Virtual Library

Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.

Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).

Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.

Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.

Background:
Ensartinib is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1, and SLK. Ensartinib has demonstrated significant anti-tumor activity in both ALK TKI-naïve and crizotinib-resistant NSCLC patients. We report on data from ALK TKI treatment naïve patients.

Method:
Pts with advanced solid tumors and ECOG PS 0-1 were treated with ensartinib 225 mg qd on a continuous 28-day schedule. In expansion phase, pts were required to have measurable ALK+ NSCLC with tissue confirmed centrally via FISH or IHC. Asymptomatic brain metastases were allowed. Targeted NGS of cfDNA was performed retrospectively at baseline and on study and compared with tissue results.

Result:
As of 01Apr2017, 102 pts enrolled. In the ALK TKI naïve cohort, 15 (8 female, 7 male) ALK+ NSCLC pts treated at doses ≥ 200 mg evaluable for response. 4 pts had received prior chemotherapy. Median age 59 (34-80) yrs, 60% had ECOG PS 1. Partial response (PR) achieved in 13 pts (87%). Six pts had ALK detected via plasma NGS. In two patients who did not respond to ensartinib, tissue was positive via FISH and plasma was negative. Seven patients had insufficient plasma for NGS evaluation. Median PFS in the initial 13 evaluable ALK+ pts was 25.6 mos with the longest being 44+ mos. The PFS for all patients is still maturing. In 3 pts with central nervous system (CNS) target lesions and no prior radiation, 1 had a complete response (CR) and 2 had PR for an ORR of 100%. Most common drug-related AEs (>20% of pts) included rash (54%), nausea (34%), pruritus (26%), vomiting (25%), and fatigue (21%). Most AEs were Grade (G) 1-2. Most common G3 tx-related AE was rash (12 pts).

Conclusion:
Ensartinib was well-tolerated and induced responses in ALK TKI naïve ALK+ NSCLC pts, including pts with CNS lesions. Enrollment is ongoing in the phase 3 study of ensartinib vs. crizotinib in ALK TKI naïve NSCLC patients.

Background:
The incidence of venous thromboembolic events all along the course of the disease in advanced-stage lung adenocarcinomas is approximately 15 %. It is plausible that the different molecular subtypes might influence on the risk of thrombosis. Based on our clinical observation, and supported by limited data from isolated small series, patients bearing ALK rearranged tumors could be at a particularly high-risk of thromboembolic disease.

Method:
We included consecutive patients diagnosed with advanced-stage ALK fusion positive non-small cell lung cancers (NSCLC) between January 2012 and December 2016. Clinical data were contributed by 29 Medical Centers from Spain and one large Academic Cancer Center from Portugal. Investigators at each institution retrospectively reviewed patients’ medical records. A thromboembolic event was defined as any venous or arterial thromboembolism, or both, at any site, documented by appropriate imaging studies, that occurred at the time or after advanced-stage cancer diagnosis.

Result:
A total of 241 ALK-rearranged NSCLCs were included in our study. Half of the patients were never smokers (52 %), and most had stage IV pulmonary adenocarcinomas (n=204, 85%). Baseline brain and liver metastasis were detected in 22 % and 25 % of the patients respectively. Seventy-three patients (30 %) developed thromboembolic disease. In 54 patients (74 %) thromboembolic complications occurred within the first 6 months from diagnosis. In the multivariate competing-risk regression analysis, the presence of baseline liver metastases (HR of 1.85, CI 95 % 1.09-3.15; p = 0.021) and baseline leukocyte counts > 11.0000 cells/mm3 (HR of 2.34, CI 95 % 1.43-3.82; p = 0.001) were independent predictors of thromboembolic disease. Remarkably, 50 % of the patients with either liver metastases or leukocytosis at diagnosis developed thromboembolic disease. Patients experiencing thromboembolic events had shorter median overall survival (OS) (20 months) than patients without thrombosis (36 months) (p = 0.035). In the multivariate Cox Model, thromboembolic disease remained associated with worse OS (HR of 1.70, CI 95 % 1.10-2.62; p = 0.016) when considered as a time-varying covariate. The presence of baseline thromboembolic disease (n = 24) was associated with a numerical non-significant increased risk of death (HR 1.67, CI 95 % 0.96-2.91; p = 0.068).

Conclusion:
Venous and/or arterial thromboembolic complications occur in a high proportion of patients with advanced-stage ALK fusion positive NSCLCs, particularly in the presence of baseline liver metastasis or leukocytosis. The development of thromboembolic disease is associated with a lower OS in these patients.

Background:
Brain metastases are common in patients with advanced non–small cell lung cancer (NSCLC). Approximately 1% of NSCLC patients have ROS1-rearranged, and these patients achieved prolonged survival when treated with crizotinib, which is approved for the treatment of ROS1-rearranged NSCLC. However, this efficacy might not translate to intracranial control of disease. Herein, we evaluated the clinical impact of crizotinib on brain metastases in patients with advanced ROS1-rearranged NSCLC.

Method:
Between April 2014 and October 2016, 53 ROS1-rearranged NSCLC patients treated with crizotinib were retrospectively evaluated for baseline characteristics, brain metastases status, progression patterns and the overall prognosis.

Result:
Of the 53 ROS1-rearranged NSCLC patients who received crizotinib as treatment, 13 (24.5%) patients had baseline brain metastases before crizotinib treatment. Among patients without baseline brain metastases who developed progressive disease after initiation of crizotinib (n=27), 22.2% were diagnosed with brain metastases. Among patients without baseline brain metastases, systemic progression-free survival (PFS) and overall survival (OS) after initiation of crizotinib was significantly longer than that of patients with brain metastases (median PFS: 20.4 months vs. 11.0 months, p = 0.003; median OS: not reached vs. 16.5 months, p = 0.027). There was no significant difference in systemic PFS and OS between patients developing brain metastases before and after crizotinib treatment (median PFS: 11.0 months vs. 6.4 months, p = 0.469; median OS: 16.5 months vs. not reached, p = 0.605). Among the patients with baseline brain metastases, 6 had received prior brain radiotherapy and 7 had received no prior radiotherapy. A total of 2 patients in the treated group had an event of brain metastases progression, as compared with 4 patients in the untreated group (33.3% vs 57.1%, p = 0.592). There was no significant difference in intracranial PFS in the previously brain treated patients versus the untreated patients before crizotinib treatment (median intracranial PFS: 12.5 months vs. 11.0 months, p = 0.790).

Conclusion:
Brain metastases status before crizotinib treatment was significantly associated with both PFS and OS in crizotinib-treated ROS1-rearranged NSCLC patients. Patients with brain metastases received prior radiotherapy have not prolonged survival compared with the patients treated with crizotinib alone.

Abstract not provided

Background:
Treatment of ALK-rearranged Non-Small Cell Lung Cancer (NSCLC) relies on ALK tyrosine kinase inhibitors (TKI). However, efficacy of ALK TKI is limited by the emergence of drug resistance. ALK molecular alterations (amplification or mutation) account for about 40% of mechanisms of resistance to ALK TKI. Even though clinical and fundamental data suggest variability in drug efficacy according to the mechanism of resistance, these mutations are rarely investigated in routine practice. While targeted next-generation sequencing (t-NGS) is increasingly used for detecting molecular abnormalities, the impact of this tool in routine detection of ALK alterations is unknown.

Method:
We performed a retrospective multicentric study aiming at determining the frequency of ALK alterations using t-NGS in metastatic ALK-rearranged NSCLC patients progressing upon ALK TKI. Clinical, pathological, molecular characteristics, and patients outcome were collected.

Result:
We identified 22 patients with metastatic ALK-rearranged NSCLC who underwent a rebiopsy at progression on first ALK TKI, between January 2012 and May 2017. There were 12 females and 10 males, median age was 55, 18 patients (82%) were never smokers. Crizotinib was the first ALK TKI in 21 patients (95%). 15 patients (68%) received a second-generation ALK inhibitor and 3 patients (14%) received a third generation of ALK inhibitor. t-NGS on rebiopsy was performed in 16 patients. 6 ALK mutations (37.5%) were identified, including 3 G1202R, 1 C1156Y, 1 V1180L and 1 L1196M mutations . An ALK amplification (6%) was detected in a rebiopsy (6%) by FISH, with no concomitant ALK mutation. All ALK mutations were detected in solid biopsy, 2 ALK mutation was also detected in liquid biopsy. Median Overall Survival from first ALK TKI was 797 days (IC 95% 460-1135) and tended to be longer in patients with a known mechanism of resistance (1135 days Vs 543 days p=0.2).

Conclusion:
Targeted NGS is feasible in routine practice for detection of mechanisms of resistance to ALK TKI in ALK-rearranged NSCLC patients and may help selecting the best treatment at progression upon ALK TKI.

Background:
Advanced ALK+ non-small cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes among patients treated with ALK TKIs vary, and the clinical benefit of TKI therapy is limited due to acquired resistance. To date, emerging data suggest that the specific EML4-ALK variant may impact clinical outcome, but whether variant is associated with mechanisms of TKI resistance is unknown.

Method:
We identified 108 advanced ALK+ NSCLC cases with known ALK fusion variants. Progression-free survival (PFS) on ALK TKIs and resistance mechanisms were retrospectively evaluated according to ALK variant.

Result:
The 108 ALK+ cases consisted of: 42 (39%) EML4-ALK v1 (E13;A20), 8 (7.4%) v2 (E20;A20), 45 (41.7%) v3 (E6;A20), 3 (2.8%) v5 (E2;A20), 4 (3.7%) v5’ (E18;A20), 1 (0.9%) v7 (E14;A20), and 5 (4.6%) non-EML4-ALK variants. Given the small numbers of non-v1/v3 cases, v1 and v3 cases were selected for further analysis. Among the 21 v1 and 25 v3 cases treated with first-line crizotinib, there was no significant difference in PFS (HR = 0.81 [95% CI, 0.42-1.57], p = 0.526). Similarly, there was no difference in PFS on second-generation ALK TKIs among 35 v1 and 35 v3 patients who received ceritinib, alectinib, or brigatinib following first- or later-line crizotinib (HR = 1.32 [95% CI, 0.77-2.26], p = 0.308). Interestingly, among 12 v1 and 17 v3 patients who received the third-generation TKI lorlatinib after failure of a second-generation TKI, v3 was associated with significantly longer PFS than v1 (HR = 0.250 [95% CI, 0.09-0.72], p = 0.006). From our cohort, we identified 11 v3 and 14 v1 post-crizotinib biopsies. No difference was noted in the presence of ALK resistance mutations (27% and 21%, respectively; p = 1.000). In contrast, among 30 v3 and 18 v1 post-second generation TKI biopsies, ALK resistance mutations were more common among v3 vs v1 cases (66% vs 44%, respectively; p = 0.147). Furthermore, the ALK G1202R solvent front mutation occurred more frequently in v3 vs v1 (47% vs 0%, respectively; p = 0.001).

Conclusion:
Our findings suggest that EML4-ALK variants 1 and 3 may not be associated with significantly different PFS outcomes on crizotinib or second-generation ALK TKIs. However, ALK resistance mutations, particularly G1202R, occur more frequently in v3 vs v1 post–second generation TKI. Patients with this variant may therefore derive particular benefit from third-generation, pan-inhibitory ALK TKIs. Larger, prospective studies will be needed to confirm these findings.

Background:
ALK resistance mutations are detected in 30-50% of the patients with ALK-positive non-small cell lung cancer (NSCLC) and resistance to ALK tyrosine kinase inhibitors (TKIs). Preliminary data suggests that TKI-resistant patients benefit from further ALK inhibition based on the specific resistant mutations, but clinical data are limited.

Method:
Patients with ALK-positive NSCLC were identified from our institutional database with IRB approval. Tumor specimens from patients with TKI-resistance were analyzed using next-generation sequencing (NGS). We aimed to study the relationship between specific ALK-resistant mutations, patient characteristics and clinical outcomes.

Result:
Among 82 ALK-positive NSCLC patients, we identified 29 cases with advanced disease, TKI resistance, and specimens available for NGS. Twenty-two specimens from 19 patients were adequate for genomic analyses. Patients received a median of 4 lines of treatment for advanced disease including a median of 2 ALK TKIs, with a median overall survival (OS) of 3.3 years. In 9 of 22 specimens, crizotinib was the only TKI received. Ten specimens (45.5%) showed an ALK resistance mutation: one G1128A, one L1152R, four I1171N/T, two F1174V and two G1202R. ALK-resistance mutations were more common with EML4-ALK variant 3 (4/5) than variant 1 (1/5). Three cases with sequential biopsies showed features of tumor evolution, such as a compound mutation (I1171N + C1156Y) or a mutational change (L1152R to G1128A). One case initially had an EGFR L858R mutation, then acquired an ALK rearrangement, then acquired a G1202R mutation. OS was longer in 8 patients with secondary ALK mutation (5.5y) compared to 11 patients without (1.8 y). Using these learnings from an institutional cohort of ALK resistant patients, we designed and are launching a prospective study to characterize ALK TKI resistance, which uses remote-participation and plasma NGS to enroll patients from across the US. Patients with systemic progression while on a next-generation ALK TKI submit blood to a central lab for analysis and banking. Plasma NGS results are returned to the patient and their provider, and including expected TKI sensitivities for any identified ALK-resistance mutations. Through monitoring outcomes, this study can assess if molecularly-guided therapy for ALK TKI-resistance is feasible and effective.

Conclusion:
ALK resistance mutations arise in a large portion of patients and are associated with longer survival. The SPACEW-ALK study (Study of Plasma next-generation sequencing for remote Assessment, Characterization, Evaluation of patients With ALK drug resistance) uses plasma NGS and remote consent to assess ALK resistance and the feasibility of precision resistance therapy for these patients.

Background:
ALK, ROS1 and TRK kinase inhibitors have achieved tremendous success in the treatment of lung cancer patients with abnormal ALK, ROS1 or NTRK gene. However, the emergence of drug resistance limits their long term clinical applications. An ever increasing number of acquired resistance mutations are being reported from the clinic. In addition to the gatekeeper mutations, the solvent front mutations have been recently recognized as common resistance mutations to many kinase inhibitors. For example, the solvent front ALK G1202R mutant conferred resistance to many clinical ALK inhibitors in lung cancer including crizotinib, ceritinib, alectinib, and brigatinib. The same position mutations ROS1 G2032R, TRKA G595R and TRKC G623R rendered resistance to the ROS1 inhibitor crizotinib in lung cancer, pan-TRK inhibitor entrectinib and larotrectinib in colon cancer, and larotrectinib in infantile fibrosarcoma, respectively.

Method:
A conserved glycine residue at the hinge C-terminal forms a hydrophobic sandwich with the kinase beta 1 sheet. Kinase inhibitors often use an aromatic ring or a flat motif to fit through this narrow glycine sandwich to the solvent. Alterations at the conserved glycine or the nearby residues, commonly referred to as solvent-front mutations, clash with the inhibitor motif and induce clinical resistance. Here, we designed TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current ALK, ROS1, and TRK inhibitors in the clinic to avoid the steric clash inside the sandwich.

Result:
TPX-0005 resides at the center of the highly conserved ATP site without direct contact with the solvent front glycine sandwich. As expected, TPX-0005 potently inhibited WT EML4-ALK and solvent front mutant EML4-ALK G1202R with similar activities in both enzymatic (WT Ki 0.87 nM vs G1202R 0.81 nM) and Ba/F3 cell proliferation assays (WT IC~50~ 21.1 nM vs G1202R 20.5 nM). TPX-0005 showed potent activities against CD74-ROS1 G2032R (IC~50~ 8.4 nM), LMNA-TRKA G595R (IC~50~ 0.4 nM), TEL-TRKB G639R (IC~50~ 1.9 nM) and TEL-TRKC G623R (IC~50~ 0.4 nM) in Ba/F3 cell proliferation assays. In the xenograft tumor model studies, TPX-0005 dramatically caused tumor growth inhibition and tumor regression in the tumors carrying WT and solvent-front mutations of ALK, ROS1 or TRKA fusion genes, respectively.

Conclusion:
Taken together, preclinical results demonstrated that TPX-0005 is a novel ALK/ROS1/TRK inhibitor overcoming the profound solvent front kinase mutations. TPX-0005 will bring new methods for the treatment of resistance patients with solvent front mutations in ALK, ROS1, or TRK fusion genes. A phase 1/2 study of TPX-0005 in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements (TRIDENT-1) is actively pursued (NCT03093116).

Abstract not provided

Background:
Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with vinca-alkaloid, has been approved for clinical use in HER2-positive breast cancer. HER2-alterations are detected even in non-small-cell lung cancer (NSCLC). We have launched a phase II trial of T-DM1 monotherapy for patients with HER2-positive lung cancer.

Method:
Eligible patients had pathologically diagnosed NSCLC with documented HER2-positivity (immunohistochemistry [IHC] 3+, both IHC 2+ and fluorescence in situ hybridization [FISH] +, or exon 20 insertion mutation) and were previously treated with standard chemotherapy. Thirty patients would receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate (ORR) per RECIST v1.1.

Result:
This study was early terminated due to the limited efficacy, leading that only 16 patients were registered. The demographics of the 15 evaluable patients were as follows: age (median; 67, range: 45-77), sex (male; 47%), performance status (0-1; 80%), histology (non-squamous; 100%), HER2 status (IHC3+; 33%, IHC2+/FISH; 20%, and mutation; 47%) and number of prior chemotherapeutic regimens (median; 4, range: 1-7). Of 15 patients, one, who possessed HER2 mutation achieved a partial response, resulting in ORR of 6.7%. None of the 15 patients experienced treatment-related deaths. Survival data would be presented at the meeting.

Conclusion:
T-DM1 has a limited efficacy for HER2-positive NSCLCs in our cohort. Additional molecular approaches are warranted for the precision medicine in HER2-positive tumors. UMIN registration number 000019446.

Background:
There are currently no effective targeted therapies for HER2 mutant lung cancer. Both neratinib alone or in combination with temsirolimus both have low response rates. One challenge is the lack of patient derived HER2 mutant cell line models and a platform in which to identify the most effective therapeutic strategy. Patient derived xenografts (PDXs) are emerging as an alternative tool to screen for drug efficacy, but can take months to generate and are impractical for screening of large sets of drug combinations. Here we report on a novel 3D microfluidic platform that allows for evaluating ex vivo responses to targeted therapies or targeted therapy combinations from patient derived tumor spheroids (xDOTS).

Method:
We generated xDOTS from DFCI 359, a PDX derived from a HER2 mutant (InsYVMA) NSCLC patient under an IRB approved protocol. Tumor organoids (<100 μm and >40μm) were treated with: HER2 covalent inhibitors (neratinib, afatinib); an EGFR inhibitor (gefitinib), and combinations of HER2 inhibitors and other compounds (neratinib/trastuzumab or neratinib/temsirolimus) at known peak plasma concentrations for 3 days in our 3D microfluidic cell culture device. Live/death quantification was performed by dual labeling de-convolution fluorescence microscopy using acridine orange for live and propidium iodide for dead cells. Cell type characterization was performed by immunofluorescence. The most effective combination was used to treat the DFCI 359 PDX and a HER2 InsYVMA genetically engineered mouse model (GEMM).

Result:
Both neratinib alone and afatinib alone, but not gefitinib, induced high degree of cell death in the DFCI 359 xDOTS. The combinations of neratinib/trastuzumab, and neratinib/temsirolimus enhanced the therapeutic benefit compared to neratinib alone, with the former combination being more effective than the latter. Using fluorescence microscopy we demonstrate that the effects are specific to the tumor cells, rather than the stromal component. We then went on to confirm these findings in a concomitant in-vivo efficacy experiment using the DFCI 359 PDX and the HER2 InsYVMA GEMM. In both in vivo models, the neratinib/trastuzumab combination led to significant tumor regressions and was superior to either single agents or the neratinib/temsirolimus combination.

Conclusion:
Our findings demonstrate the ability to use a 3-D in vivo microfluidic system to identify combination therapies for HER2 mutant NSCLC. Based on our studies, neratinib/trastuzumab is a promising combination for a clinical trial for HER2 mutant lung cancer.

Background:
Human epidermal growth factor 2 (HER2, ERBB2) mutations / amplifications have been identified as oncogenic drivers in 2-5% of lung cancers. It has been reported that hybridization capture-based next-generation sequencing (NGS) could reliably detect HER2 amplification in qualified breast and gastroesophageal tumor tissue samples. However, there is little data in lung cancer, especially for advance NSCLC with only ctDNA samples available.

Method:
We reviewed 2000 consecutive samples from advanced NSCLC patients sequenced in our institute between 2015 and 2016. Tumor biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59 – 1021 genes).

Result:
We identified 54 samples from 48 patients with HER2-mutation or amplification in the cohort (54/2000=2.7%). The 54 samples included 14 tissue biopsy samples, 37 ctDNA samples, and 3 pleural effusion samples. Thirty-six samples carried HER2 mutations, and 23 samples carried HER2 amplification with 5 samples have concurrent HER2 mutation and amplification. A 9-base pair (bp) in-frame insertion in exon 20 (Y772_A775dup) was detected in 18 samples (18/36=50%). In addition, there were 5 other insertions in exon 20; eight single bp substitutions (S310F) in exon 8; three exon 17 V659E mutations (from the sample patient with 3 ctDNA samples submitted at different time); one exon 19 D769H mutation; and one exon 21 V842I mutation. Amplification were identified in 23 samples, with copy number range from 3.8 to 19.6 in tissue samples (n=7, medium 11.6); from 4.3 to 51.8 in ctDNA samples (n=16, medium 7.3); 3.2 and 6 in the 2 pleural effusion samples. Interestingly, the allele frequency (AF) of HER2 mutation was the maximal in 4 of the 5 patients with concurrent HER2 mutation and amplification. Two patients were EGFR-TKI resistant with EGFR L858R mutation remaining and HER2 mutation and amplification might be the major reason for the resistance.

Conclusion:
HER2 mutations might coexist with HER2 amplification in advanced NSCLC patients, and it could be detected simultaneously with hybridization capture-based NGS sequencing both in tissue and liquid biopsy samples. Further quantative analysis of HER2 amplification / mutation and anti-HER2 therapeutic effects are underway.

Abstract not provided

Abstract not provided

Background:
Lobectomy is the preferred treatment for patients with early stage non-small cell lung cancer (NSCLC). However, stereotactic body radiation therapy (SBRT) is an attractive option due to its promising efficacy reported recently. Given that prospective comparative data on lobectomy and SBRT are limited, we compared the two treatments for early stage NSCLC.

Method:
All patients undergoing treatment with lobectomy or SBRT for clinical early stage (T size≤5cm) NSCLC between January 2012 and June 2017 were reviewed. Age, gender, tumor characteristics, Charson Comorbidity Index, pulmonary function, local control rate (LCR), recurrence-free survival (RFS), overall survival (OS) data were collected and propensity matching performed.

Result:
For the entire lobectomy cohort, 3-year OS, DFS, and LCR were 87.9%, 84.9%, and 96.4% respectively. For the entire SBRT cohort, 3-year OS, RFS and LCR were 84.4%, 60.7% and 93.4%, respectively. A total of 246 patients underwent surgery, and 117 received SBRT. There were statistically difference between surgical patient and SBRT patients in tumor histology(P<0.000). Surgical patients had tendency that have longer tumor size than SBRT patients (2.4±1.0 vs. 2.1±0.8, P=0.092). There were no statistically difference between lobectomy and SBRT group with age (68.9±6.6 vs.69.0±9.2, P=0.980), Eastern Coorperative Oncology Group performance scores, Charlson comorbidity Index, pulmonary function test result (FEV1 and predict FEV1), gender, T stage, and tumor location. A propensity matched comparison in a blinded manner (1:1 ratio, caliper distance=0.0025) based on age, gender, WHO performance status score, pulmonary function (forced expiratory volume in 1 second [FEV1] % and FEV1), and T stage resulted in 49 matched pairs. The follow-up period ranged from 0.3 to 60.0 months, with a median of 21.4 months. There were no differences between lobectomy and SBRT in LCR, respectively 97.1% and 100% (p=0.355) at 4 year. Also the 4-year RFS was comparable between groups, as 68.6% after lobectomy, versus 81.9% at 4 year after SBRT (p=0.963). The 4-year OS was similar in both groups, with 58.1% vs. 75.2% for lobectomy and SBRT (p=0.774). No patient experienced treatment-related death in both groups.

Conclusion:
This retrospective analysis found no significant difference in LCR, RFS and OS between lobectomy and SBRT. This study indicated matching these disparate cohorts of patients remains challenging. Participation in clinical trials is essential to define the indications and relative efficacy of lobectomy and SBRT in a high-risk population.

Background:
Stereotactic body radiotherapy of “ultra-central” (UC) lung tumours, PTV directly abuts/overlaps the proximal bronchial tree (PBT), trachea, esophagus, pulmonary vein/artery, are considered to be at higher risk of toxicity. The purpose of this study is to review the outcomes and toxicities of Ultra-central lung tumours, compared to central tumours.

Method:
A retrospective review based on a prospective database of patients treated with lung SBRT from January 2006- December 2015 was conducted. Patients with central tumours defined using RTOG 0813 criteria and ultracentral tumours were included. 115 patients (53%) received 60Gy/8 and 61 (28%) received 48Gy/4. At our institution, the recommended Dmax for esophagus is 45Gy and 40Gy for 8 and 4 fractions, respectively. The Dmax and D10cc constraints for trachea, proximal bronchial tree, heart, and major vessels (including pulmonary artery and vein) are 48Gy and 40Gy for 4 fractions and 64 and 60Gy for 8 fractions. Toxicity was graded using CTCAE v3.0. Log-rank test was used to compare overall and cause-specific survival. Local, regional, and distant recurrence were compared using Gray’s test.

Result:
215 tumours were analyzed (189 C and 26 UC). The median age for C and UC were 75 years and 72.5 years. Median tumour size and PTV volume were 2.2 cm (range 0.9-5.7) and 41.7 cm3 (range 9.7-246.3) (C group) and 2.5 cm (0.8-5.5) and 58.2 cm3 (16.8-238.3) (UC group). The percentage of squamous cell carcinoma was higher in the UC group (15%, n=29 in C; 38%, n=10 in UC). The median follow-up was 20.3 months (24.5 mo for patients still alive). Median overall survival (OS) and cause-specific survival (CSS) was 34 mo and 53.8 mo for C and 20.1 mo and 28.2 mo for UC, respectively. Differences in OS and CSS between the two groups did not meet statistical significance (p=0.24 and p=0.14, respectively). Local, regional, and distant failure rates were 3%, 8% and 18% in the central tumour group and 0%, 9% and 25% in the ultra-central tumour group at 2 years. There was no statistically significant difference found in the rates of recurrence between the two groups. The rates of any grade 2 or higher toxicity (hemoptysis, esophageal toxicity, cough, dyspnea, pneumonitis) was 9% (n=17) in the C and 7.7% (n=2) in UC group (p=0.89). There were no known grade 4 or 5 toxicities.

Conclusion:
In our experience, SBRT to ultra-central tumours resulted in effective local control and no excessive risk of toxicity compared to central tumours.

Abstract not provided

Background:
We hypothesized that impaired pulmonary functions tests might predict for altered lung density which would interfere with the efficacy of radiotherapy. We therefore sought to determine if there are associations between pre-treatment [preTx] forced expiratory volume in 1 second (FEV1, in L and as % predicted [%p]) and diffusion capacity (DLCO, as %p) with local failure (LF) rates seen with lung stereotactic body radiotherapy (SBRT) for medically inoperable lung cancer.

Method:
From an IRB-approved institutional prospective SBRT registry of 1330 patients, we identified 557 treated definitively for medically inoperable early stage T1-T3N0M0 non-small cell lung cancer (NSCLC) between 2003 and 2016 for whom both preTx FEV1 and DLCO were available. Lung SBRT dose/fractionation for a given pt was at the discretion of the treating physician. LF was defined as progressive and increasing CT scan abnormalities confirmed by progressive and incremental increases in lesion SUVs on serial PET imaging, with or without biopsy. Predictors of LF were determined using competing risks regression and rates of local control were determined from cumulative incidence analysis.

Result:
Pt characteristics included: female gender (52.6%); median age 74 years (range 42-95); median KPS 80 (range 50-100); median preTx FEV1 and DLCO: 1.39L (range 0.26-3.87), 60 %p (range 13-151) and 52 %p (range 10-143), respectively. Tumor characteristics included: median diameter 2.2 cm (range 0.7-7.2); median PET SUVmax 7.7 (range 0.8-56); % as T stage 1a, 1b, 2a, 2b, 3: 40.2; 35.5; 18.9; 4.5; 0.9, respectively; “central” location (per RTOG 0813) 22.6%. Median follow up was 18.3 months. At analysis, 46.9% pts were alive. Treatment characteristics included 50 Gy/5 fractions (fx) for 235 pts (42.2%), 60 Gy/3 fx for 167 pts (30%), and other schedules for 155 pts (27.8%), with the latter excluded from analysis due to variability in schedules, leaving 402 pts (72.2%). Only dose was significantly associated with LF on multivariable analysis [p=0.0057; HR =3.416, 95% CI 1.429-8.166]. Three-year cumulative incidence of LF post-SBRT for 50 Gy/5fx and 60 Gy/3 fx was 15.2% and 2.3% [p=0.024], respectively. In subset analysis of the 50 Gy/5 fx, DLCO was significant for LF both as a continuous variable and as a categorical variable. The significant cut-off for DLCO was 45%p, such that 3-year LF at <45 was 24.7% (95% CI 13.6-35.8) and at > 45 was 10.6% (95% CI 5.3-16.0), [p=0.0234; HR =0.441, %95 CI 0.217-0.895[CR1] ]. There were no significant associations between LF and pulmonary functions tests for 60 Gy/3 fx.

Conclusion:
As preTx DLCO drops below 45 %p, our findings suggest local failure increases when lung SBRT is delivered as 50 Gy/5 fx for early stage NSCLC. This warrants validation in prospective series.

Background:
Central nervous system (CNS) metastases, including brain metastases (BM) and leptomeningeal metastases (LM) represent a frequent complication of non-small cell lung cancer (NSCLC). Patients with CNS metastases comprise a heterogeneous group, with a median survival that ranges from 3 to 14 months. Local therapies, such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) or surgical resection, are available treatment strategies for BM. Introduction of tyrosine kinase inhibitors (TKIs) in clinical practice has led to individualization of therapy based upon the presence of the exact abnormality, resulting in a major therapeutic improvement in patients with NSCLC who harbor epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) gene rearrangements, respectively, but their role in combination with radiotherapy is controversial

Method:
We performed a systematic literature review of published data in PUBMED, SCOPUS and COCHRANE databases, as well as a manual search of reported data in major congresses, using the terms "EGFR-TKIs", "ALK-TKIs", "CNS", "BM" or ""LM" and "concurrent radiotherapy" or "stereotactic radiotherapy" from January 2000 through May 2017. Only prospective or retrospective clinical trials and meta-analyses reported in English language were included

Result:

Author/year	Phase	No of pts	EGFR status	Treatment groups	Control	Outcomes
Lind et al 2009	I	11	NA	Cohort 1: Erlotinib 100 mg +WBRT Cohort 2: Erlotinib 150 mg +WBRT		-Grade 3-5 toxicity in cohort 2 -High IDCR
Welsh et al 2013	II	40	EGFR mutant: 9 of 15 pts tested	Erlotinib 150 mg + WBRT		-ORR 86%, -Median OS 11.8 m -Median OS 19.1 m in EGFR mutant
Sperduto et al 2013	III	126 (closed early)	NA	Arm 2:TMZ+WBRT+ SRS Arm 3: Erlotinib 150 mg + WBRT+SRS	Arm 1: WBRT +SRS	OS not improved with addition of drugs -No difference in CNS-TTP between the three arms -49% grade 3-5 toxicity in arm 3
Lee et al.2014	II	80	EGFR mutant 1 out of 35 pts tested	WBRT + Erlotinib	WBRT	No difference in OS
Ma et al. 2009	II	21	NA	WBRT +Gefitinib		ORR 86% -Median OS 13 m -No significant grade 3 toxicity
Pesce et al 2012	Randomized Phase II	59	NA	WBRT + Gefitinib vs WBRT+ TMZ		Median OS 6.3 m (Gefitinib arm), 4.9 m (TMZ arm) -No relevant toxicity
Zeng et al 2012	Retrospective	90	NA	WBRT +Gefitinib	Gefitinib	Higher ORR and OS with WBRT+ Gefitinib
Luo et al 2015	Metaanalysis	980 (8 trials)	NA	Radiotherapy + TKI (TKI group)	Radiotherapy or Radiotherapy+ chemotherapy (non-TKI group)	-Higher RR, CNS-TTP and OS in radiotherapy +TKI group -No difference is serious AEs
jiang et al 2016I	Metaanalysis	1552 (15 trials)	NA	Radiotherapy + TKI	Radiotherapy or Radiotherapy+ chemotherapy	Higher RR, DCR, CNS-TTP and OS in radiotherapy +TKI group -Increased rate of any grade AEs

Conclusion:
At this time, concurrent use of TKIs with radiotherapy, although appearing to be safe, is not recommended outside of a clinical trial. Interestingly, data in EGFR mutant patients treated with an EGFR-TKI alone prompt the question whether this could be a front line approach in patients with asymptomatic BM, reserving WBRT for symptomatic cases. In clinical practice, burden of extracranial disease might also guide treatment decisions; physicians might select not to discontinue a TKI during WBRT in case of extensive extracranial organ involvement Ongoing clinical trials are currently evaluating the effectiveness of concomitant use of radiotherapy and TKIs.

Background:
The treatment outcomes of patients with pulmonary oligometastases treated by SBRT were evaluated; the oligometastases were classified into three groups (oligo-recurrence, sync-oligometastases, and unclassified oligometastases) and the outcomes compared.

Method:
This study was limited to patients who had a BED10 ≥75 Gy. Oligo-recurrence was defined as a primary lesion that was controlled, the number of metastases or recurrences in the lung was one to five, and the disease-free interval (DFI), the interval between initial therapy of the primary lesion and the date of recurrence in the lung, was ≥6 months. Sync-oligometastases were defined as: the primary lesion was active; the number of metastases or recurrences in the lung and the active primary lesion was one to five; and the DFI was zero. The definition of unclassified oligometastases was similar to that of oligo-recurrence, but the DFI was <6 months. All oligomtastases in this study were treated by local therapy for all active lesions including primary and metastatic lesions.

Result:
Between 2004 and 2015, 1378 patients (male/female = 893/485; PS 0/1/2/3 = 746/474/85/17) meeting the study definition of pulmonary oligometastases were treated by SBRT in 68 institutions in Japan. Their median age was 72 years (16-93 years). The primary region was lung in 421, colorectal in 348, head and neck in 113, and others in 618. Histopathology showed adenocarcinoma in 761, squamous cell carcinoma in 358, and others in 186. Oligostatus was oligo-recurrence in 1013, sync-oligometastases in 118, and unclassified oligometastases in 122. The median maximum tumor diameter (MTD) was 1.5 cm (0.3-6.5 cm). The number of target tumors was solitary in 1037 and multiple in 341. The median BED10 was 105.6 Gy (75-289.6 Gy). The median DFI was 17.9 months (0-424 months). The median follow-up time was 24.3 months (0.1-143.7 months). The 3-year overall survival (OS), relapse-free survival, and local control rates were 60.3% (95%CI: 57.1-63.3%), 32.6% (95%CI: 29.7-35.5%), and 81.4% (95%CI: 78.8-83.7%). Univariate analysis showed only oligostatus, sex, PS, DFI, MTD, primary region, and histopathology were significant. The 3-year OS was 64.0% (95%CI: 60.4-67.5%) for oligo-recurrence and 50.6% (95%CI: 42.9-57.8%; p<0.001) for the others. Multivariate analysis of OS showed that only oligostatus (others/oligo-recurrence: HR 1.43), MTD (>2 cm/<2 cm, HR 1.45), histopathology (others/adenocarcinoma: HR: 1.47), and sex (male/female: HR 1.38) were significant.

Conclusion:
Pulmonary oligometastases, oligo-recurrence, female sex, adenocarcinoma, and small-sized tumor could be factors associated with longer survival.

Abstract not provided

Background:
Immune-related pneumonitis (IR-pneumonitis) is a potentially fatal toxicity of anti-PD-1/PD-L1. This study investigates the role of chest radiotherapy (RT) and the development of IR-pneumonitis in NSCLC patients treated with anti-PD-1/PD-L1.

Method:
Between January 2011 and April 2017, NSCLC patients treated with anti-PD-1/PD-L1 either as part of a clinical trial or as standard-of-care at a tertiary academic cancer center, were identified. Patient demographics, treatment, adverse event and RT data including type of RT (SBRT, 2D/3D conformal RT, IMRT, multiple), timing of RT (pre or post PD-1/PD-L1), location of RT (chest/non-chest), and number of courses of chest-RT, were collected in an IRB-approved institutional database. IR-pneumonitis was diagnosed clinically by the treating investigator; patients with confirmed RT pneumonitis, progressive NSCLC, or active infection were excluded. Associations between patient, treatment and RT parameters, and development of any grade IR-pneumonitis were evaluated using Student’s t-test and Fisher’s exact tests.

Result:
Of 184 NCSLC patients identified: median age was 67 years (range: 39-88); 57% (n=105) were male, 75% (n=137) were former/current smokers, 64% (n=118) had adenocarcinoma histology, and 59% (n=109) had advanced NSCLC at diagnosis. Anti-PD-1/PD-L1 monotherapy was received in 74% (n=136, nivolumab: 107, pembrolizumab: 14, durvalumab: 7, other: 8) and combination therapy in 26% of patients (n=48, PD-1/CTLA-4: 13, PD-L1/CTLA-4: 5, PD-1/chemotherapy: 4, PD-1/other: 25, PD-L1/other; 1). Any RT was received by 129 patients (70%), and 96 patients received chest-RT (52%). Thirty-eight (21%) patients developed IR-pneumonitis of any grade. IR-pneumonitis incidence was numerically higher in patients receiving combination therapy compared with monotherapy (29%, n=14/48 vs. 18%, n=24/136, p=0.1). Former/current smokers had a higher incidence of pneumonitis compared with never smokers (25% vs. 12%, p=0.03). IR-pneumonitis incidence was numerically higher in patients receiving chest-RT compared with non-chest/no RT (25%, n=24/96 vs. 16%, n=14/88, p=0.15). Of 129 patients who received any RT, there was a trend towards increased IR-pneumonitis in patients who received chest RT compared with those who received non-chest RT (25%,n=24/96 vs 9%, n=3/33; p=0.08). Overall, there were no significant associations between chest-RT type, chest-RT timing, nor receipt of more than one chest-RT course, and development of IR-pneumonitis (p>0.05).

Conclusion:
IR-pneumonitis incidence is 21% and may be higher than reported in clinical trials. Smoking status is associated with the development of IR-pneumonitis. Receipt of chest-RT was numerically higher, but not statistically associated with, development of IR-pneumonitis after receipt of anti-PD-1/PD-L1 in patients with advanced NSCLC. Radiation parameters did not associate with the development of IR-pneumonitis.

Background:
With interest in the use of isotoxic dose-escalated RT in treatment of inoperable NSCLC, this study investigated the impact of DIBH using the Active Breathing Coordinator™ (ABC- Elekta, Stockholm, Sweden) device on isotoxic dose escalation potential.

Method:
Following informed consent, a four-dimensional (4D) planning CT scan and a DIBH scan using the ABC device were acquired in patients sequentially in the same session. A motion-encompassing target volume on the 4D scan and a motion-managed target volume on the DIBH scan were created. The RayStation radiotherapy treatment planning system (research version 5.99.0.16) was used to generate two corresponding volumetric modulated arc therapy (VMAT) plans for each patient, following the guidelines of the isotoxic IMRT trial (NCT01836692). The target dose was escalated up to a maximum of 79.2 Gy in 44 twice daily fractions and plans optimised to minimise dose to normal tissues. Potential to escalate target dose and differences in dose-volume metrics between the plans were compared using the Wilcoxon signed-rank test.

Result:
21 patients were included. The mean total lung volume was significantly higher with DIBH compared to 4D scans with an increase of 44.7 % ± 17.4 % (mean ± standard deviation), p < 0.001). In 20/21 patients, the maximum target dose of 79.2 Gy was achievable in both plans, however in one patient 61.2 Gy was achieved with 4D compared to 75.6 Gy with DIBH planning. In the 20 patients achieving equivalent target dose-escalation, the mean lung dose was 17.0 Gy (± 0.3Gy ) with 4D versus 14.6 Gy (± 0.3 Gy) with DIBH (p < 0.001). There was a significant mean reduction in heart dose between the DIBH compared to 4D plans of 0.3 Gy (± 0.2 Gy, p< 0.001) and significant reductions in heart D100 %, D66 % and D33 %(p < 0.01). Mediastinal envelope and oesophageal doses were similar using both techniques.

Conclusion:
The use of DIBH compared to 4D planning aids lung and cardiac sparing in isotoxic dose escalated RT and for a small number of patients may allow an increase in target dose. Particularly given the interaction between lung and cardiac toxicity in locally advanced NSCLC treated with radical RT, use of DIBH for treatment may lead to a reduction in toxicity compared to a 4D approach. In acknowledgement of the use of a mid-ventilation technique in some institutions, comparison with this method is planned.

Background:
There is no objective criteria to quantify radiotherapy-induced lung damage (RILD), leading to under-reporting of toxicity across centres and trials. Our objective is to build a radiological scoring system of RILD that correlates with decline in lung function.

Method:
Baseline and 12-month CT scans and formal respiratory function tests (FVC, FEV1 and DLCO) from 23 patients enrolled in an isotoxic chemoradiation clinical trial (IDEAL CRT) were available for central review. First, the presence of new CT findings of RILD was qualitatively scored into eleven sub-categories: consolidation, ground-glass opacities, traction bronchiectasis, reticulation, pleural thickening, pleural effusion, reduction in lung height, distortions of the diaphragm, fissures, anterior junction line and major airways. From these, three main categories were derived: parenchymal change, pleural changes and volume reduction. The correlation between number of features scored and decline in breathing function was investigated. Later, twelve imaging markers were defined to quantify the severity of the radiological findings. The correlation between each imaging marker and decline in breathing scores was also investigated.

Result:
Each patient scored either two or three (out of three) categories of damage. Differences in variation of FVC, FEV1 and DLCO between these two groups were statistically significant (p≤0.02). The number of sub-categories scored was moderately correlated with decline in FVC (ρ=-0.67, p<0.01), FEV1 (ρ=-0.41, p=0.05) and DLCO (ρ=-0.50, p=0.01). Six of the twelve imaging markers were moderately correlated with changes in FVC and FEV1 (ρ≈-0.5, p<0.05); five were weakly correlated (ρ≈-0.2, p<0.05). The strongest correlations were found for imaging markers that quantify change in lung volume and shape, mediastinal shift and pleural reaction. Figure 1 Figure- Relationship between radiological findings of RILD and changes in FVC.



Conclusion:
We investigated the relationship between radiological findings of RILD and decline in lung function. Our findings suggest that a scoring system can be proposed when investigated in a larger cohort.

Background:
The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy. Alternative treatment options include sequential chemoradiotherapy and radiotherapy (RT) alone. As the rate of local failure is high there is a rationale for treatment intensification.

Method:
Isotoxic Intensity Modulated Radiotherapy (IMRT) is a multicentre feasibility study combining a number of intensification strategies; dose escalation, acceleration and hyperfractionation. Patients with inoperable stage III NSCLC, ECOG performance status (PS) 0-2, unsuitable for concurrent chemoradiotherapy were recruited. A minimum of 2 cycles of induction chemotherapy was mandated before RT. The dose of radiation was increased until one or more of the organs at risk (OAR) met predefined constraints or the maximum dose of 79.2Gy was reached. RT was delivered twice-daily in 1.8 Gy fractions. A RT quality assurance programme was in place. The primary end point was feasibility (>80% of patients achieving >60Gy EQD2 i.e. total biologically equivalent in 2 Gy fraction), with acute/late toxicity (CTCAE version 4.0), local control and overall survival as secondary end points.

Result:
Between June 2014 and March 2016, 37 patients were enrolled from 7 UK centres. Median age = 67 years (range 46-86). Male:female ratio = 18:19. ECOG PS=0, 5 (13.51%), PS=1, 29 (78.38%), PS=2, 3 (8.11%). Stage IIIa:IIIb ratio 23 (62.2%):14 (37.8%). Out of 37 patients, 2(5.4%) failed to achieve EQD2 >60Gy due to large tumour size and inability to meet OAR constraints, they received standard RT. This was due to large tumour size and inability to meet OAR constraints. Median prescribed tumour dose was 77.4Gy (61.2 – 79.2Gy) with the maximum dose of 79.2Gy delivered to 14 (37.8%) patients. All patients completed RT as scheduled except one due to disease progression. Grade (G)3 acute toxicities included: dysphagia 1 (2.9%), dypsnoea 2 (5.7%), lung infection 3 (5.7%) and radiation oesophagitis 2 (5.7%). There were three G5 events: radiation pneumonitis, trachea-oesophageal fistula and bronchopulmonary haemorrhage, which were probably treatment related. G3 late toxicities included: fatigue 1 (2.9%), dyspnoea 3 (8.6%) and 1 (2.9%) case of late G4 lung infection. At time of analysis median follow-up was 12.8 months for 20 survivors. Overall survival and progression-free survival at 1 year was 75% and 59% respectively.

Conclusion:
In the majority, treatment intensification using isotoxic IMRT is feasible. This regime will be tested alongside other intensified treatments against standard sequential chemoradiotherapy in the ADSCAN study (ISRCTN47674500).

Abstract not provided

Abstract:
Background: Despite recent advances, lung cancer remains a disease characterised by negativity, late diagnosis and poor outcomes. The need for advocacy in lung cancer is obvious. Recent years have seen an increase in the number of organisations and individuals advocating for improvements in this disease. With limited resources across all advocacy organisations, using external data and tools from other sources is welcome. Such a source is work undertaken by the Global Lung Cancer Coalition. The Global Lung Cancer Coalition: In 2001, a global search revealed the existence of only nine not-for-profit organisations with an interest in lung cancer advocacy. Of these, only two were lung cancer–specific, the others representing generic cancer or respiratory diseases. In coming together, these organizations established the Global Lung Cancer Coalition (GLCC), an allied group of registered not-for-profit, non-government organizations, dedicated to improving lung cancer outcomes. By 2017, the GLCC has grown to 36 member organisations, from 26 countries and provides a centralised communication and referral network. In recent years, the GLCC has undertaken a number of projects, creating data and tools, for all advocates to use, in their efforts to improve lung cancer outcomes. More information on all of these are available on the GLCC website – www.lungcancercoalition.org. Key Global Lung Cancer Coalition Projects - The Global Lung Cancer e-Atlas The e-Atlas is available on the GLCC website. It is an easily accessible source of international lung cancer data, including all WHO countries. The purpose was to collate lung cancer data from across the globe and uncover international variations. This includes incidence, mortality and survival data. Also, an indication of whether the country has Cancer Registry, has signed up to the WHO Framework on Tobacco and/or has a National Cancer Plan. The e-atlas brings all of this information together in an easily accessible place. This is a data resource for lung cancer professionals and campaigners. It is easy to compare data across countries and easy to create graphs, for download into powerpoint presentations and reports. This resource has already been used by many advocates, in discussions with politicians and health policy makers, to highlight differences in inter-country survival. The e-atlas will be updated, as international data sets are updated. Where possible, we will also add links to national lung cancer data sources. International Consumer Polls GLCC commissioned IPSOS/MORI to undertake two consumer polls in GLCC member countries in 2011 and 2013. These examined issues of stigma and also of general public awareness of lung cancer symptoms. In 2017, these two polls are being repeated by Populus and will be undertaken in 25 countries. This will provide update information in GLCC countries covered by the original polls and new information for newer GLCC member countries. Smoking stigma associated with lung cancer and poor public awareness of signs and symptoms of the disease are of obvious importance. Such polls provide valuable information for advocating and campaigning for improvement and change. Global Lung Cancer Research data The GLCC commissioned researchers at King’s College in London, to undertake some bibliometric research, to map published lung cancer research, across the globe. This type of research involves the quantitative analysis of publications and research activity, using complex bespoke algorithms This work was published, as an open access article, in June 2016 in the Journal of Thoracic Oncology. (Agarwal A, et al, ‘The State of Lung Cancer Research – A Global Analysis)’. Results of this work show the relative lack of lung cancer research globally. Individual Country Toolkits have been created to raise awareness of lung cancer research nationally and advocate for more. GLCC has commissioned further research in this area, investigating how published research is used – for example, does it change practice, how is the research implemented and what research is media reported. Information on Lung Cancer – Topical Factsheets GLCC has created factsheets in topical area, available for download from the GLCC website. These include Information on Clinical Trials and the relatively new therapy field of Immunotherapy. The Immunotherapy Factsheet is available in 16 languages. Factsheets are now also available on Lung Cancer Screening and Lung Cancer and Stopping Smoking. These are available for everyone to download and distribute. Lung Cancer Awareness Information Sheets The GLCC has created Awareness leaflets. These are designed for the general public, to inform on lung cancer – What to look out for? What to do? Where to go for help and support? The leaflets have been translated into 13 languages and are available for download on the Resource section of the website. In this presentation, all of the above will be expanded on. We invite all who advocate for improvements in lung cancer to use these resources.

Abstract:
The United States has no formal system of health technology assessment, compared to, for example, the system in the United Kingdom and many countries worldwide. In the U.S., certain federal agencies review and recommend approval of drugs and devices, while others make determinations regarding reimbursement of costs of treatment and other interventions. With the cost of health care in the U.S. skyrocketing in the absence of cost controls, many organizations, e.g., the American Society of Clinical Oncology, the National Comprehensive Cancer Network, Memorial Sloan Kettering Cancer Center and others, have developed “value frameworks”. In virtually all cases, however, the frameworks were developed without input from patients, their caregivers or patient advocates. They were developed from evidence obtained in randomized controlled trials and did not include real-world evidence, such as from observational studies or patient experience reports. Decisions about what patients value were often made by clinicians and economists and not by the patients whose lives would be impacted by the recommendations.The situation becomes even more complex when one considers that all patients do not share the same values with regard to outcomes. While a younger, otherwise healthy patient might accept significant treatment toxicity in order to extend life, an older, less healthy patient might choose treatment that is likely to be less toxic. As treatment costs escalate, financial toxicity is also a consideration and varies among individual patients. A treatment that imposes significantfinancial burden on one individual might not be perceived as overly costly by another.Family/caregiver preference also needs to be taken into consideration, as all demographic groups do not share the same preferences or values. Whereas in some groups, the patient’s preference is what counts, in others, family members are much more involved in decision making.In May 2015, researchers from the American Institutes for Research and the Mayo Clinic published a study based on extensive interviews with 721 patients.

Abstract:
Regarding the main disadvantages to access: 1. Where there are structural factors that grant the right and Promote coverage, bureaucratic issues arise that Complicate access. 2. There is in general an underutilization of the available public resource, for lack of information. 3. Many patients who depend on public coverage lack of an education from which they can empower themselves situation. Many times they lack the knowledge and Tools to expand their options. 4. The delay or inefficient response by the public coverage remains, even increases, or extent a claim made by patients and their relatives. 5. Delays both in the delivery of medicines and in obtaining shifts, in order to conduct a study. Problems of transfers, Great distances to treatment centers. Mexico, Brazil, Peru, Argentina and Chile to mention some examples in Latin America we have very fragmented health systems, little or no budget for avant-garde treatments like Immunotherapy or targeted therapies. Lung Cancer patients often do not know their rights, they do not empower themselves and require the inclusion of these therapies. While efforts have been made to tighten anti-smoking laws, there is a long way to go and educate to create awareness.

Abstract:
Background of Japanese lung cancer advocacy In Asian countries, the concept of cancer advocacy has not been sufficiently recognized. In Japan, there had been few groups of lung cancer patients for a long time, and West Japan Oncology Group (WJOG) has practiced cancer advocacy learned from the USA and Europe as a citizen lecture and a guidebook for patients. We noticed that interactive efforts involving patient groups, companies, academia and governments are necessary rather than providing one way information. In recent years, Lung Cancer Society (JLCS) has led the lung cancer advocacy, and adopted the 2014 Kyoto Declaration, which Representatives of the society, lung cancer patients, citizens, medical personnel, government, companies and research institutes, declared the will to the improvement of lung cancer medical care in cooperation. First, the medical improvement committee against lung cancer was organized to to realize the goal of the Kyoto Declaration, and The committee has carried out the following activities. Initially, the ambassador was commissioned to a lung cancer survivor, a futsal professional athlete and one medical school student of a leader of the idol singer group. In line, we currently commission six medical school students, students of pharmacy, and nursing students. One of our main activities is to provide information on lung cancer medical care using websites and events. In addition to the public lecture, medical workers seminar, the event by the patient association had been supported. These activities are open to the public so that citizens and medical staff can recognize widely in cooperation with medical media. Also, in collaboration with the Lung Cancer Society, we are also requesting early approval of new therapeutic agents. Evaluation of Japan's advocacy To evaluate the awareness and attitude of lung cancer advocacy activity among patients, medical workers, and the general population in Japan, web survey was planned for the perceptions of Kyoto declaration and JLCA (Japanese alliance for lung cancer advocacy) events which were carried out by JLCS in these 2 years. Furthermore, we tried to reflect the questionnaire result in the subsequent activity plan. An internet survey was conducted which contained 6 closed-ended (selection one or free answers) and open-ended questions, depending on the JLCA network population in June 2016. Results By October 2016, 109 people of responded involving 36% of patients and their family, 25% of MD and medical worker, 19% of pharmaceutical company officials and 16% of news media. Perception of Kyoto declaration was 21% of attendee, 27% of well-known, 13% of partial known and 39% of non-awareness. Also the number of participants to the events of JLCA is, 49% of 0 times, 17% 0f 1-2 times, 24% of 3-4 times and 11% of more than 5 times. The most sympathy events ware voted to 1) lecture by a physician 57%, 2) lecture by survivor and the participants WCLC of cancer patients 46%, 3) information in the facebook and the web site 46% 4) citizen open lecture of lung cancer 39%, 5) Performance by society ambassador 38%, 6) advocacy program in annual meetings 26% and 7) Medical seminars around the country 26%. The proportion of respondents who have a certain reputation in the activities of JLCA was 76%.The requests to JLCA is, 1) is the most participation opportunities for information of new treatment and participation opportunities to clinical trial, followed by 2) wish to participate to all the programs in the Society. Looking for the next difference 1. Activities in the next fiscal year, reflecting the results of the questionnaire, citizen public lectures consisted mainly of lectures by prominent oncologist, announcements of representative survivors, moderators and lectures by public ambassadors. Events were held in major cities and various places across Japan. Also The lung cancer society organizes the patient advocacy program throughout the annual meeting every year. We provide travel grants from 2016 to facilitate patient and family attendance. 2.The committee holds medical seminars in Tokyo four times a year. The theme was the latest current information surrounding lung cancer from time to time, introduction of new treatment and activity of patients group. In addition, journalists, television reporters and medical writers were invited to provide information to the public widely by articles posting. 3. Through the website, we provide topics on diagnosis and treatment for lung cancer using video, activity policy and advocacy activities of the lung cancer society, documentary on participation of the international conference of the patient association. In conclusion, participants from different professions gathered for the purpose of improving lung cancer medical care, shared recognition was born among the participants, and empathy was also obtained with the public relations ambassador. Meanwhile, because of different professions and position, the hope of the content of activities was diverse, and it seems necessary to enhance the priority business that can be shared.

Abstract:
Smoking and lung cancer Since the 1950’s, smoking has been associated with lung cancer (US National Llibrary of Medicine, 2017). Lung cancer is the most common cancer worldwide and the biggest cancer killer (World Health Organisation, 2017). The majority of lung cancer diagnoses are due to smoking (US National Llibrary of Medicine, 2017), yet these frightening statistics have not deterred people around the globe from smoking. The World Health Organisation estimated that, in 2015, 1.1 billion people smoked tobacco. Within this cohort are lung cancer patients and their families, unable or unaware of why they should quit. This presents a great challenge to patient advocates worldwide. Awareness Awareness of the significant health risks associated with smoking vary around the world, so the role of the patient advocate also varies from country to country. In 2013 the Global Lung Cancer Coalition launched a survey, carried out by Ipsos MORI, investigating awareness of the symptoms of lung cancer and smoking prevalence in 21 countries. Researchers found that across all the countries, 22% of people surveyed admitted they could not name any symptoms of the disease. Over 17,000 people were surveyed, among them former smokers were slightly more likely to be aware of symptoms than current smokers or people who have never smoked. Multiple studies have replicated similar differences in awareness of the link between smoking and lung cancer across countries. Research performed by the Irish Cancer Society in 2015 found that; 92 out of 100 smokers know that smoking causes lung cancer. In contrast, the Global Adult Tobacco Survey (2010) found that in China; 23% of adults believe smoking causes stroke, heart attack, and lung cancer. While every country requires a message specific to their population, the common theme is stopping smoking is the most important thing the public can do to reduce their risk of lung cancer and it is never too late to benefit from stopping, even after a diagnosis of a smoking-related disease. Benefits of quitting Smoking not only increases your risk of lung cancer, but of multiple cancers, heart disease, stroke, lung disease, and fertility and pregnancy problems (US National Library of Medicine, 2017). Tobacco smoke contains around 7,000 chemicals. Many of these are poisonous and over 60 are known to be cancer causing. For people already diagnosed with lung cancer, smoking cessation can seem pointless but there are clear benefits to stopping smoking including better treatment efficacy, fewer side-effects, less risk of recurrence and less risk of developing other smoking-related health problems (American Society of Clinical Oncology, 2016). There are immediate and long-term health benefits of quitting for all smokers, including those already diagnosed with lung cancer, including (World Health Organisation, 2017): Within 20 minutes, your heart rate and blood pressure drop After 12 hours, the carbon monoxide level in your blood drops to normal Within 2-12 weeks, your circulation improves and your lung function increases At 1-9 months, coughing and shortness of breath decrease By 1 year, your risk of coronary heart disease is about half that of a smoker's Within 5-15years, your stroke risk is reduced to that of a non-smoker By 10 years, your risk of lung cancer falls to about half that of a smoker and your risk of cancer of the mouth, throat, oesophagus, bladder, cervix, and pancreas decreases Within 15 years, the risk of coronary heart disease is that of a non-smoker’s. Role of advocates Advocates have an opportunity to promote smoking cessation on a National scale as well as at an individual level. This can seem like an overwhelming task in light of the significant health burden smoking presents, however international support is available. In 2005 The World Health Organisation Framework Convention on Tobacco Control (WHO FCTC) was created. This evidence-based treaty reaffirms the right of people to the highest standard of health, provides legal dimensions for international health cooperation and sets high standards for compliance. Each MPOWER measure corresponds to at least 1 provision of the WHO Framework Convention on Tobacco Control. The 6 MPOWER measures are: Monitor tobacco use and prevention policies Protect people from tobacco use Offer help to quit tobacco use Warn about the dangers of tobacco Enforce bans on tobacco advertising, promotion and sponsorship Raise taxes on tobacco. At an individual level, advocates can play a vital role in encouraging lung cancer patients and their families to avail of behavioural support and medication to assist their smoking cessation efforts. Lung cancer patients are burdened with elevated levels of distress in comparison to other cancers (Zabora et al., 2001) and research suggests that stigma and the association with tobacco is a very real issue for lung cancer patients (Chapple et al., 2004). This is in addition to being diagnosed with the biggest cancer killer worldwide, a probable late stage diagnosis, poor prognosis and debilitating symptoms. For the lung cancer patient, advocate guidance and support is vital to successfully quit smoking. People diagnosed with cancer often keep quiet about their smoking because (American Society of Clinical Oncology, 2016): they fear judgement or blame from their family or doctor they think they might get less support for their cancer treatment the think it is pointless to stop as they already have cancer they believe smoking helps them cope with stress they have tried to stop before unsuccessfully. The challenge for patient advocates is balancing this support at an individual level with the need to evoke change at a National and International level.

Abstract not provided

Abstract:
Local therapy as the primary treatment modality of early malignant pleural mesothelioma (MPM) remains highly controversial due to lack of clear benefit in comparative clinical trials. In specialized experienced centers, the initial approach is usually surgical resection - extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D). No consensus exists with regard to the optimal use of radiotherapy (RT) in MPM. At the present time, there is no evidence to support the use of radical RT as a single modality in MPM, because of the inability to deliver a therapeutic high dose of radiation (e.g. 60Gy in 30 fractions) to the entire pleura without overdosing the surrounding organs at risk. However, RT has been used in the management of MPM in three indications: as prophylaxis to reduce the incidence of recurrence and pain at sites of diagnostic or therapeutic instrument insertion, as part of multimodal definitive treatment (following induction chemotherapy and surgical resection) to improve locoregional control in early-stage disease and for palliation of symptoms (mainly chest wall pain) in patients with advanced disease. During thoracoscopy, thoracocentesis or needle biopsy in patients with MPM, the seeding of tumor cells along the needle tract may occur, leading to painful metastases at the intervention sites in 20-50% of cases [1]. Prophylactic radiotherapy to chest wall sites of invasive procedures has previously been recommended. However, recent randomized studies (e.g. SMART trial) have shown that prophylactic RT should not be routinely used to prevent procedure tract metastases (PTMs) in MPM, as it confers no benefits in terms of chest pain control, analgesia use, survival, QoL and the data on the potential effect on PTMs' incidence reduction are discrepant [1]. Instead patients should undergo careful clinical follow-up allowing the immediate detection and treatment of PTMs. Surgical resection alone in early MPM is associated with high local recurrence rates (69% after P/D and 38% after EPP) [2]. Therefore, to reduce local failure rate conventional RT has been used as a component of potentially curative trimodality treatment. Adjuvant RT was first used in patients after EPP and was delivered with anterior posterior photon fields matched with electron boost fields. A similar hemithoracic RT technique was explored after P/D, but additional block for central part of the lungs was required. The population based studies data on the potential role of adjuvant RT in improving overall survival (OS) are conflicting [3]. However, a subsequent analysis utilizing the National Cancer Database (NCDB) revealed the improvement of the 2-year rate of OS from 20% to 34% in patients with MPM receiving conventional RT after surgery [3]. Without significant improvement in local control and overall survival after P/D, conventional RT has been shown to decrease local recurrence after EPP to 13% and result in a median survival of 17 months [3]. The benefit in local control was strongly dose-dependent and obtained with a median dose of ≥54Gy [3]. Subsequently, the IMRT technique was implemented to improve adjuvant RT outcomes after P/D (IMPRINT approach). This novel method offers better coverage of the extensive, irregularly shaped target, safer dose escalation in the target volume and optimal sparing of OARs, but results in more heterogenous dose distribution, with a larger volume of normal tissue receiving low-dose radiation than in conventional techniques. IMRT was shown to be associated with a lower incidence of local recurrence (14% vs 42%), improved overall survival (median 20 vs 12 months) and lower rates of grade ≥2 esophagitis (23% vs 47%) when compared with conventional techniques [4]. A potential disadvantage of IMRT is the dose delivered to the contralateral lung that is associated with higher risk of pneumonitis (up to 46% of fatal pneumonitis in early series) [5]. Mean contralateral lung dose >8,5Gy and higher percentage (>80%) of the contralateral lung receiving dose >5Gy were significantly associated with higher risk of pulmonary toxicity. Strict dosimetric constraints, particularly on the contralateral lung (MLD<8,5Gy, V20<10%, V5<60%) and optimal algorithms in treatment planning (e.g. accurate measurement of volumes receiving low radiation doses on the basis of Monte-Carlo algorithm), are critical for radiotherapy planning [4]. Another novel approach employs the combination of IMRT and electrons, that offers better sparing of heart, liver and kidneys [6]. The technical aspects of adjuvant IMRT for MPM can further be improved. When compared to step-and-shoot linac-based IMRT, the use of helical tomotherapy significantly improved target coverage, homogeneity index, lowered average V5<40% and MLD<5Gy for the contralateral lung [7]. Intensity-modulated arc therapy also demonstrated superior V20 and better target coverage in addition to shorter treatment delivery time [8]. Proton therapy was also evaluated in the mentioned setting, offering better sparing of OARs and possibility of further dose escalation to improve target coverage [9]. Whether these dosimetric advantages will translate into clinical benefit, should be assessed in future prospective studies. The trimodality treatment of MPM consisting of induction chemotherapy (pemetrexed+cisplatin), surgical resection and adjuvant radiation has resulted in the best survival outcome thus far in non-randomized cohorts. Accelerated hemithoracic radiation (25Gy in 5 daily fractions), followed by EPP, was evaluated as an alternative. This approach is feasible and associated with encouraging overall survival (median of 51 months) and disease-free survival (47 months) in patients with epithelial cT1-3N0M0 MPM [10]. These promising results should support further studies to clarify the role of hypofractionated pre-operative RT in the management of MPM. Radiotherapy can provide palliation of chest pain in the course of MPM in 50-60% of cases, although the duration of response is often disappointing (2-3 months) [11]. An effective palliation was observed after the dose ≥40Gy and a higher local response rate for patients treated with a 4Gy per fraction regimen compared with those receiving fractions lower than 4Gy was reported (50% vs 39%) [11]. Many aspects of RT for patients with MPM are still not standardized and warrant further investigations. Clinical trials designs will require integration of new systemic therapies, immune modulation and novel technology advances in RT, with the guidance of predictive and prognostic biomarkers, as well as genetic profiling. MPM patients with resectable disease should be encouraged to participate in clinical trials. Bibliography: 1. Arnold DT, Clive AO: Prophylactic radiotherapy for procedure tract metastases in mesothelioma: a review. Curr Opin Pulm Med 2017, 23(4):357-364. 2. Pass HI, Kranda K, Temeck BK, Feuerstein I, Steinberg SM: Surgically debulked malignant pleural mesothelioma: results and prognostic factors. Ann Surg Oncol 1997, 4(3):215-222. 3. Rosenzweig KE: Malignant pleural mesothelioma: adjuvant therapy with radiation therapy. Ann Transl Med 2017, 5(11):242. 4. Shaikh F, Zauderer MG, von Reibnitz D, Wu AJ, Yorke ED, Foster A, Shi W, Zhang Z, Adusumilli PS, Rosenzweig KE et al: Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma. J Thorac Oncol 2017, 12(6):993-1000. 5. Allen AM, Czerminska M, Janne PA, Sugarbaker DJ, Bueno R, Harris JR, Court L, Baldini EH: Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys 2006, 65(3):640-645. 6. Chan MF, Chui CS, Song Y, Burman C, Yorke E, Della-Biancia C, Rosenzweig KE, Schupak K: A novel radiation therapy technique for malignant pleural mesothelioma combining electrons with intensity-modulated photons. Radiother Oncol 2006, 79(2):218-223. 7. Sterzing F, Sroka-Perez G, Schubert K, Munter MW, Thieke C, Huber P, Debus J, Herfarth KK: Evaluating target coverage and normal tissue sparing in the adjuvant radiotherapy of malignant pleural mesothelioma: helical tomotherapy compared with step-and-shoot IMRT. Radiother Oncol 2008, 86(2):251-257. 8. Scorsetti M, Bignardi M, Clivio A, Cozzi L, Fogliata A, Lattuada P, Mancosu P, Navarria P, Nicolini G, Urso G et al: Volumetric modulation arc radiotherapy compared with static gantry intensity-modulated radiotherapy for malignant pleural mesothelioma tumor: a feasibility study. Int J Radiat Oncol Biol Phys 2010, 77(3):942-949. 9. Krayenbuehl J, Hartmann M, Lomax AJ, Kloeck S, Hug EB, Ciernik IF: Proton therapy for malignant pleural mesothelioma after extrapleural pleuropneumonectomy. Int J Radiat Oncol Biol Phys 2010, 78(2):628-634. 10. de Perrot M, Feld R, Leighl NB, Hope A, Waddell TK, Keshavjee S, Cho BC: Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2016, 151(2):468-473. 11. Davis SR, Tan L, Ball DL: Radiotherapy in the treatment of malignant mesothelioma of the pleura, with special reference to its use in palliation. Australas Radiol 1994, 38(3):212-214.

Abstract not provided

Abstract:
The recent success of checkpoint blockade in other malignancies has led a resurgence of interest in this modality for mesothelioma. Historically, occasional responses were seen with cytokine therapy, immunomodulatory gene therapy, and vaccination incorporating suicide genes or immunological adjuvants. However, the availability of checkpoint blockade and identification of mesothelioma tumour antigens has opened the field to a plethora of multicentre clinical trials and to interest in developing immunotherapy for this indication. The cytotoxic T-lymphocyte Antigen 4 (CTLA-4) blocking antibody tremelimumab was the first checkpoint blockade treatment trialled in mesothelioma, with two single arm phase II clinical trials reporting modest objective responses and encouraging stable disease(1, 2). Unfortunately, the subsequent randomised phase IIb study of tremelimumab versus placebo as second-line treatment for pleural mesothelioma, the DETERMINE trial, did not reach its primary endpoint (Kindler et al. in press). The next reported trials examined the efficacy of PD pathway blockade. Results from the phase I KEYNOTE 028 study mesothelioma cohort of 25 pre-treated patients were recently published. Using single agent pembrolizumab, the partial response (PR) rate of 20% was lower than originally reported, although a 72% disease control rate (DCR) was observed(3). All patients were selected for >1% tumour PD-L1 expression. The median duration of response was 12.0 months, with no new safety concerns. Three other trials of single-agent PD-pathway inhibition have been reported subsequently. Preliminary results have been reported from a second study of pembrolizumab as second line therapy, with PR of 21%, DCR of 80%, and median progression free survival (PFS) of 6.2 months(4). The NivoMes study of second-line single agent nivolumab reported a PR rate of 15%, with stable disease rates of 35% and a median PFS of 3.6 months(5). Neither of these studies selected for PD-L1 expression. Finally, the JAVELIN study of Avelumab, a PD-L1 inhibitor, in patients with prior therapy reported a PR rate of 9.4% and DCR of 57%(6). There is no clarity on the importance of PD-L1 expression as a predictor of response. As with other cancers, pseudoprogression and subsequent response can be seen in some patients with the use of checkpoint blockade in mesothelioma. Whilst the results of single-agent therapies have been hailed as promising, only a minority of patients derive durable benefit, and as yet there is no clear predictive biomarker. The current generation of clinical trials are focusing on a. evaluating single agent checkpoint blockade in randomised trials; b. combining immunotherapies; and c. combining checkpoint blockade with existing therapies. The MAPS-2 study recently reported on combination ipilimumab and nivolumab as second or third line treatment(7). 125 participants were rapidly recruited to this phase IIb clinical trial, and were randomised to receive either nivolumab alone, or nivolumab with ipilimumab. In the intention to treat population, the disease control rate was 51.6% for the combination and 39.7% for nivolumab alone, with PR rates of 24.2% and 17.5% respectively. PFS was 5.6 months in the combination arm vs. 4.0 months in the nivolumab arm, and there was a promising survival signal in the combination arm. Nevertheless, as with this combination in other settings, toxicity was substantial (although manageable) and three treatment-related deaths were reported. Further maturity of these data is awaited. Ongoing clinical trials of single agent checkpoint blockade included the randomised phase III CONFIRM trial, comparing nivolumab with placebo in 336 previously treated patients (NCT03063450), and the randomised phase III PROMISE-Meso study, comparing pembrolizumab with chemotherapy in the second line (plus) setting in 142 patients (NCT02991482). These studies should be sufficient to confirm results of the previous single agent/single arm trials, with further single agent studies of PD1 blockade in the second/third line setting unlikely to move the field forward substantially unless they are focussed on biomarker questions. The successful rapid recruitment of MAPS-2 augurs well for rapid completion of other combination immunotherapy studies. The CA-209-743 (CheckMATE 743) trial is comparing platinum based chemotherapy to combination nivolumab and ipilimumab in 600 patients (NCT02899299). The INITIATE trial (NCT03048474) is testing nivolumab and ipilimumab in just 33 patients, but with a biomarker focus. The completed NIBIT-Meso 1 trial is a phase II study of tremelimumab and durvalumab for which results are likely to be available soon (NCT02588131), with a further phase II trial of the same agents and similar design open in the USA (NCT03075527). Finally, in combinations of checkpoint inhibitors with conventional therapies, the most mature concepts are combinations with chemotherapy in the first line setting. Two single arm phase II clinical trials of identical design are combining cisplatin and pemetrexed first line chemotherapy with durvalumab, one Australian (ACTRN 12616001170415) and one in the USA (NCT02899195). A randomised phase II study in Canada is comparing first line cisplatin/pemetrexed with either pembrolizumab or chemotherapy plus pembrolizumab (NCT02784171). The Australian ‘DREAM’ study has completed recruitment. All trials are incorporating biomarker studies, which may prove particularly challenging in the context of concurrent chemotherapy. No discussion on immunotherapy in mesothelioma would be complete without comment on anti-mesothelin strategies. The anti-mesothelin immunotoxin SS1P has undergone phase I testing, however neutralising antibody development mandated combination with immunosuppressive pre-treatment moving forward. Durable responses have been seen in small numbers of patients(8). The chimeric monoclonal mesothelin antagonist MORAb-009 (Amatuximab) has completed early phase testing and is now in phase III combined with cisplatin and pemetrexed (NCT02357147). Mesothelin is also being used as the target antigen in Chimeric Antigen Receptor (CAR) T cell therapy in pilot testing. Finally, anetumab ravtansine is an antibody drug conjugate linking a human anti-mesothelin monoclonal antibody to the spindle poison DM4(9). Results have recently been released suggesting no benefit over single agent vinorelbine in a second-line phase IIb study (NCT02610140). This abstract is not exhaustive, with other immunotherapies under investigation including dendritic cell therapy, CAR-T cell therapy, and allogeneic tumour cell vaccine therapies amongst others. It remains unclear which immunotherapies, in which combinations, and at which point in the disease trajectory will be permanently integrated into management. Biomarker studies to predict both toxicities and outcomes are likely to be critical to guide patient selection. REFERENCES 1. Calabro L, et al. (2013) Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 14(11):1104-1111. 2. Calabro L, et al. (2015) Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. Lancet Respir Med 3(4):301-309. 3. Alley EW, et al. (2017) Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol 18(5):623-630. 4. Kindler H, et al. (2016) OA13.02 Phase II Trial of Pembrolizumab in Patients with Malignant Mesothelioma (MM): Interim Analysis. J Thorac Oncol 12(1):S293-294. 5. Quispel-Janssen J, et al. (2016) OA13.01 - A Phase II Study of Nivolumab in Malignant Pleural Mesothelioma (NivoMes): With Translational Research (TR) Biopies. J Thorac Oncol 12(1):S292-293. 6. Hassan R, et al. (2016) Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: Safety, clinical activity, and PD-L1 expression. J Clin Oncol 34:abstr 8503. 7. Scherpereel A, et al. (2017) Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial. J Clin Oncol, p LBA8507. 8. Hassan R, et al. (2013) Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci Transl Med 5(208):208ra147. 9. Golfier S, et al. (2014) Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol Cancer Ther 13(6):1537-1548.

Abstract:
Malignant mesothelioma (MM) is a mesodermally derived, primarily pleural or peritoneal tumor with aggressive behavior. The incidence of this once-rare tumor is increasing rapidly because of the widespread use of asbestos. In Japan, the annual number of MM-related deaths in 2015 was approximately 1,400, which is 3-fold higher than that observed 20 years ago. The median survival of patients with malignant pleural mesothelioma is 9 to 18 months after diagnosis, which necessitates urgent development of more effective new therapeutic modalities against this aggressive disease. Neurofibromatosis type 2 (NF2) is a tumor suppressor gene that is deleted or mutated in approximately 40% of MM tumors. The gene product of NF2, Merlin, suppresses MM cell proliferation, at least in part, by regulating the Hippo signaling pathway. Hippo signaling is a tumor-suppressive pathway, and alterations in the components of this pathway, including LATS2, SAV1, and AJUBA, have been detected in MM cells. Inactivation of the Hippo signaling pathway leads to the constitutive activation of YAP and TAZ, downstream transcription coactivators that are regulated by this pathway. We previously reported that inhibition of YAP in Merlin-deficient MM cells reduces cell proliferation and inhibits anchorage-independent growth, whereas expression of an active YAP mutant in immortalized mesothelial cells induces oncogenic transformation. While the oncogenic roles of YAP has been extensively studied in MM cells, the possible pro-oncogenic functions of TAZ, a homolog of YAP, is not well understood. Using a panel of MM cell lines, we observed that approximately 65% of these cell lines show activation (underphosphorylation) of TAZ. We knocked down TAZ with shRNA-TAZ in MM cells with high TAZ activation and detected strong inhibition of cell proliferation, anchorage independent growth, cell motility, and invasion in vitro. Meanwhile, immortalized mesothelial cells transduced with a constitutive activated form of TAZ (TAZ S89A mutant) showed enhancement of these in vitro phenotypes and tumorigenicity in nude mice. Using microarray analyses, we identified that while most upregulated genes were common between the TAZ and YAP activated cells, TAZ induced transcription of genes encoding cytokines and their receptors more than YAP. Among the upregulated cytokines, we observed that TAZ binds to the promoter region of the gene encoding IL1-beta along with TEAD transcription factors, which increased IL1-beta transcription and subsequently cell proliferation of immortalized mesothelial cells. In contrast, IL1-beta knockdown or an IL1 receptor antagonist inhibited cell proliferation of MM cells, suggesting that IL-beta signaling suppression may have stronger inhibitory effects on MM cells with TAZ activation. The mevalonate pathway has recently been reported to play a pivotal role in regulating the downstream events of the Hippo pathway. We identified antitumor effects of statin on MM cells with Hippo signaling pathway inactivation. Statin attenuated proliferation and migration of MM cells harboring a NF2 mutation by accelerating YAP phosphorylation/inactivation. Interestingly, not all MM cells with NF2-Hippo pathway inactivation exhibited statin sensitivity. All the statin high-sensitive MM cell lines had increased p-YAP/YAP ratios (inactivation) after statin exposure, whereas in statin low-sensitive cells, the p-YAP/YAP ratio was generally low or unchanged. Genetically, the statin high-sensitive MM cells harbored NF2 and/or LATS2 mutations without BAP1 mutation, whereas BAP1 mutations were frequently identified in statin low-sensitive cells. Indeed, the Y-MESO-25 cell line, carrying both NF2 and BAP1 mutations, regained moderate statin-sensitivity after transfection with a wild-type BAP1 plasmid, indicating that BAP1 mutations interfered with the anti-proliferative effects of statins on MM cells with Hippo pathway inactivation. However, the interactions between BAP1 and the Hippo pathway remain to be elucidated. In conclusion, YAP and TAZ activation via NF2-Hippo pathway inactivation is essential for MM cells to acquire more malignant phenotypes, and therefore, detailed understanding of the biology of this pathway is required to develop new therapeutic modalities against MM based on dysregulation of this pathway.

Abstract not provided

Abstract:
The UK has the highest incidence of Mesothelioma in the world with over 2700 cases diagnosed in 2014 (Cancer Research UK 2017). Data for 80% of these patients was submitted and analysed as part of the UK’s National Lung Cancer Audit Mesothelioma Report (NLCAMR) 2016 (Royal College of Physicians [RCP] 2016). The report confirmed that an increasing number of patients are receiving chemotherapy in the UK particularly patients with a good performance status; 53% compared to 41% in the audit’s 2014 report. The current audit does not identify the proportion of patients who receive their treatment as part of a clinical trial however the report recommends “All patients should be offered access to relevant clinical trials even if this requires referral outside of their network” (RCP 2016). With an increasing number of mesothelioma clinical trials now available in the UK, and more in development, facilitating seamless movement of patients from one specialist clinical team to another is essential. Mesothelioma UK, a national charity dedicated to improving outcomes for those affected by Mesothelioma, is establishing a comprehensive package of services and resources specifically to support this. The charity’s vision, for ensuring equitable access to treatment and trials is outlined in the charity’s 2016-2021 Strategy, The Next Five Years (Mesothelioma UK 2016). This presentation provides insight into readily transferable measures Mesothelioma UK has developed to support equitable access to treatment and care across the UK. References Cancer Research UK 2017 (Last viewed August 4th 2017).

Abstract:
Human being is mortal. However, people don’t want to think about death and prefer to live without considering it. Death has actually been hated in society. In general, death is thought as LOSS. Indeed, healthy body, time as a gift of life, society meaning, several experience, all achievements including money, house, family, friends, status and honor are LOST at death. In medicine which prolongation of life has been a primary purpose, death is considered as defeat. However, if we consider death as loss or defeat, theoretically goal of life itself would be futile definitely toward loss and defeat. “Human beings, who are all mortal and their own deaths are inevitable, seriously think, worry, are embarrassed and hate when they encounter death of other person. They think that death is not appropriate for them.” Gautama Buddha who was born in India 5[th] century BC thought as above, tried to find the cause of death throes and search for how to deal with terror of death throes. Teaching of Buddha from India was introduced to China in where that was developed as ZEN. Teaching of ZEN has been growing calls in the world. ZEN stresses the importance of staring DEATH. In other words, that is to learn how to live responding enough to DEATH as inquiry. It is never to pursue a world after death, just to actively find meaning of life through staring death. We would like to learn how to live while reacting DEATH that tends to evade in modern society, through historical teaching of ZEN. アジアにおける精神性 ー死から勉強するー 人は誰しも死を逃れることはできない。それにも拘わらず、人は死を見つめようとはしていない。できれば死を忘れて暮らしたいと思っている。実に死は、現代社会においても忌み嫌われていると言えよう。 一般に、死は「喪失」であると思われている。たしかに健康な肉体も、人生において与えられた時間も、社会における存在意義も、さまざまな体験も、手に入れたものすべて、貯めたお金や家、家族、友人や恋人、地位名誉などを「喪失」してしまう。 また生命を一日でも長く生かすことを考える医療において、死は「敗北」と認識されている。しかし、もしも死が「喪失」や「敗北」でしかないとしたならば、人生は「喪失」と「敗北」に向かって確実に進んでゆく空しいものとなるであろう。 「愚かな人間は、自分が死ぬものであって、また死を免れないのに、他人が死んだのを見ると、考え込んでしまい、悩み、恥じ、嫌悪している。じつは自分もまた死ぬものであって、死を免れないのに、他人が死んだのを見ては、考えこんで、悩み、恥じ、嫌悪する。このようなことは自分にはふさわしくないであろう」。 このように考えて、死の苦しみの原因を求め、死の恐怖や苦しみから如何に逃れることができるか、その道を求めたのが、紀元前五世紀にインドに生まれた、ゴータマ・ブッダであった。 ブッダの教えは、インドから中国に伝わり、中国においては「禅」という道に発展していった。「禅」の教えは、今日においても広く世界で求められている。 「禅」においては、「死」を見つめることを大切に説いている。死を問いとして、それに応えるに足る生き方を学んでいると言ってよい。それは決して死後の世界の探求ではない。あくまでも死を見つめて、積極的に生の意味を見いだすことを目指している。 現代においても、ともすれば忌避されがちな「死」について、古来の「禅」の教えを参照しつつ、「死」をどう受け止めて生きるかを学んでみたい。

Abstract:
The Buddhist traditions are rich in meditation practices, utilizing them for their spiritual development as a tool towards enlightenment, and also for physical, emotional and mental wellbeing. For centuries, these practices were only for a select group of yogis in caves or nuns and monks in monasteries, but globalization and other movements of the Twentieth century helped bring these practices to a wider population, including people with illnesses such as cancer. This presentation will focus on how some of the philosophical Buddhist concepts, like the understanding of our own mortality or impermanence, and some of the meditation practices had been applied in a non-religious way as part of the offerings for cancer patients and their caregivers within contemporary western clinical settings in our Integrative Medicine Center at MD Anderson Cancer Center in Houston. George Engel’s seminal 1977 paper in Science provides the background for a bio-psycho-social approach at our Integrative Medicine Center that is now part of the Department of Palliative, Rehabilitation and Integrative Medicine at MD Anderson. In other words, a healing focused not just on the physical (i.e., bio) but also on the psycho-social-spiritual aspects of the person, which sometimes seems to be forgotten in conventional allopathic medicine. The bio-psycho-social approach is very much in accordance to the Buddhist approach, and palliative care and integrative medicine are optimal settings. I will share how we bring these into our group classes as well as individual clinic sessions, where people with different kinds of cancers, including lung cancer, participate. In particular I will address cases of people with lung cancer, and issues of stigma, of facing one’s own mortality, and how the concepts and practices that stem from a Buddhist perspective can have positive impact in their quality of life, overall survival, and better relationship to others, in particular their family members and caregivers. In addition I will share the results of a single arm clinical study of Tibetan Yoga (meditation and simple movements) for people with lung cancer and their caregivers that was held at MD Anderson Cancer Center in collaboration with the Ligmincha Texas Center for the Tibetan Meditative and Healing Arts. The purpose of this study was to establish feasibility and preliminary efficacy of a mind-body intervention in lung cancer patients and caregivers. Patients with stage I-III non-small cell lung cancer undergoing radiotherapy and their family caregiver participated in a 15-session Tibetan Yoga (TY) program that included breathing exercises, guided visualizations, and gentle movements. This single-arm trial assessed pre/post intervention levels of mental health (CESD; BSI), fatigue (BFI), sleep disturbances (PSQI), spiritual well-being (FACT-SP) and overall QOL (SF-36). Patients (mean age: 73 yrs., 62% male, 85% stage III) and caregivers (mean age: 65 yrs., 73% female, 85% spouses) completed a mean of 12 TY sessions (range: 6-15) and 95.5% of them rated the program as useful or very useful. Paired t-tests revealed a significant increase in spiritual well-being (P=.03; d=1.12) for patients and decrease in fatigue (P=.03; d=.87) and anxiety (P=.04; d=.91) for caregivers. This first couple-based Tibetan yoga program appears to be a safe, feasible, acceptable and subjectively useful supportive care strategy for patients and their caregivers. Based on these promising preliminary findings regarding treatment gains, the next step is to conduct a randomized controlled pilot trial. Furthermore, based on this and other Tibetan meditation and Tibetan yoga studies with other cancer populations (namely, lymphoma and women with breast cancer), we have incorporated this as a new class of Tibetan meditation and movement as part of our free offerings for people with cancer and their caregivers in our Integrative Medicine Center.

Abstract:
This paper discusses the prevalence of burnout in oncology settings and strategies that can be implemented at both an individual and organizational level to maintain and create a healthy workforce. Background Lung cancer is the leading cause of death by cancer for both men and women worldwide. Most lung cancers are diagnosed at advanced stage and approximately 16% of lung cancer patients will be alive five years post-diagnosis [1]. Working in lung cancer can be gratifying and very rewarding; however it requires high levels of emotional engagement. Oncology professionals work intensively with patients, they provide sophisticated treatments, emotional support, and comfort to patients and their family across the cancer trajectory [2]. Burnout, which refers to feeling emotionally and physically exhausted is common in oncology settings. In a random sample of 1000 US oncologists, 56% experienced burnout at some point in their career [3]. In an Australian sample, 33% of staff with direct patient contact and 27% of staff with non-direct patient contact displayed high levels of emotional exhaustion [4]. Oncology staff who are younger, female, isolated and who work longer hours are more likely to experience burnout [5]. Predictors of stress and burnout include increased work demands, staff shortages, lack of communication training, lack of control or autonomy and dissatisfaction with leave arrangements [6]. Burnout has serious consequences for oncology professionals including elevated rates of mental and physical health concerns, suicidal ideation, difficulties sleeping, frequent bouts of illness, and addiction, intimacy and relationships problems. As a result, patient care is often compromised due to increased errors, turnover and absenteeism and reduced empathetic care. Assessment and strategies to combat burnout A number of tools can assist in better understanding levels of burnout in oncology staff. The most frequently used tool to determine rates of burnout is the Maslach Burnout Inventory (MBI-HSS). The MBI-HSS is a 22-item self-report questionnaire. It measures three distinct dimensions of burnout: (1) emotional exhaustion (EE) characterised by feeling emotionally overextended; (2) depersonalisation, which includes feeling disconnected, detached; and (3) personal accomplishment, the negative judgements one makes about their career and levels of success [7]. Assessing burnout can lead to early identification and interventions for stress management. To reduce burnout, both individual and organisational factors need to be implemented. Developing personal resilience is essential for combating stress and burnout. A number of individual strategies that can assist in developing and maintaining resilience, include creating a work-life balance and adopting self-care and relaxation routines [8]. At an organisational level, coping can be enhanced by the provision of supports such as supervision, professional development opportunities, and the development of work schedules that promote team engagement and address staff shortages and adequate leave arrangements. Furthermore, formal education on how to better manage stress, including mindfulness-based stress reduction, cognitive behaviour therapy and communication training interventions can improve stress management and staff wellbeing [8]. Conclusion Working in oncology can be very rewarding, but can also be emotionally and physically exhausting. The workforce is the most important resource in any organization and burnout needs to be addressed both at the individual and organisational level. At an individual level, oncology professionals need to acknowledge stress, create a work-life balance and adopt self-care and relaxation practices. To maintain a healthy workforce, organizations need to ensure adequate staffing, leave arrangements and provide access to appropriate training, professional and emotional supports. References 1. Cancer Australia. Lung cancer statistics: Australian Govenrment; 2017 2. Diggens J, Chesson T. Do factors of emotion-focussed patient care and communication impact job stress, satisfaction and burnout in radiation therapists? Journal of Radiotherapy in Practice 2014;13(1):4-17. doi: 10.1017/S146039691300006X 3. Whippen DA, Canellos GP. Burnout syndrome in the practice of oncology: results of a random survey of 1,000 oncologists. Journal Of Clinical Oncology: Official Journal Of The American Society Of Clinical Oncology 1991;9(10):1916-20. 4. Girgis A, Hansen V, Goldstein D. Are Australian oncology health professionals burning out? A view from the trenches. European Journal Of Cancer (Oxford, England: 1990) 2009;45(3):393-99. doi: 10.1016/j.ejca.2008.09.029 5. Kamal AH, Bull JH, Wolf SP, et al. Prevalence and Predictors of Burnout Among Hospice and Palliative Care Clinicians in the U.S. Journal Of Pain And Symptom Management 2016;51(4):690-96. doi: 10.1016/j.jpainsymman.2015.10.020 6. Isikhan V, Comez T, Danis MZ. Job stress and coping strategies in health care professionals working with cancer patients. European Journal Of Oncology Nursing: The Official Journal Of European Oncology Nursing Society 2004;8(3):234-44. 7. Maslach C, Jackson S E, P. LM. Maslach Burnout Inventory Manual, 3rd edition. Mountain View, CA: CPP Inc, 1 1996:1–52. 8. Gillman L, Adams J, Kovac R, et al. Strategies to promote coping and resilience in oncology and palliative care nurses caring for adult patients with malignancy: a comprehensive systematic review. JBI Database Of Systematic Reviews And Implementation Reports 2015;13(5):131-204. doi: 10.11124/jbisrir-2015-1898

Abstract:
Erik Thunnissen[1], Chris Dickhoff[2,3], Rutger Lely[4], MA (Rick) Paul[3] Departments of [1]Pathology, [2]Surgery, [3]Cardiothoracic Surgery and [4]Radiology, VU University Medical Center, Amsterdam, the Netherlands. Guidelines for gross handling are to our knowledge not formulated in the literature. However, the College of American Physicians (CAP) formulates "required elements" for synoptic reporting regarding gross handling of pulmonary resection specimen, mainly focusing at pathology staging, but does not include grossing requirements[1]. The current practice of handling resection specimen in Amsterdam involves interaction with surgeons for submission of specimen. This includes i) Information about pretreatment, type of surgery (including pneumonectomy, (sleeve) lobectomy, segmentectomy, and wedge resection), site of specimen, number of tumors; ii) eventual frozen section for diagnosis and/or resection margin; iii) eventual additional information of specimen e.g. adhesion from parietal pleura, additional wedge from adjacent lobe adhesion; iv) agreement on marking the ‘cold’ side from bronchial resection slice [see note A]; For the pathologist, the order of handling the fresh specimen is i) to maintain the 3 dimensional orientation of the resection specimen along the axial, coronal and sagital planes; ii) to describe outer surface of specimen; iii) to photograph overview from medial and lateral side; iv) to cut slice of bronchial resection margin; v) to cut tumor, preferably in axial plane for sampling of normal lung tissue and tumor for research (culture, freezing) [see notes B and C]; vi) to perform perfusion fixation of peripheral lung; vii) and to immerse whole specimen in large volume neutral buffered formalin. After 24 hours, fixation the specimen is handled in the following way: i) Intrapulmonary lymph nodes are separately embedded ii) the specimen is further cut in slices along the same plane as done for the fresh specimen; iii) the slices are positioned in order of cutting, numbered and photographs taken; iv) description of specimen with tumor characteristics: focality (size; vital, necrosis, fibrosis), distance from tumor to margins recorded (to bronchial resection, pleura). If tumor is present in sequential slices, cumulative tumor thickness is measured; v) other characteristics are described (mucus in dilated bronchi; post-obstruction pneumonia; emphysema etc.) vi) sample representative blocks from tumor, normal tissue, resection margin arteria pulmonalis, and nearest point(s) to pleura for embedding in paraffin; vii) annotate the location of sampled blocks on a copy of the gross slices. After a few days during first microscopy, the 3 dimensional orientation can be reconstructed and the pTNM parameters extracted from the gross and microscopic information. If needed, additional samples can be taken [see note C]. Classification is performed for most parts according to the WHO[2], except for not reproducible categories and immature concepts. Pathology reporting contains pTNMR [see note D]. The pathology report is usually made within 9 working days, except if bony structures are included, then the process will contain an additional week. If postoperative radiotherapy is indicated, the 3 dimensional approach also supports determination of the position(s) for radiation, especially if clips were not placed during surgery. Note A As for frozen section, the cold side of the bronchial resection margin [i.e. the side distant from the patient] is placed downwards on the frozen template, the first cut frozen section sections [representing the nearest to the patient tissue margins (warm side)] are sequentially placed on the microscope slide. In case of uneven surface maximally 6 sections, until complete circumference is achieved, are placed on two microscopic slides, and stained for H&E The bronchial resection margin is considered tumour-free, if the complete circumferential margin does not contain tumor. If needed, in this judgement sequential complementarity of the 6 sections may be taken into account. The sleeve lobectomy has two resection margins: one on the cold side and the other on the warm side (larger bronchial diameter). These are separately examined. If only tumor cells are found in lymph vessels (but no direct tumor spread), this will be reported, but not considered necessary for indication of additional bronchial margin, as lymphangitic distribution is associated with N2 disease[3,4]. Note B As it has been proven that loose tissue fragments are caused by gross cutting[5,6], the knife is rinsed and quickly wiped after each slice that happens to contain tumor. STAS is considered to be an artifact and in contrast to CAP and WHO classification, is not considered as part of the tumor. Note C In Pancoast tumor, the ‘en-bloc resection’ incorporates extrapulmonary structures directly invaded by tumor, usually ribs. During the fresh handling, the thoracic wall is cut from the lung. Subsequently, both cut surfaces are coloured to denote the artifical edges. Bone requires after fixation extra time for decalcification, extending reporting with one week. Note D The R = defined as follows: R0 = free resection margins; R1 = microscopic margins not free; R2 = margins not free during gross examination/surgery;. Peripheral wedge resections contain a parenchymal margin, which is represented by the tissue at the staple line(s). The staples are cut from the specimen, but not further examined. Adjacent tissue is sampled for microscopic examination. If this section does not contain tumor, the margin is free (R0). However, if this contains tumor, an educated guess is reasonable, encompassing the amount of tumor compared to the other sections, and the estimation of the staple thickness (±2mm). 1. College of American Pathologists. Cancer Protocol Templates. Lung cancer vs4. http://www.cap.org/web/oracle/webcenter/portalapp/pagehierarchy/cancer_protocol_templates.jspx?_afrLoop=445529225217710#!%40%40%3F_afrLoop%3D445529225217710%26_adf.ctrl-state%3Dxmm1doio_4. 2. Travis W., Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. (Travis W., Brambilla E, Burke AP, Marx A, Nicholson AG, eds.). Lyon: IARC; 2015. 3. Thunnissen FBJM, den Bakker MA. Implications of frozen section analyses from bronchial resection margins in NSCLC. Histopathology. 2005;47(6):638-640. doi:10.1111/j.1365-2559.2005.02263.x. 4. Vallières E, Van Houtte P, Travis WD, Rami-Porta R, Goldstraw P. Carcinoma in situ at the bronchial resection margin: a review. J Thorac Oncol. 2011;6(10):1617-1623. doi:10.1097/JTO.0b013e31822ae082. 5. Blaauwgeers H, Flieder D, Warth A, et al. A Prospective Study of Loose Tissue Fragments in Non–Small Cell Lung Cancer Resection Specimens. Am J Surg Pathol. June 2017:1. doi:10.1097/PAS.0000000000000889. 6. Thunnissen E, Blaauwgeers HJLG, de Cuba EM V, et al. Ex Vivo Artifacts and Histopathologic Pitfalls in the Lung. Arch Pathol Lab Med. 2016;140(3):212-220. doi:10.5858/arpa.2015-0292-OA.

Abstract:
The recent advance in personalized medicine along with minimally invasive endoscopic techniques in the field of lung cancer has brought significant complexities to handling of tissue samples. Due to the histology-directed therapy, additional stains are frequently required to achieve accurate histologic subtyping on small biopsy and cytology samples. It is recommended that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 testing be performed for patients with advanced non-squamous small cell lung cancer (NSCLC) in a reflex manner. In addition, multiplex assays, including next generation sequencing (NGS), are increasingly being used for detection of the molecular targets. Furthermore, immunohistochemistry (IHC) for programmed death ligand-1 (PD-L1) is now routinely performed in NSCLCs with wild type EGFR and ALK to determine eligibility for PD-1/PD-L1 blockade.(1) In most advanced NSCLC patients, a small biopsy or cytology specimen is often the only sample available for the diagnosis and biomarker analyses. Thus, appropriate tissue acquisition, processing and management for multiple tests are crucial and are best achieved by the interaction of all physicians involved in the patient care.(2, 3) Tissue acquisition All the necessary work-up is usually performed on a small biopsy or cytology specimen taken from a patient with advanced disease, tissue sampling should be aimed at obtaining the largest yield of tumor in the safest and least invasive manner.(4) Tissue processing Appropriate pre-analytic tissue handling is one of the keys to successful implementation of IHC-based and molecular assays in general.(3, 5) An ischemia time from tissue procurement to the initiation of fixation should be short (as short as possible), and biopsies should immediately be immersed in fixative for 6-48 hours. Of note, multiple tissue fragments in a biopsy sample (obtained from one lesion) may be submitted in a few tissue cassettes to avoid tissue exhaustion that is not infrequently seen when the single available tissue block is cut and used for multiple purposes. Neutral buffered formalin is historically the preferred and most common fixative used in the practice of histopathology.(6) Consequently, the majority of pathology laboratories typically perform the initial validation of IHC and molecular protocols on FFPE tissue. Decalcifying solutions used for bony specimens vary in their effects on retention and integrity of nucleic acids and proteins. Thus, results of IHC on decalcified specimens are unpredictable because of wide variations in specimen types and sizes, fixation time, and the particular solution(s) used.(7) Similarly, alcohol fixation used for cytology specimens, including alcohol-fixed cell blocks, decreases IHC accuracy by causing loss or decrease of immunogenicity when IHC protocols optimized with FFPE tissue samples are used.(8) For molecular assays, samples fixed with acidic solutions (including decalcifying salutations) and heavy metal fixatives are not recommended due to further degradation of nuclear acid and heavy metals hampering PCR reaction, respectively.(9) Thus, tissue sampling of a bone metastasis for this purpose should be avoided, if possible. In case the bone metastasis is the only accessible lesion for sampling, the pathologist may try to separate a soft tissue component submitted in the formalin. Up to 40% of advanced NSCLC patients are diagnosed by cytology alone. Cytology smears, cytospins and liquid-based cytology (LBC), processed from fine needle aspiration (FNA) or other modalities, are typically treated with alcohol-based solution or sprays devoid of exposure to formalin that leads to fragmentation of nuclear acids, thus often contain tumor cells with intact nucleic acid ideal for molecular testing. However, formalin-fixed paraffin-embedded (FFPE) cell blocks processed from the residual material from FNA or LBC or body fluid are the preferred samples for ancillary testing in many laboratories, since they can be handled in the same way as biopsy/resection specimens.(2) Tissue management To maximize small samples, the number of times when the tissue block needs to be cut for diagnosis, IHC and molecular testing should be minimized. It is because a decent amount of tissue is cut and wasted for trimming of the block at each round of sectioning. Thus, extra sections may be cut up front at the first cutting for diagnostic histology sections. Many pathology laboratories already have protocols in place per local requirements under close supervision by pathologists. It is also important that the pathologist is in close communication with oncologists and proceduralists to ensure that relevant clinical information is provided before sectioning is done. Diagnostic work-up between the lesion with high probability of a lung primary and a possible metastasis, and that between primary diagnosis and progression/recurrence after targeted therapy are often different, thus lack of the critical information may lead to unnecessary IHC. Last, but not least, the pathologist needs to evaluate tissue adequacy (tumor cellularity, the presence or absence of necrosis and tissue quality, etc.) before submitting samples for molecular testing. References: 1. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 8.2017 – July 14, 2017. 2. Bubendorf L, Lantuejoul S, de Langen AJ, et al. Nonsmall cell lung carcinoma: diagnostic difficulties in small biopsies and cytological specimens: Number 2 in the Series "Pathology for the clinician" Edited by Peter Dorfmuller and Alberto Cavazza. Eur Respir Rev. 2017;26(144). 3. Tsao MS, Hirsch FR, Yatabe Y. IASLC atlas of ALK and ROS1 testing in lung cancer. 2nd ed. Colorado: Editorial Rx Press; 2016. 4. Thunnissen E, Kerr KM, Herth FJ, et al. The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer. 2012;76(1):1-18. 5. Mino-Kenudson M. Programmed death-ligand 1 immunohistochemistry testing for non-small cell lung cancer in practice. Cancer. 2017;125(7):521-8. 6. Thavarajah R, Mudimbaimannar VK, Elizabeth J, et al. Chemical and physical basics of routine formaldehyde fixation. J Oral Maxillofac Pathol. 2012;16(3):400-5. 7. Fitzgibbons PL, Bradley LA, Fatheree LA, et al. Principles of analytic validation of immunohistochemical assays: Guideline from the College of American Pathologists Pathology and Laboratory Quality Center. Arch Pathol Lab Med. 2014;138(11):1432-43. 8. Zhou F, Moreira AL. Lung Carcinoma Predictive Biomarker Testing by Immunoperoxidase Stains in Cytology and Small Biopsy Specimens: Advantages and Limitations. Arch Pathol Lab Med. 2016;140(12):1331-7. 9. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 2013;137(6):828-60.

Abstract:
Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity. Its prevalence and impact on quality-of-life (QOL) has variable documentation in the literature, due to differing assessment modalities utilized. Objectives To discuss the natural history and characteristics of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving taxane- and platinum-based chemotherapy. Methods for the study Prospective longitudinal study including patients commencing on taxane or platinum-based therapy, with assessment time-points at baseline, end of each chemotherapy cycle, and 6, 9 and 12-months. Assessments of neuropathy included: sensory assessment using 10gr monofilament and cotton wool, clinician neuropathy grading systems: WHO scale(1-item) and NCI-CTCAE(2-items), and FACT&GOG-Ntx scale. Results In total, 348 patients were recruited to undergo up to 10 assessments over 12 months from three centres in Hong Kong (n=215), Singapore (n=95) and UK (n=38). Participants received taxanes (n=157,46%), platinum (n=111,32%) or a combination of both (n=78,22%). CIPN demonstrated cumulative increase through the chemotherapy cycles and reached a peak at 6 months. Each assessment method showed different CIPN incidence The sample included 343 patients providing 2,399 observations. There was wide variation in CIPN prevalence rates (14.2-53.4%) using different assessments. Patient self-reported scales tended to double or triple the CIPN estimates compared to clinician-based or objective measures. Peak prevalence was around cycle six and the 6-month assessment (Figure 1). Prevalence was highest in taxane-based chemotherapy, followed by taxane-platinum combination. Platinum-based chemotherapy showed the lowest CIPN rate. Motor symptoms were more predominant than sensory ones. Time since chemotherapy was the only predictive factor of CIPN (ORs=9.6-66 depending on the scale used). Cumulative dose had no impact in the development of CIPN. There were relatively moderately to low correlations between the scales, suggesting validity issues. Quality of Life was significantly affected (p=0.48 to <0.001 for different domains at 6-months, 9-months,12-months assessment). Conclusions CIPN is common with taxane/platinum chemotherapy although less prevalent in this largely Asian population compared to past studies involving predominantly Caucasians. Current assessment methods are suboptimal and often limited only to sensory problems, while motor disturbances receive less attention. The variability in CIPN prevalence seen in past work may be the result of the type of assessment used. CIPN prevalence may be lower than that reported in the literature. It seems that from the moment CIPN appears it will run its course over time, irrespective of the chemotherapy cumulative dose, raising issues around the current practice of dose reduction/discontinuation. Assessment in practice needs to also consider motor neuropathic problems. Current scales may not be all appropriate to measure CIPN in a valid way, and a combination of scales is needed in practice. Key References: Cavaletti G., Frigeni B., Lanzani F., Mattavelli L., Susani E., Alberti P., CortinovisD., Bidoli P. (2010). Chemotherapy-Induced Peripheral Neurotoxicity assessment: A critical revision of the currently available tools. European Journal of Cancer, 46(3):479-494. Haryani H, Fetzer SJ, Wu CL, Hsu YY. Chemotherapy-Induced Peripheral Neuropathy Assessment Tools: A Systematic Review. Oncol Nurs Forum. 2017; 44(3):E111-E123. Le-Rademacher J2, Kanwar R, Seisler D, Pachman DR, Qin R, Abyzov A, Ruddy KJ, Banck MS, Lavoie Smith EM, Dorsey SG, Aaronson NK, Sloan J, Loprinzi CL, Beutler AS. Patient-reported (EORTC QLQ-CIPN20) versus physician-reported (CTCAE) quantification of oxaliplatin- and paclitaxel/carboplatin-induced peripheral neuropathy in NCCTG/Alliance clinical trials. Support Care Cancer. 2017 Jun 20. doi: 10.1007/s00520-017-3780-y. [Epub ahead of print] McCrary JM, Goldstein D, Boyle F, Cox K, Grimison P, Kiernan MC, Krishnan AV, Lewis CR, Webber K, Baron-Hay S, Horvath L, Park SB; IN FOCUS Delphi working party. Optimal clinical assessment strategies for chemotherapy-induced peripheral neuropathy (CIPN): a systematic review and Delphi survey. Support Care Cancer. 2017 Jun 7. doi: 10.1007/s00520-017-3772-y. [Epub ahead of print] Mols F, Beijers T, Vreugdenhil G, van de Poll-Franse L. Chemotherapy-induced peripheral neuropathy and its association with quality of life: a systematic review. Support Care Cancer. 2014; 22(8):2261-9 Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain. 2014; 155(12):2461-70. Miaskowski C, Mastick J, Paul SM, Topp K, Smoot B, Abrams G, Chen LM, Kober KM, Conley YP, Chesney M, Bolla K, Mausisa G, Mazor M, Wong M, Schumacher M, Levine JD. Chemotherapy-Induced Neuropathy in Cancer Survivors. J Pain Symptom Manage. 2017 Jan 4. pii: S0885-3924(16)31243-X. doi: 10.1016/j.jpainsymman.2016.12.342. [Epub ahead of print] Alberti P, Rossi E, Cornblath DR, Merkies IS, Postma TJ, Frigeni B, Bruna J, Velasco R, Argyriou AA, Kalofonos HP, Psimaras D, Ricard D, Pace A, Galiè E, Briani C, Dalla Torre C, Faber CG, Lalisang RI, Boogerd W, Brandsma D, Koeppen S, Hense J, Storey D, Kerrigan S, Schenone A, Fabbri S, Valsecchi MG, Cavaletti G; CI-PeriNomS Group. Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin. Ann Oncol. 2014; 25(1):257-64. Acknowledgements Cheng H, School of Nursing, The Hong Kong Polytechnic University, Hong Kong SAR; Au JSK, Leung KT, Wong KH, Li YC, Department of Oncology, Queen Elisabeth Hospital, Hong Kong SAR; Lopez V, Chan A, Ng TRD, Sundar R. National University of Singapore, Singapore; Yorke J, The University of Manchester, UK

Abstract:
Patients and their family and friends consistently report that communication with health care providers has a major impact on their experience of lung cancer. In particular, being informed of treatment choices and being involved in care decisions are highly valued elements of health care by patients. Effective communication has become an increasingly important element of person centred care as treatment advances mean that patients with lung cancer are faced with more complex decisions and treatment choices. In this context, the process of advance care planning has grown in popularity as an important strategy to achieve optimal end of life care. Advance care planning is a process where a person discusses their values and healthcare preferences with their family, friends and healthcare team.[1] Advance care planning is a process that can be undertaken at any time and documented to inform health care decisions if the person can no longer communicate them. Various approaches to advance care planning have been described and a range of health care professionals can be involved in the process. Key elements of advance care planning include discussions of personal values and preferences for healthcare at end of life, establishing clear recommendation regarding future treatment, including discussions about palliative care, documenting patient values and preferences in an accessible site in the medical record, and encouraging the patient to discuss wishes with family/proxy.[2] The process also involves discussions about substitute decision makers who will act on the person’s behalf should the patient not be able to do so.[1] Studies report advance care planning improves ongoing and end-of-life care and personal and family satisfaction, and that families of people who have an advance care plan have less anxiety, depression, and stress.[3] However, studies across a number of countries suggest limited uptake by community members and by health care professionals, as well as poor knowledge and skills of health team members in advance care planning.[4] This is due to a range of factors, including health care professionals’ lack of confidence and skills in conducting sensitive and challenging conversations about end of life issues. Health care professionals are encouraged to have advance care planning conversations early, however there is no clear consensus about what early means in this context and how readiness for such conversations is interpreted from patient to patient. Advance care planning can also oversimplify the decision making process, as such decisions are inherently personal, will change of time, and are influenced by a range of sociocultural and health literacy factors. Negotiating the different perspectives of health professionals, family members, and patients is also very complex. In addition, legal issues give rise to confusion about the process in practice and current pressures to contain costs in health care means that some patients could feel pressured to make choices that do not reflect their true preferences. To address these concerns, advance care planning documentation is often extremely complex, creating even more barriers to the process. A further critical limitation of advance care plans is that even when they are documented, they are not accessible in practice, and where they are available, health care professionals and family members do not always follow the documented preferences. Significant advances are being made across many countries to address the limitations of advance care planning and optimise its use in practice. These advances are in areas including health care professional education and skills building, development of tools to guide practice, greater clarity about the inclusion of advance care planning in care pathways, and leveraging off developments in electronic medical records. Important work in terms of community awareness and understanding of advance care planning is also underway. References 1. What is advance care planning? Available at www.advancecareplanning.org.au, accessed 5[th] July 2017 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Palliative Care V.1.2016. © 2016 National Comprehensive Cancer Network, Inc. 3. Detering, KM, Hancock, AD, Reade, MC, Silvester, W, 2010, ‘The impact of advance care planning on end of life care in elderly patients: randomised controlled trial’, British Medical Journal, 340: c1345.doi:10.1136 4. Lovell, A, Yates, P. 2014, Advance care planning in palliative care: A systematic literature review of the contextual factors influencing its uptake 2008-2012. 28(8), 1026-35.

Abstract:
Around one-third of all malignancies are attributable to tobacco smoking. Diagnosis of cancer is a turning point in life and an alarming signal, motivating for smoking cessation. This is particularly true for patients with tobacco-related malignancies, such as cancers of the lung, head and neck, esophagus, pancreas, uterine cervix, kidney, bladder or stomach. Indeed, the quit and quit attempts rates shortly after cancer diagnosis are relatively high, nevertheless a significant proportion of patients continue to smoke or relapse after initial quit attempts. In consequence up to one-third to one-half of cancer patients or cancer survivors continue to smoke, and the smoking rates in cancer survival do not significantly differ from those in the general population[1,2]. Most smoking cessation efforts have been aimed at primary prevention, whereas the importance of stopping smoking in people diagnosed with cancer have been given less attention. In consequence, the provision of tobacco cessation treatment for cancer tobacco users is still not widely available. Patients with tobacco-related cancers feel more guilt and shame resulting from previous smoking, and tend to underreport their current tobacco dependence[3-5]. Many believe that there is no point to stop smoking once being diagnosed with cancer. Additionally, some health care professionals, in fear of increasing patients’ guilt and stress, do not encourage them to stop smoking. Patients who continue smoking experience several adverse effects. Apart from disease site and stage, abstinence from smoking is the strongest and independent predictor of survival in cancer patients who have ever smoked. Several studies have consistently shown that continued tobacco use compromises the effectiveness and increases the complication rates of three main cancer treatments: surgery, chemotherapy and radiotherapy[6]. In patients managed with surgery, continued cigarette smoking is associated with increasing risk of necrosis, slower wound healing, higher surgical site infection rates and prolonged hospitalization[7]. Components of tobacco smoke significantly impact clearance and delivery of many cytotoxic agents, resulting in their decreased efficacy and higher toxicity[8]. Current, compared to former smokers and patients who stopped smoking before starting treatment, have lower response rates to radiation therapy and acerbated radiation side effects, such as oral mucositis, xerostomia, weight loss and fatigue[9,10]. Smoking after a cancer diagnosis results in higher risk of developing secondary cancers, poorer general health and increased all cause mortality[11,12]. In consequence, patients who continue to smoke after cancer diagnosis almost double their risk of dying, compared to those who quit. A deleterious impact of continued smoking on survivorship is particularly high for tobacco-related cancers. Cancer survivors who continue to smoke have also poorer emotional and social functioning, vitality and quality of life[13-15]. In conclusion, quitting smoking and prevention of smoking relapse represent an important opportunity to mitigate cancer treatment complications and to improve survival, general health and quality of life. It also allows avoiding much of the excess risk of secondary cancers and other tobacco-related diseases. Enhanced focus on smoking cessation and its active promotion among cancer patients may increase their motivation to quit. All cancer patients, irrespective of treatment setting, should be screened for tobacco use and advised on benefits of tobacco cessation. Patients who continue to smoke should be offered individualized pharmacologic and behavioral therapy to assist in the quitting process. References Bellizzi KM, et al. Health behaviors of cancer survivors: examining opportunities for cancer control intervention. J Clin Oncol. 2005; 23:8884–93. Burke L, et al. Smoking behaviors among cancer survivors: an observational clinical study. J Oncol Pract. 2009;5:6-9. LoConte NK, et al. Assessment of guilt and shame in patients with non-small-cell lung cancer compared with patients with breast and prostate cancer. Clin Lung Cancer. 2008;9:171-8. Warren GW, et al. Accuracy of self-reported tobacco assessments in a head and neck cancer treatment population. Radiother Oncol. 2012; 103:45–8. Morales NA, et al. Accuracy of self-reported tobacco use in newly diagnosed cancer patients. Cancer Causes Control. 2013; 24:1223–30. Toll BA, at al. Assessing tobacco use by cancer patients and facilitating cessation: an American Association for Cancer Research policy statement. Clin Cancer Res. 2013; 19:1941–8. Sorensen LT, et al. Smoking as a risk factor for wound healing and infection in breast cancer surgery. European Journal of Surgical Oncology. 2002; 28:815–20. O'Malley M, et al. Effects of cigarette smoking on metabolism and effectiveness of systemic therapy for lung cancer. J Thorac Oncol. 2014;9:917-26. Browman GP, et al. Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med. 1993; 328:159–63. Browman GP, et al. Association between smoking during radiotherapy and prognosis in head and neck cancer: a follow-up study. Head Neck. 2002; 24:1031–7. Stewart BW, et al. Cancer and tobacco: Its effects on individuals and populations, in Robotin M, Olver I, Girgis A (eds): When Cancer Crosses Disciplines: A Physician’s Handbook. London, United Kingdom, Imperial College Press, 2010. Parsons A, et al: Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: Systematic review of observational studies with meta-analysis. BMJ 2010; 340:b5569 Berg CJ, et al. Correlates of continued smoking versus cessation among survivors of smoking-related cancers. Psychooncology. 2013;22:799-806. Garces YI, et al. The relationship between cigarette smoking and quality of life after lung cancer diagnosis. Chest. 2004; 126:1733–41. Duffy SA, et al. Effect of smoking, alcohol, and depression on the quality of life of head and neck cancer patients. General Hospital Psychiatry. 2002; 24:140–7.

Abstract not provided

Background:
Comprehensive NGS panel based genetic testing is becoming more common to help clinicians select appropriate therapies. It has been recommended that matched tumor-normal sequencing analyses are essential for precise identification and interpretation of genetic somatic mutations. Though it has been reported germline EGFR T790M mutations result in a unique hereditary lung cancer syndrome, little is known about germline mutation of other common hereditary cancer syndrome genes in lung cancer patients.

Method:
We reviewed the germline variants of 1000 consecutive lung cancer patients who had paired tumor-normal NGS panel sequencing in our institute between 2016 and 2017. Hybridization capture-based NGS panel sequencing enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations at least 59 genes (range 59 – 1021 genes). Germline variants were interpreted following ACMG guidelines, and the variants were classified into pathogenic, likely pathogenic, variant of unknown significance, likely benign, and benign 5 classes.

Result:
Twenty-seven cases were identified to carry germline pathogenic or likely pathogenic mutations in 12 gene (2.7%): 5 with ATM ; 4 with BRCA1, BRCA2 or MSH2 respectively; 2 with CHEK2 or PMS2 respectively; 1 in ATR, CDKN2A, FANCC, MSH3, PTCH2 or RET respectively (details in table). Mean age at diagnosis was 58 (30 – 84 years) for the patients with germline mutations and 61 (29-93 years) for those without. Interestingly, none of the patients had been diagnosed with other tumors. The incidence of actionable somatic mutations of the 27 patients was similar to others: 10 patients with EGFR mutation, 3 patients with KRAS mutation, 1 patient with KIF5B-RET fusion, MET copy number gain or BRCA1 mutation respectively.

No.	Gene	cHGVS	pHGVS	Mutation type
1	ATM	c.1402_1403delAA	p.K468Efs*18	frameshift
2	ATM	c.1898+1G>C	.	splice
3	ATM	c.2143_2144delCT	p.L715Cfs*22	frameshift
4	ATM	c.6019dupG	p.E2007Gfs*11	frameshift
5	ATM	c.903dupT	p.A302Cfs*3	frameshift
6	ATR	c.80_81insA	p.N27Kfs*16	frameshift
7	BRCA1	c.4185+1G>A	.	splice
8	BRCA1	c.962G>A	p.W321*	nonsense
9	BRCA1	c.3340delG	p.E1114Kfs*3	frameshift
10	BRCA1	c.81-2A>G	.	splice
11	BRCA2	c.3968_3971delAATA	p.K1323Ifs*11	frameshift
12	BRCA2	c.5054C>G	p.S1685*	nonsense
13	BRCA2	c.6132_6135delCTTT	p.F2045Hfs*5	frameshift
14	BRCA2	c.6485_6486delAA	p.K2162Tfs*13	frameshift
15	CDKN2A	c.73delG	p.V25*	frameshift
16	CHEK2	c.1010delC	p.A337Efs*10	frameshift
17	CHEK2	c.1684C>T	p.R562*	nonsense
18	FANCC	c.1257_1258insC	p.T420Hfs*15	frameshift
19	MSH2	c.1165C>T	p.R389*	nonsense
20	MSH2	c.1A>T	p.0?	init-loss
21	MSH2	c.2785C>T	p.R929*	nonsense
22	MSH2	c.340delG	p.E114Rfs*60	frameshift
23	MSH3	c.802C>T	p.R268*	nonsense
24	PMS2	c.1053delG	p.L351Ffs*5	frameshift
25	PMS2	c.943C>T	p.R315*	nonsense
26	PTCH2	c.2441_2442delCT	p.S814*	frameshift
27	RET	c.2410G>A	p.V804M	missense

Conclusion:
Germline mutations in common hereditary cancer syndrome genes is not rare in lung cancer patients, and it can be identified on routine matched tumor-normal NGS sequencing. Retrospective family history analysis and genetic counseling for those patients are underway.

Background:
A key hallmark of cancer cells is the ability to proliferate despite remarkable levels of DNA damage. Non-small cell lung cancers (NSCLC) tend to have high mutation rates, frequently related to smoking. While many genes have been functionally implicated in maintaining the integrity of the genome, for the majority of these genes there remains a lack of evidence of a direct relationship between loss-of-function and increased tumor mutation burden (TMB). Recent studies suggested an association between high TMB and cancer response to immunotherapies. The aim of this study was to comprehensively analyze the relationship between DNA integrity-related genes and TMB in NSCLC.

Method:
Whole exome DNA sequencing and copy number array data were downloaded from TCGA lung adenocarcinoma (LAC) and squamous cell carcinoma (LSCC) datasets, and mutation burdens were calculated for each of 974 tumors. We identified 150 genes across 7 pathways and 9 groups known to be involved in repairing or compensating for DNA damage. To test each gene, tumors were placed into one of three groups according to the gene’s mutation status; wild-type, homozygous deleted or mutated with loss-of-function, and non-synonymous missense mutated. We then compared the average mutation burden in each of these groups. This workflow was then repeated with pathways instead of genes.

Result:
Our comprehensive analysis demonstrates a landscape of significant alterations to genes and pathways responsible for maintaining DNA integrity in NSCLC. A loss of function mutation or homozygous deletion in at least one signature gene occurred in 49% of LAC and 59% of LSCC. We searched for genes in this signature associated with significantly higher tumor mutation burdens (one sided t-test, p < 0.05) and found 4 in LAC (RRM1 1%, TP53 17%, FANCE 1%, and MLH1 2%) and 8 in LSCC (NEIL1 0.5%, POLE 4%, POLG 0.5%, FANCE 3%, GEN1 1%, MLH1 4%, MSH6 1%, and RPA1 2%) datasets. Of note, tumors with nonsense mutations, indels, or homozygous deletions in the FANCE or MLH1 genes have significantly higher TMB in both LAC and LSCC. We repeat this process to find pathways significantly associated with increased TMB.

Conclusion:
We present a comprehensive study of the association between genes responsible for maintaining DNA integrity and TMB in NSCLC. These findings are important to the search for potential predictive biomarkers for immunotherapy.

Background:
The objective response rate of squamous cell carcinoma of the lung (SCCL) to checkpoint inhibitors, as well as the frequency of known NSCLC oncogenic drivers, is low. We performed comprehensive genomic profiling (CGP) on a large set of SCCL cases to identify new opportunities for potential benefit from targeted or immunotherapies.

Method:
Hybrid-capture based CGP of up to 315 genes was performed prospectively on DNA isolated from tissue-based FFPE samples of SCCL, and tumor mutational burden (TMB) was assessed as described previously (PMID: 28420421).

Result:
From a dataset of 958 unique SCCL cases, we identify 2.6% of cases harboring alterations in PTCH1, 0.3% in SMO1, and 01.2% in SUFU, which were primarily mutually exclusive Genes known to be oncogenic drivers in NSCLC were altered at the following frequencies in SCCL 8.0% KRAS, 6.8% EGFR, 3.4% MET, 1.9% BRAF, and less than 1% each for ALK, ROS, and RET. In PTCH1-mutated cases 96% did not harbor alterations in these driver genes (1/23 positive for co-occurrence).. The overall SCCL population has a median TMB of 9.0, with 11.3%) cases higher than 20 mutations/Mb (m/Mb). Two index cases with PTCH1 mutations and no alterations in established NSCLC driver genes were identified. A year 77-year-old male with a 40 pack-year smoking history was diagnosed with metastatic SCCL, basaloid variant, harboring PTCH1 s799fs*29 with TMB of 3.7 m/Mb, and he had a year-long complete response to vismodegib. A 69-year-old male with poorly differentiated SCCL harboring PTCH1 W197* and W460* had a 7 month response to vismodegib. On progression, biopsy of recurrent disease after vismodegib failure demonstrated the same PTCH1 alterations as well as acquisition of the 11q13 (CCND1/FGF3/FGF4/FGF19) amplicon. Both biopsies had TMB > 45 m/mb. Nine additional cases not in this series identified as the basaloid variant of SCCL by expert thoracic pathology review were assayed by CGP and 11% (1/9) harbored PTCH1 mutation, but no other alterations of the hedgehog pathway were identified.

Conclusion:
The index cases presented here suggest a subset of PTCH1-mutated SCCL may see clinical benefit from hedgehog inhibitors, regardless of TMB. In a small series of expert diagnosed basaloid histology in SCCL cases, this histology may enrich for hedgehog pathway alterations. Further investigation of underlying PTCH1 LOH and TMB will be undertaken to assess which SCCL cases can respond to respond to hedgehog pathway inhibitors.

Background:
Matched tumor-normal sequencing analyses are essential for precise identification and interpretation of somatic and germline alterations. A 2015 study of 815 paired tumor and normal genomes showed that both genomes are required for precise identification and interpretation of both somatic and germline variation. In this study, we further demonstrate the critical importance of both tumor and germline sequencing using a selected panel of genes that are relevant to cancer prognosis and treatment.

Method:
Tumor and normal (germline) genomes were sequenced using the Illumina HiSeqX platform. Data was aligned to GRCh37 using methods described previously. Tumor versus matched-normal variant analysis was performed using the NantOmics Contraster analysis pipeline to determine somatic and germline genomic variants. RNA-Seq libraries were prepared from tumor samples using KAPA stranded RNA-Seq with RiboErase kit and sequencing on the Illumina platform. RNA sequencing reads were aligned and variants were identified using methods that have been previously described.

Result:
44 patients with NSCLC with tumor-normal sequencing were analyzed. 29 patients also had RNA-Seq whole transcriptome data available for analysis. Focusing on somatic SNVs in ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, KMT2A (MLL), NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET; 427 germline plus somatic variants were detected in these 25 genes in 44 patients; 386 out of 427 (90%) variants detected in somatic tissue were also present in germline (true positive germline variant, false positive somatic variant). 5 out of 29 patients (17%) did not have detectable expression in at least one somatic variant. Focusing on germline SNVs in APC, MYH, MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, POLD1, BMPR1A, PTEN, STK11; 350 germline plus somatic variants were detected in these 12 genes in 44 patients, 10 out of 44 patients (23%) had at least one variant detected in their tumor DNA in these 12 genes that was not detected in the patient’s germline DNA (false positive germline variant, true positive somatic variant).

Conclusion:
Somatic-only sequencing may lead to false positive variant calls which has important clinical implications for highly actionable targets and for the veracity of mutational load algorithms. Calling germline variants from somatic DNA has a false positive risk---called variants may truly be somatic mutations. This is further complicated by the presence of circulating tumor DNA which may also lead to a false positive “germline” result in the absence of a true normal comparator.

Abstract not provided

Background:
Tumor spread through air space (STAS) is a newly recognized form of invasion in lung adenocarcinoma and squamous cell carcinoma and growing evidence shows it is associated with recurrence and survival. The observation that tumor STAS clusters/nests or single cells within air spaces on two-dimensional H&E slides raised the question of how these cells could survive within air spaces without a vascular supply and this has led some to speculate STAS is an artifact. Herein, we perform the high resolution-high quality 3D reconstruction and visualization of normal lung and tumor in a lung adenocarcinoma to investigate the invasive pattern of STAS.

Method:
A formalin-fixed paraffin embedded block of invasive adenocarcinoma with micropapillary pattern and extensive STAS was studied. Following our histology 3D reconstruction standard procedure, 3D reconstruction was performed for analysis from 200 serial sections of H&E stained 20x (0.5um/pixel resolution) whole slide images. The relationship to alveolar walls between micropapillary structures within the tumor and STAS clusters in lung parenchyma distant from the tumor was evaluated.

Result:
3D reconstruction and analysis demonstrated the following novel features – a) in the main tumor area, micropapillary structures within airspaces were connected to alveolar walls, b) unlike in 2D evaluation where STAS appeared as ‘free-floating’ micropapillary clusters, in 3D evaluation many STAS clusters within air spaces are attached to alveolar walls, and c) STAS clusters that appear ring-like in 2D by 3D evaluation they are actually balls of tumor cells surrounding a central space.

Conclusion:
Our 3D reconstructed image analysis for the first-time demonstrates that most STAS cells are not ‘free-floating’, rather attached to the alveolar walls. In addition within the main tumor micropapillary clusters are attached to alveolar walls. These findings raise an intriguing hypothesis that STAS cells are clusters of tumor cells spread within alveolar spaces in a non-contiguous fashion to reattach to the alveolar walls at a distance possibly by co-option of alveolar wall capillaries to support their growth. This form of spread is analogous to the phenomenon of vascular spread where tumor cells spread freely within blood vessels to distant sites where they attach to endothelium and extravasate through the vessel walls to form metastases. It is possible the ball-like configuration of STAS clusters may facilitate movement through alveolar spaces distant from the main tumor. The frequent alveolar wall attachment of STAS observed on serial 3D imaging disputes the concept this is an artifact.

Background:
Cancer cells “floating” in stroma, air space, or lymphovascular channels are often found in aggressive lung adenocarcinomas. Recently, the concept of STAS (spread through alveolar space) has been proposed, and studies have shown that STAS predicts early recurrence and poor patient prognosis. However, the biologic basis for the aggressive phenotype of the tumor with these histologic features remains elusive. In this study, we tested whether 3D (three-dimensional) low-attachment culture could be an in vitro model for STAS and “floating” cancer cells.

Method:
Lung adenocarcinoma cell lines harboring diverse driver mutations (EGFR, KRAS, BRAF, HER2, RET) were used. Cells were subjected to detached condition by using low-attachment culture dishes to generate “floating” cancer cells in vitro. Cell growth assay, immunohistochemistry and Western blotting were used to characterize the biologic properties of “floating” cancer cells. Cancer cells were inoculated in pleural cavity or left ventricle of the heart of NOD/SCID mice to test their metastatic potential in vivo.

Result:
Upon detachment, cancer cells formed solid, micropapillary, or hollow ring-like structures, admixed with single cells, recapitulating a histologic spectrum of STAS in primary tumors. Outlining with MUC1, a feature of micropapillary lung adenocarcinoma, was also demonstrated in the in-vitro-generated micropapillary clusters as well. Detached cells initially showed retarded cell growth, but some cell lines regained growth potential with time in culture. Expression analysis of various biomarkers revealed that detached cells showed features of cell stress and altered metabolism, as indicated by increased expression of phospho-p38 (a stress-activated MAP kinase) and GLUT-1 (glucose transporter-1), respectively, and these findings were confirmed by analysis of primary tumors. Finally, cancer cells that adapted to detached conditions exhibited increased metastasis in vivo. Figure 1



Conclusion:
3D low-attachment culture may be a convenient model to study the biology of aggressive lung cancer with STAS and “floating” cancer cells.

Background:
Small cell lung cancer (SCLC) is regarded as the most devastative type of human lung malignancies, with their rapid growth and we have discovered that there are FLI1 circular RNAs (circFLI1s) aberrantly expressed in SCLC tissues, such as circFLI1E2-4 and circFLI1E2-5 which are derived from exon 2-exon 4 and exon 2-exon 5 of FLI1, respectively. This study investigated the role of circFLI1s in the biological processes of SCLC.

Method:
The expression level of circFLI1s was evaluated by fluorescence in situ hybridization(FISH) in 54 primary SCLC and 50 non-small cell lung cancer (NSCLC) patients with known follow-up data. Correlation between circFLI1s expression and clinical characteristics was assessed with logistic regression. Cellular proliferation, apoptosis, cell cycle, migration and ability of colony formation were used to investigate the function of circFLI1s in SCLC. Ulteriorly, we explored the possible mechanism of circFLI1s via luciferase reporter assay, RT-PCR and FISH.

Result:
The expression of circFLI1E2-4 and circFLI1E2-5 were up-regulated in SCLC tissues compared with NSCLC tissues . The high expression of these circFLI1s was significantly associated with positive lymph nodal involvement (p < 0.05). The silencing of circFLI1E2-4 and circFLI1E2-5 but not FLI1 mRNA significantly inhibited migration of highly aggressive SCLC cell lines in vitro and vivo, while did not affect their proliferation, cell cycle, apoptosis and colony formation. Via bioinformatic analysis and luciferase screening assay, circFLI1s were observed to sponge to 2 miRNAs with 6 potential binding sites. Specifically, we showed that these circFLI1s directly binded to miR-584-3p and inhibited miR-584-3p activity, further to regulate the transcriptional activity of its target gene ROCK1 and the RhoA/ROCK1 signal pathway.

Conclusion:
This study uncovers that circFLI1s is an important driving factor that promotes tumor metastasis in SCLC through , and may serve as an attractive target for therapeutic intervention of SCLC.

Abstract not provided