Virtual Library

Abstract:
Complete surgical resection of the tumor is the treatment of choice for Bronchopulmonary Carcinoids (BCs). The goal is to resect the lesion, saving as much lung parenchyma as possible. The type of surgical approach and resection are strictly depend on: a) tumor’s location, b) tumor’s histology and c) presence of lymphnodal metastases. In case of peripheral small BC (Figure 1), the type of surgical resection (wide wedge resection vs segmentectomy or lobectomy) is still matter of debate. Few scientific evidences (1,2) report that a wedge resection could be safely proposed since, in multivariate analysis, long-term survival is not compromised when this approach is used. However, those studies are retrospective, sometimes with limited data on the patients’ follow-up and the number of wedge resections is limited: therefore it is very difficult to draw definitive conclusions with those potential biases. The statement that a wedge resection should be reserved to a small peripheral N0 Typical Carcinoid (TC) seems to be more prudent. An anatomical resection (segmentectomy/lobectomy) should be proposed in case of an Atypical Carcinoid (AC), or whenever the tumor can not be resected in a less invasive manner (e.g: centroparenchymal lesion or when the lobe is totally occupied by the tumor – Figure 2-). The aim to preserve as much lung tissue as possible is the cause of the development of tissue-sparing surgical techniques (the so called “bronchial sleeve resections” and the “sleeve lobectomies”). The first contemplates a bronchial resection with the tumor, without any lung parenchyma exeresis; in the latter, a formal lobectomy with bronchoplastic procedure, is performed to avoid major pulmonary resections (e.g.: bilobectomy or pneumonectomy). An intraoperative frozen section of the bronchial margin has to be performed in all bronchoplastic procedures to confirm that no neoplastic cells are present in the anastomosis (3). Contrariwise, a pneumonectomy should be reserved to patients with a “destroyed lung”, usually caused by long-term obstructive pneumonia, a phenomena caused by an endobronchial tumor growth which completely obstructs the bronchial lumen, or when a tissue sparing resection can not be safely performed. The type of surgical approach (thoracotomy vs. minimally invasive one) must be decided based on tumor’s size and location, as well as the type of surgical resection planned. In general, VATS approach is currently indicated for small and peripheral BCs, while a posterolateral thoracotomy is generally used when a bronchoplastic procedure must be performed. Lymphadenectomy, and in particular, systematic hilar and mediastinal lymphadenectomy, must be always performed, in accordance with the European Society of Thoracic Surgeons (ESTS) recommendations for intraoperative lymph node assessment (4). A minimum of six nodal stations, three of which mediastinal, have to be harvested, including the subcarenal ones. Lymph nodal metastases, in fact, may be present in up to 25% of TCs and in less than 50% of ACs (5,6). In case of N positive (N+) BCs, and whenever feasible, upfront surgery may be proposed: a complete resection (R0) must be performed, whilst debulking interventions are not recommended. A satisfactory overall survival for BCs with lymph nodal metastases has been reported in several papers (7,8): those patients, in fact, survive longer than those with N+ NSCLC. An endobronchial resection (usually through rigid bronchoscopy) has been sometimes advocated for purely endobronchial tumors (3): it is mandatory to determine whether the tumor may present with an extrabronchial growth, in which case a local treatment alone is not sufficient, and should be followed by surgery (with or without bronchoplastic techniques). A palliative endobronchial treatment may be offered to those patients unfit for surgery, in which severe obstructive phenomena caused by the endoluminal tumor growth cause infective and respiratory consequences. Post-resectional tumor relapses may occur approximately in 20% of ACs and in 5% TCs (3,8): the risk of recurrence is strictly dependent from the histologic tumor subtype, the presence of lymph nodal metastases and the completeness of resection (9,10). Most recurrences are distant (liver, adrenal gland, bone), but sometimes, local relapses (lung and/or mediastinum) have also been reported. Surgery, with the same aim of the elective one, may be offered to those patients, improving their survival. REFERENCES 1 Yendamuri S, Gold D, Jayaprakash V, Dexter E, Nwogu C, Demmy T: Is sublobar resection sufficient for carcinoid tumors? Ann Thorac Surg. 2011;92:1774-1778 2 Ferguson MK, Landreneau RJ, Hazelrigg SR, Altorki NK, Naunheim KS, Zwischenberger JB, Kent M, Yim AP: Long-term outcome after resection for bronchial carcinoid tumors. Eur J Cardiothorac Surg. 2000;18:156-61 3 Detterbeck FC: Management of carcinoid tumors. Ann Thorac Surg 2010;89:998-1005 4 Lardinois D, De Leyn P, Van Schil P, Porta RR, Waller D, Passlick B, Zielinski M, Lerut T, Weder W: ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer. Eur J Cardiothorac Surg. 2006;30:787-792 5 Lim E, Yap YK, De Stavola BL, Nicholson AG, Goldstraw P: The impact of stage and cell type on the prognosis of pulmonary neuroendocrine tumors. J Thorac Cardiovasc Surg. 2005;130:969-972 6 Daddi N, Ferolla P, Urbani M, Semeraro A, Avenia N, Ribacchi R, Puma F, Daddi G: Surgical treatment of neuroendocrine tumors of the lung. Eur J Cardiothorac Surg. 2004;26:813-817 7 Filosso PL, Ferolla P, Guerrera F, Ruffini E, Travis WD, Rossi G, Lausi PO, Oliaro A; European Society of Thoracic Surgeons Lung Neuroendocrine Tumors Working-Group Steering Committee: Multidisciplinary management of advanced lung neuroendocrine tumors. J Thorac Dis. 2015;7(Suppl 2):S163-S171 8 Filosso PL, Oliaro A, Ruffini E, Bora G, Lyberis P, Asioli S, Delsedime L, Sandri A, Guerrera F: Outcome and prognostic factors in bronchial carcinoids: a single-center experience. J Thorac Oncol. 2013;8:1282-1288 9 Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, Oberg K, Pelosi G, Perren A, Rossi RE, Travis WD; ENETS consensus conference participants: Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26:1604-1620 10 Öberg K, Hellman P, Ferolla P, Papotti M; ESMO Guidelines Working Group: Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii120-vii123Figure 1 Figure 2

Abstract not provided

Background:
Early detection of LC has been well established as a significant key point for patient survival and prognosis. New sensitive nanoarray sensors for exhaled Volatile Organic Compounds (VOCs) were developed and coupled with powerful statistical programs; diseases such as LC could be suspected.

Methods:
Breath samples were taken from patients who were evaluated for pulmonary nodules, LC patients before treatment and other control patients. 'Breath-prints' were recognized by nanomaterial based sensor array/Artificial Olfactory System (NaNose®) and Pattern recognition methods were used.

Results:
A total of 139 patients participated in this study, 30 patients with benign nodules, 89 LC patients (16 early and 73 advanced disease) and 20 controls. We revealed significant discrimination between all groups with accuracy of 75.6% to 90.9%. Discrimination of LC from benign nodules had 79% accuracy, while benign nodules could be discriminated from early LC lesions with positive and negative predicted values (PPV and NPV) of 87.7 and 87.5% respectively, and accuracy of 87%. Also, we could discriminate LC patients who harbor EGFR mutations (19) from wild-type (34) with an accuracy of 83%, a sensitivity of 79% and a specificity of 85%. Figure 1



Conclusion:
Breath analysis could discriminate LC patients from benign pulmonary nodules and between EGFR positive and negative mutations. In future, a portable, non-expensive, simple and user-friendly device may support evaluation of pulmonary nodules.

Background:
The LuCED test for early stage lung cancer detects rare abnormal cells that are exfoliated from tumors into sputum and promotes cancer case detection with >92% sensitivity and >95% specificity. Additionally, the LuCED test detects endobronchial lung dysplasia to triage patients with pre-cancer to chemoprevention therapy involving drugs such as Iloprost that show potential for reversing dysplasia. This test is complementary to lung cancer screening methods such as LDCT that do not detect dysplasia. We discuss the performance of the LuCED test for the non-invasive detection of endobronchial dysplasia.

Methods:
We analyzed 23,188 normal, 690 cancer, and 65 moderate/severe dysplasia cells from patient sputum. Each individual cell was imaged in 3D using the Cell-CT. Cells were analyzed to measure 594 3D structural biomarkers. Classifiers were developed with cytopathology as the gold standard to predict stages of carcinogenesis, from normal to dysplasia and cancer. The classifier output was binned into two diagnostic indications: 1) cancer vs. all other cell types; and 2) moderate/severe dysplasia vs. all other cell types.

Results:
Areas under ROC curves for the two diagnostic bins were both = 0.993. Thresholds were chosen to yield case specificity >95%. Using these thresholds, cell classification sensitivity of 75% was measured for cancer and dysplasia detection. Since abnormal sputum typically contains at least three abnormal cells the cancer case detection sensitivity is at least {100% x [1 – (1 - 0.75)[3]]} = 98%.Figure 1 Figure 1 shows ROC curves plus examples of cells imaged in 3D by the Cell-CT.



Conclusion:
This study demonstrates the feasibility of using the LuCED test to detect endobronchial dysplasia in the lung, achieving an estimated 98% case sensitivity and 95% case specificity. Future efforts will include testing on independent sets. Importantly, the non-invasive detection of dysplasia by LuCED testing may enable chemoprevention of lung cancer using drugs such as Iloprost.

Background:
LDCT screening for lung cancer often triggers follow-up scans for indeterminate nodules. The non-invasive LuCED test for detection of early stage lung cancer may resolve nodule findings and reduce LDCT false positives. In LuCED, patient sputum is analyzed by the Cell-CT® which computes 3D images of single cells allowing measurement of 3D structural biomarkers to identify potential abnormal cells. Final case disposition is determined through cytology review of these cells. Example images of abnormal cells identified by LuCED are shown in the figure. Figure 1



Methods:
Sputum samples from 127 patients were processed by LuCED: 65 patients had biopsy-confirmed lung cancer; and 62 patients were normal controls. Sensitivity was computed as the percentage of cancer cases where abnormal cells were found by LuCED. Generally, abnormal cells found in a case otherwise understood to be normal could constitute a diagnostic overcall and counted as a false positive. However, a finding of abundant (>5) abnormal cells in cases understood to be normal indicates discovery of a possible occult cancer or dysplastic lesion. Accordingly, these cases were not included in specificity calculations.

Results:
For cancer cases, the histology included adenocarcinoma (29 cases), squamous cancer (24), small cell lung cancer (5) and undifferentiated cancer (7); representing stages 1 (14), 2 (11), 3 (25), 4 (14), and unknown (1). Abnormal cells were found in 61 of 65 cancer cases for sensitivity of 93.8%. For stage 1 and 2 cancer, sensitivity was 88%. Ten cells exhibiting changes consistent with atypical adenomatous hyperplasia were found in one case. After removal, there remained two false positive cases, leading to specificity of 96.7% (N = 61).

Conclusion:
The LuCED test demonstrates accurate detection of early stage lung cancer with the potential of detecting pre-cancerous conditions of the lung. Results suggest that suspicious nodules may be efficiently reconciled by LuCED when used adjunctively with LDCT.

Abstract not provided

Background:
It is uncertain how long persistent and stable ground-glass nodules (GGNs) should be followed although a minimum of 3 years is suggested. Here, we aimed to evaluate the proportion of GGNs showing subsequent growth after initial 3 years among GGNs that had been stable during the initial 3 years, and to determine clinical and radiologic factors associated with subsequent growth.

Methods:
We retrospectively analyzed patients who underwent further computed tomography after the initial 3-year follow-up period showing a persistent and stable GGN (at least 5-year follow-up from initial CT).

Results:
Between May 2003 and June 2015, 453 GGNs (438 pure GGNs and 15 part-solid GGNs) were found in 218 patients. Of the 218 patients, 14 patients had 15 GGNs showing subsequent growth after the initial 3 years during the median follow-up period of 6.4 years. For the person-based analysis, frequency of subsequent growth of GGNs that had been stable during initial 3 years was 6.7% (14/218). For the nodule-based analysis, the frequency was 3.3% (15/453). In a multivariate analysis, age ≥ 65 years (odds ratio [OR], 5.51; p = 0.012), history of lung cancer (OR, 6.44; p = 0.006), initial size ≥ 8 mm (OR, 5.74; p = 0.008), presence of a solid component (OR, 16.58; p = 0.009), and an air bronchogram (OR, 5.83; p = 0.015) were independent risk factors for subsequent GGN growth.Between May 2003 and June 2015, 453 GGNs (438 pure GGNs and 15 part-solid GGNs) were found in 218 patients. Of the 218 patients, 14 patients had 15 GGNs showing subsequent growth after the initial 3 years during the median follow-up period of 6.4 years. For the person-based analysis, frequency of subsequent growth of GGNs that had been stable during initial 3 years was 6.7% (14/218). For the nodule-based analysis, the frequency was 3.3% (15/453). In a multivariate analysis, age ≥ 65 years (odds ratio [OR], 5.51; p = 0.012), history of lung cancer (OR, 6.44; p = 0.006), initial size ≥ 8 mm (OR, 5.74; p = 0.008), presence of a solid component (OR, 16.58; p = 0.009), and an air bronchogram (OR, 5.83; p = 0.015) were independent risk factors for subsequent GGN growth.

Conclusion:
For the individuals with GGNs having risk factors described above, the longer follow-up period is required to confirm subsequent GGN growth.

Background:
The high number of false positive screen results is a major disadvantage of lung cancer screening by low-dose chest computed tomography (CT). Measurement strategy influences the false-positive rate, and nodule morphology may influence measurement of nodule size. Comparison between inter-reader variation for semi-automatic volume measurements and manual diameter measurements are scarce. Therefore, we aimed to evaluate the influence of nodule morphology on inter-reader variability and assessment of growth for semi-automatic volume measurements and manual diameter measurements, in intermediate-sized solid nodules found in CT lung cancer screening.

Methods:
Twenty-five nodules of each morphological category: smooth, lobulated, spiculated and irregular, were randomly selected from 93 participants of the Dutch-Belgian randomized lung cancer screening trial (NELSON). Semi-automatic volume measurements were performed using Syngo LungCARE[®] software. Two chest radiologists independently measured maximum and mean diameters manually. The impact of nodule morphology on inter-reader variability was evaluated based on the systematic error and 95% limits of agreement (LoA). Inter-reader variability was compared to volume change cutoff at 3-month follow-up based on NELSON for nodule growth and Lung-RADS diameter cutoff.

Results:
For manual diameter measurements, a significant systematic deviation was found between readers in smooth, lobulated, and spiculated nodules. The deviation was up to 1.5 mm based on maximum diameter measurements, and 1.2 mm based on mean diameter measurements. For semi-automatic volume measurements, no statistically significant systematic deviation was found. For lobulated, spiculated, and irregular nodules, the 95%-LoA for mean diameter measurements was up to 66% larger than the 1.5 mm cutoff for nodule growth. For volume measurements, the 95%-LoA exceeded the 25% growth cutoff for spiculated and irregular nodules, but only by up to 12%.

Conclusion:
Nodule morphology has a greater effect on size assessment based on manual diameter measurements than based on volume measurements. The larger inter-reader variability for manual diameter measurement may cause misclassification of spiculated nodules when assessing growth in 24% of cases. Therefore, semi-automatic volume measurement is recommended for nodule size and growth determination in CT lung cancer screening.

Abstract not provided

Background:
Low Dose Computed Tomography (LDCT) screening for lung cancer (LC) is still not recommended in Europe.

Methods:
71.232 invitation letters were sent to subjects registered with local General Practitioners, aged 55­69 years. (Fig.1) From eligible respondents, we randomised 3206 eligible subjects, smokers and ex- smokers (< 10 years), to the active arm receiving 4 annual LDCT (n=1613) and to control arm receiving usual care (n=1593). Each LDCT was read by 2 radiologists and size of Non Calcific Nodules measured manually. Study design and performance data were already published. All subjects, enrolled from 2004-2009,were followed up for lung cancer incidence and mortality (average: 8.3 and 9.3 years, respectively); characteristics of enrolled subjects are presented in Table1. Figure 1Figure 2





Results:
Reductions of 17% (RR=0.83; 95%: 0.67-1.03) for overall and 30% (RR=0.70; 95%CI: 0.47-1.03) for LC-specific mortality were estimated. 67 lung cancers were diagnosed in the active, compared with 72 in the control group (RR=0.92; 95%CI: 0.66–1.28). A greater proportion of Stage I (36% vs 6%, (p<0.0001) was observed in the active group.

Conclusion:
LDCT screening could reduce LC-specific and overall mortality. The number of Lung cancer diagnosed in the two groups did not suggest over-diagnosis, after 8.5 years of follow-up time.

Background:
In BRELT1 we found a significant number of low dose CT (LDCT) considered positive (nodules > 4mm). The aim of this study was to assess the effect of applying ACR Lung-RADS and Pre-Test Probability of Malignancy (PTPM) in suspicious nodules > 8mm founded in a clinical CT lung screening program.

Methods:
Clinical LDCT (baseline and follow up) containing nodules > 8mm were retroactively reclassified using the new ACR Lung-RADS™ structured reporting system and PTPM. The model used in this study to predict the probability of malignancy was designed by Swensen et al and included patient’s age, current or former smoker, diameter of the nodule, speculation and location. All LDCT had initially been interpreted by radiologists accredited in CT lung screening reporting following the National Comprehensive Cancer Network’s Clinical Practice Guidelines in Oncology: Lung Cancer Screening (version 1.2012), which considered as positive the same criteria from the National Lung Screening Trial.

Results:
In BRELT1 were recruited 790 current or former smokers, with a heavy smoking history. A total of 552 nodules were found in 312 positive LDCT at baseline (39%). LDCT follow up was performed in 89.1% of this population. From them 74 patients presented solid or semi solid nodules > 8mm in the highest diameter. According to ACR Lung-RADS™ 39 baseline LDCT were classified as 4A (52.7%), 6 as 4B (8.1%), 17 as 4X (22.9%) and 10 as 2 (13.5%). Follow-up LDCT showed reduction in the category in more than 80% of cases. Using the PTPM, 44 cases were considered at moderate risk (between 6 and 60%) and 30 cases of high risk for malignancy (over 60%). None was considered low risk (5% or less). Among 26 patients who underwent biopsy in BRELT1, we found 12 cases of lung cancer, of which 90% were stage IA or IB.

Conclusion:
The application of ACR Lung-RADS and PTPM associated with careful multidisciplinary assessment can help in the decision process. The follow-up of patients with positive nodules requires careful analysis of the main factors related to malignancy.

Background:
Lung cancer is the leading cause of cancer deaths both in men and women in either Wielkopolska and the whole Poland. Wielkopolska is one of Polish regions (voivodships) with about 3,4 mln inhabitants and incidence of lung cancer aprox. 1900 new cases every year. Screening by low dose computer tomography (LDCT) showed reduction of lung cancer mortality in NLST trial. Regional authorities covered this program from local budget beside Polish health system.

Methods:
Since october 2009 program of early detection of lung cancer started in 5 centers of Wielkopolska region. Till the end of 2015 N=17222 subjects were screened. The entry criteria were: age between 55 and 70 years and smoking ≥ 20 packyears. Every person has the LDCT performed. Results were first clasified as normal or abnormal. Abnormalities were divided into 6 categories: <5mm single, <5 mm multiple, 5-15 mm single, 5-15 mm multiple, >15 mm single, >15 mm multiple. Patient received also recomendation for further actions. Results presented are based on annual reports for regional authorities.

Results:
More than 85% of the images were clasified as abnormal. Nodes of any kind were found in about 47% of entire population. More than 3000 patient received recomendation for further diagnostic evaluation. Finally 108 patients underwent surgery (37 lobectomies, 41 wedge resections, 30 thoracotomies/thoracoscopies). There were 92 cases of lung cancer confirmed (11 SCLC, 78 NSCLC, 3 carcinoids) and 1 case of mesothelioma.

Conclusion:
Lung cancer screening program identifies magnitude of lung changes. Many patients requires further diagnostic procedures. Most of them are fibrotic, post inflammatory changes. It is possible to diagnose lung cancer in early presymptomatic stage but numbers are low and risk models or biomarkers should be implemented to better define patients / nodules at risk.

Abstract not provided

Background:
The balance of benefits and harms of screening programs depends on multiple factors such as the scenario of patient selection, the triage algorithm and the imaging methods. Because of the multifactorial nature of the outcome of screening programs, it is important to evaluate the performance of its components. We modeled the triage algorithm of the NELSON program for lung cancer screening in different scenarios in order to assess the robustness of the chosen approach. We are looking to develop a model that allows for testing the imaging protocol performance using various high-risk screening populations. Our Objective is to work out a simulator adaptive to multiple screening scenarios. In a first step, we tested a simulation of the NELSON triage algorithm by using published statistics as input data: the distribution of nodule size, the precision of nodule volume measurements and the distribution of nodules growth.

Methods:
We modeled the baseline round of NELSON triage algorithm. We simulated 10,000,000 ground truth (GT) data where the axial diameter of nodules followed a chi2 (df=1) distribution between 3 mm and 20 mm. For each of the GT nodule, we modeled also a chi2 (df=1) distribution of volume doubling time between 90 and 1000 days. We included into the model a Gaussian distribution of the time between visits (average: 105 days, standard deviation: 5 days). We modeled volume measurement of the nodules by adding a Gaussian random error as documented by the Quantitative Imaging Biomarker Alliance (QIBA) screening profile. We performed a by-nodule comparison between nodule classification by the triage algorithm and the corresponding GT in the first round. At each step of the triage algorithm, we evaluated Sensitivity (Se), Specificity (Sp), Positive Predictive Value (PPV) and Negative Predictive Value (NPV).

Results:
Sensitivity of the triage algorithm for classifying nodules into size categories was for 96,6% for NODCAT2, 86.9% for NODCAT3 and 90.7% for NODCAT4. Classification of GROWCAT C yielded Se=66.2% / Sp=21.2%. We found an overall performance of the NELSON triage algorithm of Se/Sp 94.0%/80.3%.PPV was 11.3%, and NPV was 99.8%

Conclusion:
Mathematical modeling gives valuable insights into the performance of different components of triage algorithms in lung cancer screening. We found a markedly different test performance for size versus growth assessment of the NELSON triage algorithm. Future work will extent the model to non-solid nodules and multiple rounds of screening. Moreover, it may have the potential to optimize triage algorithms in the design of screening programs.

Background:
Based on two single-arm, multicentre, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]), the FDA approved the ALK inhibitor alectinib for use in ALK+ NSCLC patients after prior crizotinib. Alectinib was well tolerated in both phase II studies and showed efficacy against both systemic and central nervous system (CNS) disease, the latter being a common progression site in ALK+ NSCLC. This analysis uses pooled data from the latest cut-offs (22 Jan 2016 for NP28761; 1 Feb 2016 for NP28673) to examine the long-term CNS efficacy of alectinib.

Methods:
Both studies enrolled crizotinib-refractory patients ≥18 years with ECOG PS 0–2 and locally advanced or metastatic ALK+ NSCLC (confirmed by FDA-approved test). CNS metastases were permitted if asymptomatic. Patients received 600mg oral alectinib BID. The primary endpoint in both studies was objective response rate (ORR) by independent review committee; secondary CNS endpoints included CNS ORR, CNS duration of response (DoR), and CNS disease control rate (DCR). CNS response and progression were determined by RECIST v1.1. All patients had baseline imaging to assess CNS metastases, with further imaging every 6 or 8 weeks for NP28761 and NP28673, respectively.

Results:
The overall pooled analysis population comprised 225 patients (n=87 from NP28761; n=138 from NP28673); median follow-up for this updated analysis was 18.8 (0.6–29.7) months (>6 months additional follow-up). At baseline, 50 patients had measurable and 86 had non-measurable CNS disease; together, these groups comprised 136 patients, 60% of the overall pooled population. Seventy percent of patients had prior CNS radiotherapy; 58% of these completed radiotherapy >6 months before study entry. Updated CNS data are shown in the Table and are consistent with systemic results.

	Measurable CNS disease at baseline (n=50)	Measurable and non-measurable CNS disease at baseline (n=136)
CNS ORR, n (%) [95% CI]	32 (64.0) [49.2–77.1]	60* (44.1) [35.6–52.9]
Complete response (CR), n (%)	11 (22.0)	39* (28.7)
CNS DCR, n (%) [95% CI]	45 (90.0) [78.2–96.7]	117 (86.0) [79.1–91.4]
Median CNS DoR, months [95% CI] Patients with event, n (%)	11.1 [7.6–NE] 18 (56.3)	13.8 [11.0–21.5] 32 (53.3)
* N.B. Non-measurable disease response can only be classified as CR, non-CR/non-progressive disease (PD) or PD

Conclusion:
This updated pooled analysis with mature data confirms that alectinib can provide long-term control of CNS metastases in ALK+ NSCLC, with a high CR rate.

Background:
Alectinib, a CNS-active and highly selective ALK inhibitor, has efficacy in patients with ALK-positive NSCLC with and without previous crizotinib treatment. Updated efficacy and safety from the alectinib phase 2 North American NP28761 study (NCT01871805) of patients with ALK-positive NSCLC previously treated with crizotinib, with 15 months’ additional follow-up from the primary analysis and 9 months’ additional follow-up from the previous analysis are presented.

Methods:
Patients ≥18 years old with ALK-positive NSCLC (FDA-approved FISH test), disease progression following crizotinib, and ECOG PS ≤2 were enrolled. Patients received oral alectinib (600mg) twice daily until progression, death or withdrawal. Primary endpoint: overall response rate (ORR) by independent review committee (IRC; RECIST v1.1.) Secondary endpoints: investigator-assessed ORR; progression-free survival (PFS); overall survival (OS), CNS ORR (CORR); disease control rate (DCR); safety.

Results:
At the updated cut-off (22 January 2016) an additional 15 months' follow-up from the primary analysis, 87 patients were enrolled. Median follow-up: 17.0 months (range 1.1–28.6). ORR in the response evaluable population (REP; n=67) by IRC: 52.2% (95% CI 39.7–64.6), median duration of response: 14.9 months. Median PFS and OS: 8.0 and 22.7 months, respectively. Table 1 presents other efficacy endpoints. Grade ≥3 AEs were reported in 41% of the safety population (n=87); most common: elevated levels of blood creatine phosphokinase (8%), alanine aminotransferase (6%), aspartate aminotransferase (5%). Two patients withdrew due to AEs; 28% had AEs leading to dose modification/interruption. Mean dose intensity was 92.0%.

IRC REP Responders, n CR, n (%) PR, n (%) SD, n (%) PD, n (%) Missing/NE, n (%) DCR, % (95% CI)	n=67[*] 35 0 (0) 35 (52.2) 18 (26.9) 11 (16.4) 3 (4.5) 79.1 (67.4,88.1)
Investigator REP Responders, n ORR, % (95% CI)	n=87 [46[†]] 52.9 (41.9, 63.7)
Measurable baseline CNS lesions (IRC)‖ Responders, n CORR, % (95% CI) Measurable/non-measurable baseline CNS lesions (IRC) Responders CORR,[‖] % (95% CI)	n=16 12[‡] 75.0 (47.6, 92.7) n=52 21[§] 40.4 (27.0, 54.9)

*n=20 did not have measurable disease per IRC and were not included in the IRC REP; [†]2 CR;[ ‡]4 CR;[ §]13 CR; [‖]non-measurable disease classified as CR, non-CR/non-PD or PD; NE=not evaluable/estimable

Conclusion:
Alectinib demonstrated durable responses, encouraging OS findings, good tolerability and an acceptable safety profile consistent with previous reports in this update of the NP28761 study with extended follow-up.

Background:
ALK inhibitors are the standard treatment for ALK+ NSCLC and the comparison between 2 ALK inhibitors will be valuable in determining therapeutic strategy for ALK+ NSCLC patients (pts). We conducted the randomized open-label Phase III trial designed to prove the superior PFS of ALC to CRZ in ALK-inhibitor naïve ALK+ NSCLC.

Methods:
ALK+ NSCLC pts were randomized 1:1 either to receive ALC (300 mg b.i.d.) or CRZ (250 mg b.i.d.) and stratified by ECOG PS (0/1 vs 2), treatment line (1[st] vs 2[nd]), and clinical stage (IIIB/IV vs recurrence). Primary endpoint was PFS according to the blinded independent review board. Secondary endpoints included overall survival, objective response rate, and safety. Under an assumption of expected hazard ratio (HR) of 0.643, 164 events were required to have 80% power with 2-sided alpha of 0.05. Three interim analyses (IA) for early stopping due to efficacy were planned after 33%, 50%, and 75% of required PFS events occurred.

Results:
207 pts were enrolled at 41 centers in Japan between November 2013 and August 2015. Independent data monitoring committee recommended the release of study data because the superiority in PFS had been demonstrated for ALC based on second IA. The PFS HR of ALC arm to CRZ arm was 0.34 (99.6826% CI: 0.17-0.70, stratified log-rank p<0.0001). Median PFS was not reached (95% CI: 20.3-Not Reached (NR)) in ALC arm while it was 10.2 months (95%CI: 8.2-12.0) in CRZ arm. ALC demonstrated favorable result of PFS in each sub-group for instance, treatment line (1[st] line: HR = 0.30, ALC: NR vs CRZ: 10.2 months, 2[nd] line: HR = 0.39, ALC: 20.3 months vs CRZ: 8.2 months), brain metastases at baseline (yes: HR = 0.08, ALC: NR vs CRZ: 10.2 months, no: HR = 0.39, ALC: 20.3 moths vs CRZ: 10.0 months) and clinical stage (stage IIIb/IV: HR = 0.31 ALC: 20.3 months vs CRZ: 8.3 months, recurrence: HR = 0.49, ALC: NR vs CRZ: 11.6 months). Grade 3-4 AEs (ALC: 26% vs CRZ: 52%), discontinuation of study drug due to AEs (ALC: 9% vs CRZ: 20%) and dose interruptions due to AEs (ALC: 29% vs CRZ: 74%) occurred with lower rate in the ALC arm. There were no treatment-related deaths in either arm.

Conclusion:
ALC demonstrated prolonged PFS compared with CRZ in all sub-groups with a favorable AE profile representing a potential new standard treatment for 1[st] line ALK+ NSCLC pts.

Abstract not provided

Background:
ROS1 rearrangements are present in the tumors of 1-2% of patients with lung adenocarcinoma (LAD). This patient subgroup is characterized by non-smoking history and younger than average age compared to the overall NSCLC population. In a phase I trial the ALK/ROS1/MET inhibitor crizotinib has shown to be highly effective in these patients (NCT00585195). EUCROSS is a prospective phase II trial of the Lung Cancer Group Cologne in collaboration with the Spanish Lung Cancer Group to evaluate crizotinib in ROS1-positive LAD. Here, we present preliminary data on efficacy and safety.

Methods:
Patients with advanced LAD harboring ROS1 rearrangements as confirmed by central FISH were eligible for the trial irrespectively of the number of prior treatment lines. Patients received treatment with crizotinib 250 mg BID - doses were adapted for management of AEs. Trial design: Fleming’s single stage phase II design. Primary endpoint: ORR (95% CI, H~0~: ORR≤20% vs. H~1~: ORR>20%). Secondary endpoints: a.o. PFS, OS and safety. All efficacy endpoints were assessed by investigator’s RECIST v1.1 and will be analyzed by IRB at a later stage. Baseline tumor tissue was analyzed by DNA-sequencing to identify the translocation Partners of ROS1, to validate FISH results and to identify additional biomarkers for prediction of response. Data-cut off for this report was March 2016.

Results:
In total, 34 patients were enrolled in EUCROSS at the time of data cut-off. Twenty-nine patients were eligible for efficacy assessment. Tumor tissue of 20 of these patients was suitable for further sequencing - 18 were sequenced positive for ROS1 fusion. The fusion partners involved were CD74 (N=9;50%), EZR (N=4;22%), SCL34A2 (N=3;17%), TPM3 and SDC4(N=1;6% each). The investigator assessed ORR was 69% (95% CI, 49.1-84.3) in the overall trial population and 83% (95% CI, 67.7-94.2) in the ROS1-positive by sequencing population (N=18;P=0.324 for difference of ORR). Three patients (10.3%;95% CI, 3.6-26.4) exhibited primary progression, two of them were sequenced ROS1-negative. All patients were included in the safety population (N=34). Most common AEs irrespectively of relatedness or grade were visual disorders (N=16;48%), edema (N=14;41%), diarrhea (N=13;38%) and bradycardia (N=11;32%).

Conclusion:
Crizotinib is a highly effective and safe treatment in the subset of ROS1 rearranged NSCLC patients as determined by FISH and DNA-sequencing. Although, the number of patients with tissue available for sequencing was low at the time of data cut-off, sensitivity and specificity support sequencing as the potential new gold-standard for the identification of clinically relevant ROS1 gene-rearrangements.

Background:
Crizotinib is an orally active inhibitor of receptor tyrosine kinases effective in NSCLC with ALK rearrangement. Recent data showed that this agent is dramatically effective in patients with ROS1 rearrangement and at least in some patients with MET deregulation, particularly individuals with exon 14 skipping mutations or with high levels of MET amplification.

Methods:
The METROS trial is a multicenter prospective phase II study designed to assess the efficacy and safety and tolerability of Crizotinib in pretreated metastatic NSCLC with MET amplification or MET exon 14 mutation or ROS1 rearrangement. The co-primary end-point was response rate to crizotinib in two cohorts of patients: cohort A) ROS1+: patients with ROS1 rearrangement; B) MET+: patients with MET amplification defined as ratio MET/CEP7 >2.2 on FISH testing or MET exon 14 skipping mutations. Eligible patients were treated with with crizotinib at the standard dose of 250 mg BID p.o.

Results:
At the time of the present analysis, preliminary data on the MET cohort are available. A total of 249 patients were screened and 18 resulted as MET+ (12 amplified and 6 mutated). Among them, 10 patients (9 amplified and 1 mutated) were included onto the study and received at least one dose of crizotinib, 6 patients were not eligibible beacause of not progressing to front line therapy, whereas 2 patients did not received crizotinib due to rapidly progressive disease. Characteristics of enrolled patients were: median age 68 years (range 39-77); male/female 8/2; ECOG PS 0/1/2: 6/3/1. In 8 cases crizotinib was offered as second-line therapy. All but one patients were current or past smokers. According to RECIST criteria, 2 partial responses and 4 stable disease were so far documented, with an overall disease control rate of 60%. Three patients are still on treatment. Therapy was generally well tolerated, with only 1 patient delaying therapy due to adverse events. Enrollment is still ongoing.

Conclusion:
Preliminary analysis of the METROS trial supports the potential efficacy of crizotinib in patients with MET deregulation, with a favorable toxicity profile. Updated results including median progression-free survival and survival were will be presented at the meeting.

Background:
ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC.

Methods:
We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization (FISH). ROS1 immunohistochemistry (IHC) and next-generation sequencing (NGS) was performed in available tumor samples. Ceritinib 750mg was administered once daily and the primary endpoint was objective response rate (ORR) by central independent radiologic review. The secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), toxicity and concordance between FISH and IHC. ROS1 fusion partners were identified with the use of next-generation sequencing (NGS) in available tumor samples.

Results:
Between June 7, 2013, and February 1, 2016, a total of 404 patients underwent ROS1 prescreening, and 32 ROS1+ (by FISH) patients were enrolled. All patients except two (who did not respond to ceritinib) were crizotinib naïve. The median age of all patients was 62 years, and there were 24 females (75%). The majority of patients (84%) were never smokers, and all had adenocarcinoma histology. The median number of previous treatments before study enrollment was 3 (range, 2-7) and 17 (53%) patients had received three or more lines of chemotherapy. At the time of the data cut-off (April 18, 2016), the median follow-up was 7.5 months, and 15 (47%) patients had discontinued treatment. Of the 32 patients enrolled, 28 patients were evaluable for response by independent radiologic review. ORR was 63% (95% CI, 45.7-79.3), with 1 complete response and 19 partial responses. The median duration of response was 10.0 months (range, 0.4+-18.4+). Among 11 tumors that were tested by NGS, we identified 7 ROS1 fusion partners including ROS1-CD74, ROS1-SLC34A2, and ROS1-EZR. The median progression-free survival was 19.3 months (95% CI, 7.2-not reached), with 17 (53%) patients still in follow-up for progression. The median overall survival was not reached at the time of the data cut-off. Of 5 patients with retrospectively confirmed brain metastases, intracranial disease control was reported in 4 patients (80%). Gastrointestinal adverse events (vomiting, nausea, diarrhea) mostly grade 1-2, were the most frequent adverse events (80%); these events were manageable.

Conclusion:
Ceritinib demonstrated potent clinical activity in patients with advanced, ROS1-rearranged NSCLC, who received at least one prior line of platinum-based chemotherapy. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which ceritinib is highly active (ClinicalTrials.gov number, NCT01964157).

Abstract not provided

Background:
Drug resistance emergence is a daunting obstacle that limits long-term outcome benefits in precision cancer therapy. Mechanism of the initial emergence of molecular tumor resistance is still not fully understood. Recently, we identified an early precision drug escape mechanism with adaptive tumor cellular reprogramming emerging within days after drug initiation. Here we present a mass spectrometry imaging (MSI) approach to profile the biomolecular changes emerging within residual drug resistant tumor cells under precision ALK inhibitor (ALK-i) treatment.

Methods:
EML4-ALK fusion (ALK+) H3122 lung adenocarcinoma xenograft as well as an ALK+ patient biopsy-derived cell line (Ma-ALK001.S) were adopted for the MSI studies. MSI was carried out on FFPE tissues to compare peptide profiles between control tumors and 7- and 14-day ALK-i treated tumors using a histology guided mass spectrometry approach. Additionally, frozen control and ALK-i treated tumors were subjected to full section MSI to determine the ALK-i drug distribution as well as the changing landscape of lipids and metabolites. In parallel, Ma-ALK001.S cell line was treated with alectinib (ALK-i) in culture with samples collected at 0 hr, 8 hr, 3 days, 7 days, and 14 days. Cells were subjected to both MALDI-MS profiling analysis and Laser Ablation Electrospray Ionization (LAESI)-MS analysis. Statistical analyses were performed using MarkerLynx and SCiLS.

Results:
ALK+ H3122 lung adenocarcinoma murine xenograft model in vivo under treatment with/without ALK-i TAE684 was used in MSI studies at treatment day 0, day 7 and day 14, during tumor response. Pairwise and 3-way Wilcoxon rank sum tests were carried out and a Bonferroni correction applied. The greatest number of significant peaks were observed between day 0 and day 14 (677). Pairwise linear discriminant analysis classification algorithm models were generated resulting in over 94% classification accuracy in all comparison. Direct MS/MS fragmentation revealed that ALK-i was detected within the frozen ALK-i dosed tumors in early drug-escape. Several lipids were identified to expression landscape changes emerging under ALK-i. Biomolecular (peptides, lipids, and metabolites) profiling of Ma-ALK001.S cell line using combined MALDI and LAESI MSI analysis was successful, which provided novel insights into the early mechanisms of molecular drug resistance emergence.

Conclusion:
MSI allowed for direct in situ determination of the evolving expression landscape of biomolecules in ALK+ lung cancer under ALK-i precision therapy. These results provide a rationale to advance our MSI profiling studies for biomarkers discovery to gain deeper insights into molecular mechanisms of adaptive precision drug resistance emergence.

Background:
ALK rearrangement, most commonly EML4-ALK, is detected in approximately 3–7% of non-small cell lung cancer (NSCLC). Crizotinib, an ALK tyrosine kinase inhibitor (TKI), shows dramatic clinical efficacy in ALK-rearranged NSCLC patients. However, almost all patients acquire resistance after only 1 to 2 years. A variety of mechanisms, including ALK-secondary mutations, ALK amplification, and activation of alternative pathway, have been reported to mediate acquired resistance to crizotinib. While epithelial–mesenchymal transition (EMT) was recently reported to be associated with resistance to crizotinib in EML4-ALK lung cancer cells in vitro, the underlying mechanism has not been defined and no optimal therapy to overcome EMT-associated resistance has been identified.

Methods:
We continuously gave crizotinib treatment to SCID mice inoculated with EML4-ALK lung cancer cell line A925L into thoracic cavity and established crizotinib resistant A925LCR cells. After the limiting dilution of A925LCR cells, we obtained several single cell clones. The effects of the HDAC inhibitor quisinostat on the EMT state and the growth of the cells were examined in vitro and in vivo.

Results:
We found that some clones acquired EMT phenotypes, such as spindle shape morphology, expression of EMT-related proteins, and increased cell motility. Interestingly, Histone deacetylase (HDAC) inhibitor, quisinostat, induced mesenchymal-epithelial transition (MET) of A925LCR clones in vitro. Quisinostat reduced ZEB1 expression, induced MET, and thus restored sensitivity to crizotinib. Knockdown of ZEB1 expression in the A925LCR clones by si-RNA also induced MET and restored sensitivity to crizotinib, suggesting that quisinostat-induced MET depends on ZEB-1 suppression. MicroRNA profile analysis revealed that the A925LCR clones expressed significantly lower levels of miR-200 family including miR-200c which targets ZEB1, compared with parental A925L cells. Furthermore, quisinostat recovered miR-200c expression and antago-miR-200c abrogated quisinostat-induced MET in the A925LCR clone cells. These results indicate that quisinostat induced MET by up-regulating miR-200c expression which target ZEB1 and thereby re-sensitizing to crizotinib. In a pleural carcinomatosis model with A925LCR clone cells, quisinostat induced MET and caused remarkable tumor regression during the subsequent crizotinib re-challenge. Furthermore, we analyzed tumor tissue obtained at autopsy from an ALK-rearranged NSCLC patient who acquired resistance to crizotinib. We found that EMT was induced in both primary and metastasis lesions after crizotinib treatment, indicating that EMT is associated with crizotinib resistance in clinical therapy.

Conclusion:
Our findings suggest that EMT is possibly occurred in acquired resistance to crizotinib and intermittent use of HDAC inhibitor could be a novel therapeutic strategy for overcoming EMT-associated crizotinib-resistance in EML4-ALK lung cancer.

Background:
Patients with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) NSCLC often become resistant to tyrosine kinase inhibitor (TKI) therapy; central nervous system (CNS) relapse is common. Lorlatinib is a selective brain-penetrant ALK/ROS1 TKI, active against most known resistance mutations.

Methods:
In Ph I of the ongoing Ph I/II study NCT01970865, patients had ALK+ or ROS1+ NSCLC ± brain metastases and were treatment naïve or had disease progression after ≥1 TKIs. Patients received lorlatinib on day –7 and then once or twice daily from day 1. Primary objective was identification of MTD and recommended Ph II dose (RP2D). Other objectives were safety and efficacy by RECIST v1.1 including intracranial activity.

Results:
Of 54 patients treated in Ph I (cutoff Jan 15, 2016), 41 were ALK+, 12 ROS1+, and 1 had mutation status unconfirmed for ALK+ or ROS1+. Patients were heavily pretreated: 27 had received ≥2 prior TKIs and 20 had 1 prior TKI; 39 patients had CNS metastases at baseline. Patients were treated across 10 dose levels (total daily dose of 10–200 mg). Response rates were:

	N	CR	PR	uCR	uPR	Overall RR (CR + PR)
		n (%)
ORR in ALK+ and ROS1+	53	3(6)	22(42)	-	1(2)	25(47)
ORR in ALK+ with 1 prior TKI	14	1(7)	7(50)	-	-	8(57)
ORR in ALK+ with ≥2 prior TKI	26	2(8)	9(34)	-	1(4)	11(42)
IC ORR (target + non-target lesions) in ALK+ and ROS+	39	10(26)	4(10)	1(3)	2(5)	14(36)
IC ORR (target lesions) in ALK+ and ROS+	23	7(30	4(17)	-	2(9)	11(47)
ORR, objective response rate; IC ORR, intracranial objective response rate; CR, complete response; PR, partial response; RR, response rate; u, unconfirmed

Median duration of response was 10.5 months (95% CI 2.9– not reached [NR]) and 12.4 months (95% CI 6.5–NR) for ALK+ and ALK+/ROS1+ pts, respectively. 26 patients remain on treatment. The most common treatment-related adverse events (TRAEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade ≥3 TRAE. No patient discontinued due to a TRAE. Analyses of ALK resistance mutations in archival tumor tissue and plasma circulating free DNA collected before lorlatinib treatment are ongoing.

Conclusion:
Lorlatinib was well tolerated and demonstrated durable responses, including intracranial responses, in ALK+ and ROS1+ NSCLC, most of whom had CNS metastases and ≥1 prior TKIs. The RP2D was identified as 100 mg once daily. Ph II is ongoing.

Abstract not provided

Background:
Brain metastasis in non-small cell lung cancer (NSCLC) develop in 20-40% of all patients and represent a major cause of NSCLC morbidity and mortality. The mechanisms driving metastatic potential across the blood-brain-barrier remain poorly understood.

Methods:
Affymetrix microarray was performed on RNA extracted from 75 pairs of snap-frozen primary lung adenocarcinoma and matched normal lung tissue. Changes in gene expression from the primary lung adenocarcinomas that did not ever metastasize to brain over up to 15 years of follow up were compared to the lung adenocarcinomas that ultimately seeded a brain metastasis. From these 75 patients, tissue from 5 paired snap-frozen brain metastases was also available and gene expression changes between the primary lung adenocarcinomas and matched brain metastases were investigated to identify genes and pathways of interest in the development of brain metastasis. Affymetrix Transcriptome Analysis Console software was used for data analysis and interpretation with fold changes >2.0 and p-value of <0.05 for significance.

Results:
From the 75 patients 20 (27%) ultimately developed a brain metastasis from their primary lung adenocarcinoma and 55 (73%) were followed long term without development of brain metastasis. Microarray identified 71 genes that were differentially expressed in lung adenocarcinomas that later produced brain metastasis. S100 calcium binding protein, RAP1GAP, GPR160, and immunoglobins were among the upregulated genes in primary lung adenocarcinomas that developed brain metastasis. Within the matched sets of brain metastasis, hierarchical clustering showed clear distinction in expression patterns comparing brain metastasis verses normal lung, as well as primary adenocarcinomas verses normal lung. 267 genes were identified to be significantly differentially expressed between paired brain metastasis and primary lung adenocarcinomas. Significant changes in focal adhesion, angiogenesis, matrix metalloproteinase pathways, and immunoglobulins were found in the brain metastasis compared with the paired primary lung tumor.

Conclusion:
This study represents the largest microarray analysis of snap frozen pairs of primary lung adenocarcinoma and brain metastasis to date. S100 calcium binding protein, RAP1GAP, GPR160 genes, immunoglobulins, and focal adhesion, angiogenesis, and matrix metalloproteinase pathways were among the upregulated genes in primary lung adenocarcinomas that developed brain metastasis.

Background:
There are still limited data on the extent of intratumoral heterogeneity of cancer gene mutations and genome-wide copy number aberrations between primary tumors and metastases in non-small cell lung cancers (NSCLC). Deconvolution of the intermixture of tumor and stromal components remains a major challenge for such analysis. To overcome these limitations, we applied a refined nuclei flow sorting approach on matched longitudinal biopsies (primary/metastasis) from pulmonary adenocarcinomas.

Methods:
Multiparameter Ploidy Profiling (MPP) comprises the isolation of nuclei from frozen or formalin-fixed and paraffin embedded (FFPE) tissues, followed by multiparameter flow sorting by DAPI for DNA content (ploidy) and TTF1 as a lineage marker to enrich for tumor cell nuclei. Homogenous TTF1 expression was ascertained by immunohistochemistry. Sorted populations were subjected to genomic profiling by high resolution aCGH and NGS with the Ion Torrent™ Comprehensive Cancer Panel. This approach allows for the detection of genome-wide copy number aberrations and provides all exon-coverage of 409 well-known cancer genes. Sequencing was performed with a mean depth of 965x.

Results:
MPP was successfully applied on 44 frozen or FFPE tissue specimens from 19 patients. Clonally unrelated secondary primaries were found in three patients, defined by the absence of both shared copy number (CN) transition and somatic mutations. The concordance rate between primary tumor and corresponding metastases was 65.2% and reached 85.5% for mutations and copy number amplifications/deletions in the top 12 affected genes (including CDKN2A, KRAS, ATM, KEAP1, EGFR and STK11). The correlation of the allele frequencies between primary tumors and metastases was linear (r=0.87, p<0.001), irrespective of the time interval between the tissue resections. Overall, ploidy was not different between primary tumors and metastases. Additionally, the metastases did not bear a higher burden of private events (CN transitions and somatic mutations) than the primary tumors.

Conclusion:
MPP is a powerful method to increase the precision of downstream analysis due to unprecedented purity of tumor DNA. Our data argue for a high concordance rate of mutations and CN transitions between primary tumors and their corresponding metastases. Intriguingly, the ploidy remains remarkably stable during progression even after long time-periods, which suggests chromosomal stability with a limited degree of macroevolutionary shifts over time and space. Taken together, our data suggest the presence of at least two evolutionary patterns: 1) early/branched and 2) late/linear progression, with a continuum from high to low genetic divergence of the primary tumor and metastases to their most recent common ancestor.

Background:
Evidence supports the existence of genomic discrepancy in multiple primary lung cancers (MPLC). This study identified genomic alterations of MPLC by targeted next-generation sequencing (NGS) and assessed whether inter-tumor heterogeneous somatic mutations could be detected in circulating tumor DNA (ctDNA).

Methods:
94 tumor samples originating from 45 clinically considered multiple primary lung cancer patients (including multiple solid tumors and multifocal tumors) were available for genomic alteration analysis (NCT02833467). DNA and RNA were extracted from fresh tumor tissue or formalin-fixed, paraffin-embedded tissue. 143 cancer-related genomic alterations including single nucleotide variations (SNVs), short insertions and deletions (InDels), copy number variations (CNVs) and gene rearrangements were identified by Oncomine Comprehensive Panel (OCP), Ion Torrent techniques. High frequency clinical relevant mutations (EGFR, KRAS, BRAF, PIK3CA) were identified in circulating tumor DNA by droplet digital PCR (ddPCR).

Results:
The median age of the patients was 61 years and 71% were female. 91% patients were stageⅠ. Molecular analysis performed with a good quality. One hundred and thirty-six mutations and twenty four fusions were detected. Alterations were found in 81 of the 94 lesions (86%), involving EGFR (50.0%), TP53(10.6%), KRAS (8.5%), BRAF (4.3%), ERBB2 (4.3%), PIK3CA(2.1%),PTEN(2.1%),ALK (2.1%),ROS1 (1.1%), RET (7.4%), NF2(2.1%), CDKN2A(2.1%), APC(5.3%), ATM(5.3%),etc. Forty-two (93.3%) patients harbored discordant gene distribution between multiple tumors. CNVs were much higher in patients with more than 2 lesions. Forty-eight lesions harbored detectable somatic mutations by ddPCR, in which 30(62.5%) lesions were identified positive in circulating tumor DNA. 76.9% (20/26) solid dominant lesions were positive, which is significantly higher than ground glass opacity(GGO) dominant lesions(45.5%, 10/22, p=0.037). Figure 1



Conclusion:
Targeted NGS by OCP is feasible to detect multiple mutations simultaneously in early stage multiple primary lung cancers. Circulating tumor DNA has the ability to detect discordant somatic mutations and may represent of the overall mutational load and inter-tumor heterogeneity in multiple solid lung tumors.

Abstract not provided

Background:
Morphological and genetic heterogeneity predict prognostics, impede continuous responses to systemic regimens and foster inevitable treatment failure. But how morphological and genetic features evolve in tumorigenesis still remains controversial.

Methods:
Single(n=1112) and multiple(n=91) primary adenocarcinoma patients receiving surgeries with specific prominent subtypes were screened. Six patients with mixed ground glass opacities and maximum cross-sections of primary tumors were randomly selected. Intra-tumoral regions with different subtypes and imaging densities related to relative distributions, were resected for target region sequencing and further molecular evolutionary analyses.

Results:
Clinical data revealed certain preferences of driver gene mutations and discrepant survival benefits. Driver gene heterogeneity was higher in multiple primary lung cancers(51.7%, 15/29) than single ones(1.4%, 1/70). Copy number alterations implied more consistence within the same subtype and tended to be higher in lepidic subtype. Somatic nucleotide variants revealed highest homogeneity between different regions within the same tumor lesion. Sequencing data indicated larger fractions of geographically ubiquitous mutations than pathologically ones, and higher mutation frequencies of shared mutations in the lepidic than acinar subtype. Phylogenetic trees exhibited higher geographically private mutation burdens of lepidic than acinar region in lesions with mixed subtypes; while in lesions with the same subtype, the central region bore higher mutation burdens than in the periphery, implying a linear accumulation of genetic mutations. Functional analyses of private mutations verified that lepidic subtypes promoted intracellular organism and structure development, promoting growth and proliferation. Acinar subtypes lead to metabolic and signaling transduction pathway. Preferences of divergent pathway alterations delineated branched evolutions from low to higher grade subtypes. Figure 1



Conclusion:
We propose a model that the same morphological subtype evolves with a linear accumulation and mixed subtypes in branched evolutionary trajectories with preferences to pathway alterations. Couple with relatively geological distributions of different subtypes, tumor microenvironment might contribute more to genetic instability and thus tumor evolutions.

Background:
Patient-derived tumor xenografts (PDXs) have high fidelity to their histological origins, and maintain the molecular heterogeneity and genetic aberrations of the donor patient tumors more faithfully than established in non-small cell lung cancer (NSCLC) cell lines. This study evaluated whether our panel of PDX models recapitulate known cancer-related gene mutations.

Methods:
Whole-exome sequencing was completed on 103 NSCLC PDX models, 47 adenocarcinoma (AdC) and 56 squamous (SqCC), with a mean coverage of 84x. After filtering for contaminating mouse reads, the exome data were aligned using the Burrows-Wheeler Aligner, processed using the standard GATK pipeline, and mutations were identified using MuTect. Additional filtering using dbSNP, ExAC and ESP was performed for cases without corresponding normal adjacent lung exome data (n = 80). The identified mutations were compared to 1260 frequently mutated cancer-related genes, which were compiled from a panel of cancer-related mutated genes (555) and a panel of lung cancer-specific mutated genes (1082).

Results:
High rates of somatic mutations were observed in both AdC (mean of 12.4 mutations/megabase) and SqCC (mean of 11.7 mutations/megabase) PDX models. Compared to the rates observed in primary lung cancers in The Cancer Genome Atlas studies (mean of 8.9 mutations/megabase in AdC; 8.1 mutations/megabase in SqCC), these values appear higher, but may be inflated due to the lack of data from corresponding normal tissues. AdC models had a total of 953 mutated genes (median: 57 genes/model; range: 5-307), while SqCC models were characterized by 1007 mutated genes (median: 55 genes/model; range: 21-354). Specific mutation frequencies were compared to those determined in a recent study involving genomic alterations in human primary lung AdC and SqCC (Nature Genetics 2016; 48; 607–616). This comparison, based on mutated genes common in both studies, demonstrated significant correlation of the frequencies in 791 genes in AdC (ρ=0.78; p<2.2×10[-16]), as well as in 799 genes in SqCC (ρ=0.73; p<2.2×10[-16]). Three genes that were reported as significantly mutated in both AdC and SqCC primaries, and had higher mutation frequencies in SqCC, were also observed to be higher in our SqCC PDX models (TP53: 48.9% in AdC vs. 55.4% in SqCC; CDKN2A: 4.3% vs. 7.1% and PIK3CA: 2.1% vs. 23.2%); however, the statistical significance of these differences needs to be tested.

Conclusion:
Mutation landscapes in cancer genes are recapitulated in AdC and SqCC PDX models. The fidelity of these landscapes in matched patient primary tumour samples is being investigated.

Background:
CT imaging is standard-of-care for surveillance following definitive lung cancer therapy but is complicated by difficulties in distinguishing recurrence from treatment-related fibrosis and inability to detect microscopic disease. CAPP-Seq is a novel blood-based assay that uses next-generating sequencing to quantitate circulating tumor DNA (ctDNA). We performed a prospective study to compare disease surveillance by CAPP-Seq to CT imaging after definitive treatment for localized lung cancer.

Methods:
We prospectively enrolled 34 patients treated definitively for non-metastatic primary lung cancer at Stanford University between June 2010 and September 2015. Our cohort included 22 (64.7%) patients with stage III, 6 (17.6%) patients with stage II and 6 (17.6%) patients with stage I disease. All patients received pre-treatment evaluation by thoracic CT and PET/CT scans as well as ctDNA quantitation by CAPP-Seq. Twenty-one (61.8%) patients were treated with conventionally fractionated radiotherapy, 8 (23.5%) with hypofractionated radiotherapy, 3 (8.8%) with surgery, and 2 (5.9%) with both surgery and radiotherapy. Twenty-five (73.5%) patients received platinum-based doublet chemotherapy. Following treatment completion, patients underwent disease surveillance by CT scans and CAPP-Seq every 3-6 months. CT scans were evaluated using RECIST v1.1. CAPP-Seq was performed at each time point as previously described (Newman et al, Nature Medicine 2015 and Nature Biotechnology 2016).

Results:
A total of 222 scans and 107 plasma samples were analyzed. Median follow-up time was 21.1 months and median overall survival was 30.0 months. Eighteen (52.9%) patients progressed based on RECIST criteria and CAPP-Seq detected ctDNA at or before the time of RECIST progression in all patients (18 of 18; 100%) with a lead-time of 121 +/- 39 days (mean +/- SEM). For 13 of 16 (81.3%) evaluable patients who progressed, ctDNA was detected at the first time-point after completion of all treatment (median 2 months post treatment), indicating detection of minimal residual disease. Two-year overall survival for patients with detectable post-treatment ctDNA was 25.3% versus 92.9% for those with no detectable post-treatment ctDNA (p=0.0003, HR=6.8, 95% CI=2.6-17.9). This difference remained significant in multivariate models controlling for stage, age, sex, and tumor volume (P=0.01).

Conclusion:
We found that noninvasive ctDNA profiling appears to be useful for evaluating response to lung cancer treatment. Quantitation of ctDNA allowed identification of minimal residual disease, which was strongly associated with outcome. These results suggest that ctDNA assessment after definitive intent treatment could potentially be used to guide risk-adapted treatment strategies for localized lung cancer.

Abstract not provided

Background:
Tumor-associated fibroblasts (TAFs) are increasingly regarded as essential co-conspirators for tumor progression in all solid tumors including non-small cell lung cancer. While most TAFs exhibit activation markers indicative of a myofibroblast-like phenotype, senescence markers have been reported in a growing list of selected cancer types only. However, the presence of senescent TAFs in lung cancer remains undefined. Assessing senescence in lung TAFs is important because previous studies have reported that senescent TAFs enhances tumor growth, which is in marked contrast with the widely accepted tumor-suppressive role of senescence in cancer cells.

Methods:
We examined common senescence markers in patient derived lung TAFs from the 3 major non-small cell lung cancer (NSCLC) subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Given the difficulties in gathering LCC-TAFs owing to the lower prevalence of LCC compared to the other subtypes, primary fibroblasts from 2 independent fibroblast collections were used. Senescence markers included senescence-associated beta-galactosidase, permanent growth arrest and spreading.

Results:
We found an enrichment of the myofibroblast-like phenotype in TAFs regardless their histologic subtype, yet senescence was observed in LCC-TAFs only regardless their neuroendocrine status. Likewise, co-culturing normal lung fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to induce senescence, and this induction was prevented in the presence of an antioxidant, indicating that it is mediated through oxidative stress. Remarkably, senescent fibroblasts provided growth and invasive advantages to LCC cells in culture and in vivo beyond those effects provided by control (non-senescent) fibroblasts.

Conclusion:
Our findings expand recent evidence that challenges the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless their histologic subtype. Of note, because LCC often distinguishes itself in the clinic by its aggressive nature, our findings support that senescent or senescent-like TAFs may contribute to the selective aggressive behavior of LCC tumors.

Background:
Next-generation sequencing techniques have allowed the discovery of driver mutations in non-small cell lung cancer (NSCLC) that can be translated into advances in cancer diagnosis and treatment. However, specific oncogenic alterations are still unknown in a high proportion of NSCLC patients, that therefore cannot benefit from targeted therapies. The challenge is to identify new genetic alterations that allow the use of molecular-targeted therapies. In previous studies from our group (Aramburu et al. BMC Genomics 2015), the analysis of tumor molecular profiles from patients with NSCLC allowed us to identify the DNA copy number amplification of YES1 kinase (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) as a prognostic marker in lung cancer. YES1 kinase is member of the Src family of non-receptor protein tyrosine kinases that are involved in the regulation of cell growth, apoptosis, cell-cell adhesion, cytoskeleton remodeling, and differentiation. The aim of this project is to evaluate if YES1 is a driver gene in NSCLC, and if targeting its activation may be a potential new therapeutic strategy.

Methods:
We first evaluated the prognostic role of YES1 protein expression in two independent series of 76 and 234 NSCLC patients, respectively. In both series, the multivariate analysis revealed that high YES1 expression is an independent poor prognostic factor for overall survival (CUN series HR: 3.416 [0.933-12.508]; MD Anderson series HR: 1.570 [1.032-2.391]). We next evaluated the effect of YES1 knockdown in 5 NSCLC cell lines with YES1 amplification and overexpression, and in 3 cell lines without YES1 amplification and with low protein expression. YES1 downregulation by two specific siRNAs decreased proliferation and cell survival only in those cells overexpressing YES1. Congruently, YES1 inhibition led to apoptosis only in those cells.

Results:
Consistent with these results, constitutive overexpression of YES1 in cells with low YES1 expression significantly enhanced cell proliferation. We next evaluated the effect of the multitarget Src kinase inhibitor dasatinib on the proliferation of NSCLC cell lines with high (8 cell lines) or low (4 cell lines) YES1 expression. Dasatinib dramatically inhibited proliferation in high YES1-expressing cell lines, whereas low YES1 cell lines were more resistant to dasatinib treatment (GI50s were four orders of magnitude higher in resistant cells).

Conclusion:
In conclusion, our results indicate that YES1 is a promising therapeutic target in NSCLC. Furthermore, amplification and high expression of YES1 may define a subset of patients who may potentially benefit from dasatinib treatment.

Background:
Akt2 (Protein Kinase B isoform 2) is an essential protein, which is involved in tumor cell proliferation, differentiation, motility, and cell death in non small cell lung cancer (NSCLC). Raf1 is also a key protein regulating the functions in NSCLC. However, the relationships between Akt2 and Raf1 are unknown. This study aimed to investigate the influence of Akt2 knockdown and its interaction with overexpression Raf-1 in non-small cell lung cancer cells.

Methods:
Small interfering RNA was used to knockdown Akt2 and lentivirus was introduced to overexpress Raf1 in H1299, A549, Sk-mes and H460 cell lines. Western blot was performed to investigate expression levels of relevant proteins in the pathway. Cell survival, proliferation and apoptosis were evaluated in vitro and vivo. Then we examined Akt2 and Raf1 expressions via immunohistochemistry (IHC) in 65 NSCLC patients.

Results:
Knockdown of Akt2 suppressed cell proliferation, arrested tumor cells in G0/G1 phase and induced apoptosis in all cell lines distinctively. Raf1 phosphorylation was also inhibited after Akt2 knockdown in the cell lines. When Raf1 overexpression combined with Akt2 knockdown in these cell lines, cell proliferation was enhanced, and apoptosis rates was decrease compared with Akt2 knockdown alone. These trends were also observed in vivo experiments. Furthermore, the downstream proteins of Raf1, such as MEK, ERK, p-MEK and p-ERK were observed decrease in Akt2 knockdown groups. Of all NSCLC specimens, Akt2(+)/Raf1(+) patients had the worst prognosis of 5-year overall survivals. Figure 1



Conclusion:
Our study demonstrates that knockdown of Akt2 suppresses tumorigenesis by attenuating cell proliferation, increasing apoptosis and interfering cell cycle in non-small cell lung cancer. Raf1 overexpression partly offsets these effects by enhancing cell proliferation, suppressing apoptosis and affecting downstream proteins. Thus, there may be existing Akt2/Raf1 pathway in NSCLC, which plays an important role in tumorigenesis.

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Abstract:
Small cell lung cancer is the prototype of a smokers cancer and therefore with changing smoking patterns and decreasing prevalence of smoking this is a tumour that happily we are seeing less frequently. However the nature of the disease, the morbidity and suffering it causes, and the tantalising chemo and radiotherapy sensitivity of this tumour make it of great medical and academic interest to us. More attention is now given to the morphology of small cell lung cancer and the blurred boundary with large cell neuroendocrine tumours and non small cell lung cancer with neuroendocrine features. At the end of the EGFR mutation driven lung cancer natural history, small cell lung cancer appears once resistant has developed to EGFR mutation therapies. If we start from the early stage disease and look at radical approaches and how these have changed in the last 20 years we see that the gains made by systemic treatment have been stable while outcomes have been improved by intensive local and focused treatments in the form of prophylactic cranial irradiation and consolidation radiotherapy to the mediastinum. Small gains have also been made by the timing of radiotherapy both quickly after last chemotherapy or when given in a concurrent fashion. The Convert study has now given us a faster twice a day delivery with equal effectiveness and toxicity to a higher dose once daily schedule. Surgery has never really taken off as a widely used treatment for SCLC. For all the anecdotal cases who have been cured with combined treatment involving surgery, we will also remember those patients who have failed to recover or have delayed recovery from surgery and lost the window of opportunity for systemic treatment in a disease that can rapidly change from asymptomatic to very symptomatic. Despite little change in systemic therapies, it is important that what we have, we use well and to this end patients with SCLC should be carefully monitored during treatment for treatment induced neutropenia as this is readily treated and prevented by the use of GCSF which has become cheap and readily available in most countries. In addition SCLC was also one of the solid tumours that benefited from denosumab in the trials of patients with bone metastases and thus denosumab or zometa should be added to patients with SCLC who have bone metastases to decrease bone morbidity. Extensive stage small cell lung cancer is still a challenge and currently a graveyard for drugs development. The drugs that are looking promising are the PD-L1 inhibitors, although PD-L1 in itself does not appear to be a biomarker. Anti- PD1 and PD-L1 antibodies, while active in some cases of SCLC are not as broadly active as in NSCLC. Indeed it does not appear that PD-L1 expression on tumour cells is not a predictors of response. On could argue that the patients with SCLC who have a response to anti PD1 therapies may have heterogeneous disease and have areas of NSCLC which drive the response. It has always been thought that SCLC must be a problem of proliferation of abnormalities at the stem cell level. Indeed now it is no surprise that an anti DDL3 antibody (rovalpituzumab tesirine) is showing activity in relapsed disease – a situation where responses are few but results of trials are rapid. It also appears that DDL3 expression is a biomarker to predict response. Once again this biological pathway like the PD1 pathway, is unpatentable and thus we can expect a florry of antibodies targeting in and around these receptors on stem cells. The PARP inhibitors are again a group of drugs that held much promise but as yet have failed to deliver a treatment option at any point in the SCLC pathway. Further trials are ongoing. Positive benefits from radiotherapy in extensive stage as in limited SCLC, tells us that any treatment that can control a site of disease and can improve outcome, and suggests that removal of clones is important as either a form of debulking treatment or indeed these clones are a future source of resistance. Thus research on the treatment of oligometastatic sites either at presentation, residual after treatment or on relapse, as in the ongoing work in NSCLC (e.g the Saron study) may lead to future gains in survival. The biology of SCLC should be approached in the same way as NSCLC i.e. when disease relapses, rebiopsies should become the norm with as large a piece of tissue as possible. SCLC also sheds tumour cells into the circulation, which are a source of material for interrogation. Despite the negative trials, it is still rewarding to treat SCLC patients – for the rapid improvement in symptoms with treatment and the small but real group who get long term responses, in addition the rapid results makes this still an area for many more years of research.

Abstract:
Performance status (PS) captures a patient’s ability to perform daily activities and provides a measure of impairment as a function of tumor burden. The Eastern Cooperative Oncology Group (ECOG) scale is the most frequently used and ranges from 0 (fully ambulatory without symptoms) to 5 (dead). Typically, patients with an ECOG PS of 0 and 1 are labeled as “good PS”, are typically treated with combination regimens, and are the focus of the majority of the clinical trials. Patients with “poor PS”, mostly ECOG 2, but also 3 and occasionally 4, have been largely excluded from clinical trials. Patients with a PS of 2 account for approximately 30-40% of patients diagnosed with advanced non-small cell lung cancer (NSCLC) in clinical practice (1). As a result of the lack of dedicated research, current guidelines are equivocal with respect to the optimal therapy for these patients and their management remains inconsistent, ranging from best supportive care to combination chemotherapy. Cooperative group studies in the 1980’s and 1990’s suggested that poor PS patients (ECOG ≥2) derived little or no benefit from systemic chemotherapy and had high rates of treatment-related morbidity and mortality (2). This perspective permeated clinical research and clinical practice for over 2 decades. While concerns about safety and benefit remain appropriate, the advent of better supportive care, along with more effective and tolerable carboplatin-based doublets have led to new trials in this subset of patients. Two large phase III randomized trials in PS 2 patients in the mid-2000’s provide insights into this heterogeneous cohort. In one trial, 400 patients were assigned to standard carboplatin plus paclitaxel or carboplatin plus another formulation of paclitaxel (3). In the other trial, 400 patients were assigned to single agent gemcitabine or vinorelbine (4). The identical eligibility criteria led to a separate publication comparing single agent vs. combination chemotherapy (5). The response rate (38 versus 16 percent) and the median time to progression (4.6 versus 3.5 months) were statistically superior with combination chemotherapy. Overall survival trended in the same direction, but the difference was not significant (8.0 versus 6.6 months). Toxicity, as expected, was higher with combination chemotherapy. The question of single agent vs combination chemotherapy was addressed in a definitive manner by a phase III randomized trial that compared pemetrexed alone or in combination with carboplatin in 205 eligible patients with PS 2 (6). Respectively, the response rates were 10% vs 24%; the median progression free survival was 2.8 vs. 5.8 months; and the median survival was 5.3 vs. 9.3 months, all statistically significant in favor of the combination regimen. Toxicity was manageable but 4 treatment-related deaths were observed in the combination arm. This trial has set a new standard for treatment of advanced NSCLC patients with a PS of 2. The advent of targeted agents led to the exploration of these agents as a “gentler approach” to PS 2 patients, irrespective of the presence or absence of the mutation. In a phase II randomized trial, patients were assigned to either erlotinib or a combination of carboplatin and paclitaxel (7). Patients treated with erlotinib had a significantly shorter median survival compared to chemotherapy (6.5 vs 9.7 months, HR 1.73, 95% CI 1.09-2.73). As shown in other trials, EGFR inhibitors should not be given to untreated patients without the mutation, regardless of the PS. Guidelines from the American Society of Clinical Oncology (ASCO) state that the data for patients with PS 2 are insufficient to make a strong recommendation for combination chemotherapy, and single agent therapy may be appropriate if the perception of risk outweighs the perception of benefits (8). The European Society of Medical Oncology (ESMO), after reviewing the same body of data, came up with a straightforward recommendation for carboplatin-based combinations to all eligible PS 2 patients (9). The National Comprehensive Cancer Network (NCCN) merged PS 2 patients into the PS 0-1 group for recommendations regarding first line therapy, with no obvious distinction between the subsets (10). This progressive approach recognizes the advances made in the management of PS 2 patients in the past decade and extends the benefits of systemic therapy to a large group of patients who were, until recently, offered inferior treatments. References: Lilenbaum RC, Cashy J, Hensing TA, et al. Prevalence of poor performance status in lung cancer patients: implications for research. J Thorac Oncol 2008; 3:125 Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma . Cancer 2001; 92:2639 Langer CJ, O'Byrne KJ, Socinski MA, et al. Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol 2008; 3:623 O'Brien ME, Socinski MA, Popovich AY, et al. Randomized phase III trial comparing single-agent paclitaxel Poliglumex (CT-2103, PPX) with single-agent gemcitabine or vinorelbine for the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer. J Thorac Oncol 2008; 3:728 Lilenbaum R, Villaflor VM, Langer C, et al. Single-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2: prognostic factors and treatment selection based on two large randomized clinical trials. J Thorac Oncol 2009; 4:869 Zukin M, Barrios CH, Pereira JR, et al. Randomized Phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small cell lung cancer and Eastern Coopertaive Group performance status of 2. J Clin Oncol 2013; 31:2849–2853 Lilenbaum R, Axerold R, Thomas S, et al. Randomized Phase II Trial of Erlotinib or Standard Chemotherapy in patients with Advanced Non-Small Cell Lung Cancer and a Performance Status of 2. J Clin Oncol 2008; 26:863-869 Masters GA, Temin S, Azzoli G, et al. Systemic therapy for stage IV non-small cell lung cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol 2015; 62:1342 Reck M, Popat S, Reinmuth N, et al. Metastatic non-small cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol 2014; 25 (suppl 3): iii27 National Comprehensive Cancer Network. Non-Small Cell Lung cancer (Version 4.2016). http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. Accessed September 15, 2016

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Abstract:
In non-small cell lung cancer (NSCLC) chromosomal rearrangements involving the gene encoding for the receptor tyrosine kinase ROS1 have been first described in 2007 (1). These aberrations have been shown to trigger constitutive kinase activity and activation of downstream pathways like the MAPK pathway. ROS1 rearrangements can be found in about 2% of lung adenocarcinoma and are associated with female gender and never-smoking status (2). Different fusion partners have been described. In routine diagnostics ROS1 fusion genes can be reliably detected by fluorescence in situ hybridization (FISH; e.g. dual color break apart FISH), RT-PCR or next-generation sequencing (NGS). ROS1 fusions occur mutually exclusive of aberrations in EGFR, ALK and KRAS. However, using NGS, co-occuring mutations, preferentially in TP53, but also in other genes involved in oncogenic pathways, can be found in about 50% of these patients (3). ROS1 fusions also seem to be of prognostic relevance, since remarkable long survival times have been described in patients treated with chemotherapy only (3). The ALK/MET/ROS1 inhibitor crizotinib has been evaluated in a US-American cohort of 50 ROS1 positive patients with advanced, mostly pretreated lung adenocarcinoma and showed impressive activity (4). The overall response rate (ORR) was 72% (95% CI 58 to 84) with 3 complete responses. Median progression free survival (PFS) was 19.2 months (95% CI 14.4 to not reached). Treatment was well tolerated and the side effect profile resembled that observed in the treatment of ALK positive lung cancer with crizotinib. A similiar ORR of 80% was reported in a retrospectively analyzed European cohort (5). However, PFS was only 9.1 months in these patients. The EUCROSS trial, a collaborative study of the German Lung Cancer Group Cologne and the Spanish Lung Cancer Group, is a prospective European phase II trial which recruited 34 ROS1 positive patients between June 2014 and September 2015. ROS1 fusion genes were diagnosed using dual color break apart FISH and the results were confirmed by next-generation sequencing. With an ORR of 69% (95% CI, 49.1 to 84.3) similar efficacy has been reported (6). Based on its high activity and favorable toxicity profile, crizotinib is now approved for the treatment of ROS1-positive NSCLC by the FDA since March 2016 and by the EMA since August 2016. Treatment of ROS1-positive NSCLC with crizotinib thus has become standard first-line treatment in the leading international guidelines. Current challenges for the further development and improvement of targeted treatment of ROS1-positive patients are (I) implementation of ROS1 diagnostics in routine molecular diagnostics and (II) development of next-generation ROS1 inhibitors overcoming crizotinib resistance. The increasing number of actionable mutations in NSCLC including ROS1 requires implementation of molecular multiplex testing, since sequentially conducted single gene assays are no more feasible given the usually limited biopsy tissue specimens. However, conventional NGS technology is restricted to point mutations and does not cover copy number variations (CNV) and gene fusions. Thus, new NGS technologies have to be integrated in routine diagnostics like hybrid capture-based NGS, which does not require DNA amplification by PCR and thus allows to detect reliably CNV and gene fusions. While increasing knowledge of the molecular mechanisms underlying TKI resistance has led to the development of a series of highly potent next-generation inhibitors in ALK-positive NSCLC now, resistance of ROS1-positive patients to crizotinib is incompletely understood. In preclinical studies as well as in biopsy tissue, somatic mutations in the ROS1 kinase domain associated with acquired crizotinib resistance have been described (7). In functional studies these mutations were associated with different degrees of resistance. Alternatively, bypass activation of oncogenic signal transduction pathways has been described as mechanism underlying resistance. For instance, a cKIT activating mutation and EGFR pathway activation have been reported in single cases (8). In vitro, the multikinase inhibitors cabozantinib, foretinib and lorlatinib have been shown to overcome crizotinib reistance triggered by secondary mutations in ROS1. Response to cabozantinib has also been described in a ROS1-positive patient with a mutation confering resistance to crizotinib (10) and was also observed in a phase I trial of lorlatinib in the same clinical setting. In summary, ROS1 positivity characterizes a subgroup of patients with a major benefit from treatment with crizotinib. Consequently, crizotinib has become the current standard of care for these patients. ROS1 status thus should be available before decision on first-line treatment. Acquired resitance to crizotinib may be caused by mutations in the ROS1 kinase domain or by activation of bypass pathways. The multikinase inhibitor cabozantinib and the next-generation ALK/ROS1 inhibitor lorlatinib have shown promising efficacy in early clinical evaluation. (1) Rikova K et al. Global survey of phosphotyrosine sgnaling identifies oncogenic kinases in lung cancer. Cell 2007, 14; 131(6):1190-203. (2) Bergethon K et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012, 30(8):863-70. (3) Scheffler M et al. ROS1 rearrangements in lung adenocarcinoma: prgnostic impact, therapeutic options and genetic variability. Oncotarget 2015, 6(12):10577-84. (4) Shaw A et al. Crizotinib in ROS1-rearranged non-small cell lung cancer. NEJM 2014, 371(21): 1963-71. (5) Mazieres J et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol 2015, 33(8):867-76. (6) Michels e al. EUCROSS: a prospective European phase II trial to evaluate efficacy and safety of crizotinib in advanced adenocarcinoma of the lung harboring ROS1 translocations. WCLC 2016 (oral presentation). (7) Awas MM et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. NEJM 2013, 368(25):2395-401. (8) Dzadziuszko R et al. Activating KIT mutation induces crizotinib resistance in ROS1-positive lung cancer. J Thorac Oncol 2016, 11(8):1273-81. (9) Davies KD et al. Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer. PLoS One 2013, 13 (8):e82236. (10) Drilon et al. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clin Cancer Res 2016, 22 (10):2351-8.

Abstract:
"Lung adenocarcinoma" is a genetically heterogenous disease entity, characterized by a wide spectrum of different mutations. Some of these mutations lead to constitutive activation of receptor tyrosine kinases, which can be inhibited by small molecules (tyrosine kinase inhibitors, TKIs). EGFR mutations (2004) and ALK rearrangement (2007) were among the first actionable driver mutations identified in lung adenocarcinomas. Today, several drugs are approved for the treatment of advanced lung adenocarcinomas with EGFR mutations or ALK/ROS1 rearrangement. Combined, these molecular subgroups make up at least 20% of all lung adenocarcinomas or more, depending on the poplulation. Further actionable driver mutations include the genes BRAF, HER2, MET, and RET. These genes are less frequently mutated than EGFR/ALK, nevertheless, rare drivers are clinically relevant because of the availability of targeted therapies approved for other indications in oncology (ALK-lung, HER2-breast, RET-thyroid, and BRAF-melanoma). The discussant will summarize current knowledge about rare driver mutations, with a strong clinical focus. HER2 insertion 20, present in about 1% of lung adenocarcinomas, was initially proposed by Cappuzzo et al as a potential indication for trastuzumab-based therapy [1]. Prospective trials with HER2 targeting drugs are currently ongoing. BRAF V600E, present in about 3% of lung adenocarcinomas, was associated with high activity of combined therapy with dabrafenib and trametinib in a prospective phase II trial by Planchard et al [2]. Crizotinib, recently approved by the FDA for the treatment of ROS1-NSCLC, is also active in tumors harboring MET exon 14 mutations as demonstrated by Drilon et al [3]. Cabozantinib and vandetanib are active in tumors with RET rearrangement as shown by three recent phase II trials [4-6]. Entrectinib showed preliminary activity in tumors harboring TRK rearrangement in an early basket Trial [7]. These results will be discussed in detail, together with the results of international registries (EUHER2, EURAF, EUROS1 and GLORY [8]). Moreover, current treatment recommendations for patients with advanced lung adenocarcinomas and rare driver mutations will be summarized. References 1. Cappuzzo et al. N Engl J Med. 2006;354(24):2619-21. 2. Planchard et al. Lancet Oncol. 2016;17(7):984-93. 3. Drilon et al. J Clin Oncol 34, 2016 (suppl; abstr 108) 4. Drilon et al. Cancer Discov. 2013;3(6):630-5. 5. Seto et al. J Clin Oncol 2016;34(suppl; abstr 9012) 6. Lee et al. J Clin Oncol 2016;34(suppl; abstr 9013) 7. Drilon et al. AACR 2016 (abstract CT007) 8. Gautschi et al. WCLC 2016 (abstract 4325)

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Abstract:
Superior sulcus tumors (SST) are unique among lung cancer in that they have a tendency for the invasion into the chest wall and a spread superiorly outside the lungs, namely into the brachial plexus and the sympathetic chain, therefore causing a well-defined constellation of symptoms and signs, such as chest wall/arm/shoulder pain, Horner’s syndrome, spinal cord compression, upper extremity edema etc. A primary surgical resection is rarely performed, and bi- or trimodality therapies are most often implemented, depending on tumor stage. A comprehensive evaluation of the tumor extent is mandatory before any intervention is undertaken. Following tumor biopsy to establish a diagnosis of non-small cell lung cancer, standard lung cancer staging studies need to be obtained, such as the chest and upper abdomen computerized tomography (CT) scan with intravenous contrast, a PET CT scan and contrast-enhanced brain imaging (CT or MRI). Routine blood work and pulmonary function testing are standard as well. However, there are two additional radiographic studies which are necessary for each superior sulcus tumors: (1) MRI scan of the brachial plexus; (2) MRI scan of the cervical and thoracic spine. The rationale for imaging of the brachial plexus is not to confirm that the plexus is invaded (which is evident based on the presenting symptoms and a physical examination), but rather to assess the degree of its vertical involvement, since only the lowest trunks of the brachial plexus can be safely resected without fear of causing paralysis of the upper extremity. The MRI of the vertebral column serves a double purpose: (1) to assess the degree (if any) of vertebral involvement and resulting resectability; (2) to image the proximity of the tumor to the spinal cord, which is crucial for radiation planning. SSTs can cause thecal sac or spinal cord compression by extending into the spinal canal through neural foramina, without apparent spine invasion, hence the need for the MRI, which provides a superior image quality than a chest CT scan. The overall treatment strategy depends on the nodal status (“N” stage). For those patients without nodal involvement (“N0”) or with involvement only of the ipsilateral hilar lymph nodes (“N1”), a common approach is to use concurrent induction chemo-radiotherapy, followed by the surgical resection. If obvious mediastinal nodal involvement is seen (“N2 or N3”), the recommendation is for definitive concurrent chemo-radiotherapy without subsequent surgery. Therefore, invasive staging of the mediastinum, either with mediastinoscopy or with EBUS, is mandatory, since it may result in avoiding surgery as part of management. General thoracic radiation therapy (RT) principles apply to the SSTs, such as: (1) use of the CT simulation for tumor and normal tissue imaging; (2) use of 6-10 MV photon energies (unless protons are applied); (3) careful definition of the GTV, Gross Tumor Volume, to include the visible tumor on lung windows and the abnormal lymph nodes on soft tissue windows; (4) adequate margins for the CTV, Clinical Target Volume, and the PTV, Planning Target Volume. In particular, a tendency to have very tight margins around the tumor which is in close proximity to the spinal cord should be avoided at all cost, since this may result in a marginal tumor failure. In comparison to lung cancers in other locations, local tumor progression of a SST can have devastating clinical consequences, resulting in unmanageable pain, limb paralysis and a low quality of life. The commonly used total RT doses are: 45-60 Gy in trimodality therapy (chemo-RT, then surgery) or 60-70 Gy in bimodality therapy (chemo-RT) in 2 Gy daily fractions. The dose-limiting normal structures are usually the spinal cord and brachial plexus. The maximum allowed dose to the spinal cord may need to be higher (54-55 Gy) in SSTs than in other lung cancers (50 Gy) in order not to compromise the minimum dose prescribed to the PTV by attempting to “spare” spinal cord. In patients presenting with severe pain, a simple field arrangement (such as anterior and posterior opposed fields) treating the tumor with wide margins is a good initial option allowing for a quick start, followed by a more advanced planning technique, such as 3-dimensional RT, intensity modulated RT (IMRT) or VMAT. The tolerance of brachial plexus was classically described as a maximum dose of 65 Gy, with recent publications suggesting that higher doses, up to 78 Gy result in 12% risk of Grade>3 radiation-related brachial plexopathy, and that brachial plexopathy is more common as a result of tumor progression than radiation damage. The most quoted prospective clinical trial reporting on treatment outcomes of SSTs is a landmark Phase II SWOG 9416 study, in which 95/110 enrolled patients without disease progression (86%) received thoracic RT to 45 Gy in 1.8 Gy fractions with concurrent cisplatin and etoposide chemotherapy, followed by surgery and further adjuvant chemotherapy. Eligible patients were those with T3-T4 primary tumors and N0 or N1 nodal status. The resection rate was 80% and 75% achieved a complete (R0) resection. The pathologic response rate (no tumor in the specimen or microscopic residual) was 56%; the overall 5 yr survival rate was 44% for all patients and 54% for those with a complete tumor resection. Since then, recognition in the surgical community that operating after RT doses higher than 45 Gy is safe, led to a more common use of the full RT dose, i.e. 60 Gy. If the patient initially planned for trimodality therapy is no longer a surgical candidate or refuses surgery, thoracic RT should continue to definitive dose without interruption. Therefore, it is crucial to perform re-imaging for response assessment in the last week of chemo-RT (if doses of <60 Gy are used) rather than schedule those several weeks later. References: Rusch, V.W., Giroux, D.J., Kraut et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus (initial results of Southwest Oncology Group trial 9416 (Intergroup trial 0160)) . J Thorac Cardiovasc Surg 121: 472–483, 2001. Kwong KF, Edelman MJ, Suntharalingam M et al. High-dose radiotherapy in trimodality treatment of Pancoast tumors results in high pathologic complete response rates and excellent long-term survival. J Thoracic Cardiovasc Surg, 129:1250-57, 2005. Eblan MJ, Corradetti MN, Lukens JN et al. Brachial plexopathy in apical non-small cell lung cancer treated with definitive radiation: dosimetric analysis and clinical implications. Int J Radiat Oncol Biol Phys.85:175-81, 2013.

Abstract:
Backgroud: Lung cancer is the leading cause of cancer deaths in the world. For patients with advanced non-small cell lung cancer (NSCLC), survival prognosis is very poor with chemotherapy and radiotherapy. However, the possibility of occult metastases may lead to discrepancy between clinical and pathologic staging and underestimation of the disease severity, and how to individualized choose the appropriate patients with locally advanced non-small cell lung cancer for surgery is controversies. In this study, we presented here the Chinese experience: individual precision surgery for locally advanced non-small cell lung cancer based on molecular staging.Methods: We developed several molecular biomarkers and molecular models from Circulation Tumor Cell (CTC ) detection, mi-RNA chip, Gene Chip from 1990. We used these Molecular biomarkers and molecular models for molecular staging, molecular typing, choosing indication of operation and neoadjuvant chemotherapy, predicting postoperative recurrence and prognosis of locally advanced non-small cell lung cancer.Results: We developed two molecular staging model for individualized surgical treatment for locally advanced non-small cell lung cancer involving heart, great vessels or both. 3308 patients with locally advanced non-small cell lung cancer were underwent completely resection of the cancer in the three medical center. The 1-, 3-, 5- and 10 year survival rate were 74.5%,62.3%,31.5% and 22.9%, respectively. We used our molecular staging model for neoadjuvant chemotherapy for 665 patients with locally advanced lung cancer. The 1-, 3-, 5- and 10-year survival rate were 79.35%, 51.46%, 27.39% and 20.34% of the patients, respectively. We used our molecular model to divide N2 lung cancer into invasive N2 and Non-invasive N2 group. We used our molecular models adenocarcinoma and squamous carcinoma to divide T4 lung cancer into high recurrence and low recurrence groups, and help postoperative adjuvant therapy.Conclusion: Our molecular staging and typing models can help us carry out individual precision surgery, predicting prognosis and cancer recurrence of the cancer for locally advancer no-small cell lung cancer.

Abstract:
Molecular alterations that are characteristic of lung tumors have been shown to be present in normal-appearing airway epithelium adjacent to lung tumors suggestive of an airway field cancerization phenomenon (1, 2). These field effects include altered gene expression, loss of heterozygosity (LOH), gene mutation and methylation and microsatellite instability (3-7). Microarray studies have pointed to expression profiles that are dissimilar between airways in smokers with and without lung cancer (8, 9). It has been recently demonstrated gene expression profiles that are shared between normal-appearing airway cells and nearby NSCLCs and that can distinguish airways of smokers with lung cancer from those without the malignancy (8). Studies from several groups suggest that the field cancerization provides biological insights into non-small cell lung carcinoma (NSCLC) ad small cell lung carcinoma (SCLC) pathogenesis and clinical opportunities for lung cancer detection (6, 8). It is important to note that smoking perpetuates inflammation throughout the exposed airway epithelium (10). This effect is pronounced in patients with Chronic Obstructive Pulmonary Disease (COPD) (10). Notably, among smokers, even after smoking cessation, airway inflammation persists while the risk of lung cancer continues to increase (10). It is not known which tumor promoting profiles in the airway field cancerization may drive lung cancer development in COPD patients. Using microarray profiling, studies have pointed to expression profiles that are dissimilar between airways in smokers with lung cancer and airways in smokers without cancer (11-13). Importantly, these gene-expression changes within the “field of injury” have been leveraged for development and validation of a clinically-relevant biomarker that can improve the diagnostic performance of bronchoscopy for detection of lung cancer (predominantly NSCLC) among smokers with suspect disease (8, 12). In addition, gene expression array analysis pointed to airway field expression profiles that are spatially and temporally modulated in early stage patients following surgery and that may be associated with disease relapse (13). Further, we have recently demonstrated that there is significant enrichment in gene expression profiles measured in both small (adjacent to tumor) and large (mainstem bronchus) airway compartments of the airway field of injury, suggesting that gene-expression changes in the large airway can serve as a surrogate for the molecular changes occurring in the airway epithelium adjacent to the tumor (9). Taken together, studies from our group and others suggest that, by sampling “normal” and relatively accessible tissue (e.g., bronchial airway), the airway field of injury provides biological insights into the earliest phases in the development of lung malignancy and potential valuable clinical opportunities such as early detection (1, 2). Identifying molecular aberrations that precede cellular morphological changes will provide biological insights into why some smokers develop lung cancer and, thus, clinical opportunities for improved lung cancer detection. References: 1. Kadara H, Wistuba, II. Field cancerization in non-small cell lung cancer: implications in disease pathogenesis. Proceedings of the American Thoracic Society. 2012;9(2):38-42. 2. Steiling K, Ryan J, Brody JS, Spira A. The field of tissue injury in the lung and airway. Cancer Prev Res. 2008;1(6):396-403. 3. Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, Baylin SB, Herman JG. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci U S A. 1998;95(20):11891-6. 4. Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM, Lee JJ, Ro JY, Broxson A, Yu R, Morice RC, Kemp BL, Khuri FR, Walsh GL, Hittelman WN, Hong WK. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst. 1997;89(12):857-62. 5. Tang X, Shigematsu H, Bekele BN, Roth JA, Minna JD, Hong WK, Gazdar AF, Wistuba, II. EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients. Cancer research. 2005;65(17):7568-72. 6. Wistuba, II, Behrens C, Milchgrub S, Bryant D, Hung J, Minna JD, Gazdar AF. Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma. Oncogene. 1999;18(3):643-50. 7. Wistuba, II, Lam S, Behrens C, Virmani AK, Fong KM, LeRiche J, Samet JM, Srivastava S, Minna JD, Gazdar AF. Molecular damage in the bronchial epithelium of current and former smokers. J Natl Cancer Inst. 1997;89(18):1366-73. 8. Spira A, Beane JE, Shah V, Steiling K, Liu G, Schembri F, Gilman S, Dumas YM, Calner P, Sebastiani P, Sridhar S, Beamis J, Lamb C, Anderson T, Gerry N, Keane J, Lenburg ME, Brody JS. 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Abstract:
Low-dose computed tomography for high-risk individuals has for the first time demonstrated unequivocally that early detection save lives. The currently accepted screening strategy comes at the cost of a high rate of false positive findings while still missing a large percentage of the cases. Therefore, there is increasing interest in developing strategies to better estimate the risk of an individual to develop lung cancer, to increase the sensitivity of the screening process, to reduce screening costs and to reduce the numbers of individuals harmed by screening and follow-up interventions. New molecular biomarkers candidates show promise to improve lung cancer outcomes. This review discusses the current state of biomarker research in lung cancer screening with the primary focus on risk assessment. The rationale for developing biomarkers for the early detection of lung cancer is very strong and well established. It stems from the fact that, at the population level, the earlier we detect the disease, the better the outcome and the lower the health care cost. The impetus for biomarker development has grown stronger since the NLST trial demonstrated that early detection via chest CT screening reduced the relative risk for lung cancer death in the high risk individuals. Low dose chest CT in this group alone may save up to 12,000 lives a year, but it represents only about 8 % of individuals dying of this disease every year. Thus, much is to be done to capture these lung cancers that escape chest CT screening as currently recommended despite its high sensitivity and specificity. The reason for limited detection relates to how many at-risk individuals are studied with CT and to how we best define this risk. Detection and careful management of indeterminate pulmonary nodules are integral parts of this effort. Lung cancer screening using chest CT also raises many questions, some of which could be addressed with well poised biomarkers. For example, who is at utmost risk for lung cancer? How do we expand the screening criteria from the NLST without causing more harm than good? Once the CT screening studies are done, how do we approach a non-invasive diagnosis of lung cancer? How do we prevent the overdiagnosis bias? Here we focus on biomarkers that could be used in a risk assessment evaluation for screening programs. We will discuss current molecular biomarkers of risk assessment in those without measurable disease and before a chest CT has been done. Consideration of the use of such biomarkers should trigger a discussion with the patient before ordering it to address the intent of the test and the implications of the possible results. Many biomarkers have been developed over the years to predict tumor development. Let us consider the characteristics of such a biomarker to assess the risk of lung cancer. For screening purposes, given the low prevalence of disease, a strong negative predictive value (NPV) of a test is a very attractive feature. High specificity on the other hand is always desirable so we do not overcall cancers (false positive). Should such a test be positive, it would push individuals into a higher risk group to consider appropriate surveillance. The biomarker could measure a genetic risk (e.g. altered metabolism of carcinogens, DNA repair machinery abnormalities, predisposition to inflammation, or germline mutations) or the influence of the environment on tumor development (exposure to carcinogens or surrogates of risk such as epigenetic changes in the airway epithelium or the prevalence of preinvasive lesions). There has been recent interest in the potential for genetic variants to give insight into the pathogenesis of lung cancer. These variants indicate that there is great heterogeneity in mechanisms of disease development that is modulated by inherited genetic variation. With these come the opportunity to improve models predicting lung cancer risk. A larger question of timeliness of biomarker use in clinical practice will be discussed during the presentation. What are the risk and benefits of precision screening? Are current risk prediction models safe to use or robust to guarantee an advantage over current standard of care? There is a clear need to evaluate the benefit of risk assessment biomarkers with repeated measures over time. The assumption is that as risk increases, molecular moieties should be more readily available (e.g. in the circulation) over time. This may be true for tumor specific antigens and ctDNA, but would not apply to genetic risk. Statistical models could test the ability of different biomarkers to complement each other in a single population, in order to eventually determine those that could be tested prospectively. Given biomarkers' non-specificity and commonality in predicting diseases, modeling multiple markers of the same clinical diagnostic criteria can be used to develop more accurate individual and cumulative risk estimates for specific diseases. We should therefore consider a joint effects approach to determine individual biomarker associations as well as to ascertain the impact of simultaneous increases in multiple biomarker concentrations on the diagnosis of lung cancer. Biomarkers of risk would ideally be tested prospectively in a randomized clinical trial. However, given the relatively low prevalence of this disease, the number needed to screen may be prohibitive; therefore the development of registries is most appropriate. Registries are longitudinal cohort prospective studies where a biomarker is introduced but does not force providers to change their management. The lead time to diagnosis may be sufficient to cause a stage shift and therefore improve outcome. Finally, it is through better understanding of the biology of cancer development and of preinvasive lesions that we will shed further light into the field of biomarker research.

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Abstract:
The UKLS Trial and cost effectiveness The pilot UKLS lung cancer RCT screening trial recruited 4,000 individuals [1], using the LLP~v2~ risk model (5% risk over 5 years) [2]. The lessons learnt from the UKLS CT pilot screening trial are: UKLS – A Population based trial – all IMD’s (socioeconomic groups) included [1]. Risk Stratification (LLP~v2~ 5 % risk over 5 years) [2] Volumetric assessment of CT detected nodules [3]. Care Pathway – Management pathway implemented [3]. Early Stage Disease (Stage 1 68%: Stage I&II 86%) [4] High Proportion suitable for Surgery (83%) [4] 1.7% lung cancers identified at baseline scan [1] Benign Resection rate – 10.3% (NLST 27%)[1] Psychological impact – transient not significant [5, 6] Cost effectiveness modelling within NICE parameters [1] The cost effectiveness of the UKLS trial has been modelled and compared with that of the US National Lung Screening Trial (NLST), which has published an estimate of $81,000 per quality-adjusted life-year (QALY) as its mean incremental cost-effectiveness ratio (ICER) [7]. All UKLS cost estimates were based on 2011-12 NHS tariffs (Costs provided in $: £1=$1.5 on 30-11-15). Owing to the brief duration of the trial, observations relevant to economic evaluation were limited to cost-incurring events associated with screening and the initial management of screen-detected cancers. Expected outcomes of the cancers detected were simulated on the basis of both life tables and published survival data from other studies. The costs incurred from UKLS are those of baseline and repeat screens ($424,072), diagnostic workup ($113,478), and treatment ($449,243), which totaled $1,036794 (95% CI, $719,332 to $1,350,766). Recruitment costs ($15) per person for invitation and selection) were modelled from the UK colorectal screening programme and we assumed a participation rate of 30% of those invited. The gross current costs of the programme amounted to $1,133,217 (CI $817,887 to $1,450,610). Summary of findings: The ICER of screen-detection compared with symptomatic detection was estimated at $9495 per life-year gained. Using data from previous studies, we associated quality of life weights with the estimated survival gains, enabling us to report outcomes as QALYs. On this basis, the ICER equaled $12,709 per QALY gained (CI $ 8280 to $18966). The difference in cost effectiveness between NLST and UKLS as suggested by the estimated ICERs is more apparent than real. Most of the discrepancy can be explained by differences between settings in (i) local unit costs, (ii) intensity of resource use, (iii) number of screening rounds and (iv) disease prevalence in the target population. Thus, UKLS selected high-risk subjects only whereas NLST screened a general population, yet the latter reported an ICER as low as $32,000 for its highest-risk quintile. Expected QALY gains from screen-detection were similar in both trials. Figure 1