula is rare complication of rib resection or thoracotomy. The patients experience severe pain and restriction of movement in their shoulder, and they are treated conservatively or surgically.

Method:
A 72-year-old woman underwent right upper lobectomy and extended combined resection of the posterior chest wall (via a standard posterolateral thoracotomy and resection of the 2nd to 4th ribs), to treat a stage3A lung cancer. Chest wall reconstruction was not performed. Her immediate postoperative course was uneventful, she was discharged from our hospital on 7th operative day. One year after operation, severe pain appeared in her right shoulder while she put on her underwear. She was referred to our hospital.

Result:
Physical examination revealed that resting pain was not so severe, but the range of shoulder motion was restricted due to severe pain. We suspected that the inferior angle of the scapula was caught inside the 5th rib. Chest x-ray showed that scapula prolapsed into the intrathoracic cavity through the resection site in the right chest wall (figure). The manipulative closed reduction was successful, then her symptoms were resolved. We advised her to pay attention to her right shoulder movement especially in over 90 degrees abduction. Five month later, no recurrences were observed. Figure 1



Conclusion:
As to rib defects like this case, the necessity of the reconstruction is controversial because the defect is completely covered by scapula. Moreover scapular prolapse into the intrathoracic cavity is rare and implants have a potential to infection. We conclude that the partial resection of the inferior angle of the scapula should have been performed at her operation in order not to be caught inside the rib.

Background:
We report two rare cases of complete resection for endobronchial protruded tumors.

Method:
Case 1; a-46-year old man with a history of several pneumoniae consulted us because of chest X-ray abnormality. A chest-CT showed atelectasis at medial segment of the right lung with bronchial obstruction. Case 2; a-68-year-old woman was referred to our hospital for persistent couch. Enhanced CT scan showed an endobronchial tumor at basal segment of the right lung with peripheral atelectasis.

Result:
In case 1, bronchoscopic findings showed a smooth-surfaced polypoid tumor which occluded the medial bronchi of the right lung. An endobronchial biopsy was performed, and it suspected mucoepidermoid carcinoma. He underwent a right middle lobectomy with VATS. The tumor grew as an endobronchial polyp with 25mm in a diameter. On Histopathological findings, the tumor consisted of epithelial cells and myoepithelial cells with tubular or alveolar formation, and it diagnosed epithelial-myoepithelial carcinoma. In bronchoscopy in case 2, the basal segment bronchi were obstructed by a whitish endobronchial tumor, and it caused obstructive pneumonia. A biopsy from the tumor showed no evidence of malignancy. A right lower VATS lobectomy was performed. The tumor showed endobronchial growth without fibrous capsules. Spindle cells with mild atypia were scattered in the tumor. With immunohistological examinations (positive for smooth muscle actin and desmin, negative for estrogen receptor), the tumor was diagnosed as bronchial leiomyoma.

Conclusion:
Epithelial-myoepithelial carcinoma belongs to carcinomas of salivary-gland-type. Bronchial leiomyoma, arising from bronchial smooth muscle, should be distinguished from benign metastasizing leiomyoma. These tumors are usually covered with normal bronchial epithelium. Endobronchial biopsy is necessary for histological diagnosis. Bronchoscopic examination followed by surgical resection is recommended for endobronchial protruded tumors.

Background:
The lung is still pneumatized and we cannot take a broad view of the chest cavity. As for surgeons, the prediction of lung prolapse is valuable for surgical manipulations. We estimated the degree of the collapsed lung ten minutes after thoracotomy (collapsed lung index; CLI). We also evaluated the relationship between CLI and pre-operative pulmonary function test.

Method:
From December 2016 to June 2017, we included 38 patients undergoing video-assisted thoracoscopic surgery (VATS) without pleural adhesion. CLI was determined as the degree of collapse of the lung ten minutes after opening the first thoracic port. CLI definition was as follows; Grade 1: the distance between visceral pleura and chest wall was less than 1cm, Grade 2: the distance was less than 3cm, Grade 3: the distance was less than 5cm, Grade 4: the distance was more than 5 cm and the lung parenchyma was partially deflated, and Grade 5: the lung was completely collapsed.　We also checked the relationship between CLI and pre-operative pulmonary function test of the patients.

Result:
The patients are 47 years old to 83 years old. They consist of 25 males and 13 females. The numbers of CLI Grade 1 were 0 cases, Grade 2 were 4 cases, Grade 3 were 18 cases, Grade 4 were 14 cases, and Grade 5 were 2 cases. VATS were easily undergone with broad surgical view Grade 4 and Grade 5. The 42% of the cases are included in CLI Grade 4 and Grade 5. The mean value of %VC was 102.6 %, FEV1.0G was 76.8 %, and FEV1.0% was 100.3 % in Grade 4 and Grade 5 patients. The preoperative pulmonary function tests were better in Grade 4 and 5 than the other Grades.

Conclusion:
We proposed CLI to estimate the surgical views at the beginning of VATS. The preoperative pulmonary function will predict the surgical field. We are waiting for some methods to deflate the lung in CLI Grade 1, 2, and 3 to Grade 4 or 5. The complete collapsed lung should make a good contribution for Single port VATS.

Background:
No large series of oncologic emergencies in thoracic surgery has been reported. Such patients are usually in critical condition and need immediate intervention of various types. Here, we present the surgical interventions that have occurred in our experience with oncologic emergencies.

Method:
We retrospectively analyzed 28 patients with oncologic emergencies who underwent surgical intervention at our hospital in 2002‒2016. The mean patient age was 76 years, and there were 19 (68%) males and 9 (32%) females. The primary disease was primary pulmonary carcinoma in 13 cases, including adenocarcinoma and squamous cell carcinoma in 4 and 6, respectively, other-organ carcinomas in 12, and mediastinal tumors in 3. Airway stenosis was the complaint in 19 (68%), including hemoptysis in 2, superior vena cava syndrome in 3 (11%), infectious diseases in 2 (7%), tumor bleeding in 2 (7%), and pneumothorax in 2 (7%).

Result:
The goal of surgery was a radical operation in 8 (29%), biopsy in 3 (11%), and palliative therapy in 17 (60%) patients. The surgical procedure was lobectomy in 4 patients, bronchoplasty in 4, wedge resection in 3, pneumonectomy in 1, tumor removal in 2, pleural decortication in 1, excisional biopsy in 4, airway intervention (stent or laser cauterization) in 11, and tracheostomy in 6. The mean hospital stay was 32±39 (range 3–155) days. The outcome was hospital death in 7 (25%) and discharge in 21 (75%). Of the discharges, 3 (11%) patients were transferred to another hospital, and 18 (64%) were sent home. The mean survival was 743±743 (range 3–3798) days. Of the 21 discharges, 7 (25%) patients are alive, including 4 (14%) who are cancer-free and 3 (11%) with cancer. As treatment, radical surgery was more effective than conservative therapy.

Conclusion:
The oncologic emergencies experienced in thoracic surgery included obstruction/stenosis, bleeding, infection, and rupture. Stenosis comprised the majority and was caused by tumor growth in the airway and compression and invasion by tumors. Good outcomes were expected in patients with slow-growing tumors who underwent laser cauterization or airway stent placement.

Background:
Postoperative chest tube drainage is essential in pulmonary surgery. After chest tube removal, the patient can be discharged from the hospital promptly. Therefore, it should be a close relationship between hospital stay and drainage duration. Removing chest tube in the early postoperative period leads to reduction of pain and early discharge from the hospital. However, there are few reports about removal chest tube on the first day after surgery. In this study, we examined cases where chest tube was removed on the first day after surgery.

Method:
From January to December 2016, 48 patients with lung cancer underwent lobectomy in our institute. They were consisted of 35 males, 13 females, and median age was 72 (53-87) years old. Among them, chest tube was removed on the postoperative day (POD) 1 in 24 patients (Group 1) and on the POD2 in 24 patients (Group 2). Patients complicated of postoperative lung fistula and infection were excluded.

Result:
Patients were discharged from the hospital on 5.4 days after surgery in Group 1 and on 5.6 days in Group 2. There was no significant difference between them (p=0.48). The CRP values on POD1, 2, and 3 were 5.49±2.38, 12.0±4.71, and 11.6±6.12 mg/dl in Group 1, and 7.27±3.28, 15.5±6.31, 12.9±5.87 mg/dl in Group 2, respectively (p=0.03, p=0.03, p=0.46). In addition, the period until CRP peaked out was 2.5 days in Group 1, and 2.1 days in Group 2. Group 2 showed obviously short period until CRP peaked out (p=0.03).

Conclusion:
Removing the chest tube on the first day after surgery will not lead to an early hospital discharge, conversely it will prolong the inflammatory response such as CRP.

Background:
Isolated fibrinogen deficiency is rare disease in Korean; especially extremely rare in patient with preoperative normal level of PT/aPTT.

Method:
I present a 62-year-old female patient who was admitted with lung cancer (adenocarcinoma, RUL, cT2aN0M0). She underwent VATS right upper lobectomy with mediastinal lymph node dissection. During operation, there was no need for transfusion (EBL 200cc) and no evidence of hemodilution.

Result:
On the first postoperative day (POD), PT was prolongated over 100 seconds (INR was over than 10). Coagulating factors were evaluated and isolated fibrinogen deficiency was diagnosed. As serum level of fibrinogen was fallen below 40mg/dL, spontaneous bleeding such as subcutaneous hemorrhage on trunk and persistent minor air leakage was observed. Bleeding tendency and air leak was improved since repeated transfusion of cryoprecipitate made the serum level of fibrinogen over 60 mg/dL. On POD 24, she was discharged without complication, however, she still had low level of fibrinogen. Although she was stable without any signs of spontaneous bleeding and prolongation of PT, the serum level of fibrinogen was still low around 60mg/dL at last visit in out-patient clinic which needed intermittent transfusion of cryoprecipitate. Figure 1



Conclusion:
She refused genetic evaluation for fibrinogen deficiency and I still don’t know what caused isolated fibrinogen deficiency in this patient, which could lead to a critical situation. To prevent any other disaster caused by this, I think there needs countermeasure for this.

Background:
The lung contains a large volume of air and have thus been unsuitable for observation with ultrasound. However, recent advancements in ultrasound have enabled the diagnosis of pneumothorax and tumor invasion of the chest wall, and fine-needle aspiration of tumors abutting the pleura can now be performed using ultrasound. Here, we investigated whether ultrasound is capable of predicting internal tumor properties.

Method:
TOSHIBA aplio 400 was used. Of 64 patients with tumor lesions undergoing preoperative ultrasound at our hospital between June 2015 and April 2017, we investigated 42 patients in whom internal tumor properties were visualized before surgery. There were 27 men and 15 women; 37 patients had malignant and 5 had benign lung tumors. Solid components were present in the tumor in 25 patients, liquid components in 3, a cavernous lesion in 9, a ground-glass opacity (GGO) lesion in 4, and pulmonary sequestration in 1. The tumor diameters ranged from 0.7 to 10.4 cm (median, 2.4 cm), and the distances from the lung surface ranged from 0 to 8.9 cm (median, 0.57 cm).

Result:
Ultrasound was useful for identifying an anomalous vessel originating from the aorta in a case with pulmonary sequestration. According to internal tumor properties, lesions containing a large volume of air (cavernous or GGO lesions) were visualized as hyperechoic areas, while many solid lesions appeared hypoechoic with a hyperechoic periphery on images. The posterior echo was enhanced in tumors containing liquid components and also in many cases with benign tumors. Thus, ultrasound is potentially useful for determining whether tumors are malignant or benign before surgery.

Conclusion:
Although ultrasound was not capable of visualizing the internal tumor structures in all cases, the internal tumor structure, if visualized by ultrasound, could be assessed. Moreover, ultrasound has the potential for differentiating benign from malignant tumors. Our results suggest that ultrasound merits future study, with further accumulation of cases.

Background:
“Peripheral” is ubiquitously used in thoracic surgery literature, but definitions differ. Our purpose was to ascertain opinions of thoracic surgeons on CT images and assess the frequency of peripheral nodules according to their definitions.

Method:
We developed a survey and obtained an IRB exemption. Surgeons were asked to choose one of methods A-D to define the peripheral pleura: A=costal pleura, B=costal and mediastinal pleura (diaphragmatic pleura also on coronal and sagittal views), C=costal and fissural pleura, D=any pleural surfaces on: Question#1) axial images, Question#2) coronal images, Question#3) sagittal images. Question#4 asked whether the peripheral lung was: 1, 2, or 3 cm, outer 1/3, outer 1/2 or outer 2/3. Question#5 asked whether the measurement from the nodule to the pleura started at the inner edge, center, or outer edge of the nodule. By applying the possible choices to a database of 76 patients with documented lung cancer we determined the frequency of peripheral cancers for each combination.

Result:
Ten thoracic surgeons participated, all had different answers. The most frequent response to Question#1 was Method A (n=4), Question#2 Method A (n=5), and Question#3 Method B (n=4). The most frequent answer for Question#4 was the outer 1/3 of the lungs (n=6), and for Question#5, the outer border of the nodule, closest to the relevant pleura (n=5). The frequency of nodules classified as peripheral according to these answers ranged from 13% (10/78) to 91% (71/78).

Conclusion:
There was no consensus. Standardization and rationale for this would be highly useful.

Background:
With the increase in number of individuals undergoing CT screening, lung cancers are now being detected at an earlier stage. Curative treatment can thus be performed on these patients, resulting in better lung cancer survival. Effective surgical decision making depends upon the degree of knowledge and experience the treating surgeon has about the outcome of actions, ability to assess risk and its subsequent impact. Use of a gnostic expert system would increase cost-effectiveness and efficiency. Our objective is to garner experts’ tacit knowledge about surgical decision making in a form of probability function.

Method:
Nine surgeons with extensive experiences in thoracic surgery were presented with a set of hypothetical cases, specified by indicators for surgical treatment (lobectomy or limited resection). Their choice of surgery and probability of performing limited resection were recorded for each case. Probabilities were translated into a logistic probability function for limited resection by 1) taking logits of the probabilities: Y=log[P/(1-P)], then 2) applying a general linear model for the mean of Y, Ŷ=β~1~+ β~2~X~2~+ β~3~X~3~+ β~4~X~4~+ β~5~X~5~+ β~6~X~6~+ β~7~X~7~ + ε. Standardized coefficients were computed and ranked to determine the effect of each indicator on limited resection.

Result:
Across the 24 cases, the median probabilities of limited resection among experts ranged from 0.0% to 100.0%, their case-specific IQR had values from 5 to 90 (Q3-Q1) percentage points, and ranges had values from 10-100(max-min) percentage points. Considering the expert-specific median probabilities, five out of eight experts favored lobectomy (median probabilities of limited resection ≤12.5%). Two other experts had median probabilities of 42.5% and 49% while the remaining expert favored limited resection (median probability 65%). The effect of each indicator on preferring limited resection over lobectomy varied between surgeons. Overall, distance from relevant pleura and nodule size were important factors for considering limited resection.

Conclusion:
There was great inter-surgeons variability on surgical decision making. Garnering experts’tacit knowledge on surgical decision making will enhance efficiency of health care and potentially change surgical practice.

Background:
Digital drainage system (DDS) has been recently recognized as a useful device in postoperative chest drainage. However, there is no past study predicting the efficacy of pleurodesis using DDS for postoperative air leak. The aim of this study is to identify predictive factors of the efficacy of pleurodesis including the observed data in DDS log.

Method:
The 857 patients underwent pulmonary resection and were made use of DDS for chest drainage postoperatively from January 2015 to December 2016. We retrospectively reviewed clinical database and log data of DDS, and compared the patient who stopped postoperative air leak by single pleurodesis with the patient who needed two or more pleurodesis. Fisher’s exact test was used to compare categorical values, and Mann-Whitney U test was used to analyze continuous values. The cut-off values were decided by receiver operating characteristic curve.

Result:
The 40 patients underwent pleurodesis for postoperative air leak. The median age was 70 years (range, 51 to 86), and 83% of patients were men. The most common type of surgery was lobectomy (90%). Postoperative air leaks in the 23 patients (58%) were stopped by single pleurodesis, and those in the 17 patients (42%) needed pleurodesis more than two times to stop air leak. The predictive factors to stop air leak by single pleurodesis were lower air leak flow at the time of pleurodesis (P = 0.02), and lower average of air leak flow for 24 hours before pleurodesis (P = 0.05). The cut-off value of air leak flow was 100 ml/min, and average of air leak flow for 24 hours was 130ml/min.

Conclusion:
Air leak flow at the time of pleurodesis and the average for 24 hours in DDS log were useful predicters of stopping air leak by single pleurodesis.

Background:
Recently, the improvement of ability of Computed tomography (CT) scans permits us to identify a large number of small peripheral, undefined pulmonary lesions that require a diagnosis. Although the large majority of these cases are benign, diagnostic approaches to discriminate benign nodules from malignant nodules remain most-unsatisfactory.　 So we often have to perform thoracoscopic resection with the primary objective of diagnosis. In this study, we examined the clinicopathological findings in the cases of indeterminate pulmonary nodules in which thoracoscopic or open excisional biopsy was performed.

Method:
From a single institutional database, a total of 253 patients diagnosed with lung cancer or suspected lung cancer underwent resection between January 2014 and March 2017. In 155 patients, a histological diagnosis was not obtained preoperatively. This study was intended for 108 patients diagnosed with lung cancer after surgery among the 155 indeterminate pulmonary nodules.

Result:
Out of 155, 108 patients were diagnosed as primary lung cancer by intraoperative frozen section or postoperative pathological examination. Twenty-six patients were diagnosed as metastatic lung tumors, and 21 patients were diagnosed as other, such as benign inflammatory changes. Surgical resection of indeterminate　lung　nodules (mean diameter 20.6mm, range 3 to 53 mm) were performed in 108 primary lung cancer cases, which represented 52.4% of the 206 resections for lung cancer performed during the study period. There were 57 men and 51 women with an average age of 70.6 years old (47-91 years old). A biopsy needle (13cases) or wedge resection (61cases) was used to the methods of intraoperative diagnosis. The remaining 34 cases performed a final pathological examination after surgery without intraoperative diagnosis. Nineteen small pulmonary nodules that include ground-glass attenuation required preoperative computed tomography-guided lipiodol marking to identify the position of a nodule. The postoperative stage was 0 in 17 patients （16％）, IA in 66 （61％）, IB in 11 （10％）, IIA in 1 （1％）, IIA in 3 （3％）, IIIA in 8 （7％）, and IV in 2 （2％）.

Conclusion:
The small pulmonary nodules that include ground-glass attenuation are tricky to diagnose. When CT findings are highly suggestive of lung cancer, we think that positive lung biopsy under thoracoscopic surgery is necessary to detect lung cancer.

Background:
Pulmonary carcinoids (PC) are rare malignant neuroendocrine tumors with indolent course. It is estimated that PC overall encompass 1% to 5% of all lung neoplasms. The surgical resection is the preferred treatment modality but the indolent nature of the disease makes interpretation of survival numbers problematic.

Method:
Aims: We report a single institution experience with PCs over a 17-year period to gain a better understanding of prognostic factors related to the management of these rare tumors. Material and Methods: Patients who underwent operations for primary pulmonary carcinoid tumor at National Tuberculosis and Lung Diseases Research Institute in Warsaw, Poland between 1998 and 2015 were identified from the database. Their medical records were reviewed for clinical presentation, tumor spread, pathology, treatment modalities, and survival.

Result:
There were 329 cases of PCs: 217 (66%) typical (TC) and 112 (34%) atypical (AC) carcinoids, with a median follow-up time of 7,6 years. There were 230 females (69,9%) and 99 males (30,1%). The most common symptoms were cough (38,7%), dyspnea (15,9%) and hemoptysis (14%). No patients showed a carcinoid syndrome. There was no correlation between smoking status and PCs. The majority of patients were in stage I disease (67,4%), only 6,4% in stage III and IV (6,4%). Involvement of lymph nodes was present in 49 cases (14,9%), N1 -34 (10,3%) and N2 – 15 (4,6%). Infiltration of bronchial or vessel margin (R1) was revealed in 10 cases (3%). Surgical treatment consisted of: 247 lobectomies (75,1%), 30 pneumonectomies (9,1%), 36 bilobectomies (10,9%), 5 anatomic segmentectomies (1,5%), 8 wedge resections (2,4%), 3 – bronchoplastic procedures without lung resection (0,9%). Radical mediastinal lymphadenectomy was added in all cases. The number of death among the patients with TC and AC was 7 (6,3%) and 31 (14,3%) respectively. Kaplan-Meier 1-, 5-, 10- and 15-year overall survivals for the entire group were 98,8%, 92,8%, 86,8% and 78,6% respectively.

Conclusion:
• PCs are tumors with an excellent prognosis, even in the presence of metastases in lymph nodes and positive surgical margin. • None of the symptoms and stage of tumors as well as the distance of the tumor from the surgical margin did not affect significantly the overall survival. • The age of patients, the type of operation and performance status (ECOG score) had vital importance for overall survival. • Surgical resection is the best and adequate therapy for PCs with high overall survival and disease-free survival but long-time observation is necessary.

Background:
Inadvertent phrenic nerve injury (PNI) during lung cancer surgery is not well-studied. It is not always easy to make a clear-cut diagnosis with routine methods. Very few cases have been reported in literature. The aim of our study is to find an easily accessible and precise way to diagnose PNI and then to evaluate the incidence and its impact in early-stage lung cancer patients undergone minimally invasive surgery.

Method:
The first step was to examine the extent of diaphragm elevation in patients with invasive thymomas in whom phrenic nerve was certainly divided. The distance between the diaphragm and the apex of the chest was calculated on chest X-Ray before (DB: Distance before) and after (DA: Distance after) surgery. The following formula was used: [(DB-DA)/DB]x100. The result (mean+SD) was used as criteria for diagnosing PNI. The second step was to study PNI in early-stage lung cancer patients undergone VATS lobectomy using the above criteria.

Result:
Diaphragm elevation was found to be 24.24 +/- 6.2% in 22 invasive thymoma-patients and therefore, 30% was adopted as criteria for the diagnosis of PNI. Among 567 consecutive patients with early-stage lung cancer recruited from January 2014 to December 2016, 43 (7.6%) were diagnosed to have PNI (Table 1). No correlation was detected between PNI and location of the lesion or extent of lymph node dissection. Neither was there any difference in post-operative complications or length of hospital stay. But comparing spirometry data before and 6 months after surgery, reduction in FEV1, FVC, and DLCO was significantly greater in patients with PNI.Figure 1



Conclusion:
We found an easily accessible way to diagnose precisely PNI in lung cancer patients receiving VATS lobectomy. Inadvertent PNI during minimally invasive surgery seems to be underestimated, and it is associated with significant reduction in pulmonary function of the patient.

Background:
Poor pathologic nodal staging impairs overall survival (OS) after curative-intent surgical resection of NSCLC. We implemented a LN collection kit and previously demonstrated how it improves pathologic nodal staging. We now report its survival impact.

Method:
Using a prospective step-wedge design, kits were implemented for curative-intent surgical resections from 2009-2017 in 11 hospitals within 4 contiguous US Dartmouth Hospital Referral Regions. OS was analyzed with the Kaplan-Meier method. Crude (HR) and adjusted (aHR) hazard ratios with 95% confidence intervals (CI) are presented from Proportional Hazards Models adjusted for clustering by surgeon. Covariates in adjusted models include: age, sex, histology, tumor grade, extent of resection, T and M categories, and number of comorbidities.

Result:
The LN kit was used in 734 of 2,547 (29%) resections. All demographic and clinical characteristics, including age, sex, race, health insurance coverage and preoperative stage distribution were similar between kit and non-kit cases. Aggregate 1, 3, 5-year OS: 89%, 74%, 66%(kit) vs. 83%, 65%, 53% (non-kit) (p< 0.0001, Fig.1). Clinical stage stratification (kit v non-), 5-year OS: I, 68% vs. 58%, (p-value=0.0038); II, 68% vs. 40%, (p=0.0045); III, 57% vs. 42%, (p=0.0412). Pathologic stage stratification (kit v non-) 5-year OS: I, 72% vs. 59% (p=0.0082), II, 60% vs. 44% (p=0.0403); III, 48% vs. 36%, p =0.0179). For both clinical and pathologic Stage IV, survival did not differ. Kit cases had a 30% lower hazard of death compared to non-kit cases: HR 0.67 (CI[0.55,0.80], p<0.0001) and aHR: 0.70 (CI[0.54,0.92], p<0.0001). Results remained statistically significant after multiple sensitivity analyses excluding sub-lobar resections, 60-day mortality, non-adopting surgeons, and excluding the 48 months of retrospective baseline control data (aHR: 0.28 to 0.73). Operating time, perioperative complication rates, and duration of hospitalization were similar between groups. Figure 1



Conclusion:
Intraoperative specimen collection with a LN kit improves long-term NSCLC survival.

Background:
With the recent advances of diagnostic imaging modalities such as high-resolution computed tomography (HRCT), the detection rate of multiple synchronous lung cancer with ground-glass opacity (GGO) has increased. In clinical practice, preoperative pathological diagnosis of GGO lesions by transbronchial biopsy is difficult. It is necessary to develop the optimal surgical strategy that achieves both accurate diagnosis and curative resection. We recently encountered three cases of synchronous multiple lung cancer with GGO.

Method:
Case 1: A 68-year-old male had abnormal shadows detected on chest computed tomography (CT). HRCT showed a 3.5cm-in-diameter part-solid nodule in the right upper lobe (RUL), a 2.5cm-in-diameter part-solid nodule in the right lower lobe (RLL), and a 1.5cm-in-diameter pure ground-grass nodule (GGN) in the left lower lobe (LLL). Thoracoscopic right upper lobectomy and right S6 segmentectomy was performed. The histopathological diagnosis of the RUL tumor was well-to-moderately differentiated adenocarcinoma and RLL tumor was well differentiated adenocarcinoma. These tumors were found to harbor different epidermal growth factor receptor (EGFR) gene mutation. The LLL tumor is followed up by CT scan. Case 2: A 71-year-old female had an abnormal shadow incidentally detected on chest radiography. HRCT showed a 1.0cm-in-diameter pure GGN in RUL and a 3.0cm-in-diameter part-solid nodule in left upper lobe (LUL). To achieve a minimal invasive approach for bilateral lesions, we planned to perform staged bilateral surgery that the limited resection precedes the anatomical resection. Thoracoscopic wedge resection of RUL was performed as the first operation, then thoracoscopic left upper lobectomy was performed as the second. The histopathological diagnosis of both tumors were well-to-moderately differentiated adenocarcinoma with different EGFR mutation status. Case 3: A 68-year-old female had abnormal shadows detected on chest CT. HRCT showed a 1.5cm-in-diameter pure GGN in RUL and a 1.0cm-in-diameter pure GGN in LLL. Thoracoscopic wedge resection of LLL was performed as the first operation, then thoracoscopic right S3 segmentectomy was performed as the second. The histopathological diagnosis of the LLL tumor was well-to-moderately adenocarcinoma and the RUL tumor was well differentiated adenocarcinoma.

Result:
All three cases had an uneventful postoperative course with no evidence of recurrence.

Conclusion:
In case of multiple tumors, we decide surgical procedures based on the size, number, location, and radiological findings of the tumors. We select combination surgery with anatomical resection and limited resection, and avoid bilobectomy if possible. Additionally, the thoracoscopic approach for multiple lung cancer seems to be a good option to perform minimally invasive surgical procedures.

Background:
Malignant melanocytic neoplasm is a highly malignant tumour derived from melanocytes. It occurs most commonly in the skin and mucous membranes while occurrence in the mediastinum is extremely rare.

Method:
Section not applicable

Result:
Section not applicable

Conclusion:
We report a case of a young female who presented with shortness of breath and chest tightness. Further imaging revealed a large anterior mediastinal mass with compression of the pulmonary vessels and a few lung nodules. A Chamberlain procedure was performed and showed a highly pigmented lesion. The histology returned as malignant melanocytic neoplasm. She was then started on pembro.

Background:
We have initiated a new multi-center, international collaborative cohort study, the Initiative for Early Lung Cancer Research for Treatment (IELCART), which focuses on identifying optimal treatment for early stage lung cancer An issue under discussion is the extent of surgery (i.e., sublobar resection and no mediastinal lymph node resection) in order to decrease the length and morbidity of the surgical procedure, preserves pulmonary function, and increases the likelihood of resection of future new occurrences of lung cancers. The role of Stereotactic Body Radiation (SBRT), and for certain cases, Watchful Waiting (WW) also needs to be better delineated. Increasingly, the power of large prospective databases collected in the context of clinical care is being recognized as providing important information.

Method:
Based on an extensive literature review, scientific articles, and a series of focus sessions with patients and treating physicians, a common protocol has been developed. Relevant data forms were developed for both physicians and patients, both for pre- and post-surgery to account for potential confounders. These forms have been tested and entered into a web-based data collection system that also includes relevant imaging data. Initial enrollment focused on surgery.

Result:
Initial enrollment was limited to surgical clinics of 8 surgeons and a total of 174 patients (94 women, 80 men) agreed. Average age was 67.5 years and pack-years of smoking was 31.4. Patients stated that the internet was the most frequent source of information (35%), while family/friends, medical literature were used much less frequently (each <20%). Factors influencing the patient pre-treatment choice was that the physician thought it was best (93%) or what would provide the best outcome (87%); only 38% got a second opinion. The surgeon’s choice of procedure depended mainly on the location (75%), size of the nodule (64%), and the ability to have negative parenchymal margin (40%), with other considerations being much less likely (<26%). There was good agreement between patients’ and surgeons’ perceptions of the procedure, although the patients not fully prepared about the post-treatment consequences of surgery. Patients also thought that support groups were important in patients’ decisions on what was the best surgery.

Conclusion:
These results together with quality of life information and focus sessions suggest that more support in the post-operative phase of the treatment would be beneficial. Within the next 3 years, we anticipate to have statistically meaningful results to start to compare outcomes of alternative treatments.

Background:
Radiologists focus on the anatomic changes in the lung itself when interpreting postoperative surveillance CT scans, but the anatomic and physiologic effects of lung resection on the other organs of the thorax, specifically the pulmonary artery (PA), have not been well studied. Potential variations in PA size over time have been recognized as predictors of post-surgical complications and the development of pulmonary hypertension.

Method:
The International Early Lung Cancer Action Program (I-ELCAP) database was queried for lung cancer patients who underwent lobectomy and had both preoperative and postoperative CT imaging. Case-specific details were previously recorded in the database as per I-ELCAP protocol. All surgeries were performed by general thoracic surgeons. All CT imaging for each patient was reviewed by a fellowship-trained chest radiologist. Figure 1



Result:
Among the 142 subjects who underwent lobectomy, the median follow-up time from the pre-surgical CT to the last reviewable CT was 53.2 months (IQR: 27.9-100.4 months). The average increase in the size of the main pulmonary artery (mPA) was 1.5 mm (19.9 mm to 21.4 mm, P < 0.0001). There was also a significant increase between the pre-surgical CT and the initial postoperative CT which was on average 12.6 months later from 19.9 mm to 20.7 mm (P = 0.0002). Considering patients with and without CT evidence of emphysema, the 82 with emphysema had a smaller average change of the main PA between the pre-surgical and the last reviewable CT than the 60 without emphysema (1.0 mm vs. 1.8 mm, P = 0.08).

Conclusion:
Patients undergoing lobectomy appear to be at increased risk for enlargement of their pulmonary artery diameters after surgery. These results show that a focus on all the organs in the thorax, not just the lungs themselves, is important when evaluating postoperative lung resection CTs.

Background:
The anatomic and physiologic effects of lung resection for early stage lung cancer patients have not been extensively reported. We hypothesize that patients who have undergone lobectomy or wedge resection will have reduced lung volume on the affected side immediately after surgery while the lung volume on the opposing side may increase to compensate.

Method:
The Mount Sinai database was queried for stage 1 lung cancer patients who underwent lobectomy or wedge resection and had both pre-operative and postoperative CT imaging. Surgeries were performed by thoracic surgeons. The lung volumes on all CT scans were measured using previously published research software including actual volumes for each lung (left and right) at each time point as well as a set of volumes normalized to the overall chest volume in order to compensate for differences in inspiration.

Result:
In the cohort of 21 patients who met the above criteria, the median follow-up time from the date of surgery to the most recent CT was 44.6 months (IQR: 23.5-94.7 months). The median age was 63 and the median pack years was 40. There were 2 patients for which only one post-op scan was successfully analyzed; the remaining cases all had two postop scans. In 20 of the 21 patients, the lung volume on the side where the surgery occurred was reduced in the first postop CT scan (average reduction in volume of 5.6%). The change in volume of the contralateral side (not undergoing surgery), was highly variable, with 11 cases showing an increase in volume on both post-op scans, 2 cases showing a decrease, and 8 cases showing an increase in volume at the first postop scan followed by a decrease in volume on the second post-op scan.

Conclusion:
Stage 1 lung cancer patients undergoing resection have reduced lung volume on the side of surgery, however there was marked variability in the contralateral lung suggesting that the extent to which patients compensate post operatively is complex and dependent on many factors.

Background:
A solitary pulmonary nodule (SPN) is a common and increasing clinical problem, mainly due to the lung cancer (LC) screening programs and easier access to complementary diagnostic tests. Differential diagnosis is broad and often challenging for decision making, particularly in small and not accessible lesions. The process of selecting the right strategy must address the probability of malignancy, nodule characteristics observed on CT/PET-CT, patient preferences and institutional-related expertise. The aim of this study was to evaluate the accuracy of the multidisciplinary lung cancer tumour (MLCT) board team in the management of SPN.

Method:
We retrospectively reviewed all SPN patients who underwent surgical resections between January 2015 and March 2017. All patients were evaluated at a MLCT meeting. We characterised demographic, clinical and radiological features, surgical procedure, histology and outcomes.

Result:
We included 73 patients, 37 male (50.7%), with a mean age of 63.3±10.2, 64.4% smokers (current or former) and none with asbestos/radon exposure. Twenty-five patients (34.2%) had previous history of cancer and 5 (6.8%) of tuberculosis. Emphysema was present in 21 patients (28.8%). Fifty-six were solid SPN (6–20 mm) and 17 subsolid SPN (9-18 mm): 15 with solid component (2-13.5 mm) and 2 pure ground glass nodules (10 and 12.3 mm). Of the 73 patients, 11 (15.1%) had a definitive histological result before the surgical intervention: 10 LC and 1 metastasis. Among patients without diagnosis (n=62), frozen section was performed in 45 patients (61.6%): 31 of these (70%) were malignant disease (25 LC and 6 metastasis) and 14 were benign lesions. In this group, we performed 17 lobectomies, 15 anatomic segmentectomies and 13 wedge resections. All patients with LC underwent mediastinal lymph node dissection (MLND). Among the 25 patients with LC, 7 were adenocarcinoma in situ and 18 invasive lesions (17 in stage I). In the other 17 cases without previous diagnosis, a direct surgery was performed, based either on the location of the lesion, size or clinical suspicion. Twelve of these patients (70.6%) were confirmed to have LC in the final pathology evaluation (all invasive LC in stage I). They underwent an upper bilobectomy, 10 lobectomies, 3 anatomic segmentectomies, all with MLND, and 3 wedge resections. No major complications were reported.

Conclusion:
This study suggests that surgery is a safe strategy in the diagnosis and treatment of SPN without previous diagnosis.

Background:
Sarcomas are known to be malignant and aggressive tumors, and often develop multiple pulmonary metastasis. Although systemic therapy is a treatment of choice for metastatic lung tumors, effective treatments have not yet been established. Surgical resection for metastatic lung tumors is a therapeutic option to control the disease, while it is not a curative therapy.

Method:
Between 2006 and 2014, 129 sarcoma patients who underwent pulmonary metastasectomy in Okayama University Hospital were retrospectively reviewed. In total, 229 pulmonary resections were performed. We analyzed the following factors: age, sex, site of primary lesion, histology, operative procedures, size of the largest lesions resected, maximum number of the resected tumors, postoperative complications, and survival rate.

Result:
In total, 939 metastatic nodules were resected. Average number of tumors per intervention was 4.1 (range 1-19). These sarcoma patients consisted of 31 males and 98 females, and their average age was 53.6 years (range 14-80 years). Leiomyosarcoma was the most common histological subtype (n = 72, 55.8%) and uterus was the most common location of the primary disease (n = 55, 42.6%). Operative procedures were composed of 173 partial resections, 31 segmentectomies with or without partial resections, 24 lobectomies with or without partial resections, and 1 basal segmental auto-transplantation after pneumonectomy. The postoperative complications were limited, showing that pulmonary metastasectomies for sarcomas are acceptable. Overall 3-year survival after the first pulmonary metastasectomy was 49.5%, and the survival was significantly better for the group with disease-free interval of more than 2 years or the size of the largest resected lesion less than 30 mm.

Conclusion:
Surgical resections for metastatic lung tumors of sarcoma were performed without major complication, indicating acceptable feasibility. If disease-free interval is more than 2 years and the size of the largest resected lesion is less than 30 mm, patients may maximally benefit from surgical resection.

Background:
After pulmonary resections, one or two chest tubes are used, and the choice is based mainly on local habits rather than on evidence. The aim of the study was to evaluate the efficacy of chest drainage after lung resection using single chest tube versus two chest tubes in patients with non-small cell lung cancer (NSCLC).

Method:
Single-centre prospective randomized trial including patients who underwent anatomical lung resection for NSCLC between February 2016 and may 2017. At the end of the operation, patients were randomized in a 1:1 ratio, to the single tube group or to the two tubes group. On the day of surgery, controlled suction of -20 mmHg was used, switched on the 1st postoperative day to -8 mmHg. Chest tubes were removed in the absence of air leak for more than 24 hours, and the chest tube output <250 mL/day.

Result:
There were 357 patients enrolled, including 219 men, mean age 64.43 years (range: 22-84) and 138 women, mean age 64.06 years (range: 24-85). One chest tube was used in 176 patients, including 50 cases of VATS lobectomy and 126 cases of open lobectomy. Two chest tubes were used in 181 patients, including 35 patients after VATS lobectomy and 146 after open lobectomy. In the single chest tube group there was significantly shorter air leak time (4.25 vs. 4.5 day; p = 0.001, drainage time (3.6 vs 4.7 day; p = 0.0001), and postoperative hospital stay (6.15 vs 7.5 day; p <0.0011. Multivariate regression analysis demonstrated that time of chest tube drainage after cessation of the air leak depends on the volume of chest tube output in the first 6 hours (p = 0.00001) and the time of air leak (p = 0.0014), regardless of the number of drains.

Conclusion:
Single chest tube after anatomical lung resections is associated with shorter air leak, shorter drainage time, shorter hospital stay compared to two chest tube drainage. Routine use of single chest tube is safe and effective treatment.

Background:
The ability to constantly metastasize remains a truly challenging obstacle for cancer patients . Historically in the past , any local surgical treatment in patients with systemic malignant disease is considered without any prognostic benefit , this has since evolved with many studies confering huge success rates with excellent prognostic benefits . We hereby report our experience over the last 5 years at Wellington Regional Hospital , Cardiothoracic unit .

Method:
A retrospective study was undertaken in series of cancer patients with colorectal , melanoma , breast , sarcoma & renal metastatic disease undergoing pulmonary metastasectomy , from year 2011 to 2015 . These data was identified & stratified into groups using hospital patient database & ORSOS theatre database

Result:
Total of 61 patients had pulmonary metastatectomies in 5 years , of which 14 were done via VATs wedge resection .Population age between 34 to 86 years old with a M: F ratio of 2:1 . Average age was 63 years . A further 4 patients had multiple metastatectomy on ipsilateral side . 45 patients were non-smoker in this cohort . Average in-hospital stay was 7.83 days , with 3 patients requiring post op ICU admission . 47 patients had pre-op epidural catheter for pain management . Complications include 6 patients needing to return to theatre for suspicion of lung torsion , bronchopleural fistula , haemothorax and 3 patients had torrential air leaks .No major complications noted . Majority had colorectal & melanoma metastases . No mortality at 30 days . 87% survived at 1 year . Total of 38 patients are still alive at present .

Conclusion:
Using MDM as a tool , these carefully selected surgical patients underwent pulmonary metastasectomy for metastatic diseases which confers continual prognostic & survival advantage in this group . Overall 1 year survival seems resonable & surprisingly excellent given the overall bad prognosis of metastatic disease in general .

Background:
Lung cancer is the leading cause of cancer death in New Zealand, resulting in over 1600 deaths per year. Indigenous New Zealanders (Māori) have a higher lung cancer mortality rate than non-Māori (Female RR 4.3, Male RR 2.8). Data from our local thoracic multidisciplinary meetings (MDM) was presented to our regional cancer network (Northern Regional Alliance) and identified that only 9% of Māori lung cancer patients received curative intent surgery compared to 18% of New Zealand Europeans. The Treaty of Waitangi is a founding document of New Zealand that defines the relationship between Māori and the British Crown and gives responsibility to the New Zealand government to reduce inequities in health. The aim of this audit was to review the documented reasons for not proceeding to surgery in Māori lung cancer patients.

Method:
Electronic clinical records were retrospectively reviewed for the 100 identified Maori patients in the Auckland/Northland region who were presented at the thoracic multidisciplinary meeting between January and December of 2014. Patients were included if clinical records were available, Māori ethnicity was documented and treatment recommendations were made locally. Descriptive analysis is presented.

Result:
87 of 100 patients met criteria for inclusion. 65% were female with a median age of 65(47-83). 48% were current smokers, 63(72%) had pathologically confirmed NSCLC and the majority had advanced stage disease (IASLC 7[th] Edition TNM staging: I 24%, II 6% , IIIa 18%, IIIb 11%, IV 40%).Fourteen (16%) were recommended to have surgery by the MDM, with 9 (10%) completing surgery. Of the 5 who did not complete recommended surgery, two patients were found to have advanced disease intra-operatively and three declined surgery.Of the 78 not undergoing curative intent surgery, the documented reason was advanced disease (64%), comorbidities (21%), small-cell lung cancer (8%), declined by patient (4%) and one patient was recommended stereotactic radiotherapy. Analysis will be updated to include, and compare to, 100 age/sex matched New Zealand European patients.

Conclusion:
Presentation with advanced disease and comorbidities were documented as the reason for not proceeding to surgery in the majority of Māori patients with lung cancer discussed at the thoracic MDM. Within the limits of retrospective analysis, these findings suggest that addressing comorbidities and earlier detection of lung cancer may best improve access to curative treatment options for Māori.

Background:
ALK is a receptor tyrosine kinase that was discovered in anaplastic large cell lymphoma in the form of a fusion protein. To pick-up the patients with ALK-rearrangements is important to select the individual therapy as ALK inhibitor for mainly lung adenocarcinoma. There are several fusion partners with ALK 3’ region.

Method:
A 35-year-old woman with a short-breath and cough was referred and admitted taking a therapy for lung tumor in our hospital. By the bronchoscopic biopsy, she was suspected pulmonary IMT, but correct diagnosis was not indicated. Right upper wedge lobectomy was done. By the pathological examination of the permanent surgical resected tissue, the final diagnosis was pulmonary IMT.

Result:
The immunohistochemistry of ALK by using the iAEP method was positive. We extracted the RNA from frozen surgical resected tumor tissue, and prove the TPM4-ALK by 5’ RACE and RT-PCR. The preoperative bronchial biopsy specimen was also found positive for anti-ALK immunohistochemistry with iAEP method.

Conclusion:
The molecular therapeutic drug was expected as personalized therapy for the tumor with ALK translocation as oncogenic driver. We should examine the ALK protein expression and translocation about the cases of lung cancer and IMT by using adequate ALK immunohistochemistry system. We experienced a case of pulmonary IMT with TPM4-ALK translocation.

Background:
Tumors originating from chromaffin cells are located in 90% of cases in the adrenal gland and called pheochromocytomas, while in 10% of cases have an extra-adrenal origin (paraganglionic cells scattered throughout the body) and are termed paragangliomas. Endothoracic paragangliomas can arise in the lung and mediastinum, may have neuroendocrine activity, secreting catecholamines, or be non-functional, incidental, in asymptomatic patients or causing mass effect symptoms. Even if rare and with low grade of malignancy, they can present an aggressive behaviour, developing local infiltration of surrounding organs and distant metastases. A correct pathological diagnosis and radical surgical treatment are fundamental to obtain clinical recovery. We report our experience with three cases of endothoracic paragangliomas, in order to point out difficulties in diagnosis and problems related to surgical treatment.

Method:
From January 2009 to December 2016, we treated 3 patients (2 women, 1 man), mean age 67 years, with histological diagnosis of paraganglioma: 2 pulmonary, 1 mediastinal. All patients were asymptomatic for catecholamine-secreting syndromes; the two cases with pulmonary localization showed no other symptoms, while the mediastinal one had cough and dyspnea, due to compression by the mass, and blepharospasm. Imaging diagnosis was based on chest CT scan in pulmonary cases, chest CT and MRI scan for the mediastinal mass, which allowed to define vascularization and relationships with adjacent structures. No patient had preoperative histological diagnosis. Intraoperative pathological examination of the two pulmonary forms was suggestive for malignancy (extensive necrosis, high proliferative index, hypervascularization), thus a right pulmonary wedge resection was performed in one case, a right upper lobectomy in the other one. The hypervascularized mediastinal lesion, located in the middle mediastinum, tenaciously adherent to the superior vena cava, the aortic arch, the right branch of the pulmonary artery and the trachea, was completely removed after challenging isolation and section of numerous vascular pedicles.

Result:
Postoperative course was uneventful in all cases. No patient received adjuvant treatments. At a median follow-up of 35 months (range: 6-90 months), two patients are alive, without local or distant recurrence; one patient (with pulmonary involvement) died 6 months after surgery, due to disease progression.

Conclusion:
Endothoracic paragangliomas, rare and often asymptomatic tumors, are of difficult diagnosis and should be considered malignant tumors, due to the potential aggressive behaviour of cases with high mitotic index and the frequent possibility of recurrence. After complete excision, long-term prognosis is generally good. However, even after surgical removal, a close and periodical follow-up is mandatory.

Background:
Surgical resection for mediastinal germ cell tumors is one of important modality to cure. But it sometimes shows severe adhesion to greater vessels, complete resection without vessel replacement is difficult. But, no viable cells are found in the resected specimen in many cases. Is vessel replacement really needed for this situation? The aim of this study is to confirm whether complete resection is really needed for mediastinal germ cell tumor.

Method:
The data of 13 patients with resected mediastinal germ cell tumor were retrospectively analyzed for recurrence.

Result:
Median follow up period was 72.2 months. All cases were male. Mean age was 33.1 years old. Pathological diagnosis was mature teratoma in 5 cases, seminoma in 5 and non-seminomatous malignant germ cell tumor in 3. Seven cases received preoperative chemotherapy. Mean tumor size before surgery was 7.1cm. Median sternotomy was performed in 10 cases and posterolateral approach in 3 cases. Mean operative time was 225 minutes and blood loss was 228 g. Mean postoperative in-hospital duration was 8.2 days. There were not any life-threatening postoperative complications. Macroscopic residual tumor (R2) was found in 5 cases; 2 mature teratoma and 2 seminomas and a germ cell tumor because of severe adhesion to aorta. Four cases received adjuvant therapy. But in R2 case; 2 of mature teratoma and a seminoma without viable cell did not receive adjuvant therapy. Only a case of non-seminoma with complete resection, which did not achieve negative tumor marker preoperatively, showed distant metastases 4 months later after surgery.

Conclusion:
The surgery for mediastinal germ cell tumor in selected situation can show good survivability without recurrence. To balance the invasiveness and curability, minimizing the extent of surgery; not performing greater vessel replacement is one of choice.

Background:
Germ cell tumors of testicular origin are the most common malignancy in young males. The lungs and the retroperitoneal space are frequently the initial sites of metastatic disease. Salvage surgery is an important treatment modality for residual post-chemotherapy pulmonary masses. We analyzed the prognostic predictors of survival in the patients after pulmonary metastasectomy.

Method:
Between September 1989 and December 2015, 32 patients underwent pulmonary resection of thoracic metastases following cisplatin-based chemotherapy. Germ cell tumors of mediastinal origin were excluded. These patients’ records were subsequently reviewed.

Result:
All patients underwent high orchidectomy and cisplatin-based chemotherapy.　　The primary tumor histology demonstarated 2 seminomas and 30 nonseminomatous germ cell tumors. Twenty-three patients (72%) received two or more chemotherapy regimens. International Germ Cell Cancer Collaborative Group classification, TNM factors, and serum tumor marker level at diagnosis were not associated with prognosis after pulmonary metastasectomy. The mean age at pulmonary surgery was 31.9 years. The surgical procedures included wedge resection in 23 (72%) and segmentectomy/lobectomy in 9 (28%). There were no perioperative deaths and major postoperative complications. The overall 5-year survival rate was 73% after an average follow-up of 55 months. The pathology of residual pulmonary masses revealed viable tumor cells in 12 patients (38%), necrosis alone in 18 patients (56%), and mature teratoma alone in 2 patients (6%). Preoperative increased lactic dehydrogenase (LDH) levels were significantly associated with the viable tumor cells of residual masses. The size of pulmonary metastases has not been found to be statistically related to malignant tumor cells. A significantly poor survival was observed using univariate analysis in patients with preoperative high free-βHCG (p=0.012), high intact HCG (p=0.031), high LDH (p<0.001), removing 5 or more lung metastases(p=0.012), and viable tumor cells of residual masses (p=0.026).

Conclusion:
We conclude that pulmonary resection in metastatic testicular tumors is a safe and effective treatment strategy. Increased tumor marker levels, free-βHCG/intact HCG or LDH, removing 5 or more lung metastases, and viable tumor cells of residual masses were identified as prognosis-related criteria for a poor prognosis.

Background:
The treatment for stage IV non-small cell lung cancer relies on molecular diagnosis on tumor DNA for guiding systemic therapy. Liquid biopsy provides a timely and non-invasive way of detecting potential therapeutic targets and spares the need of performing a confirmatory biopsy procedure in patients with a positive result.

Method:
We report local experience on epidermal growth factor receptor (EGFR) mutations detected by two platforms (droplet digital polymerase chain reaction (ddPCR) technique and Cobas EGFR v2) on cell free tumor DNA from radiological stage IV lung cancer patients, guiding first- and second-generation EGFR tyrosine kinase inhibitor (TKI) therapy. All these patients who had either plasma EGFR platforms done from Nov 2015 to May 2017 are retrospectively identified and analyzed.

Result:
97 patients identified. 11 out of 39 (28.2%) and 16 out of 58 (27.6%) has detectable EGFR mutation in plasma by using ddPCR and Cobas techniques respectively. Much higher detection rate is noted in never smokers (23/46, 50.0%) compared with chronic/ever smokers (4/41, 9.8%) and is highly statistically significant for difference (p-value: <0.001 ). The types of EGFR mutations detected are as follows: ddPCR method: 4 (36.4%) del 19, 7 (63.6%) L858R. Cobas method: 5 (31.3%) del 19, 9 (56.3%) L858R, 2 (12.5%) G719X. 20 (74.1%) patients were eventually put on 1[st] or 2[nd] EGFR-TKI as first line treatment and, among those, 17 (85%) attained partial response as the best treatment response and the median PFS and OS of is not reached. Among the 56 patients who obtained tissue biopsy/cytology along the course of disease, 6 (10.7%) of which carries histology (3 squamous cell carcinoma, 1 peripheral nerve sheath tumor, and 1 small cell carcinoma and 1 large cell tumor neuroendocrine tumor) that's not normally sent for EGFR molecular testing, as well as 11 (19.6%) patients having NSCLC-NOS histology only.

Conclusion:
ddPCR and Cobas EGFR v2 platforms have similar detection rate and chance of avoiding the need of a confirmatory tissue biopsy. A simple clinical history of smoking status determines the yield of a positive result. Plasma liquid biopsy provides a non-invasive and promising way for treatment initiation in radiological lung cancer.

Background:
Almost all EGFR-mutant lung cancers develop resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Several mechanisms for this acquired resistance have been identified, including development of an EGFR T790M mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, loss of PTEN expression, epithelial to mesenchymal transition (EMT) and transformation to small cell lung cancer.

Method:
We presented a lung cancer patient with EGFR exon 19 deletion who was resistant to EGFR TKI treatment during disease progression. The original lung tumor started to enlarge and bred a secondary growing nodule adjacently. A left upper lobectomy plus systematic mediastinal lymphadenectomy by VATS was performed after a whole body evaluation which had no sign of extrapulmonary abnormalities. The pathological examination, genetic sequencing, and histological staining of E-cadherin and Vimentin were performed on the TKI resistant postoperative specimens.

Result:
The original lung tumor was confirmed to be adenocarcinoma according to the typical morphology and positivity of TTF1 and CK7. The secondary lung tumor has sarcomatoid histology showing a more spindle-like mesenchymal morphology with CK and Vimentin positivity. Next generation sequencing (NGS) test confirmed that the original lung adenocarcinoama retained EGFR exon 19 deletion but was also found T790M mutation in EGFR exon 20. The secondary sarcomatoid carcinoma retained EGFR exon 19 deletion as well. Besides, sarcomatoid carcinoma had genetic mutation on FANCL and BCL2L2, and amplification on CDK4, MDM2, APFRP1, GNAS, CIC, FANCE, Notch4 and AKT2. In addition, in comparison with adenocarcinoma from biopsy and postoperative specimens, the second growing sarcomatoid tumor is strongly positive for Vimentin and nearly negative for E-cadherin, indicating that sarcomatoid histology probably underwent EMT.

Conclusion:
The clinical implication of this case provides significant insights into our understanding that two or more mechanisms might be involved simultaneously in the EGFR TKI resistance. Therefore, if possible, it is necessary to perform tumor biopsies after the development of resistance to identify the best treatment options for patients.

Background:
To investigate the relationship between EGFR mutation status and bone metastasis in lung adenocarcinoma.

Method:
We collected the data of 331 patients with advanced lung adenocarcinoma, and the status of EGFR mutation was detected by RT-PCR. Follow-up these patients was performed.

Result:
331 cases of advanced lung adenocarcinoma, EGFR mutation rate was 52.2%. The incidence of bone metastases (54.9%) and brain metastases (29.4%) with EGFR mutant patients was higher than that wild type. Compared with the number of metastases, EGFR mutant bone metastases were more than 2 and more, and the proportion of wild type single-site metastasis was more. The median survival of bone metastases in advanced lung adenocarcinoma was 14.7 months. EGFR gene mutant group, bone metastasis group median survival in 18.2 months, no bone metastasis group median survival in 21.8 months. In the wild-type group, the median survival of the bone metastases group was 11.5 months, and the median survival in the non-bone metastases group was 15.5 months.

Conclusion:
EGFR mutations in patients with advanced lung adenocarcinoma are more likely to develop bone metastasis and brain metastasis.

Background:
The aim of the current study was to examine the clinical application of BWF samples in detecting epidermal growth factor receptor (EGFR) mutations in a large sample set of NSCLC patients.

Method:
In diagnostic bronchoscopic examinations, before or after biopsy to target lesions, subsequent bronchial washing by saline was performed. Thereafter, EGFR mutation testing for both supernatant and sediment of BWF and histologic tissues was performed via amplification refractory mutation system real-time PCR (ARMS RT-PCR) assay.

Result:
A total of 127 cases of histologic and corresponding BWF samples of patients underwent bronchoscopy for suspected lung malignant tumor lesions on chest radiography were successfully obtained. Of these, 72 cases were pathologically confirmed to be NSCLC based on forceps biopsy samples and EGFR mutations were identified in 26 cases. In 70 of 72 cases, the results of EGFR mutation status were concordant for BWF and histologic samples, and the concordance rate was 97%. In 13 cases that were not pathologically diagnosed with NSCLC with forceps biopsy samples but other samples, five cases (38.46%) with EGFR mutated-type were detected by BWF. The overall EGFR mutation concordance rate between supernatant and sediment specimens was 100%. The detection of EGFR mutations with supernatant/sediment of BWF samples showed a sensitivity of 86.5%, a specificity of 100%.

Conclusion:
This study demonstrates a clear comparison of supernatant/sediment of BWF samples and histologic tissues for EGFR mutation testing with largest clinical samples to date. Both supernatant and sediment of BWF samples showed high credibility and concordance via highly sensitive PCR analysis. BWF is considered a simple, rapid and effective alternative for histologic samples in EGFR mutation testing.

Background:
Osimertinib is a third-generation, CNS active EGFR-TKI that potently and selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations in non-small cell lung cancer (NSCLC). We report interim clinical and molecular diagnostic testing results from a predefined interim analysis of the ongoing ASTRIS study (NCT02474355).

Method:
Patients (pts) received osimertinib 80 mg once daily. Eligible pts had advanced NSCLC that had progressed on prior EGFR-TKI therapy and with a T790M mutation determined by local validated molecular test, WHO performance status (PS) 0−2, acceptable organ and bone marrow function and no history of interstitial lung disease or QTc prolongation. Asymptomatic, stable CNS metastases were permitted. The primary efficacy outcome was overall survival; other outcomes included local test methods, specimen type, EGFR mutations identified, investigator-assessed response rate (RR), progression-free survival and time to treatment discontinuation. Safety data are also reported.

Result:
From 18 Sept 2015 to the planned 3 Nov 2016 data cut-off (DCO), 1217 pts received osimertinib 80 mg once-daily across 14 countries with a median age 64 yrs (27–92 yrs), 67% female, 61% White, 37% Asian, 87% WHO PS 0/1, 44% prior chemotherapy, 45% prior radiotherapy. All pts tested positive for T790M; T790M was reported alone in 185 pts (15%). The most common testing methods were PNA-Clamp 317 pts (27%), Qiagen therascreen 254 pts (22%), and Roche cobas 204 pts (17%). Exon 19 deletion was the most common co-occurring mutation with T790M (57%), followed by L858R (27%). Tissue or cytology specimens were used in 720 pts (59%), plasma in 433 pts (36%), and other specimens in 64 pts (5%). At DCO, the median duration of exposure was 3.8 months (<1–13.2 months) with a median follow-up time of 4.1 months (<1−14 months). In pts evaluable for response, the investigator-assessed RR was 64% (569/886; 95% CI 61, 67). Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 122 pts (10%) and 54 pts (4%), respectively. Serious AEs were reported in 165 pts (14%) and AEs leading to death in 28 pts (2%).

Conclusion:
ASTRIS is the largest reported global study of osimertinib in pts with T790M-positive NSCLC identified by a wide array of molecular testing methods and from various specimen types. Considering this breadth of T790M testing, the clinical activity of osimertinib is like that observed in the clinical trial program and no new safety signals were identified.

Background:
Leptomeningeal carcinomatosis (LC) is a detrimental complication of non-small cell lung cancer (NSCLC). Osimertinib is the current standard therapy for pretreated EGFR T790M-positive NSCLC patients. However, the efficacy of osimertinib for these patients with LC is unknown.

Method:
Retrospective case series of 5 patients with pretreated EGFR T790M-positive NSCLC who developed LC and received osimertinib therapy in an Expanded Access Program was reviewed. We evaluated the clinical outcomes of these patients.

Result:
Four female patients and one male patient (age, range 51-67) with EGFR T790M-positive NSCLC and LC received osimertinib therapy at a starting dose of 80 mg/day. EGFR T790M mutation was detected in three re-biopsied specimens and two plasma samples. Four patients had Eastern Cooperative Oncology Group performance status (PS) ≧ 2. One patient received whole-brain radiotherapy after commencing osimertinib therapy. Osimertinib dose escalation to 160 mg/day or 160 mg every other day was administered to 3 patients who did not respond to standard dose therapy. Radiologically decreased leptomeningeal enhancement was seen in 3 out of 4 evaluable patients, and improvement of clinical symptoms was recorded in 2 patients. Two patients died of aspiration pneumonia, and one died of hypoxic respiratory failure of unknown cause. Osimertinib therapy is ongoing in two patients at 80 mg/day for 9 and 10 months, respectively, with good tolerability.

Conclusion:
Osimertinib is well tolerated even in patients with poor PS. Clinical benefits were seen in some patients, and the optimal dose should be explored.

Background:
Patients with epidermal growth factor receptor (EGFR) gene-mutated NSCLC initially show substantial clinical benefit from EGFR Tyrosine-Kinase Inhibitors (TKIs), but will ultimately develop resistance with a median progression-free survival of 9-15 months. However, the type and timing of TKI-resistance cannot be predicted and several mechanisms may occur simultaneously/subsequently during TKI-treatment. We present a patient case with advanced non-small cell lung cancer (NSCLC) of adenocarcinoma subtype (ADC) with EGFR-mutation and Erlotinib-treated Different mechanisms of TKI-resistance were detected in tumor biopsies during treatment time.

Method:
The patient was a 49 year-old, previously healthy, Caucasian male with metastatic ADC. A diagnostic biopsy from hepatic metastasis, cytology from metastatic pleural effusion at first progression during TKI-therapy and a biopsy from new liver metastasis at second progression were analyzed by histology, immunohistochemistry and targeted next-generation sequencing (NGS) of hot-spot mutations in 50 cancer-related genes (Ion AmpliSeq Cancer Hotspot Panel v.2, Ion Torrent, Thermo Fisher Scientific).

Result:
CT-scans revealed tumor in the right upper lobe with mediastinal infiltration and multiple pulmonary and hepatic metastases, stage T4N2M1b. Diagnostic liver biopsy revealed ADC (mucin-producing, CK7- and TTF1-positive epithelial acinar structures), which concomitantly harbored an EGFR exon 19-mutation (p.E746_A750delELREA) and a previously unreported 2 bp microdeletion in the fibroblast growth factor receptor 3 (FGFR3; p.D785fs*31) gene. The patient received first-line Erlotinib but progressed after 7 weeks with metastatic pleural effusion, in which transformation to small cell lung cancer (SCLC) and maintenance of EGFR-mutation and FGFR3-mutation was identified. The progression was treated with standard Carboplatin-Etoposide regimen for SCLC together with Erlotinib continuation. The second progression 7 months later was a new liver-metastasis with persistence of the original EGFR- and FGFR3-mutated ADC-phenotype and additional emergence of the Erlotinib-resistant T790M EGFR-mutation. The patient rapidly deteriorated and deceased.

Conclusion:
Thus, in this advanced EGFR-mutated NSCLC rapid onset and heterogeneous mechanisms of TKI-resistance occurred at different times of metastatic disease: 1. Concomitant FGFR3-mutation prior to and during TKI-treatment as potential intrinsic resistance-mechanism; 2. Transformation to SCLC at 1st progression during TKI-therapy; 3. Acquisition of T790M EGFR-mutation at 2nd progression. This suggests a continuous variation of TKI-resistant cells’ genetic and phenotypic behavior. Therefore, re-biopsies are important to provide the current status of the disease and better define subsequent treatment options. “Liquid biopsies” may potentially help identify heterogeneous genetic resistance-mechanisms; however assessment of mechanisms such as SCLC-transformation needs tissue biopsies

Background:
Advanced non-small cell lung cancer(NSCLC) studies indicated a potential association between chemotherapy efficacy and circulating tumor cells (CTC) counts in peripheral blood. The icotinib efficacy and circulating tumor cells (CTC) counts in non-small cell lung cancer remain unknown. The aim is to investigate association between the icotinib efficacy and CTC counts in advanced NSCLC patients.

Method:
A total of 74 advanced NSCLC patients consented to provide 5ml of peripheral blood before systematic therapy, and divided into two groups (those with high CTC counts and those with low CTC counts) based on the patients′ median CTC counts. All the patients were treated with icotinib, and the icotinib efficacy and prognoses were compared.

Result:
The treatment efficacies were 46.88% (15/32) and 23.81% (10/42) for the low CTC group and the high CTC group, respectively. The median overall survival was 22.0 months (95%CI: 19.6-28.7 months) for the low CTC group and 18.3 months (95% CI: 15.3-25.4 months) for the high CTC group. The median progression-free survival was 11.6 months (95% CI: 8.7-15.6 months) and 7.2 months (95% CI: 3.4-8.7 months) for the low group and the high CTC group, respectively.

Conclusion:
The CTC counts can be used as a important biomarker for therapy monitoring the icotinib effect on patients with advanced NSCLC. Efficacy and prognosis of icotinib and CTC counts were considered important, and the CTC counts could be used to predict the efficacy of icotinib and prognosis of advanced NSCLC. The change in CTC count levels can be used as a biomarker for evaluating the prognosis of patients with advanced NSCLC.

Background:
EGFR exon 18 E709X mutation is only reported in small case numbers of non-small cell lung cancer (NSCLC) in the literature, and their influences on the effectiveness of icotinib have not been fully understood. The study of this aim is to investigate the efficacy of icotinib in patients with NSCLC that carrying EGFR exon 18 E709X mutation.

Method:
Three cases of EGFR exon 18 E709X mutations were retrospectively analyzed until the progress of the disease or the emergence of the side effects and clinical efficacy was observed after months of followed-up.

Result:
The median progression-free survival (PFS) of three cases with EGFR exon 18 E709X (E709_T710>D, E709A, E709K plus L858R) was 3.1 months, patients with complex mutations showed a better PFS than those with single mutations (7.2 months vs. 2.7 months, P=0.225). Clinical efficacy of icotinib with advanced NSCLC harboring EGFR exon 18 E709X mutation (ORR: 66.67%, DCR: 66.67%).

Conclusion:
Icotinib is effective in patients with exon 18 E709X mutations. Patients with complex mutations benefited more from icotinib than those with single mutations.

Background:
Lung cancer is the leading cause of cancer death in men and women worldwide. Brain metastasis (BMs) of NSCLC is the most important cause of death. This study aimed to explore the association of epidermal growth factor receptor (EGFR) mutations and brain metastases (BMs) in non-small cell lung cancer (NSCLC).

Method:
We analyzed 50 NSCLC patients with BMs and 50 match-paired NSCLC patients with no brain metastases (NBMs). The EGFR mutation status of primary lesions was detected using the amplification refractory mutation system (ARMS) polymerase chain reaction.

Result:
The BMs patients had a higher frequency of EGFR mutations than the NBMs patients (52.0% vs. 22.0% respectively, P＜0.001), in both adenocarcinoma (60.5% vs 30.6%, P=0.003) and squamous carcinoma (37.5% vs. 0%, P=0.04). The incidence of BMs in patients with EGFR mutations was higher than in patients with wild-type EGFR (70.3% vs. 38.1%, P=002).

Conclusion:
NSCLC patients with BMs had a higher incidence of EGFR mutations and those with mutant EGFR had a higher frequency of BMs. EGFR mutations may promote brain metastasis growth of NSCLC.

Background:
Brain metastases are often seen in Eastern-Asian lung adenocarcinoma in which most common oncogenic driver mutations are EGFR sensitive mutations or EML4- ALK fusions, occurring in about 60% patients. Elucidation of EGFR and ALK-driven mutation prognostic factors in patients with brain metastases has important clinical implications.

Method:
Lung adenocarcinoma harboring EGFR mutations or ALK fusions were studied for their occurrence of brain metastases and relevant prognostic factors.

Result:
Of 602 lung patients with lung adenocarcinoma, 516 had EGFR mutations and 86 had EML4-ALK fusions. EGFR-mutation patients had much more brain metastases than ALK-fusion patients, whether at first diagnosis (40.1% vs 28%, P=0.03) or followed up two years (63.8% vs 42.7%, P＜0.01). Brain metastasis is a significant indicator for poor survival in the EGFR-mutation patients (P＜0.001), but not in the ALK-fusion patients (P=0.79). In the EGFR-mutation patients, late occurred brain metastases （after one year） predicted better survival (P=0.001). Meanwhile, female or young age was associated with better survival in the brain metastatic patients with ALK fusions (P＜0.05). Moreover, multivariate analysis indicated that tyrosine kinase inhibitor (TKI) treatment, no symptomatic brain metastases and cranial radiotherapy were the significant indicators for better survival in both EGFR-mutation and ALK-fusion patients (P＜0.05). Although there was no difference in overall survival between EGFR mutation and ALK fusion patients with brain metastases (P=0.23), in the TKI-treating subgroup ALK-fusion patients had longer survival time than EGFR-mutation patients(NR vs. 36 months, P=0.15). Furthermore, in the EGFR-mutation patients with brain metastases erlotinib was associated with better survival compared with gefitinib as first-line treatment (38 months vs 34 months, P=0.03)

Conclusion:
EGFR-mutation and ALK-fusion lung adenocarcinoma patients with brain metastases have distinct clinical characteristics and prognostic factors. However, while doing targeted treatment ALK-fusion indicated better survival than EGFR-mutation in the patients with brain metastases.

Background:
Patients with non-small-cell lung cancer (NSCLC) experience high disease burden due to many cancer-related symptoms (eg, cough, dyspnea, pain, and fatigue). Decreasing tumor burden may reduce/delay symptoms and favorably impact global health-related quality of life (HRQoL). Dacomitinib is an irreversible, small-molecule inhibitor of EGFR/HER-1, HER-2, and HER-4 tyrosine kinases. In a global, multicenter, randomized, open-label phase 3 study (NCT01774721) for first-line treatment of NSCLC, dacomitinib improved the primary objective of progression-free survival per independent radiologic review (median, 14.7 vs 9.2 months; hazard ratio, 0.59; 95% confidence interval [CI], 0.47–0.74; P<0.0001) over gefitinib. Median duration of treatment was longer with dacomitinib than with gefitinib (67 vs 52 weeks, respectively).[1] A secondary objective was to explore HRQoL. Here, we report the impact of dacomitinib and gefitinib treatment on core lung cancer symptoms.

Method:
Patients were randomized 1:1 to receive oral dacomitinib (45 mg) or gefitinib (250 mg) once daily. Disease-related symptoms were measured using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13). Scores were summarized by the mean and 95% CI for each group and plotted over 30 cycles and at the end of treatment; the number of cycles (n=30) chosen for this analysis was not prespecified. Mean changes from baseline (cycle 1, day 1 [C1D1]) were reported for each group.

Result:
Between 9-May-2013 and 20-March-2015, 452 patients were randomly assigned to dacomitinib (n=227) or gefitinib (n=225). Baseline scores were similar between treatment arms. On-study completion rates were high, with >90% of patients answering all questions for most treatment cycles. Statistically significant improvements from baseline (95% CI excludes 0; no adjustment for multiplicity) for most cycles were seen in fatigue, pain, dyspnea, and cough in both arms. Improvements were reported as early as C1D8. Clinically meaningful improvements (≥10 points score change) were recorded for pain in chest (23/30 cycles) and cough (28/30 cycles) with dacomitinib and for cough (22/30 cycles) with gefitinib; hence, improvements appear to be more frequent with dacomitinib. Symptom burden at end of treatment was generally higher than during treatment. As treatment duration was longer with dacomitinib, key lung cancer symptom improvements were seen for a longer time in patients treated with dacomitinib.

Conclusion:
Dacomitinib, along with gefitinib, demonstrated favorable clinical benefit and improvements in key NSCLC symptoms. These findings are important when considering choice of therapy. Reference 1. Mok T, et al. J Clin Oncol. 2017;35(Suppl):abstract LBA9007.

Background:
EGFR mutation positive (EGFRm) NSCLC patients commonly progress in the CNS. We reviewed CNS disease development and its impact on resource utilization and outcomes in EGFRm patients who received first-line EGFR TKI.

Method:
Methods: A retrospective review was completed of all advanced EGFR+ patients referred to the BC Cancer Agency and treated with a first/second-generation EGFR TKI from 2010-2015. Baseline characteristics, systemic treatment and CNS management was collected. Comparison was made between the CNS positive (CNS+) and negative (CNS-) patients’ health resource utilization from median time of CNS+ diagnosis to death/last follow-up (8.9 m) and for no CNS metastases group, 9 months preceding death/last follow-up, using the Chi squared test and t-test.

Result:
499 patients were identified. Baseline characteristics: Female 68%, median age 66 (30-90), adenocarcinoma 89%, Asian 51%, never/former/current smoker 67/24/9%, exon 19/21/other/not specified 57/37/3/3%. 229/499 patients (46%) developed CNS+; 39% at diagnosis, 61% during the course of disease. Systemic treatment: first-line EGFR TKI 95%, first-line platinum doublet 5%; 40% (202/499) second-line EGFR TKI 24%, second -line platinum doublet 56%, single agent chemo 13%, osimertinib 7%, third-line therapy 47%. CNS+ management: surgery+/-WBXRT 13%, WBXRT alone 73%, SRS+/-WBXRT 5%, no CNS directed therapy 9%. Median time from diagnosis to CNS+ was 7.6 m. Median time from development of CNS+ diagnosis to death was 8.9 m. Median OS was 24m in CNS+ versus 33m in CNS- (p<0.001).

Events in 9m preceding death or last follow-up (consistent with median time from CNS+ to death)	No CNS Metastases n=270	CNS Metastases n=229	p value
Average number of clinic visits	8.53	12.71	<0.001
Average number of hospitalizations	0.43	0.76	<0.001
Average number of CNS imaging investigations	0.52	2.65	<0.001
Average number of ER visits	0.03	0.14	0.001
Palliative Care Unit admission	22 (8%)	22 (10%)	0.64
Hospice admission	9 (3%)	43 (19%)	<0.001

Conclusion:
The incidence of CNS+ in EGFRm patients is high and associated with increased Health Resource Utilization. Prevention or delay of CNS+ with newer systemic therapy options may result in decreased interactions with health care providers, which may translate into lower resource utilization and cost savings.

Background:
Both first and second generation EGFR tyrosine kinase inhibitors (TKIs) have efficacy in NSCLC with activating EGFR mutations (EGFRM+). Previous studies showed a differential benefit of second generation TKIs based on mutational subtypes but failed to show a difference in overall survival (OS). We aimed to characterize the patterns of use and outcomes of first and second generation TKIs and describe any differences with mutation subtype in the real world setting.

Method:
A retrospective review of all advanced EGFRM+ NSCLC patients treated with TKIs between the years 2010-2015 at the British Columbia Cancer Agency was performed. All time to event analyses were performed from date of diagnosis of metastatic disease. Multivariate regressions were performed to examine for associations of OS, treatment and mutation subtypes.

Result:
500 patients were eligible for analysis: 283 patients had an exon 19 deletion (del19), 185 had an exon 21 L858R mutation and 32 were not specified or have mutational variants such as G719var. Patient characteristics in the del19 vs. L858R group were similar: 69%/66% were female, 66%/71% were never smokers, 90%/89% were adenocarcinoma, 20%/20% had CNS metastases at diagnosis, 85%/84% had de novo metastatic disease and 41%/37% received ≥2 lines of therapy (all p>0.05). The del19 cohort had less Asians (46% vs 58%, p=0.02) and were younger (median age 63 vs. 69, p=0.02) compared to L858R group. In the del19/L858R cohorts, 81%/19% and 84%/16% received a first and second generation TKI respectively. 43% of patients receiving a second generation TKI required a dose reduction to manage the toxicity and one patient discontinued the medication. OS in the entire cohort was 26 months, with the del19 group surviving longer compared to the L858R cohort (27 vs. 22 months, p<0.01). In multivariate analysis, factors associated with improved OS were del19 (HR0.7, p<0.01 95%CI0.6-0.9), treatment with a second generation TKI (HR0.6, p=0.01 95%CI0.5-0.9) and absence of CNS metastases (HR0.7, p<0.01 95%CI0.5-0.9). First line treatment with a second generation TKI was associated with better OS compared to a first generation TKI (HR0.6, p=0.04 95%CI0.3-1.0). This was statistically significant only in the del19 subgroup (HR0.4, p=0.04 95%CI0.2-1.0).

Conclusion:
Use of a second generation TKI in EGFRM+ advanced NSCLC is associated with improved OS in multivariate analyses controlling for other prognostic factors. This was significant in the entire group and in the del19 cohort, supporting the use of mutational subtype to guide therapy decisions.

Background:
First-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) offer an advantage compared to doublet chemotherapy in progression free survival, tolerability, and quality of life (QOL) in EGFR-mutated advanced non-small cell lung cancer (NSCLC) patients. In Taiwan, gefitinib, erlotinib and afatinib are all reimbursed as first-line therapy. It provides a rare opportunity to investigate factors associated with the extent of symptoms and QOL improvement in real-world patient population.

Method:
We conducted a multicenter, prospective, observational study to evaluate the QOL and disease-related symptoms at baseline, 2, 4, and 12 weeks in EGFR-mutated advanced NSCLC patients with first-line EGFR TKI treatment. QOL was assessed by the instrument of Functional Assessment of Cancer Therapy-Lung questionnaire (FACT-L) and Treatment Outcome Index (TOI) derived from FACT-L. Symptoms assessment was evaluated by the Lung Cancer Subscale (LCS). The mean change from baseline of QoL and LCS score was analyzed by paired t-test.

Result:
The average age was 65.1± 12.5 (range 31.4–92.9) years old, with a larger proportion of females (62.6%) than males, and more never-smokers (74.0%) than ever-smokers. Patients were treated with gefitinib 250 mg (72.4%), erlotinib 150 mg (18.9%) or afatinib 40 mg (8.7%). For FACT-L, the total score was increased by 4.0 ± 15.49 at week 2, 4.9 ± 18.31 at week 4, and 4.1 ± 20.44 at week 12 (all p<0.001). Similarly, increased TOI of 2.4 ± 11.61 (p<0.001), 3.1 ± 13.48 (p<0.001), and 2.4 ± 14.35 (p=0.009) were observed at week 2, 4, and 12, respectively. For LCS, it was slightly increased by 1.7 ± 4.59 at week 2, 2.0 ± 5.48 at week 4, and 1.9 ± 5.35 at week 12 (all p<0.001). In general, subgroup analyses indicate that patients with more than 2 metastatic sites and ex-smokers were associated with clinically meaningful improvement in terms of LCS (change in LCS ≥ 2 points). Other subgroup analyses show that patients with characteristics such as at least 3 metastatic sites, ex-smoker, PS of 1, and treatment with gefitinib group, were associated with improved QOL in terms of TOI and FACT-L.

Conclusion:
In EGFR mutated NSCLC patients, first-line EGFR-TKI treatment was associated with improvement in disease-associated symptoms and QOL. Patients with 2 or more metastatic sites and ex-smokers were associated with symptoms and QOL improvement. In addition, PS of 1 and treatment with gefitinib were associated with clinical meaningful improvement in global QOL.

Background:
Osimertinib (AZD9291) is a third-generation EGFR TKI specific against T790M resistance mutations in patients with metastatic EGFR-mutant (EGFRm+) NSCLC after prior first-line TKI therapy. We aimed to evaluate the clinical efficacy of osimertinib in patients treated under the AZD9291 Early Access Program (EAP) at our local institution.

Method:
This retrospective study included 57 patients who were enrolled on the AZD9291 EAP between Jul 2015 and Nov 2016 after being tested T790M+ on tumor (by direct Sanger sequencing or Roche COBAS EGFR mutation test v2) and/or plasma (cfDNA) specimens (by Lung Colon Panel v2 or ARMS PCR). Of these patients, 52 were treated with osimertinib. Tumor responses were independently assessed by radiologists using RECIST 1.1 criteria. DOR, PFS and OS were estimated by Kaplan-Meier method.

Result:
The median age at diagnosis was 58 years (range: 35-76), 80.7% patients were non-smokers, 89.5% had ECOG 0-2, 96.5% had adenocarcinoma subtype and 87.8% had either EGFR exon 19/ exon 21 mutations. Median line of therapy when osimertinib was administered was third-line (range 2nd – 9th), and 30 (53%) had brain metastasis at osimertinib initiation. RR by RECIST 1.1 was 46% (95% CI 32.2 – 60.5%) (4 CR + 20 PR) with median DOR of 8.7 months. With median follow-up of 6.2 months from osimertinib initiation, median PFS was 10.3 months (95% CI 7.52 to 15.87 months). For the 52 patients treated with osimertinib, EGFR T790M mutation was tested on the following specimens: tumor-only (n=43), plasma-only (n=25), and both (n=17). In patients with paired tumor/plasma T790M testing, 4/17 had concordant results (RR 75%), while 13 patients with discordant results [T790M+ in 8 tumor-only: RR 25% (95% CI 3.2% - 65.1%) or in 5 plasma-only: RR 40% (95% CI 5.3% - 85.3%)] had overall RR 31% (95% CI 9.1% – 61.4%). ECOG status was associated with PFS by univariable analysis, with higher ECOG 2-4 associated with shorter PFS (HR=6.54, 95% CI: 2.48 to 17.26; p<0.001) than ECOG 0-1. Line of osimertinib treatment and presence of brain metastases at osimertinib initiation were not associated with clinical outcome.

Conclusion:
Osimertinib is effective in patients with advanced EGFR T790M+ NSCLC after progression on prior EGFR TKI, regardless of presence/ absence of CNS metastasis or line of therapy. Notwithstanding ongoing optimization of plasma-based assays, T790M tumor-plasma discordance in our patient cohort is likely a reflection of overall burden of T790M subclones, and may represent a potential negative predictive biomarker of response to osimertinib.

Background:
To detect the mutation abundance and sites of epidermal growth factor receptor (EGFR), and to investigate their influence on the therapeutic efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced non-small cell lung cancer (NSCLC).

Method:
A total of 2,417 NSCLC patients with EGFR gene mutations were retrospectively analyzed using an amplification refractory mutation system (ARMS). Of 861 patients, 407 patients had exon 19 deletions and 454 patients had exon 21 (L858R) site mutations of the EGFR gene. Next we analyzed the mutation abundance of lung adenocarcinoma patients who received EGFR-TKI therapy and complete follow up. 194 patients diagnosed with stage IIIB or stage IV lung adenocarcinoma with an ECOG score of 0-3 were enrolled. The primary endpoint was to determine associations between progression-free survival (PFS) and mutation abundance or mutation sites after EGFR-TKI therapy. The secondary endpoint was to evaluate the objective response rate and effects when EGFR-TKI was administered as the first-line treatment, as well as risk factor analysis for PFS.

Result:
Of the 194 enrolled patients, the median PFS was 9.3 months (95% CI, 8.2–10.8 months). The PFS was significantly different with EGFR gene mutation abundance after EGFR-TKI therapy (P = 0.014). The median PFS was significantly longer when the cut-off value of EGFR mutation abundance of exon 19 or exon 21, exon19 was > 26.7% and 61.8%, respectively. For patients who received EGFR-TKI as first-line treatment, the median PFS was significantly longer in the high mutation abundance group than in the low mutation abundance group (12.7 m vs 8.7 m, P = 0.002). However, there was no significant correlation with gender, age or smoking status and PFS.

Conclusion:
The PFS benefits were greater in patients with a higher abundance of exon 19 mutations in the EGFR gene after EGFR-TKI treatment.

Background:
Plasma detection of EGFR T790M mutations in circulating tumour DNA (ctDNA) of advanced lung cancer patients with acquired resistance to EGFR tyrosine kinase inhibitor (TKI) has been proposed as alternative to tumor re-biopsy. This national validation study across Canadian centres aimed to establish the sensitivity and specificity of plasma detection of T790M as a clinical test using digital droplet (dd)PCR and next generation sequencing (NGS) assays.

Method:
Canadian patients at 7 centres undergoing screening for ASTRIS (NCT02474355) were invited to participate in this companion blood-based study. Patients with acquired resistance to EGFR TKI consented to collection of blood samples and demographic data. Samples were analysed using ddPCR and/or NGS platforms available at 4 molecular diagnostic laboratories across Canada. Concordance between the results of plasma T790M assayed in these 4 laboratories with reference tissue/plasma testing conducted for ASTRIS was assessed.

Result:
63 patients participated; the median age was 64 years (range 31-87), 69%(40/58) were Asian; 55%(33/60) were male. All patients received prior EGFR TKI, 17%(10/60) also received prior chemotherapy. Reference testing for EGFR T790M for ASTRIS eligibility identified positive T790M(+) results for 31(49%), negative(-) for 30(48%) and indeterminate(i) results for 2(3%) patients. One laboratory tested all 63 patient samples using both ddPCR and NGS (Oncomine Lung cfDNA assay), another laboratory tested 18 samples using ddPCR and NextSeq, a third tested 10 samples using ddPCR and COBAS EGFRv2, and a fourth tested 6 samples using Ion Torrent PGM. A total of 188 tests were performed including 91 by ddPCR, 87 NGS and 10 COBAS assays. Combining test results for each patient, 60%(38/63) of patient plasma samples were T790M+, 23(37%) were T790M-, and 2(3%) were inconclusive. Of 31 patients with reference T790M+ results from ASTRIS, 23(74%) had T790M detected in plasma, 6(19%) did not (T790M-), and 2(7%) had indeterminate (T790Mi) plasma results. For 30 patients with T790M- reference results from ASTRIS, 13(43%) had plasma T790M+ and 17 plasma T790M- results. The 2 patients with T790Mi by reference testing both had T790M+ results from plasma. Altogether, 47%(15/32) of patients deemed to have T790M-/i tumours by reference testing were found to have T790M+ results by plasma in this multicentre study. Combining results from both tissue and plasma testing, 73%(46/63) of study patients had T790M+ results.

Conclusion:
Plasma ctDNA testing in this multicentre Canadian study identified a significant number of additional patients eligible for osimertinib therapy beyond routine biopsy tissue testing for EGFR T790M.

Background:
Brunei is indifferent to its neighbouring South East Asia countries whereby the highest cancer mortality rate is attributed to lung cancer. EGFR mutations are present in a subset of patients with non-squamous NSCLC that predict a favourable response to EGFR tyrosine kinase inhibitor (TKI) therapy. Thus far, the prevalence of EGFR mutations in Brunei patients with NSCLC remains unknown. This study was conducted to characterise non-squamous NSCLC patients with EGFR mutations in Brunei.

Method:
Retrospective data collection from clinical case notes of patients with non-squamous NSCLC diagnosed from January 2010 to March 2017 was undertaken at The Brunei Cancer Centre to determine the frequency of EGFR mutations and correlation with clinico-pathological variables. The progression-free survival (PFS) of EGFR mutated patients on EGFR TKI and the overall survival (OS) of patients with mutated and wild type EGFR were estimated and compared using Kaplan-Meier curves and log-rank tests.

Result:
EGFR mutation status was evaluable in 71 out of 191 lung adenocarcinoma cases. The overall mutation frequency was 43.7 % with a mean age of 63.3 years. EGFR mutations were significantly more common in female (71%) and never smokers but 33.3% of patients with EGFR mutations were current smokers. The most prevalent EGFR mutation was exon 21 point mutation (L858R) (43.3%) followed by exon 19 deletion (40.0%). 87% of patients with EGFR mutations received EGFR TKI therapy and the objective response rate (ORR) was 65.2%. The median PFS for patients on EGFR TKI was 7 months and there was no significant differences between the two most common mutations. The median PFS of patients treated with EGFR TKI upfront and after first line chemotherapy was 8 and 6 months (p=0.045) respectively. Although not statistically significant (p=0.232), our result showed a trend of improvement in median OS for EGFR mutated patients (29 months) compared to wild type (17 months).

Conclusion:
This is the first study to reveal the clinical characteristics of patients with EGFR mutated non-squamous NSCLC in Brunei. The prevalence of EGFR mutation in our study is high and comparable to other Asian NSCLC patients. Interestingly, PFS rate on EGFR TKI observed in our population was inferior to published studies despite the high ORR and this warrants further exploration. Nevertheless, EGFR mutation analysis should be performed in all patients with non-squamous NSCLC to identify the subset of patients who may benefit from EGFR TKI.

Background:
EGFR mutation plays a dominant role in the precise treatment of non-small cell lung cancer (NSCLC), and EGFR-TKIs has been recommended for patients with positive EGFR-sensitive mutation as a standard regimen in clinical practice. In China, application of EGFR-TKIs without knowing EGFR mutation status has been a common phenomenon due to various reasons including the vast territory, uneven distribution of medical resources, differences level of testing technology and others. Therefore, we prospectively conducted a real-world investigation to understand the actual situation of EGFR testing in Northern China, and identify the underlying causes affecting EGFR detection, in order to provide references to improve the standardized treatment.( NCT02620657)

Method:
The patients with IIIB/IV NSCLC who were firstly diagnosed or postoperative recurrence between 2014-1-1 and 2014-12-31 in 28 research centers of Northern China were analyzed. The primary endpoint was testing rate，the secondary endpoints were factors affecting EGFR testing, EGFR mutation status, detection methods and the survival outcomes of patients.

Result:
Among 2809 patients, 2250(90.78%) were adenocarcinoma, 208(7.40%) were squamous carcinoma, 51(1.82%) were other pathologic types. Testing rate was 42.54%(1195/2809) and was significantly related to city level (first-tier cities vs. new first-tier cities vs. second-tier cities vs. third-tier and above cities : 69.04% vs. 38.08% vs. 34.05% vs. 14.11%, P < 0.001), smoking status (never smoking vs. ever smoking vs. smoking: 45.42% vs. 51.10% vs. 33.37%, P<0.001), ECOG PS(0 vs.1vs.2vs.≥3:47.93%vs. 44.48vs.34.89%vs.20.37%, P=0.011), pathological type (adenocarcinoma vs. squamous carcinoma: 44.94% vs.19.23%, P=0.003) and medical insurance situation (social basic medical insurance vs. new rural cooperative medical insurance vs. own expense: 44.98% vs. 36.49% vs. 29.55%, P=0.001). EGFR sensitive mutation rate was 46.44%, the most common subtype was 19Del(42.16%), followed by L858R(40.00%), Exon 20 insertions(1.62%) and other subtypes(16.20%). The most common methodology is ARMS(63.77%), the second common one is DNA sequencing(5.36%). The 1-year and 2-year survival rate in patients receiving EGFR testing was 73.6%and 51.9%, compared with 64.3% and 43.7% respectively in patients without EGFR testing.

Conclusion:
There were regional differences in EGFR testing rates among IIIB/IV NSCLC patients in Northern China. The intention of doctors and patients, medical insurance coverage and differences technical level are major factors affecting the testing rate of EGFR. Approaches should be taken to improve the situation, such as strengthening the training, expanding the coverage of medical insurance, and relying on commercial gene detection companies, and further standardize the molecularly pathological diagnosis and treatment of NSCLC.

Background:
Sensitizing Epidermal Growth Factor Receptor (EGFR) mutations confers a better prognosis and predicts a favorable response to treatment with EGFR tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). We sought to determine the prognostic utility of a comprehensive panel of clinical, immune and biochemical markers in EGFR-mutant advanced NSCLC patients treated with first-line EGFR TKIs.

Method:
A retrospective analysis was conducted on a cohort of NSCLC patients treated at our institution. Only patients who met the following criteria were included: NSCLC with EGFR mutations, diagnosed with Stage 4 disease at initial diagnosis or incurable disease recurrence, and received first-line EGFR TKI treatment. Statistical analysis on descriptive and survival data was performed using IBM SPSS Statistics, version 20.

Result:
We identified 74 patients based on predefined criteria. The mean age of the patients was 63.8 years with 38 (51.4%) female patients and 36 (48.6%) male patients, 51 (68.9%) were never smokers and 39 (52.7%) harbored EGFR exon 19 deletion. 15 (22.7%) out of 66 patients with available data had high serum LDH (median: 456 U/L; normal range: 250-580 U/L). In addition, 19 (25.7%) had brain metastasis, 12 (16.2%) had liver metastasis and 12 (16.2%) had adrenal metastasis at stage 4 diagnosis. These represent the descriptive data of the variables that were later identified to carry prognostic significance. The median PFS and OS for this cohort of patients were 12 and 30 months respectively. On our multivariable Cox-PH regression analysis, old age (>=60; HR = 2.35; 95% CI = 1.18-4.69, p-value = 0.015), female gender (HR = 2.05; 95% CI = 1.05-4.00, p-value = 0.036) and high LDH levels (HR = 2.45; 95% CI = 1.04-5.81, p-value = 0.041) retained their association with unfavorable PFS and only high LDH levels (HR = 2.84; 95% CI = 1.25-6.49, p-value = 0.013) is an independent prognostic indicator of unfavorable OS. Total leukocyte count, hemoglobin levels, absolute neutrophil, lymphocyte and platelet counts at diagnosis were not statistically significant for PFS or OS.

Conclusion:
We identified old age, female gender and high serum LDH levels as independent prognostic predictors of progression-free survival on multivariable analysis. The strong association between elevated LDH and unfavorable overall survival is in line with recent published studies. Further studies confirming the prognostic utility of these markers are necessary to potentially develop a prognostic scoring system that can guide risk stratification in patients with EGFR mutations treated with EGFR TKIs.

Background:
The efficacy of first-line afatinib was demonstrated for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) in large randomized trials, and it has been approved and reimbursed in South Korea since year 2014. This study evaluated clinical outcomes of afatinib in real world practice.

Method:
Patients treated with first-line afatinib for advanced EGFR-mutant NSCLC in Samsung Medical Center (Seoul, South Korea) from October 2014 to December 2016 were included into the analyses.

Result:
In total, 165 patients were analyzed. One hundred fourteen had deletion in exon 19, 37 L858R, and 14 patients had uncommon EGFR mutations including 4 de novo T790M. Median progression-free survival (PFS) was 19. 1 months (95% CI: 12.3- 25.9 months). There was difference in median PFS according to EGFR mutation type: deletion in exon 19 (19.1 months), L858R (15.8 months), de novo T790M (4.7 months), and uncommon EGFR excepting for T790M (not yet reached) (P = 0.01). Though 112 patients (67.8%) had to reduce afatinib dose from 40 mg per day into 30 mg or 20 mg per day due to adverse events, it did not impair its efficacy in terms of PFS (23.5 months in a reduction group vs. 12.4 months in no reduction group). Among 29 patients with evaluable follow-up brain MRI for non-irradiated brain metastatic lesions, significant response was documented in 22 cases (75.9%). Out of 20 patients who were biopsied again at disease progression (excluding one case with de novo T790M), T790M appeared in 7 the repeat-biopsied specimens (35.0%).

Conclusion:
In the real practice in South Korea, first-line afatinib showed comparable or better efficacy data compared with previous clinical trials.

Background:
Not all the patients with EGFR-mutant non-small cell lung cancer (NSCLC) could benefit from EGFR-TKIs and both the predictive and prognostic markers remain undetermined. Previous study demonstrated that EGFR activation could up-regulate the PD-L1 expression and then contribute to immune escape, indicating the critical role of PD-L1 in EGFR-driven lung tumors. Therefore, we aimed to investigate the predictive and prognostic significance of PD-L1 expression in EGFR-mutant NSCLC treated with EGFR-TKIs. Characterization of PD-L1 expression in this populations were also explored.

Method:
We analyzed a cohort of 73 NSCLC patients with EGFR mutations. PD-L1 expression were assessed by immunohistochemistry and staining > 5% of tumor cells were considered as positive. Published studies that assessed the predictive or prognostic value of PD-L1 expression in EGFR-mutant NSCLC patients treated with EGFR-TKIs were included.

Result:
19 (26.0%) patients had positive PD-L1 expression. Positive PD-L1 expression was significantly associated with non-adenocarcinoma histology in this population (P = 0.028). Two cases with positive PD-L1 expression had KRAS mutation while none of those with negative PD-L1 expression harbored KRAS mutation (11.8% vs. 0%, P = 0.109). Five publications had reported both the predictive and prognostic value of PD-L1 expression in EGFR-mutant NSCLC patients treated with EGFR-TKIs. The pooled analysis including the current study showed that overall survival (OS) was significantly shorter in PD-L1 positive group than in PD-L1 negative group (HR, 1.92; 95% CI, 1.15-3.22; P = 0.01). However, positive PD-L1 expression was not correlated with progression-free survival (PFS: HR, 0.82; 95% CI, 0.51-1.30; P = 0.39).

Conclusion:
Positive PD-L1 expression tends to correlate with non-adenocarcinoma histology and KRAS mutation in EGFR-mutant NSCLC. Positive PD-L1 expression was significantly associated with better OS instead of PFS in EGFR-mutant NSCLC patients treated with EGFR-TKIs.

Background:
Limited data are available on treatment experience of advanced lung adenocarcinoma with unknown EGFR gene status (UN-EGFR-GS). We studied the demographic profile and treatment outcomes of advanced lung adenocarcinoma patients, which the EGFR gene status was unknown.

Method:
Retrospective study of patients with UN-EGFR-GS advanced lung adenocarcinoma over a 5-year period at a tertiary hospital in China. Patients diagnosed with stage IIIB or IV were included for analysis during 2010 and 2014.

Result:
In total, 140 patients were included, females and males constituted 48.6% (n=68) and 51.4% (n=72), respectively. The mean age was 58y. Among the 113 patients, 79 were non-smokers and 61 were smokers. Majority of patients had stage IV disease (90.0%), only 14 patients had stage IIIB disease. Most of the patients performance status (PS) score were 0 or 1 (n=128). Ninety-two patients were advanced stage when diagnosed and 48 patients were relapsed disease once received surgical resection. Nineteen patients received adjuvant chemotherapy, which were not relapsed in 6 months after finishing last cycle. In the140 patients, eighty-six had EGFR-TKIs ever, the rest were had chemotherapy only and never received EGFR-TKIs ever. The common regimens of first-line treatment were pemetrexed plus platinum (n=44), gemcitabine plus platinum (n=40), and paclitaxel plus platinum (n=18). Other drugs included docetaxel, novelbine. Twenty patients received EGFR-TKIs as first-line treatment. The commonest second-line treatment was oral EGFR-TKIs (n=47). Nineteen patients received EGFR-TKIs as third-line treatment and four received EGFR-TKIs as fourth-line treatment. At the end of follow-up (2016-7), 104 patients were dead and 36 patients were alive or lost follow up. The median survival of this whole cohort was 19.9m.Those who had a chance taken EGFR-TKIs lived longer than never; the median overall survival was 20.5 months and 16.4 months, respectively. EGFR-TKIs was associated with an improvement of overall survival, respectively in univariate analysis (p=0.027) and multvariate analysis (p=0.007). PS score was also associated with survival, respectively in univariate analysis (p＜0.01) and multvariate analysis (p＜0.01). The overall survival was not associated with sex (p=0.336), and smoking (p=0.414), TNM stage (p=0.565), age (p=0.100). The overall survival was also not associated with the chemotherapy drugs used in the first-line treatment.

Conclusion:
EGFR-TKIs have efficacy improved overall survival in patients with UN-EGFR-GS advanced lung adenocarcinoma, compared with conventional chemotherapy only. Oral EGFR-TKIs appear to be useful for this group of patients.

Background:
In patients with advanced EGFR mutation-positive (EGFRm+) NSCLC, first-line afatinib significantly improved PFS and objective response rate (ORR) versus platinum-doublet chemotherapy in the phase III LUX-Lung (LL) 3 and LL6 studies, and PFS, time-to-treatment failure (TTF) and ORR versus gefitinib in the phase IIb LL7 study. Here, we present post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in LL3/6/7.

Method:
Treatment-naïve patients with stage IIIb/IV EGFRm+ NSCLC who were randomized to 40mg/day afatinib in LL3/6/7 and remained on treatment for ≥3 years were defined as LTRs. In these patients, we assessed efficacy and safety outcomes, as well as PROs measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire and the EQ-5D™ health status self-assessment questionnaire; these included scores on the EORTC Global Health [GH]/QoL scale (0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).

Result:
In LL3/6/7, there were 24/229 (10%)/ 23/239 (10%)/ 19/160 (12%) afatinib-treated LTRs; 6/9/14 remained on treatment at time of analysis. Baseline characteristics were similar to the overall study populations, except for the proportion of women (LL3/6 only [LTRs versus overall]: 92/78% vs 64/64%) and Del19+ patients (LL3/6/7: 63–79% vs 49–58%). In LL3/6/7, 4–11% of LTRs had brain metastases at enrolment. Median (range) duration of treatment in LL3/6/7 LTRs was 50 (41–73)/56 (37–68)/42 (37–50) months. Due to few deaths, median OS could not be estimated. Median follow-up for OS in LL3/6/7 was 64.6/57.0/42.1 months. ORR among LTRs in LL3/6/7 was 70.8% (complete response: 4.2%; n=1)/78.3% (13.0%; n=3)/89.5% (5.3%; n=1). The frequency of afatinib dose reductions due to treatment-related AEs, and the frequency/duration of subsequent treatments were similar to the overall LL3/6/7 populations. In afatinib-treated LTRs in LL3/6/7, PROs appeared stable between ~Week 24 to ~Week 160, with slight improvements after ~3 years afatinib treatment versus scores at the start of treatment.

Conclusion:
In LL3/6/7, 10%–12% of afatinib-treated patients were LTRs. Afatinib was well tolerated among these patients. Long-term treatment was independent of tolerability-guided dose adjustment or presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment. In afatinib-treated LTRs, PROs were not negatively affected by long-term treatment, and were slightly improved after ~3 years of treatment versus scores at treatment initiation.

Background:
Overcoming acquired resistance to EGFR TKIs remains challenging, identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. In our previous study, we performed mutational profiling in a cohort of 83 NSCLC patients using targeted next generation sequencing (NGS) and identified TET2 mutations in 12% of patients. This study aims to further explore the role of TET2 mutation in acquired EGFR-TKIs resistance in NSCLC cell lines with mutant EGFR.

Method:
CRISPR/Cas9 system was used to knock out TET2 gene in NSCLC cell line PC-9. Quantitative real-time PCR was performed to detect mRNA levels of TET2 gene, and western bot was performed to detect the expression levels of TET2 protein, thus cell line of TET2 silencing can be selected; positive for Annexin V and/or propidium iodide by flow cytometry was used to determine apoptotic rate. Bisulfite sequencing PCR (BSP) and real-time PCR for detection of EGFR promoter methylation status and mRNA expression.

Result:
By applying combined analyses of gene expression, apoptotic rate, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of TET2 to segregate EGFR-dependent cells. We show that in EGFR-dependent cells, TET2 loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib resistance. Figure 1



Conclusion:
Our study is expected to provide new ideas and put forward corresponding relevant tactics for patients with secondary resistance to the first-generation EGFR TKIs.

Background:
CNS (central nervous system) involvement is common in advanced NSCLC (non-small cell lung cancer). Osimertinib has shown activity in CNS in preclinical studies and phase II, III trials (AURA2, AURA3). We reported the efficacy of CNS metastases from an open label, multinational, multicenter, real world treatment study (ASTRIS, NCT02474355) in patients with T790M-positive advanced NSCLC who have progressed on or after prior epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKI) therapy.

Method:
Patients with T790M-positive (from tissue, plasma or other fluids) advanced NSCLC received osimertinib 80mg once daily. Of the 88 patients who were enrolled in ASTRIS at Yonsei Cancer Center, 10 patients who did not have baseline brain workup and 15 patients without CNS metastases at the beginning of study were excluded from this analysis. A subgroup analysis was conducted in patients with CNS metastases at the baseline, as assessed by neuroradiologist, to define CNS overall response rate (ORR), duration of response (DOR), and progression-free-survival (PFS) by RECIST(Response Evaluation Criteria in Solid Tumors) v1.1. The CNS full analysis set (cFAS) included patients with ≥ 1 measurable and/or non-measurable CNS metastasis present on baseline scan; the CNS evaluable for response set (cEFR) included only patients with ≥ 1 measurable CNS metastasis.

Result:
Among the 63 patients who had CNS metastases at baseline, fifty-four (61.4%) patients were included in the subgroup analysis as cFAS, except for the 9 patients who did not follow up brain image during ASTRIS. In patients without brain metastases at the time of initiation of osimertinib (n=15), no experienced CNS progression during ASTRIS. CNS ORR was 81.3% (95% confidence interval [CI] 73.2-89.4) in the cEFR and 40.7% (95% CI 30.4-50.9) in the cFAS. In the cEFR and cFAS, median CNS DOR was “not reached” vs 40.1 weeks (95% CI 36.95-43.25). The median CNS PFS was not reached in both cFAS and cEFR. CNS ORR of 33.3%(95% CI 11.7-64.9) and 42.2% (95% CI 28.9-56.7) were observed for patients with CNS metastases within 3 months brain radiation and without prior radiation or ≥ 3months brain radiation, increasing to 75.0% (95% CI 28.9-96.6) and 83.3%(95% CI 54.0-96.5) respectively, for patients with measurable CNS disease only. CNS ORR of T790M-positive patients in tissue and plasma were 37.5%(95% CI 21.1-57.4) and 46.4% (95% CI 29.5-64.2) in the cFAS, vs 100%(95% CI 55.7-100.0) and 70.0%(95% CI 39.2-89.7) in the cEFR.

Conclusion:
Osimertinib had good CNS efficacy irrespective of radiation history in T790M-positive advanced NSCLC.

Background:
Osimertinib is an oral, potent, irreversible 3[rd] generation EGFR tyrosine kinase inhibitor(TKI) approved for the treatment of T790M positive non-small cell lung cancer (NSCLC) patients who failed 1[st] or 2[nd] generation EGFR TKIs. Interstitial lung disease (ILD) is a rare complication with osimertinib, accounting for 1-3%. Recently, relatively high incidence of transient asymptomatic pulmonary opacities (TAPOs) which are different from ILD has been described (Noonan et al, JTO 2016). However, its clinical implication has not been fully determined yet.

Method:
We retrospectively analyzed 75 EGFR mutant NSCLC patients treated with osimertinib at Samsung Medical Center. Serial CT findings were reviewed by radiologist (Dr. HY Lee) and TAPO was classified according to its radiologic pattern. We also analyzed the correlation of TAPO with clinical outcomes.

Result:
Among 74 patients, TAPO was found in 15 (20.3%). The median time to TAPOs development was 23.5 weeks (1 – 72 weeks) and the median duration of TAPOs was 6.0 weeks (5 – 24 weeks) during continued osimertinib treatment. The most common radiological patterns of TAPO include cryptogenic organizing pneumonia and/or simple eosinophilic pneumonia (SEP). There was no significant difference in patient characteristics between TAPO positive and negative group. The duration of exposure to osimertinib is longer in TAPO positive than negative group (25.2 months vs 14.0 months, p=0.016 ). The progression free survival (PFS) and overall survival (OS) was numerically longer in patients with TAPO positive than negative group (PFS : 15.0 m vs 12.5 m, p= 0.201/ OS : 37.0 m vs 24 m, p=0.155)

Conclusion:
TAPOs are frequently observed with osimertinib treatment and may be mistaken for isolated pulmonary progression or ILD. Given the lack of serious clinical deterioration, it is reasonable to continue osimertinib with regular CT scan follow-up. For further clinical validation of TAPOs, long-term and large studies are warranted.

Background:
The overall survival (OS) of patients with EGFR mutation positive (EGFRm) lung cancer has changed dramatically due to the combined benefit of targeted systemic therapy, local management of oligometastatic disease and incorporation of judicious use of radiotherapy. We reviewed EGFRm NSCLC patients who were diagnosed with CNS metastasis to determine the prognostic importance of the initial CNS presentation.

Method:
A retrospective review was conducted of EGFR+ referred to the BC Cancer Agency between 2010 and 2015, treated with a first/second-generation EGFR TKI who developed CNS metastases (CNSm). Baseline characteristics, presenting symptoms and CNS-targeted treatment data was collected. Cox regression was conducted to determine the prognostic implications of the most common clinical presentations on OS.

Result:
229 patients were identified; 90 presented with CNSm and 139 developed CNSm during the course of their disease. Method of CNSm detection: CT only 61%, MRI only 8%, CT and MRI 30%, PET 1%. 80% of patients were symptomatic at CNSm diagnosis. Baseline characteristics: female 66%, median age 62 (34-90), Asian 51%, exon 19/exon 21/rare mutation/not specified 56/39/3/2%. CNS management: 13% surgery+/- whole brain radiotherapy (WBRT), 73% WBRT alone, 5% stereotactic radiosurgery (SRS)+/-WBRT, 9% no CNS directed therapy. OS was 21.6 months in patients who presented with CNSm vs. 27.1 months in those who developed CNSm during the course of disease (p=0.39). On multivariate analysis, the only presenting symptom associated with increased risk of death was cognitive dysfunction.

	Frequency of symptom at presentation	Univariate Analysis		Multivariate Analysis
		HR	P value	HR	P value
Cognitive Dysfunction	19%	1.26	0.01	1.21	0.04
Motor Dysfunction	18%	1.04	0.69
Balance and Ataxia	11%	1.04	0.46
Cranial Nerve Changes	8%	0.94	0.65
Headache and Dizziness	30%	0.94	0.41
Nausea and Vomiting	13%	0.92	0.48
Visual Disturbance	10%	0.99	0.97
Speech and Aphasia	10%	1.19	0.16
Seizures	7%	0.75	0.09	0.78	0.13
Leptomeningeal disease	12%	1.25	0.04	1.20	0.10

Conclusion:
The most common symptoms at initial presentation of CNSm in EGFRm patients were headache and dizziness, cognitive dysfunction and motor dysfunction. In multivariate analysis, only cognitive dysfunction was associated with poorer survival. Clinicians should have a low threshold for CNS screening based on the varied clinical symptoms experienced by patients

Background:
EGFR mutation in plasma circulating free tumor-derived DNA (ctDNA) by ARMS methods has been widely used in clinical settings in China. However, the prevalence of EGFR mutations in ctDNA was still unknown in the real world. This large-scale study (NCT02623257) aimed to explore the prevalence of EGFR mutations and determine the correlation of EGFR mutation status with clinical characteristics.

Method:
Plasma DNA samples from 721 patients with stage III/IV NSCLC who received ≤1 line chemotherapy were collected from 65 hospitals. EGFR mutations were tested by ARMS method. The EGFR mutation rate was calculated and the associations between EGFR mutant and patients’ demographic data, disease status as well as treatment pattern were explored.

Result:
EGFR mutations were detected in 176 of 721 (24.4%) patients, 165 of 620 (26.6%) in adenocarcinoma and 8 of 85 (9.4%) in squamous carcinoma. 138 (19.1%) harbored sensitizing mutations (66 19del, 62 L858R, 7 G719X, 2 L861Q, and 1 S768I) alone, 20 (2.8%) had resistance mutations (13 T790M, 7 Ins20) alone, 2 (0.3%) had a combination of activating mutations, and 16 (2.2%) had a combination of activating and resistance mutations. Twenty-eight (3.8%) patients were detected de novo T790M mutation either existed alone or combination, but no difference of clinical characteristics was observed. Higher detection rate was observed in 566 chemotherapy-naïve patients than in 155 patients received 1[st] line chemotherapy (27.2% versus 14.2%; p<0.001). Of which, the mutation rate of exon 19 deletion was 11.3% for naïve patients and 8.4% for the patients with 1[st] line chemotherapy; while the mutation rate of L858R decreased most obviously from 11.9%(naïve) to 1.9%(1[st] line). We also noticed 117 patients had ≥ 2 organ metastases and the mutation rate was 35.0% in these patients. Multivariate analysis showed female, chemotherapy native, or patients with ≥2 metastatic organs had higher percentage of EGFR mutation. Additionally, in 194 patients who had the follow-up treatment records, 34 of 49 patients (69.4%) with sensitive EGFR mutations received EGFR-TKI, 96 of 136 (70.6%) patients without sensitive EGFR mutation received chemo±radiation.

Conclusion:
Using plasma samples to detect EGFR mutation is feasible. ctDNA based EGFR mutation test could be a surrogate when tissue biopsy is not available due to limited tissue availability and procedural feasibility.

Background:
De-novo EGFR T790M mutations are rare, occurs less than 5% in the world and resistant to EGFR-TKI treatment. In Persahabatan Hospital, patients with De novo EGFR T790M mutations are given systemic chemotherapy with or without radiotherapy. No data on clinical profiles and 6 months survival rate in this group. the purpose of this preliminary study is to evalaute clincal profiles and 6 months survival of EGFR-T790M mutation in lung adenocarcinoma in Persahabtan Hospital Jakarta Indonesia.

Method:
Subjects was recruited consecutively from lung cancer Adenocarcinoma with De-novo EGFR T790M mutations. EGFR mutation is routinely assesed in lung adenocarcinoma in Persahabatan Hospital using PCR-High Resollution Melting, RFLP Analysis and direct sequencing. Subjects' clinical characteristics (race, age, gender), smoking habits, family history of malignancy, occupation, date at diagnosis (through anatomic pathology examination), complete diagnosis, stage, performance status, metastasis, chemotherapy and radiotherapy, RECIST evaluation, date of death were recorded.

Result:
Fourteen subjects were elligible and included in this study of which 9 subjects were male (64,2%), 5 subjects female (35,7%). Smoking status were 8 subject were smoker (57,1%), never smoke (35,7%), ex smokers (7,14%). Two subjects ( 14.2%) has family history of malignancy. All subjects were stage 4 with 42.8% pleural effusion (6 subjects), 21.4% pleural effusion and bone metastasis (3 subjects), 21.4% ( 3 subjects) with distant lymph nodes metastasis, 7.2% brain metastasis ( 1 subjects), 7.14% brain and bone metastasis. Mutation in ONLY exon 20 T790M 85,7% ( 12 subjects); double mutation did exist with Exon 19 ins/del and exon 20 T790M (1 subject); exon 19 ins/del and exon 20 T790M (1 subject); exon 21 L861Q and exon 20 T790M in 1 subject. Systemic chemotherapy were done in 9 subjects (64,3%), systemic chemotherapy and radiotherapy were done in 5 subject (35,7%). Six months survival rates in this group was 50%; and 1 year survival were 21,42%; Interestingly 4 subjects (28,6%) survived more than 1 year.

Conclusion:
De-novo EGFR T790M mutations are rare (< 5%). The presence double mutation ie. De-novo EGFR T790M mutations and other activating EGFR mutation did exist. these group has variable clinical responses with chemotherapy and warrant further investigation.

Background:
Personalized treatment based on the molecular markers in tissue of patients have crucial role in clinical practice. However, Obtaining Tumor tissue samples are not always available, and rebiopsy is not easy to do. The liquid biopsy with blood samples will be a good alternative diagnostic method. We compared the detection rate of EGFR mutation detection techniques between matched tumor tissue and peripheral blood sample in patients with lung adenocarcinoma.

Method:
We collected the paired samples from plasma and paraffin-embedded tumor tissue in patients before EGFR-TKIs treatment or after progression of EFGR-TKIs treatment. EGFR mutation analysis was done by two detection methods. One is the PNAClampTM (Clamp) which is the PNA-based PCR clamping that selectively amplifies only the mutated target DNA sequence as minor portion in mixture with the major wild type DNA sequences. The other is the PANAMutyperTM EGFR kit (Mutyper), which use PNA clamping-assisted fluorescence melting curve analysis to perform mutation detection and genotyping. The tissues were tested by Clamp method, and blood was tested in two ways. We compared the sensitivity of EGFR mutation detection techniques from tumor tissue and plasma circulating tumor DNA in patients.

Result:
Total patients were thirty two (17 male, 15 female) with advanced stage, mean age was 62.8 years-old, all patients were adenocarcinoma, and fifteen patients were never smoker. EGFR mutation positive rate of tissue was 31.3%. In plasma samples, there were 21.9% in Clamp method and 31.3% in Mutyper method. EGFR plasma detection rate of Mutyper was higher than Clamp. Two patients who showed wild type in tissue Clamp method have EGFR 19 deletion by Mutyper method. Both patients were female never smoker. In two cases, T790M was detected only in tissue but not in liquid biopsy. The overall concordance and degree of agreement between two samples were better in Mutyper (75%, gamma=0.872, p<0.001) than Clamp (71.3%, gamma=0.824 p=0.003).

Conclusion:
The plasma detection rate and the degree of agreement of Mutyper test were better than Clamp test. This method can be useful to detect EGFR mutation in circulating cell-free DNA sample. Liquid biopsy is an excellent resource, and had additional effect in choosing available drug for EGFR rich lung cancer population.

Background:
Pleural effusion is a highly efficient sample for liquid biopsy due to cancer cell enriched components. Liquid biopsy for EGFR genotyping is mostly being done using cell-free DNA. Extracellular vesicles (EVs) are known to carry oncogenic double stranded DNA that is considered as a noble biomarker. We set up to investigate the liquid biopsy using cell-free (cf) DNA and extracellular vesicular (EV) DNA of pleural effusion for EGFR genotyping in pulmonary adenocarcinoma patients.

Method:
Forty nine pleural effusion samples of pulmonary adenocarcinoma patients were evaluated. Non-cellular components after removing cell pellets by centrifuge (400g, 10 min, 4[0]C) were used for liquid biopsy and EVs were isolated by ultracentrifuge method (200,000g, 1 hr, 4[o]C). EV DNA and cf DNA were extracted separately and EGFR genotyping was done by PNA-clamping method. For the analysis of T790M detection, cell block slides were used as rebiopsy sample, when compared with liquid samples.

Result:
Among 31 EGFR-TKI naïve patients with known tissue EGFR genotyping, liquid biopsy using effusion EV DNA showed 100% matching with tissue EGFR genotyping in 19 EGFR mutant cases and detected 3 more EGFR mutant cases in tissue wild type (WT) patients, while liquid biopsy using effusion cf DNA missed 2 cases of tissue-based EGFR mutant patients and found 2 more EGFR mutant cases in tissue WT patients. In 18 patients with acquired resistance to EGFR-TKI, EGFR genotyping using effusion EV DNA detected T790M mutation in 13 of 18 (72.2%) patients, while 11 of 18 (61.1%) patients were detected by using effusion cf DNA, respectively. In contrast, only 3 patients were found to have T790M when using cell block slides.

Conclusion:
Liquid biopsy using pleural effusion is particularly effective for EGFR genotyping than conventional cytology or cell block sample. Liquid biopsy using effusion EV DNA is highly promising for EGFR genotyping, especially detecting T790M mutation, when compared with cf DNA.

Background:
This is a prospective, post-marketing surveillance study (NCT02131259) to evaluate safety and effectiveness of the irreversible ErbB family blocker, afatinib, which is approved in Japan for the treatment of inoperable/recurrent EGFRm+ NSCLC.

Method:
Patients with inoperable/recurrent EGFRm+ NSCLC received afatinib at the approved dose (20–50 mg/day) and were observed following treatment initiation for 52 weeks/until premature discontinuation. Data were included for all patients who received afatinib during the investigational period of this study, thus minimizing patient selection bias. The incidence/severity of adverse drug reactions (ADRs)/serious ADRs (sADRs) was the primary endpoint. Other endpoints included effectiveness (objective response rate [ORR]) and the incidence/severity of ADRs of special interest (diarrhea, rash/acne, nail effects [NEs] and interstitial lung disease [ILD]).

Result:
As of February 2017, 1,602 patients were included in the analysis (59% female, 81% aged <75 years, 86% ECOG PS 0–1, 83% BMI <25 kg/m[2]). 97% of patients had adenocarcinoma, and 64%/26% had EGFR Del19/L858R mutations. 70% had ≥1 line of prior chemotherapy; 48%/30% had prior gefitinib/erlotinib. Afatinib starting dose was 40 mg in 77% of patients. 95% had ADRs (36% grade ≥3). The most frequently reported ADRs (all grade/grade 3–4) were diarrhea (78%/15%), rash/acne (59%/6%), stomatitis (31%/4%), and NEs (38%/4%). ILD (all grade/grade 3–4/grade 5) occurred in 4%/2%/1% of patients. Median (range) time to initial onset was 5.0 (1–316) days for diarrhea, 11.0 (1–406) days for rash/acne, 9.0 (1–327) days for stomatitis, 38.0 (1–526) days for NEs, and 35.5 (3–329) days for ILD. Four patients (<1%) had creatinine elevation following grade ≥3 diarrhea. Dose reductions/permanent discontinuations occurred in 8%/7% of patients following diarrhea, 6%/4% following rash/acne, 3%/2% following stomatitis, 5%/2% following NEs, and <1%/4% following ILD. 33% of patients experienced sADRs. ADR frequency was associated with starting dose (96%/91% with 40/<40 mg afatinib), but was not unfavorably impacted by age, ECOG PS, number of prior chemotherapies, or previous EGFR TKIs. ORR with afatinib was higher in EGFR TKI-naïve patients than those who had previously been treated with EGFR TKIs (68% versus 21%).

Conclusion:
Consistent with previous studies, afatinib was effective in inoperable/recurrent EGFRm+ NSCLC, particularly as first-line targeted treatment (ORR ~70%). ADRs were predictable and generally manageable. ADR frequency was not notably affected by age, ECOG PS or number of previous therapies. In clinical practice, patients should be closely monitored and ADRs, particularly diarrhea and ILD, treated early to prevent sADRs.

Background:
In the Phase III LUX-Lung (LL) 3 and LL6 trials, first-line afatinib significantly improved PFS vs platinum-doublet chemotherapy in patients with EGFRm+ NSCLC (independent review; LL3: 11.1 vs 6.9 months, HR=0.58; p=0.001; LL6: 11.0 vs 5.6 months, HR=0.28; p<0.0001). In the Phase IIb LL7 trial, afatinib significantly improved PFS and TTF vs gefitinib in patients with EGFRm+ NSCLC harboring common EGFR mutations (PFS, independent review: 11.0 vs 10.9 months, HR=0.73; p=0.017; TTF: 13.7 vs 11.5 months, HR=0.73, p=0.0073). Here we report interim analysis results of a large Phase IIIb study of afatinib in a broad population of EGFR TKI-naïve patients with EGFRm+ NSCLC.

Method:
In this Phase IIIb trial with a similar setting to ‘real-world’ practice, EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC were recruited from centers in China, Hong Kong, India, Singapore and Taiwan and received afatinib 40mg/day until investigator-assessed progression or lack of tolerability. Primary endpoint: number of patients with serious adverse events (SAEs). Secondary endpoints included: number of patients with afatinib-related AEs; time to symptomatic progression (TTSP). Other assessments included PFS (investigator review).

Result:
At data cut-off (13 Feb 2017) 479 patients were treated with afatinib (median age: 59.0 years; female: 52.4%; common [(Del19 and/or L858R) with or without uncommon]/uncommon only EGFR mutations: 86.0%/14.0%; ECOG PS 0/1: 19.8%/78.1%; brain metastases: 19.2%; 0/1/≥2 lines of prior chemotherapy: 59.7%/30.1%/10.2%. 24.8% of patients required dose reductions to 30mg; 6.1% had further reductions to 20mg. Median (range) treatment time was 9.7 months (0.2–38.6). SAEs were reported in 115 (24.0%) patients and afatinib-related SAEs in 29 (6.1%) patients. Grade ≥3 afatinib-related AEs occurred in 122 (25.5%) patients; diarrhea (n=50; 10.4%) and rash/acne (n=38; 7.9%) were the most common (≥5%). 18 (3.8%) patients discontinued treatment due to afatinib-related AEs. Median TTSP (15.3 months [95% CI: 13.4–17.5]) was 3 months longer than PFS (12.1 months [10.8–13.7]), suggesting afatinib may be continued beyond progression, and both were longer in patients with common (with/without uncommon) vs uncommon only EGFR mutations (PFS: 12.6 vs 9.1; TTSP: 15.8 vs 10.0 months).

Conclusion:
The safety data of afatinib from this interim analysis of a large-scale population of EGFR TKI-naïve EGFRm+ NSCLC patients are consistent with LL3/6/7 and confirm that most afatinib-related AEs are manageable and result in few treatment discontinuations. Afatinib also demonstrated encouraging efficacy in patients with common and uncommon EGFR mutations. Data from larger patient populations will be evaluated in further analyses of this trial.

Background:
Epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism for resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKI). Osimertinib has been demonstrated to overcome EGFR T790M non-small cell lung cancer (NSCLC). However, most of these patients eventually developed resistance after 10 months. Here we performed a comprehensive next generation sequencing (NGS) using circulating tumor DNA (ctDNA) to study resistance mechanisms in patients with advanced NSCLC who had developed resistance to osimertinib, and to provide potential opportunities for treatment.

Method:
10 advanced NSCLC patients were enrolled in this study after progression from first-generation EGFR-TKI treatment. Patients received osimertinib with 80mg daily, the response rate and progression-free survival (PFS) was assessed during treatment. 10ml peripheral blood was collected from patients after progression from osimertinib, and ctDNA genotyping was performed by next-generation sequence (NGS).

Result:
There were 3 patients received gefitinib and 7 patients received erlotinib before osimertinib therapy. All patients confirmed a partial response (PR) on osimertinib, the median PFS was 13.3 months. The initial gene mutation patterns before osimertinib therapy could be classified into two groups: L858R/Exon 19 Deletion (19Del) +T790M, and L858R/19Del+T790M unknown or wild-type. However, after progression from osimertinib, mutation patterns varied from groups. In the L858R/19Del+T790M group, two of six patients detected with L858R/19Del+T790M+C797S, two patients with L858R (+T790M) +HER2 amplification, and two patients with only 19Del+T790M; In the L858R/19Del+T790M unknown or wild-type group, there was only one patient detected with L858R/19Del+C797S mutation, the other three patients detected with only L858R mutation. For the C797S-mutated patients, it showed that T790M and C797S mutation presented in the same allele (cis) in two patients, while in both trans and cis in one patient. Other EGFR mutations were also detected, such as A750P, L792F, E709K, A1013V, L718V, and EGFR amplification.

Conclusion:
Genotyping of ctDNA in osimertinib resistant patients showed that the resistance might be related to specific gene mutation, e.g., EGFR C797S and HER2 amplification. Our findings provide insight that resistance to osimertinib might be different between T790M-mutated patients and T790M wilt-type patients. Combination therapy of osimertinib with other agents may be candidate to overcome the acquired mutation.

Background:
EGFR TKI treatment is standard of care in patients with metastasized NSCLC carrying an activating EGFR mutation. Targeted therapies achieve a higher ORR, OS, PFS and a better quality of life than chemotherapy. With the advent of 2[nd] and 3[rd] generation TKI´s effective in 1[st] generation TKI resistant tumors, we wanted to study the impact of these drugs on the outcome of patients in a real life setting in 3 lung cancer centers.

Method:
1473 patients from three cancer centers diagnosed with non-squamous cell NSCLC stage IV (UICC 7) were examined. Methods for the mutation testing was performed according to the German Oncopedia guidelines using either Sanger Sequencing or COBAS ® or Next Generation Sequencing.

Result:
964/1473 (65%) consecutive patients with non-squamous cell NSCLC were studied for the presence of tumor mutations. The EGFR mutation rate was 16% (147/943), and the ALK-translocation rate 4% (26/695). Median OS in EGFR mt+ patients was 27 months (n=147) compared to 11 months (n=796) in patients with EGFR WT (p<0.000). Median OS in EGFR mt+ patients depending on the center was 27 (n=95) vs. 28 (n=38) vs. 16 (n=14) months respectively (center 1 vs. center 2 vs. center 3). Median OS in ALK mt+ patients was 24 months (n=19) in center 1 and 11 months (n=5) in center 2 (p<0.025). The ORR in the CR/PR group was 54.2% for patients treated with chemotherapy and 77% for patients treated with TKI on 1[st] line therapy. The chance to reach a CR/PR is 2.83 higher for patients on TKI than for patients on chemotherapy (p<0.02). The use of 3[rd] generation TKI Osimertinib (n=19) lead to a significantly higher OS (n=19, median OS 67 months) than the use of only 1[st] and 2[nd] generation TKI (n=119, median OS 23 months, p<0.000). The hazard ratio for patients treated without Osimertinib was 4.66 [95% CI 2.006-10.81] (p<0.000). Patients treated with 3[rd] gen TKI had significantly longer PFS (11 months, n=7) than patients treated without (5 months, n=20) (p<0.037). Similarly, use of 2[nd] and 3[rd] generation ALKi impacted significantly on median OS: Crizotinib alone (n=8) 17 months, Crizotinib followed by Ceritinib and/or Brigatinib/Alectinib (n=12) median OS not reached and 3 months for other therapies (n=6) (p<0.000).

Conclusion:
Small differences in OS were observed, depending on the treatment centers, but the use of multiple EGFR and ALK-I impacted highly significantly on the outcome of patients with EGFR and ALK-alterations in a real life setting.

Background:
Clinical trials have demonstrated the efficacy and safety of EGFR tyrosine kinase inhibitors (TKIs), as first-line therapy in patients with metastatic non-small-cell lung cancer (NSCLC) whose tumours harbour activating mutations in the EGFR gene. However, there are limited data in the real-world setting describing TKI use among patients with EGFR-mutated NSCLC.

Method:
A retrospective non-interventional study was conducted using the Flatiron Health database, a longitudinal database containing electronic health record data, of patients seen in over 265 United States cancer clinics (~800 sites of care). Adult patients with histologically confirmed stage IIIB or IV NSCLC, with documented EGFR-mutated disease (del 19 or L858R), and who had received the first sequence of systemic therapy between January, 2011 and March, 2016 were included. Patient demographic and clinical disease characteristics were analysed and time-to-next treatment (TTNT) was used as a surrogate measure for progression-free survival. If validated in time, overall survival data will be presented.

Result:
Overall 20,924 adult patients with advanced NSCLC were identified, of whom 12,148 (58.1 %) were tested for EGFR mutations. Among these, 1,919 (15.8 %) patients had a positive EGFR result with 1,412 patients carrying del 19 or exon 21 mutations. Of these, 886 patients were treated with regimens in the first-line setting. Median age was 69.0 years; 67.7% were female; 55.5% were Caucasian; 54.3% were non-smokers; 97.5% had non-squamous histology and 57.3% received at least one subsequent treatment. Most patients received a TKI (71.8%) and 28.2% received other therapy. There were no differences observed in a patient’s type of insurance and the type of treatment (TKI or chemotherapy) that they were likely to receive. Patients treated with an EGFR TKI had a significantly longer median TTNT [erlotinib (13.2 months [95% CI 12.2–14.4; p=<0.001]) afatinib (12.6 months [95% CI 8.6–16.2; p=<0.001]), gefitinib (not evaluable; due to small sample size n=9) than those treated with other anti-cancer agents (4.6 months [95% CI 4.0–5.4]).

Conclusion:
These real world data mirror the results shown in randomised clinical trials, with the exception of patients being generally older. Importantly, patients who did not receive a TKI had significantly shorter TTNT. A large proportion of patients (42%) are not being tested for EGFR mutations, although there was an improvement over time. The reasons for not testing all eligible patients for EGFR mutations should be investigated further.

Background:
The analysis of EGFR mutations in plasma cell-free DNA (cfDNA) may become an auxiliary tool in the molecular diagnosis of advanced NSCLC patients from whom sufficient tumor tissue/cells specimens cannot be obtained. We evaluated the diagnostic performance of the two most common real-time PCR-based platforms for detection of EGFR mutations in plasma cfDNA that we use in our routine laboratory practice.

Method:
EGFR mutations were analyzed in plasma cfDNA collected from 107 NSCLC patients (non-SQC type, stages I-IV) before treatment (n=80) or at the time of progression on EGFR-TKIs (n=27) using two IVD-marked assays: ‘Cobas EGFR Mutation Test v2’ (Roche) and ‘Therascreen EGFR Plasma RGQ PCR Kit’ (Qiagen).

Result:
The overall concordance between EGFR mutation status in plasma cfDNA and paired tumor tissue samples was 62% (46% for Cobas and 32% for Therascreen test) for all patients regardless the NSCLC stage. The concordance increased to 88% (83% for Cobas and to 56% for Therascreen) when only samples from advanced NSCLC patients were evaluated. Accordingly, the Cobas test showed higher positive percent agreement between cfDNA and tissue results (PPA=83%) than did the Therascreen test (PPA=56%). Both test showed 100% negative percent agreement. The T790M mutation was detected in 26% cfDNA samples from patients upon progression on EGFR-TKIs. In 12 (44%) cases with progressive disease, the plasma cfDNA was the only specimen available for EGFR mutation analysis.

Conclusion:
In our laboratory setting, Cobas test demonstrated superior diagnostic performance over Therascreen assay in detection of EGFR mutations in plasma cell-free DNA from advanced NSCLC patients. Since analysis of mutated EGFR cfDNA in plasma is troublesome laboratory procedure, we recommend to validate the true diagnostic performance of each commercial assay in a specific laboratory conditions despite its IVD certification. The study is on-going.

Background:
The Compassionate-Use-Program (CUP) was available in Thailand for requesting afatinib during 2012-2014 for patients whom had failed at least one-line of platinum-based-chemotherapy and progressed following at least 6 months on 1[st]-generation EGFR-TKIs. This is a multicenter-retrospective-study in Thailand aimed to explore the efficacy and tolerability of afatinib in this group of patients.

Method:
Full medical-records of 79 patients from 7 institutions were reviewed. Clinical and tumor characteristics were analyzed using descriptive statistics. The efficacy in brain metastases was explored. Survival curves were constructed using the Kaplan-Meier method. All analysis was done in Stata version14.

Result:
Sixty-eight percent of patients were younger than 65 years old, 60% were female, and 67% received more than 2 of prior-regimen. EGFR-mutation was tested in 75% of patients; comprise of 86% common-mutations, 14% uncommon-mutations. Eleven patients had T790M acquired-resistance in combination with sensitive-mutation before receiving afatinib. One patient had De-novo-T790M. The mOS, mPFS, and mTTF were 11.5, 3.9, and 5.1 months, respectively. Eighteen patients had brain-metastases at enrollment and 6 patients had new brain-metastases during afatinib treatment. The mOS, mPFS, and mTTF were not statistically different among new brain-metastases or pre-existing brain-metastases. There was no dose-reduction in 38%, 1 dose-reduction 44%, 2 dose-reductions 12%, and 3 dose-reductions 6% of patients. The mean dose for every patient was 35 mg. Time-to-first-dose-reduction significantly affected the mPFS and mTTF as shown in Table. Furthermore, number of prior-treatment more than 2 was the significant factor causing first-dose-reduction within 1 month and age younger than 65 years-old was the significant factor causing first-dose-reduction within 2 and 3 months in multivariate and univariate model, respectively.

Time to 1[st] dose reduction	OS		PFS		TTF
	Hazard ratio (95%CI)	P-value	Hazard ratio (95%CI)	P-value	Hazard ratio (95%CI)	P-value
> 1 month <= 1 month	1 1.59 (0.74-3.41)	0.23	1 1.52 (0.82-2.82)	0.19	1 1.45 (0.77-2.74)	0.25
>2 month <= 2 months	1 1.54 (0.72-3.3)	0.27	1 2.11 (1.14-3.92)	0.02	1 1.63 (0.88-3.04)	0.12
>3 months <= 3 months	1 2.31 (0.98-5.45)	0.06	1 2.67 (1.38-5.20)	0.004	1 2.12 (1.09-4.12)	0.03

Conclusion:
The mOS, mPFS, and mTTF of our study were comparable with LUX-Lung1 study. Number of prior-treatment and age were the significant factors causing dose-reduction. Taken together with time-to-first-dose-reduction also affected the survival of patients.

Background:
In LUX-Lung 8 (LL8), second-line afatinib (an irreversible ErbB family blocker) significantly improved OS (median 7.9 versus 6.8 months; HR [95% CI]: 0.81 [0.69‒0.95]; p=0.0077), and PFS (2.6 versus 1.9 months; 0.81 [0.69‒0.96]; p=0.0103) versus erlotinib in lung SCC (N=795). Comprehensive genetic analysis in LL8 patients assessed whether afatinib efficacy varied according to genetic aberrations in cancer-related genes, including ErbB family mutations.

Method:
Tumor genetic analysis (TGA) was performed using Foundation Medicine FoundationOne™ next-generation sequencing (NGS). The cohort was enriched for patients with PFS >2 months, reflecting a range of responsiveness to EGFR-TKIs. EGFR expression was assessed by immunohistochemistry (IHC) in a largely separate cohort. Cox regression analysis correlated PFS/OS with genetic mutations (individual/grouped) and EGFR expression.

Result:
Of 440 patients selected for TGA (PFS >2 months: n=320; ≤2 months: n=120), samples from 245 were eligible (afatinib: n=132; erlotinib: n=113). In the selected TGA population, PFS/OS outcomes were improved in the afatinib versus erlotinib arm. Baseline characteristics were similar in TGA and IHC cohorts and LL8 overall. In the TGA subset, 53 patients (21.6%) had ≥1 ErbB family mutation (EGFR: 6.5%; HER2: 4.9%; HER3: 6.1%; HER4: 5.7%). Beyond the benefit seen for afatinib in the overall population, in afatinib-treated patients, PFS/OS were longer when ErbB mutations were present (PFS: 4.9 versus 3.0 months; OS: 10.6 versus 8.1 months). Conversely, survival outcomes in erlotinib-treated patients were similar with/without ErbB mutations. Presence of HER2 mutations predicted favorable PFS/OS with afatinib versus erlotinib. The Table shows outcomes in patients with/without ErbB family mutations, and by EGFR expression levels (afatinib: n=157; erlotinib: n=188).

Conclusion:
These data are provocative and suggest that NGS may enable identification of lung SCC patients who would derive additional clinical benefit from afatinib. Differential outcomes with respect to ErbB mutations for afatinib and erlotinib are hypothesized to reflect afatinib’s broader mechanism of action.

Subgroup	n	Afatinib vs erlotinib
		PFS		OS
		HR (95% CI)	p~interaction~	HR (95% CI)	p~interaction~
ErbB mutation-positive ErbB mutation-negative	53 192	0.56 (0.29–1.08) 0.70 (0.50–0.97)	0.718	0.62 (0.35‒1.12) 0.76 (0.56‒1.03)	0.683
EGFR mutation-positive EGFR mutation-negative	16 229	0.64 (0.17–2.44) 0.67 (0.50–0.91)	0.981	1.01 (0.32–3.16) 0.72 (0.54–0.95)	0.529
HER2 mutation-positive HER2 mutation-negative	12 233	0.06 (0.01–0.59) 0.72 (0.54–0.97)	0.006	0.06 (0.01–0.57) 0.76 (0.58–1.00)	0.004
HER3 mutation-positive HER3 mutation-negative	15 230	0.52 (0.16–1.72) 0.69 (0.51–0.94)	0.692	0.84 (0.27–2.59) 0.73 (0.56–0.97)	0.998
HER4 mutation-positive HER4 mutation-negative	14 231	0.21 (0.02–1.94) 0.67 (0.50–0.91)	0.909	0.22 (0.05–1.04) 0.75 (0.56–0.99)	0.272
EGFR IHC positive EGFR IHC negative	292 53	0.74 (0.56–0.97) 0.76 (0.41–1.40)	0.985	0.82 (0.63–1.06) 0.75 (0.41–1.40)	0.882
EGFR amplification present EGFR amplification absent	17 228	0.72 (0.18–2.90) 0.68 (0.50–0.92)	0.994	0.50 (0.15–1.65) 0.76 (0.58–1.00)	0.413
HER2 amplification present HER2 amplification absent	9 236	0.94 (0.20–4.38) 0.68 (0.50–0.91)	0.861	1.10 (0.27–4.48) 0.72 (0.54–0.94)	0.388

Background:
In EURTAC, ENSURE and OPTIMAL, first-line erlotinib was associated with higher response rates and improved PFS versus chemotherapy in EGFR Mut+ NSCLC. OS benefit was not observed, possibly due to high crossover. We present statistical analyses of OS adjusting for crossover in the three studies.

Method:
Rank Preserving Structural Failure Time (RPSFT) analysis is a retrospective statistical methodology that estimates the effect of active treatment and then removes that effect from the control patients, during the period of active treatment. Separately, post-hoc OS analyses were conducted on non-randomized subgroups of patients who received a single line of therapy, chemotherapy only or erlotinib only; or a sequence, chemotherapy followed by TKI or erlotinib followed by chemotherapy. Impact of sequencing on OS was evaluated (Kaplan-Meier methodology).

Result:
RPSFT analyses (Table) show OS was numerically longer with erlotinib versus chemotherapy in EURTAC and ENSURE. OS was not longer with erlotinib in OPTIMAL, possibly due to low treatment adherence in the erlotinib arm, where >50% of patients refused chemotherapy or did not complete four cycles. In the non-randomized analyses, patients receiving erlotinib as the sole treatment had longer OS versus patients treated with only chemotherapy, in all three studies. Patients who received erlotinib followed by chemotherapy had longer OS versus patients who received chemotherapy followed by erlotinib in EURTAC and ENSURE. Patients who received chemotherapy followed by erlotinib in OPTIMAL had longer OS than patients who received erlotinib then chemotherapy, again possibly due to erlotinib patients refusing the full extent of post-progression chemotherapy.

Conclusion:
RPSFT analysis showed increased OS between erlotinib and chemotherapy in EURTAC and ENSURE versus the original ITT analysis. Similar impact in OPTIMAL was not apparent. Post-hoc analysis of non-randomized subgroups (patients treated with a single therapy) showed longer OS for erlotinib versus chemotherapy, notwithstanding caveats of such an approach.

OS (RPSFT analysis)
Study	Treatment Group	N	Median OS, months	HR (95% CI)
EURTAC	Erlotinib	86	22.9	0.64 (0.44, 0.95)
	Chemo	88	15.4
ENSURE	Erlotinib	110	26.3	0.47 (0.32, 0.69)
	Chemo	107	17.1
OPTIMAL	Erlotinib	82	22.7	1.78 (1.21, 2.64)
	Chemo	72	30.5
Influence of sequencing on OS in patients who crossed over (Kaplan-Meier analysis)
Study	Treatment Group	N	Patients crossing over, %	Median OS, months
EURTAC	Erlotinib/chemo	49	57	24.9
	Chemo/TKI	72	82	22.6
	Erlotinib alone	37		17.2
	Chemo alone	16		1.6*
ENSURE	Erlotinib/Chemo	69	63	27.0
	Chemo/TKI	89	83	25.6
	Erlotinib alone	41		23.2
	Chemo alone	18		22.9
OPTIMAL	Erlotinib/ Chemo	49	60	26.8
	Chemo/TKI	52	72	31.4
	Erlotinib alone	33		18.6
	Chemo alone	20		11.2
*There were 5 deaths and 5 censored observations that occurred in the first two months

Background:
Circulating-free tumor DNA (ctDNA) has emerged as a sensitive and feasible non-invasive blood-based approach alternative to tissue biopsies to screen for genetic drivers in advanced non-small cell lung cancer (NSCLC) patients. Recently, the COBAS Mutation Test has been FDA-approved for the detection of EGFR mutation (EGFRm) in peripheral blood but other approaches are currently used in clinical practice. Here, we aimed to correlate two different platforms for EGFRm monitoring ctDNA in an enriched cohort of tissue-genetically phenotyped EGFRm advanced NSCLC patients.

Method:
Blood samples were prospectively obtained from an enriched cohort of EGFR+ advanced NSCLC patients. Formalin-fixed paraffin-embedded (FFPE) tumor was characterized by NGS (Ion AmpliSeq Lung Cancer Research Panel v.2) in all patients at diagnose. Plasma ctDNA derived from peripheral whole blood was evaluated by COBAS EGFR Mutation Test v2 and a Peptide Nucleic Acid (PNA) probe–based real-time polymerase chain reaction blinded to baseline tumor genotype. Diagnostic accuracy and concordance of both blood techniques was used for direct comparison with respect to the molecular status of FFPE tissue.

Result:
A total of 80 matched pairs of peripheral blood samples from 40 patients were collected. Baseline tissue NGS reported mutations at exon 19 del (n=23), exon 21 (n=10), exon 18 (n=2), exon 20 (n=2) and T790M (n=3). Four wild-type EGFR tumors were used as controls. Blood samples were obtained at diagnose (n=12) and during tyrosine-kinase inhibitor (TKi) treatment for monitoring (n=28). Overall, concordance between both blood-based techniques with respect tissue-NGS was 100% (4/4) for negative controls and 55% (20/36) for positive tissue-NGS samples. Detection based on PNA and COBAS was negative in 60% (24/40) and 32.5% (13/40) patients respectively. Among 19 samples negative by PNA at monitoring, COBAS allowed plasma EGFRm detection in 11 patients. At baseline, the only two negative samples patients by both techniques were found in patients with localized brain disease. Six patients had detectable driver T790M mutation; among three patients with T790M+ in tissue, COBAS allowed detection in plasma in one patient whereas none was identified with PNA. The other three patients had acquired T790M mutations identified only in blood, all by COBAS.

Conclusion:
In this prospective blinded validation cohort, both methods retained high specificity. However, major differences between techniques were observed for longitudinal monitoring of EGFRm in blood.

Background:
Detection of actionable mutations using circulating tumor DNA (ctDNA) isolated from patient plasma is now accepted as clinical practice in NSCLC. Nevertheless, the full extent to which longitudinal plasma analysis can be utilized to guide clinical decision-making has yet to be realized. We prospectively incorporated serial next-generation sequencing (NGS) of ctDNA into the ongoing SWOG S1403 clinical trial (NCT02438722) of afatinib+cetuximab vs afatinib in treatment-naïve NSCLC patients with EGFR-mutant tumors.

Method:
Time points for specimen collection were pre-treatment, after two months of therapy on Cycle 3 Day1 (C3D1) and at progression. Objectives were to: 1) determine the prognostic and predictive significance the EGFR mutant allele frequency (MAF) at each time point; 2) correlate changes in MAF over time with regard to patient outcome, and 3) identify putative emergent resistance mechanisms and companion mutations. Specimen analysis was conducted using the Guardant360 73-gene digital NGS panel.

Result:
To date, 53 patients with advanced EGFR-mutant NSCLC have contributed baseline samples. Of these, 46 had ctDNA detectable at baseline (87%). 39 of these 46 (85%) had detectable, tissue-identical EGFR mutations, for an overall EGFR detection rate of 74% (39/53). A positive finding for EGFR amplification (Amp) in plasma correlated with high ctDNA MAF: median for Amp 16.9 vs nonAmp 0.9 (range/n: 11.6-43.7/10 vs 0.11-7.7/17; p<0.0001). Of patients with detectable EGFR mutation at baseline, 27 had analyzable ctDNA collected at C3D1. Of these, 26/27 showed decreasing MAFs on-treatment (mean for baseline: 9.8 vs C3D1: 0.14; p<0.0001), with 20 cases having no detectable EGFR mutation at C3D1 (mean of 7 positives at C3D1: 0.55). At progression, samples were collected from 14 patients and 10 had EGFR mutations detectable, with T790M present in 3. Another patient had an FGFR3 fusion at PD, but no previous draws were available to determine if it was emergent.

Conclusion:
Longitudinal analysis of plasma ctDNA in S1403 patients demonstrated significant treatment-induced changes in mutation burden and identified resistance mechanisms at progression. EGFR gene amplification, as assessed in plasma, was significantly associated with increased ctDNA MAFs. Patients showed a significant, one-to-two orders of magnitude decline in EGFR MAF after two months of therapy, with 74% dropping below detectable levels. At progression, EGFR mutation detection rates increased, often concomitantly with a putative emergent resistance factor. Accrual to S1403 is ongoing and patient treatment and outcomes remain blinded. The prognostic and predictive utility of baseline and therapy-induced changes in ctDNA MAF kinetics will be determined at study unblinding.

Background:
Erlotinib is a thyrosine kinase inhibitor which prevents epidermal growth factor receptor(EGFR) by blocking intracellular phosphorylation. Various cutaneous side effects have been associated with EGFR inhibitors. We present a case with ectropion and conjunctivitis followed by erythemato papulopustular skin rash.

Method:
Figure 1A 72 year old male who has suffered from non small cell carcinoma (adenocarcinoma)of lung stage IV since one year ago came to our clinic with bilateral ectropion and conjunctivitis. He has received erlotinib 150 mg/d since three to four months ago.



Result:
Figure 1We prescribed supportive care and symptomatic treatment and discontinued erlotinib for one week due to the severity of eye disease. It resolved gradually after two weeks but erythemato papulr rash appeared



Conclusion:
EGFR inhibitors are one of the most important treatment modalities among patients with lung adenocarcinoma.Cutaneous side effects of these agents are reported frequently. Eye disease including ectropion is a rare adverse effect of these factors. We describe this case to consider the newly diagnosed eye edverse effect of this important agents.

Background:
Third generation EGFR inhibitors are efficacious in patients with NSCLC harboring EGFR sensitizing mutations. Acquired resistance includes alternative mechanisms of EGFR activation and activation of other signaling pathways. Here we report a patient with a CBL mutation as a potential mechanism of acquired resistance to 3[rd] generation EGFR TKI effectively treated with sitravatinib, a spectrum-selective RTK inhibitor of TAM receptors (comprised of TYRO3, AXL, and MER), PDGFRA, KIT, and MET.

Method:
In Study 516-001, a phase 1/1b study of sitravatinib in patients with advanced solid tumor malignancies, patients are selected based on mutations in targeted pathways. Eligible genetic alterations include inactivating mutations of CBL, which encodes an E3-ubiquitin ligase that regulates degradation of activated RTKs that include EGFR, TAM receptors, PDGFRA, KIT, and MET and which account for ~2-3% of NSCLC. Based on overlap of sitravatinib and CBL RTK targets and supporting cancer cell line and tumor model data, we hypothesize that inactivating CBL mutations predict response to sitravatinib.

Result:
After Phase 1, patients were enrolled by mutational profile, and here we report on a patient enrolled into the CBL mutation cohort. The patient is a 77 year-old female, lifelong non-smoker with metastatic lung adenocarcinoma characterized by EGFR exon19del initially treated with erlotinib with a partial response (PR) of 9 months. Upon disease progression (PD), a new EGFR T790M mutation led to treatment with rociletinib (an experimental inhibitor of EGFR T790M) with stable disease for 11 months. Upon PD she was treated with osimertinib without response. She then received carboplatin/pemetrexed with a PR. Brief erlotinib re-challenge resulted in PD, with post-progression NGS revealing loss of EGFR T790M, presence of the original EGFR exon19del, and a new CBL C384R, a mutation located in the RING domain and predicted to result in the loss of CBL ligase adaptor function resulting in sustained activation of relevant RTKs. The patient then started sitravatinib treatment in Study 516-001. After 36 days on-study, restaging demonstrated PR, which was later confirmed with a maximum decrease in unidimensional target lesion measurement of 77%. She remains on-study.

Conclusion:
Loss of function mutations in CBL represent a unique class of mutations that may be responsible for acquired resistance to 3[rd] generation EGFR TKI. Sitravatinib has demonstrated clinical activity in a patient with NSCLC characterized by EGFR exon19del and CBL C384R mutations. The clinical trial with sitravatinib is currently enrolling patients with CBL loss of function mutations. (NCT02219711).

Background:
All EGFR mutated lung cancers will eventually develop acquired resistance to first-line EGFR tyrosine kinase inhibitors (TKi). The most common cause is the EGFR T790M point mutation. Recent studies demonstrated the utility of liquid biopsies (LB) as initial detection strategy. The mutation may be indicative of a more indolent disease and plasma positivity seems to be related to more extensive disease.

Method:
Retrospective evaluation of T790M status and clinical characteristics of patients with advanced or recurrent non-small cell lung cancer (NSCLC) who progressed under EGFR-TKi was performed at our institution. The T790M mutation was assessed in circulating cell-free DNA (cfDNA) in plasma as initial strategy; if negative, a tumor biopsy (TB) was obtained. Samples were analyzed using Cobas® EGFR Mutation Test v2. The purposes of this study were: to explore the feasibility of T790M mutation detection in our practice; to evaluate objective response rate (ORR) and progression-free survival (PFS) on first-line TKi therapy according to T790M status and clinical characteristics.

Result:
We identified 29 patients. Regarding the pre-treatment activating EGFR mutations, 59% (n=17) harbored an exon 19 deletion, 38% (n=11) the L858R mutation and one case had both mutations (two primaries). All patients were treated with EGFR-TKi, 90% (n=26) in the first-line treatment setting. The T790M mutation was positive in 18 patients (12 plasma+ and 6 plasma-/tissue+). The remaining 11 negative results, 7 were assessed only by plasma and the other 4 were confirmed on TB. The resistance mutation was more frequent in patients with EGFR exon 19 deletions (71%, 12/17). In patients with a positive T790M result, those with extra-thoracic disease had detectable T790M mutation in plasma in the majority of cases (86%, 12/14), while all patients with exclusive intra-thoracic disease (n=4) had negative result in plasma. Patients who developed a T790M mutation had a longer PFS under first-line TKi, but not statistically significant (14 months in T790M+ [CI 95% 7.8-20.2] vs. 9 months [CI 95% 6.8-11.2] in T790M-, p=0.201) with similar ORR (55.6% in T790M+ vs. 45.5% in T790M-, p=0.597).

Conclusion:
The evaluation of EGFR T790M mutation is feasible in LB (cfDNA) in patients progressing under EGFR-TKi, but TB is recommended in the negative cases. The likelihood of detection of T790M in plasma is greater in patients with extra-thoracic disease, probably related with higher disease burden. Tumors which develop T790M tend to have a more indolent course, but the conclusion is limited due to the small sample size.

Background:
ASTRIS (NCT02474355) is an open-label, single-arm, multination, real world treatment study, investigating the safety and efficacy of osimertinib in patients with T790M-positive advanced non-small cell lung cancer (NSCLC), who have previously received EGFR-TKI. We report the first results of Korean subset from ASTRIS which is the largest real world treatment study of osimertinib to date.

Method:
Eligible patients had advanced NSCLC harbouring a T790M mutation determined by local validated molecular tests, received prior EGFR-TKI therapy, acceptable organ and bone marrow function and no history of interstitial lung disease (ILD) or QTc prolongation. Enrollment of patients with asymptomatic, stable CNS metastases were permitted. Patients received osimertinib 80 mg once daily. The primary efficacy outcome was overall survival; other outcomes included investigator-assessed response rate (RR), progression-free survival (PFS) and time to treatment discontinuation (TTD). Safety assessment was also conducted. Data cut-off (DCO) was 3 November 2016; results from 1,217 patients in the global study have been presented previously (ASCO 2017 Abstract 9036).

Result:
A total of 371 patients received at least one dose of osimertinib from 30 Korean sites (full analysis set); at DCO, 319 patients (81.4%) were ongoing and median follow-up time was of 3.1 (0–8) months. Baseline patients’ characteristics were median age 61.1 (27–85) years old, female 65.5%, PS 0/1 88%, prior chemotherapy 47%, prior radiotherapy 48%. Tissue was the most common specimen source to test T790M mutation as well as other EGFR mutations (287/371, 77.4%) and plasma was the next (39/371, 13.1%). Fifty two patients (13.3%) had discontinued treatment; median duration of exposure 3.3 (0–7) months, 30 pts (7.7%) had disease progression and 24 patients (6.5%) died. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, the investigator-assessed RR was 72.1% (212/294; 95% CI 66.6 – 77.2). Due to limited follow-up period, OS, PFS, and TTD were immature to analyze. Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 26 patients (7%) and 14 patients (3.8%), respectively. Serious AEs were reported in 50 patients (13.5%) and AEs leading to death in 8 patients (2.2%). ILD/pneumonitis-like events were reported in 9 patients (2.4%), and QTc prolongation (>470ms) in 5 patients (1.3%).

Conclusion:
At DCO for the 1[st] interim analysis of ASTRIS, Korean subgroup results demonstrated similar clinical activities (RR) to that observed in the osimertinib clinical trial program with no new safety signals.

Background:
T790M inhibitor, a third-generation epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), was significantly superior to chemotherapy for EGFR-mutant patients with advanced non-small-cell lung cancer (NSCLC) harboring T790M mutation after resistance to the first-generation EGFR-TKIs. However, for those without acquired T790M mutations or MET amplification, few data showed whether the second-generation EGFR-TKI could overcome resistance to the first-generation EGFR-TKIs.

Method:
EGFR mutation was detected by amplification refractory mutation system (ARMS) technology. Overexpression of MET was determined by immunohistochemistry (IHC), and MET amplification was detected by FISH. Next generation sequencing (NGS) was used to test tumor tissues before and after resistance to TKIs.

Result:
Patient 1 was a 53-year-old Asian male, who underwent surgery followed by adjuvant chemoradiotherapy with an 11 months of disease-free survival. A biopsy was performed and revealed an activating deletion mutation in exon 19 of the EGFR. He started gefitinib 250mg once daily and achieved an initially good partial response (PR) followed by continuously stable disease for a progression-free-survival (PFS) about 29 months. A rebiopsy showed that exon 19 deletion mutation still existed without an acquired T790M mutation or MET amplification. He refused to receive chemotherapy so we prescribed afatinib 40mg daily. He then achieved a dramatic PR 23 days later which was confirmed 1.5 months after that. We sent tumor tissue of the patient before and after TKI therapy for NGS, the result showed a decreasing abundance of EGFR exon 19 deletion without T790M mutation, MET amplification and Her2 mutation/amplification. Patient 2 was a 63-year-old Asian female harboring EGFR exon 20 insertion (A763-Y764 ins), who received first and second lines of chemotherapy with short PFSs. He was enrolled in the trial of allitinib (AST-1306) as the third line therapy with the best response of stable disease(SD) and the PFS of 7 months. A later rebiopsy showed the strong overexpression of MET, but the forth-line therapy crizotinib failed. He then received chemotherapy as the-fifth line therapy, 4 cycles later he progressed. So he started afatinib 40mg daily. His symptoms were relieved significantly 5 days later, and PR was confirmed 1.5 months later.

Conclusion:
Afatinib might overcome resistance to the first-generation EGFR-TKIs for EGFR-mutant patients with advanced NSCLC without acquired T790M mutation or MET amplification. Further investigations are warranted.

Background:
The prevalence of EGFR mutation has been well elucidated in different ethnicities. Recently, increasing attention has been given to dual EGFR mutations. However, less attention has been invested in dual in cis EGFR mutations. Until now, none of retrospective or prospective research has focused on dual in cis EGFR mutations except case reports.

Method:
In this real world study, we performed capture-based ultra-deep targeted sequencing on circulating tumor DNA to identify and investigate the prevalence and genotype distribution of dual in cis EGFR mutations in 3,000 Chinese advanced NSCLC patients. This cohort consisted of both treatment-naïve and previously treated patients. Ten milliliter of peripheral blood was collected from every patient and a minimum of 50ng of ctDNA was needed for library construction. The panel covered critical exons and introns of 168 genes (160kb of human genomic regions).

Result:
1,266 patients harbored EGFR mutant in this cohort; among them, 501 patients harbored 19 deletions, 489 harbored L858R, and the remaining harbored other EGFR mutations. We identified 1.5% patients (19/1,266) harboring dual in cis EGFR mutations. Among them 37% (7/19）carried two rare EGFR mutations and the remaining 63% (12/19) carried EGFR L858R in combination with a rare mutation. No patient carried EGFR 19 del in combination with other rare mutations was identified in this cohort, suggesting EGFR 19del is a stronger oncogenic driver than EGFR L858R (p=0.000197, Fisher’s exact test). For patients carried two rare mutations, both mutations were either located on exon 18 or exon 21. The allelic fractions (AF) of both mutations were similar. The AF of either EGFR mutations was the maximum AF in all patients, demonstrating the clones harboring EGFR mutations were major clones. Interestingly, 1 patient carried additional KRAS mutation and 2 patients had EGFR amplification.

Conclusion:
In cis dual EGFR mutation was rare (1.5%) in EGFR mutant Chinese advanced NSCLC patients. EGFR L858R was significantly more likely to couple with a rare in cis dual mutation than 19 del. EGFR 19del might be a stronger oncogenic driver than EGFR L858R.

Background:
Epidermal growth factor receptor (EGFR) mutation can predict the response to EGFR tyrosine kinase inhibitor (TKI) in non small cell lung cancer (NSCLC). In this study, we determined the limit of detection of different methods, such as sequencing, restriction frament length polymorphism (RFLP), high resolution melting (HRM) and reversed dot blot (RDB) hybridization to detect for EGFR mutation detection.

Method:
Mutation detections of exons19 and 21 in EGFR gene were performed using sequencing, restriction fragment length polymorphism (RFLP) and high resolution melting (HRM) analysis method. Moreover, we also developed Reversed Dot Blot(RDB) method hybridization as an alternative procedure. Genomic DNA of H1975, HCT116 cell line as well as specially designed oligonucleotides were used to determine the limit of detection of these procedures. We also determine the sensitivity and specificity of RDB method compared to existing methods.

Result:
Limit of detection of each method was determined by titration of mutant allele in wildtype background. HRM analysis and RFLP were able to detect mutation in samples containing 6.25% to 12.5% mutated DNA.Limit of detection of RDB method was around 12.5%. Analysis of 40 patients had shown that the specificity for to detect mutations in exon 19 and 21 was 100% and 89.5% and the sensitivity for both exon was 62.5%.

Conclusion:
RDB method maybe used as an alternative method to standard procedure such as sequencing. This method is specific, but need further improvement to increase its sensitivity.

Background:
The existence of circulating tumor DNA (ct-DNA) in urine as a noninvasive and alternative sample to tissue biopsy has been promising. However, it still has some challenges. Common mutations of epidermal growth factor receptor (EGFR), such as L858R in exon 21 mutation has been used to predict lung cancer treatment response to tyrosine kinase inhibitors (TKI). The study aimed to demonstrate that DNA from urine can be detected using simple methods with high sensitivity, enabling early Non-Small Cell Lung Cancer (NSCLC) detection from these noninvasive samples.

Method:
Cytological smear and urine samples from 59 NSCLC patients had been collected and processed to obtain genomic DNA. EGFR common mutations in exon 21 were analyzed using polymerase chain reactions (PCR) and restriction fragment length polymorphism (RFLP) methods that having analytical sensitivity of detecting 3% EGFR mutant alleles. Diagnostic sensitivity and specificity test was used to evaluate the feasibility of urine as source of noninvasive samples compared with cytological samples.

Result:
We were able to detect EGFR exon 21 L858R mutations in 17 of 59 (28,81%) urine samples while 27 of 59 (45,76%) cytological samples were EGFR positive mutations. Agreement between urine and cytological slide was 45.76%. Diagnostic sensitivity and specificity were 22,22% and 65.62% respectively.

Conclusion:
EGFR mutation of lung cancer patients were detected from urine using RFLP methods. In this study, mutation rate in urine (28,81%) was similar to mutation rate from plasma (22%) of Asian Lung cancer patients as described Han, B et al 2015. However, poor sensitivity (22.22%) and specificity (65.62%) of urinary ctDNA L858R analysis may not lead to treatment decision. More in-depth studies focusing on urine collection techniques and more sensitive technology may lead to useful application of urine as an alternative noninvasive liquid biopsy sample for NSCLC detection.

Background:
Non-small-cell lung cancer (NSCLC) patients with activating mutation of epidermal growth factor receptor (EGFR) gene inevitably develop disease progression to EGFR-tyrosine kinase inhibitors (TKIs). T790M gatekeeper mutation accounts for approximately 60% of the acquired resistance, and osimertinib, third generation EGFR-TKI, is effective against such tumors. Demonstration of T790M requires second biopsy, which is inconvenient and sometimes hazardous. Liquid biopsy of circulating tumor DNA (ctDNA) in the plasma is a non-invasive alternative, but clinical relevance of this method is yet to be fully elucidated.

Method:
NSCLC patients with EGFR mutation undergoing 1st- or 2nd-generation EGFR-TKI treatment are monthly or bi-monthly monitored for plasma ctDNA EGFR mutations, including T790M, by Cobas EGFR mutation test® via 10 ml blood sampling. The treatment could be changed on the attending physicians’ discretion, including osimertinib in patients with documented T790M mutation, with continuation of the monitoring. The primary endpoints are T790M positivity rate of ctDNA among patients with tissue-confirmed T790M mutation, and T790M positivity rate of ctDNA at landmark points, such as radiological progression, clinical deterioration or second biopsy of the tumor. The secondary endpoints include EGFR mutation detection rate of plasma ctDNA at landmark points, the interval of tissue and plasma T790M detections, and response rate and progression-free survival in patients treated with osimertinib according to plasma/tissue T790M status.

Result:
From Oct 2016 to Mar 2017, 121 eligible patients were enrolled. The median age 73 years (range, 42-92), 42 male (34.7%), PS 0, 1 and 2 were 64 (52.9%), 54 (44.6%) and 3 (2.5%) respectively. EGFR mutation types were 61 patients (50.4%) del 19, 55 (45.5%) L858R and 5 (4.0%) others. 80 (66.1%) were never smokers. At the time of EGFR-TKI initiation, 82 (67.8%) had advanced and 39 (32.2%) had recurrent diseases. 65 (53.7%) had any prior therapy, including 21 (14.8%) with prior cytotoxic chemotherapy. Used EGFR-TKIs were gefitinib 50 (41.3%), erlotinib 40 (33.1%), and afatinib 31 (25.6%). Newly-diagnosed/on TKI therapy at enrollment was 18 (14.9%)/103 (85.1%). The median follow-up is 12[鈴木1] months. So far, plasma T790M was detected in 8 patients.

Conclusion:
This observational study will elucidate the clinical usefulness and limitations of monitoring of ctDNA for T790M mutation in the real-world setting.

Background:
Osimertinib is an effective, irreversible EGFR-TKI selective for EGFR-TKI-sensitizing (EGFRm) and T790M[+] resistance mutations. Intracranial activity of osimertinib has been reported in T790M[+] patients; however its activity in EGFR-TKI naïve setting has not been investigated yet. Here, we present preliminary data of a phase II study assessing the intracranial activity of osimertinib in EGFRm NSCLC patients with asymptomatic brain metastases as 1[st] line therapy for naïve patients and as 2[nd] line therapy for EGFRm patients who progressed on EGFR TKI and harbor T790M[+]. Dose escalation from 80 mg QD to 160 mg QD was allowed in cases of brain progression.

Method:
A phase II, open label, two arm study is presented. Treatment-naïve (arm A) advanced NSCLC with sensitizing EGFRm and previously treated (arm B) with 1[st] or 2[nd]-generation EGFR TKIs (gefitinib, erlotinib or afatinib) in whom T790M[+] was diagnosed were enrolled to this study. Intracranial response was assessed by brain MRI scans every 6 weeks and systemic evaluation by PET-CT scan every 3 months unttil progression. The study plans to enroll 20 patients in each arm aiming to reach a statistical power of 0.8.

Result:
As of May 31 2017, 22 patients were enrolled; 15 patients in arm A and 7 patients in arm B, age 67.8±10.4 years, 14 females and 8 males. Preliminary outcome analysis is presented for 16 patients with a median follow up of 6.1 months (range 1.4-11.4 months). On May 31[st] 2017 data cut-off was performed. The Intracranial response rate (ICRR) was 81% (13/16 pts); 82% (9/11 pts) in arm A and 80% (4/5 pts) in arm B. Time to response was 6 weeks (1[st] MRI) in all responding patients. Intracranial disease control rate (IDCR) was 81% (13/16 pts) for the current follow up time of 6.1 months; median PFS not reached. Dose escalation was performed in 2 cases and data is not mature yet. Toxicity profile is similar to previous reported data.

Conclusion:
Osimertinib shows a promising intracranial response rate in naïve EGFRm NSCLC patients (82% ICRR) and in 2[nd] line T790M (+) setting with 80% ICRR. This study is still recruiting.

Background:
There has been a marvelous paradigm shift in the diagnosis and management of lung cancer, with the discovery of driver mutations that can be targeted by specific inhibitors. Personalized therapy is driving the demand for mutation testing in cancer. Especially, molecular testing of lung adenocarcinoma for the epidermal growth factor receptor (EGFR) is now considered one of the most important standard of care with other driver mutations. However, sampling tumor tissue other than surgical resection has inevitable limitations. It may be difficult to obtain enough DNA for EGFR mutation test if biopsy tissue was inadequate. There is a promising ctDNA detection technology, that is PANA Mutyper technology, which is a novel technology that integrates PNA clamp and PANA S-melting. We investigated effectiveness of both methods for the detection of EGFR mutation.

Method:
Ninety patients with malignant pleural effusion of lung cancer were enrolled. EGFR mutations were assessed by PANA Mutyper and PNA clamping using tumor tissues, cell blocks, pleural effusions, and bloods separated by serum and plasma. The diagnostic performance of both methods was investigated.

Result:
Among the 90 patients with malignant pleural effusion of lung cancer, 56 patients were adenocarcinoma of lung, 11 were squamous carcinoma of lung, and 17 were small cell lung cancer. PANA Mutyper using bloods showed that 70% sensitivity, 100% specificity, 100% positive predictive value and 83% negative predictive value comparing to the combination of PANA Mutyper and PNA clamping through tumor tissues, cell blocks and pleural effusions (p=0.014).

Conclusion:
PANA Mutyper using bloods had a diagnostic performance for the detection of EGFR mutations in NSCLC that was comparable to that of tumor tissues, cell blocks and pleural effusions. The diagnostic performance of PANA Mutyper was better than that of PNA clamping. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2014R1A2A1A11052422).

Background:
To perform a retrospective analysis of patients with brain metastases (BM) from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) to evaluate the preferred treatment timing of EGFR-tyrosine kinase inhibitors (TKIs) in this population.

Method:
Of 94 initial or recurrent patients diagnosed BM from EGFR-mutant NSCLC between Jan 1, 2012, and Jun 31, 2016, 30 received upfront brain RT followed by EGFR-TKI, 39 EGFR-TKI combined with concurrent brain RT, and 25 upfront EGFR-TKI then brain RT. Disease-specific-graded prognostic assessment was similar among all 3 groups. The primary endpoint was overall survival (OS), and the second endpoint was intracranial progression-free survival.

Result:
Although the median OS was not significantly different among the upfront RT, concurrent treatment, and upfront EGFR-TKI groups (29.0 vs 24.0 vs 17.0 months; P=0.186), however, it was longer in the upfront RT group compared with the upfront EGFR-TKI group (P=0.035). On subgroup analysis, the exon 19 deletions patients had longer OS than the exon 21 mutations patients in upfront EGFR-TKI group (23.0 vs 15.0 months; P=0.048), but the upfront RT (34.0 vs 23.0 months; P=0.186) and the concurrent treatment groups (24.0 vs 13.0 months; P=0.827) did not. According to multivariate COX analysis, KPS (≥ 70) and intracranial metastasis alone was associated with a longer OS. The median intracranial progression-free survival was significantly improved in patients receiving upfront RT compared with those receiving concurrent treatment or upfront EGFR-TKI (not reached vs 40.0 vs 9.0 months; P=0.003).

Conclusion:
The present study suggests that the use of upfront brain radiotherapy, and the deferral of EGFR-TKI may result in superior OS in patients with brain metastases from EGFR-mutant NSCLC. Also, upfront brain radiotherapy management could significantly reduce the risk of intracranial progression. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI then RT versus upfront RT followed by EGFR-TKI is urgently needed, especially based on different subgroup population.

Background:
EGFR T790M mutation is responsible for 50 to 60% cases of resistance to first and second generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in patients who have lung cancer with an activating EGFR mutation.

Method:
We administered osimertinib 80 mg once daily in 11 patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with first and second-line EGFR tyrosine kinase inhibitors.

Result:
We treated 11 patients with osimertinib with stage IV lung adenocarcinoma. Three patients were males and eleven were females, median age 64 (raging from 54 to 82). Seven patients were never smoker, and four were ex-smokers. Ten patients had initially deletion 19 in EGFR gene and one had L858R in exon 21 and then developed T790M mutation. In all patients T790M was proven from tumor tissue. Majority of patients were ECOG 1. All patients were previously treated with first or second line EGFR TKIs (erlotinib, gefitinib or afatinib) and had radiologically documented disease progression. Two patients received osimertinib in 2[nd] line setting, three patients in third line setting, 3 in fourth, one in fifth, one in seventh and one even in tenth line setting. Median time to response was 4 weeks (raging from 3 to 7). All11 patients had partial response (PR) with progressive disease in only one patient after 12 months of treatment. Median duration of response is at the moment 12.5 months, (4 to 60). No significant side effects were observed.

Conclusion:
Osimertinib is highly active in patients with lung adenocarcinoma which harbor EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. Efficacy in Croatian population is similar to previously observed. There were no serious side effects of treatment.

Background:
Next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) enables a non-invasive option for comprehensive genomic analysis of lung cancer patients. In this study, we evaluated the impact of ctDNA sequencing on outcomes and treatment strategy.

Method:
In this retrospective study, data was collected from files of advanced non-small cell lung cancer (NSCLC) patients at the Thoracic Cancer Unit, Rabin Medical Center, Israel, between 2014-2017. Plasma samples were analyzed by a commercial test (Guardant360[TM]), using massively parallel paired-end synthesis to sequence a targeted 68-73 gene panel.

Result:
116 consecutive NSCLC patients were included in this study. Median age at diagnosis was 63 years, 74% had adenocarcinoma. 41% performed ctDNA analysis before 1st line therapy (Group A) and 59% on progression (Group B), among them 41% after progression on EGFR TKIs (Group B1) and 59% on other treatments (Group B2). ctDNA analysis yielded actionable mutations (EGFR, ALK, RET, BRAF, MET, ERBB2 (HER2)) in 40.5%: 31% in group A, 47% in group B, 71% in group B1 and 30% in group B2. Treatment decision was taken toward targeted therapy subsequent to NGS in 26%.

Genetic alterations frequencies among groups A, B, B1 and B2

Group A 19 individual mutations	Group B 52 individual mutations	Group B1 34 individual mutations	Group B2 18 individual mutations
EGFR Sensitizing 52.5% (10/19)	EGFR Sensitizing 42% (22/52)	EGFR Sensitizing 59% (20/34)	MET 55.6% (10/18)
MET 16% (3/19)	MET 27% (14/52)	EGFR T790M 23% (8/34)	ERBB2 16.7% (3/18)
ERBB2 10.5% (2/19)	EGFR T790M 15% (8/52)	MET 12% (4/34)	RET 16.7% (3/18)
BRAF V600E 10.5% (2/19)	ERBB2 8% (4/52)	ERBB2 3% (1/34)	EGFR Sensitizing 11.1% (2/18)
RET 10.5% (2/19)	RET 6% (3/52)	ALK 3% (1/34)
	ALK 2% (1/52)

Response assessment (RECIST) to targeted therapy showed complete response in 4%, partial response in 44%, stable disease in 37% and progressive disease in 15%. Response rate was 44% for group A, 50% for group B, 60% for group B1, 37.5% for group B2. Total objective response rate was 48% and disease control rate was 85%. Overall survival was evaluated for 40%, median was 14.4 months for patients who received targeted therapy vs 13.6 months for patients who received standard treatment.

Conclusion:
Comprehensive ctDNA testing revealed treatment options for 40.5% of patients analyzed. The highest impact was seen in progressors on EGFR therapy. These positive results emphasize the utility of liquid biopsy analysis to guide clinicians to select the most efficacious therapy for each patient.

Background:
To investigate the efficacy of gefitinib combined with recombinant human endostatin (endostar) as a salvage therapy in patients who failure to benefit from gefitinib in previous treatment of advanced non‐small cell lung cancer (NSCLC) due to resistance with T790M mutant negative or unknown.

Method:
Patients with pathologically confirmed stage IV NSCLC who had failed of disease control by gefitinib were retrospectively reviewed. In total, twenty patients were enrolled incluing two patients with squamous disease, eighteen patients were adenocarcinoma. The median age was 61.6, ranging from 43 to 75. After acquired gefitnib treatment resistance, six patients were tested their tumor samples by re‐biopsy and confirmed T790M negative. Fourteen patients refused to re-biopsy, therefore the T790M status were unknow among them. In our analysis, from September 2009 to May 2014, all patients met the selection standards above received endostar (15 mg/day, i.v. day 1‐7, 21 days per cycle) additionally and keep taking gefitinib after preious treatment failure. The efficacy and toxicities of the combined treatment were observed.

Result:
Two patient achieved partial response (PR) (10%) , twelve patients had stable disease (SD) (60%) , six of those patient had progressive disease (PD) (30%) . The objective response rate (ORR) was 10% and the disease control rate (DCR) was 70%. Median progression free survival was 4.2 months (95% CI, 3.21 ‐ 5.19 months) , whereas median OS time was 8.0 months (95% CI, 4.96 ‐ 11.04 months). The results of efficacy accessed in terms of DCR, PFS and OS were not correlated with the sex, age, performance status (PS) score, histologic types or the treatment duration of gefitinib.

Conclusion:
After the failed attempting of gefitnib treatment, the combination of Endostar with gefitinib treatment could stabilize disease in T790M negative or unknown patients, and prolonged their survival time with tolerable toxicities.

Background:
Plasma detection of circulating tumour DNA (ctDNA) with T790M mutation in the context of EGFR tyrosine kinase resistance has been shown to have high concordance with tissue biopsy specimens. In a public healthcare system, patients’ perceived value of a test and willingness to pay can inform policy decisions regarding implementation and funding of a novel technology.

Method:
As part of screening for the ASTRIS clinical trial (NCT02474355), Canadian patients were invited to participate in a national validation study of blood-based ctDNA T790M testing. Eligible patients had acquired resistance to EGFR TKI and consented to collection of blood samples, demographic data, and completion of a structured interview measuring their perceived value of blood-based ctDNA testing as an alternative to tumour biopsy. They were asked about their willingness to pay for testing using both open-ended and iterative bidding approaches. The study was supported by a grant from AstraZeneca.

Result:
60 patients were accrued to the study. Median age of the cohort is 64 years (range 31-87); 69% are Asian (40/58); 55% (33/60) are male. All patients had received prior EGFR kinase inhibitor treatment, with 67% (45/60) receiving gefitinib. 17% of patients also received chemotherapy (10/60). A median of 1 prior line of therapy had been received (range 1-6). All patients preferred to have the blood test over repeat tumour biopsy. Patients estimated a mean reasonable price to pay for the test of $954; median $300 (range 0-10,000; IQR 150-800). Patients were personally willing to pay a mean of $281; median $100 (range 0-2500; IQR 33-350).

Conclusion:
In a public health system that covers the cost of standard diagnostic tests, Canadian patients indicated a willingness to pay out of pocket for peripheral blood detection of ctT790M. Patients have high perceived value of ctDNA and prefer it to tumor biopsy.

Background:
The concomitance of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). We investigated the factors associated with the efficacy of targeted therapy and resistance mechanisms in EGFR/ALK co-altered NSCLCs.

Method:
EGFR mutation was identified with direct sequencing or Scorpion amplification refractory mutation system (ARMS). Relatively low EGFR-mutant abundance is considered as sequencing (-)/ARMS (+), while high abundance as sequencing (+). ALK-positive is assessed with any of the 3 methods: fluorescence in situ hybridization (FISH), rapid amplification of cDNA ends -coupled polymerase chain reaction and sequencing or Ventana immunohistochemistry (IHC). Next-generation sequencing was employed to analyze genetic profiles in patients with specimens before and after targeted therapy.

Result:
From December 2011 to December 2016, sixteen patients were identified with concomitant EGFR/ALK co-alterations, accounting for 0.6% (16/2632) in NSCLC patients, 1.8% (16/867) in EGFR-mutant and 8.6% (16/185) in ALK-positive patients. Five ALK-IHC (-)/FISH (+)/EGFR (+) patients with EGFR-TKIs experienced 3 PR, 1 SD and 1 waitiing for response evaluation, with median PFS of 11 months. Three with relatively low EGFR-mutant abundance achieved PR with crizotinib, while three with relatively high EGFR-mutant abundance obtained 2 PR and 1 SD with EGFR-TKIs. Spatial and inter-tumoral heterogeneity was observed in one EGFR/ALK co-altered patient. (Figure 1B) Two patients with T790M, one with Met pathway activation and two with loss of EGFR mutation were found after resistance to EGFR-TKIs. One with KRAS mutation was found pre- and post-EGFR-TKIs. ALK_F1174C mutation was observed in one patient after progression to crizotinib and ALK_G1202R mutation after resistance to ceritinib.Figure 1



Conclusion:
ALK protein expression, EGFR mutation abundance and tumor heterogeneity were associated with efficacy of targeted treatment for EGFR/ALK co-altered patients. Most mechanisms resistance to EGFR-TKIs and crizotinib were similar to those in typical EGFR mutation and ALK rearrangement respectively.

Background:
Detection of EGFR mutations in circulating tumor DNA using plasma samples is non-invasive and safety method. Cobas EGFR mutation test v2 with tumor tissue has been approved for detection of EGFR mutations to offer EGFR-TKI therapy in Japan. Recently, cobas test v2 using plasma samples at disease progression after prior EGFR-TKI therapy was approved for detection of T790M mutation. However, diagnostic accuracy of this test using plasma samples has not yet known in clinical practice.

Method:
This study is a single-center retrospective study. Between May 2016 and June 2017, we obtained 70 plasma samples from 53 advanced NSCLC patients harboring EGFR mutation in our hospital, and evaluated concordance rate of tissue and plasma EGFR mutation status using sensitivity and specificity. All plasma samples were tested using cobas EGFR mutation test v2.

Result:
70 samples were classified into three cohorts, diagnostic cohort(n=22), continuing response cohort(n=10), and acquired resistance cohort(n=38) by clinical setting. In diagnostic cohort, sensitivity for major mutations was 89%(ex19=100%, L858R=83%, respectively). In all cohorts, sensitivity for major mutations was 70%(ex19=80%, L858R=65%, respectively). T790M detection was evaluated in acquired resistance cohort, sensitivity was 67%, and specificity was 74%, respectively.

Conclusion:
The cobas EGFR mutation test v2 using plasma samples had good accuracy for detection of EGFR mutation in diagnostic setting. On the other hand, there was moderate accuracy for T790M detection in acquired resistance setting.

Background:
Along the past 10 years determination of EGFR mutational status has becoming part of the standard clinical practice for NSCLC patients. It is also acknowledged that median age of NSCLC patients is progresively increasing and nowadays a significant percentage are elderly when diagnosed. The aim of this paper is to analize the characteristics of NSCLC-EGFR-mutated patients that were 75 years or older at diagnosis and assess their survival.

Method:
EGFR-mutated patients with advanced NSCLC treated betweeen June/2010 and June/2016 in our Department were analyzed. The subgroup of those >75 years have been reviewed for assessment.

Result:
Out of the 73 patients with EGFR mutation, 22 (30.1%) were 75 years or older. Median age was 80.5 y (75-86). Performance status: 0 3p, 1 8p, 2 10p, 3 1p. Gender: male 36.4%, female 63.6%. Stage IIIb 18.2%, IV 81.8%. 20p (90.9%) received therapy, all with a TKI (erlotinib, gefitinib or afatinib). The other 2p refused therapy. Median survival was 16 moths (m) (range 1-31). It was greater for patients with PS 0-1 (31m) and for females (32m) vs male (8m). No significant differences existed by stage or TKI. Lnadmark 2-year survival was 18.2% and 3-year 4.5%. These figures were lower than the corresponding for younger patients (median 21 months, 2-y 35.3%, 3-y 13.7).

Conclusion:
A significant percentage of NSCLC with EGFR mutation were older than 75 years. They tended to be more females and slightly worse PS than youger patients. Survival was also lower. These patients merit an specific approach, careful evaluation and follow-up.

Background:
The incidence of CNS metastases among patients (pts) with pulmonary adenocarcinoma harboring EGFR-activating mutations seems to be increasing, probably related to their prolonged overall survival. A multidisciplinary approach, including radiation therapy, surgery and EGFR-TKIs, is absolutely essential for the management of these pts. We aimed to study the effectiveness of this multidisciplinary approach of CNS metastases in pts not previously treated with EGFR-TKis.

Method:
It is a retrospective, uni-institutional study, and all pts were consecutively identified and treated between 2009 and 2017. Eligible pts had to be diagnosed with pulmonary adenocarcinoma harboring EGFR-activating mutations (Sanger sequencing performed in either archived, or new, formalin-fixed and paraffin-embedded samples). CNS involvement was diagnosed based on CT scans, MRI and/or cerebrospinal fluid findings. All studied pts were treated with EGFR-TKIs (erlotinib or gefitinib) and other multimodality therapies including radiation therapy (whole brain or stereotactic radiosurgery), metastasectomy and/or intrathecal methotrexate, based on the decision of the multidisciplinary team.

Result:
35 pts were studied, with a median age 63 y.o. (35-90), being 26 (74%) female, 19 (54%) never-smokers, and 26 (74%) ECOG-PS 0-2. All pts received an EGFR-TKI (erlotinib or gefitinib), and 26 also were treated with radiation therapy, 11 were submitted to surgery, 2 to stereotactic radiosurgery and 1 received IT-MTX; 4/35 were treated with an EGFR-TKI only. Median treatment time with an EGFR-TKI was 7.6 mo. Median progression-free survival (mPFS) was 8.2 mo and the median overall survival (mOS) was 11.9 mo. Among those 25 pts whose tumors were diagnosed with an exon 19 deletion, mPFS was 8.2 mo. and mOS 11.9 mo., and among those 9 pts with L858R mutation, mPFS was 10.8 mo. and mOS 13.8 mo.

Conclusion:
Those pts diagnosed with pulmonary adenocarcinoma harboring EGFR-activating mutations treated with a multidisciplinary approach (including an EGFR-TKI) may derive promising PFS and OS results. The approach must be individualized, considering patient characteristics, tumor biology aspects and also the available healthcare resources.

Background:
Activating mutations in the epidermal growth factor receptor (EGFR) are strongly predictive of EGFR-tyrosine kinase inhibitor (TKI) activity in non-small cell lung cancer (NSCLC). However, primary resistance to EGFR-TKIs occurs in approximately 20-30% of NSCLC patients with EGFR mutations, acquired resistance is inevitable. The aim of study is to discover unknown resistant mechanisms and contribute to more precisely administrate advanced and metastatic NSCLC with EGFR mutations.

Method:
60 NSCLC patients with EGFR sensitive mutation were enrolled this study. All of patients received EGFR-TKI treatment. 21 of patients were primary resistance and 39 acquired resistance according to Jackman standard. Tumor tissues of all of patients were collected before EGFR-TKIs treatment, and rebiopsy tissues were gained after acquired resistance in 39 NSCLC patients. Whole exome sequencing were performed in Illumina HiSeq2000 platform. The captured sequencing data was further processed to identify somatic mutations, including single nucleotide variants (SNVs), short insertions/deletions (indels) and copy number variations (CNVs).

Result:
In primary resistance patients, 13 patients occurred rapid progress (PFS ≤60 days) were put into group 1, and other 8 patients with PFS within 90-180 days were into group 2; in acquired resistance patients, 9 patients were observed long-term clinical benefit (PFS≥540 days) were into group 3; remaining 30 patients with PFS between 180 to 540 days were into group 4. Median PFS were 29, 95, 761 and 311 days from group 1 to 4, respectively. More signaling pathways were activated in group 1, relative to other groups, including bypass activation, downstream signal activation, apoptotic pathways disturbance and EMT activation. Meanwhile, the activation of more signaling pathways were found in samples after acquired resistance compared with paired baseline samples. In all of baseline samples, 60.0% patients harbored TP53 mutations, and these mutations distributed in exon 2,4,5,6,7,8 and 11, respectively. Interestingly, TP53 mutations of 23% patients were in exon 6 in group 1, mutations in exon 5 occurred in 33.3% patients with long-term clinical benefit (group 3). Patients with exon 6 mutation had more shorter PFS than those with exon 5 mutation (105 days vs 284 days).

Conclusion:
For patients resistant to EGFR-TKI, more signal pathways were activation, and the heterogeneity of tumor cloning were complicated. TP53 mutations in different exons may have distinct effect on response to EGFR-TKI of patients with EGFR sensitive mutation.

Background:
IGNITE was a large multi-national, non-comparative, non-interventional diagnostic study whose objective was to in part determine the concordance in EGFR mutation status between tissue/cytology and plasma testing in the real world setting[1]. Locally advanced or metastatic NSCLC patients were enrolled from 9 countries in Asia-Pacific including Russia. A very significant difference was observed in performance of plasma testing in Russia (PPV=39.3%) vs. Asia Pac (PPV=92.5%) vs tissue results with only 51/84 ctDNA EGFR mutation positive results from Russian labs confirmed by the corresponding tissue result. No single lab appeared to contribute predominantly to the questionable overall performance. 1. Han, B et al.; ‘Determining the prevalence of EGFR mutations in Asian and Russian patients (pts) with advanced non-small-cell lung cancer (aNSCLC) of adenocarcinoma (ADC) and non-ADC histology: IGNITE study’ (ELCC 2015 Abstract No. 96O).

Method:
142 of the 941 evaluable plasma samples from Russia were selected to include originally discordant samples and a similar number of concordant positive and concordant negative samples. All samples were shipped to an experienced lab and re-tested for TKI sensitizing mutations using the QIAamp Circulating Nucleic Acid Kit and the Therascreen® EGFR Plasma RGQ PCR test (Qiagen). The central laboratory was blinded to the origin of the samples and original EGFR mutation result.

Result:
Adhering to package insert defined criteria for the internal control, 38 of 112 (34%) of cases were re-classified (19 to pos. and 19 to neg.). By independent clinical laboratory interpretation of the results, 55 of 142 (39%) cases were re-classified (25 to pos. and 30 to neg.). A marked improvement was seen in concordance with the local tissue result after re-testing from 38% to 69% with the false positive rate decreasing from 18.8% to 3.6%. Re-classification of 17 (81%) original ‘false positive’ and 17 (35 %) original ‘false negative’ plasma results validates the original tissue results and appropriate collection and handling of plasma.

Conclusion:
Low concordance between original tissue and plasma EGFR status for the TKI sensitizing mutations observed in the Russian cohort from the IGNITE study was primarily due analytical issues in plasma test methodology. The contribution of the specific analytical process (extraction, testing or analysis) could not be determined. This follow-up study has been communicated back to the Russian laboratories resulting in the appropriate validation and proficiency programs being put in place to ensure quality plasma EGFR ctDNA testing.

Background:
Brain metastases (BM) are a common cause of morbidity and mortality in patients with non-smallcell lung cancer (NSCLC). EGFR-TKIs, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) and chemotherapy are treatment options available. But the optimal management, the combination or sequence, remains undefined. This study evaluated the efficacy of EGFR-mutant NSCLC patients with BM receiving multiple regimens and analyze the prognostic factors.

Method:
We retrospectively studied 45 EGFR-mutated NSCLC patients with BM, who had received EGFR TKIs、radiation therapies (WBRT or SRS) and pemetrexed based chemotherapy successively between 2010 and 2015 at Zhejiang Cancer Hospital. Patient follow-up by telephone was done until January 2016. Treatment response was evaluated and survival data were collected and analyzed.

Result:
Among the 45 patients, 22(48.9%) had an EGFR exon 19 deletion and 23(51.1%) had an EGFR exon 21 L858R mutation. Thirty (66.7%) patients received upfront radiation therapies (RT). 28 patients (62.2%) were treated with pemetrexed based chemotherapy as the first line treatment while 17 (37.8%) received first line EGFR TKIs instead. The median overall survival (OS) from diagnosis of BM was 28.0 months for the whole cohort (95% CI, 17.3-38.7 months). Patients with the exon 19 deletion had a longer median OS than patients with the exon 21 L858R mutation (not reached vs. 23.2 months, P=0.031). There was no difference in OS between the upfront RT group and the deferral group (26.5 vs. 28.0 months, P=0.57), and similar results were found between the first line chemotherapy group and the TKIs group (28.0 vs. 23.2 months, P=0.499). Patients with a higher GPA score showed better survival. In multivariate analysis, the prognosis was correlated with EGFR mutation type (P=0.017). Patients with extracranial metastases showed the strongest trend toward decreased OS, although it did not reach statistical significance (P = 0.070).

Conclusion:
Applying three treatments can significantly improve OS of patients, especially those with EGFR exon 19 deletion. Different sequences of treatments and timing of RT need further studies to identify the optimal treatment model.

Background:
Seveal studies have demonstrated targeting EGFR mutations and tumor angiogenesis simultaneously has synergistic effect in the 1[st] line setting in EGFR mutant NSCLC. However, in JO25567 trial, the ≥grade 3 hypertension incidence with combination therapy was much higher (60%) when compared to historic incidence of hypertension with bevacizumab (10-15%). Considering relatively shorter half-lives for small molecule tyrosine kinase inhibitors, it might be a better choice to combine EGFR TKI and VEGFR TKI when it comes to hypertension management. Fruquintinib is a potent and highly selective oral kinase inhibitor targeting VEGFR and it has demonstrated favorable benefit-to-risk profile in third line treatment in NSCLC patients.Thus it is important to assess safety, tolerability and efficacy of this new combination in the 1[st] line setting in EGFR mutant NSCLC patients. NCT02976116

Method:
This is a single arm, open-label, multi-center study. All patients will receive gefitinib continuously at 250 mg qd. Fruquintinib will be given at 4 mg as starting dose for 3 weeks followed by 1 week off in the first 4-week cycle. Fruquintinib dose can be escalated to 5 mg with the same 4-week cycle if no ≥grade 3 adverse event (AE) or ≥grades 2 liver dysfunction occurs in the first cycle. Treatment continues until disease progression, unacceptable toxicity, or patient withdrawal. The primary objective is to assess the safety and tolerability of this combination. Key eligibility criteria include: histologically or cytologically confirmed NSCLC, ECOG PS 0-1, no prior systematic treatment, no brain metastasis. Key exclusion criteria include: known T790M mutation and bleeding history within 1 month before enrollment.

Result:
As of Jun 20, 2017, 9 patients have been enrolled and received at least one dose of fruquintinib and gefitinib. Six patients had L858R mutations, and three patients had exon 19 deletions. All patients reported AEs, but only one patient (11.1%) had grade 3 proteinuria. No SAE was reported. The most common AEs were increased ALT (3 [33.3%] patients), increased AST (3 [33.3%] patients), increased TBIL (3 [33.3%] patients), proteinuria (3 [33.3%] patients) and rash (3 [33.3%] patients). Fruquintinib dose reduction occurred in 3 patients due to grade 3 proteinuria, grade 2 increased ALT and grade 2 hemoptysis, respectively.

Conclusion:
The study is ongoing. As of the cut-off date, no unexpected toxicities were identified. The combination of fruquintinib and gefitinib showed an expected and manageable preliminary safety profile. Additional patients and follow-up data are required to further confirm the full potential of this combination treatment.