Virtual Library

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Background:
Although lung cancer is the second most-often diagnosed malignancy in both men and women, and the biggest cancer killer of both genders, evidence suggests that the lung cancer experience differs in women compared to men. Lung cancer incidence in men has steadily decreased since the mid-1980s, while in women it has increased. Partly, these patterns reflect sex differences in smoking behavior over the previous two decades. Additional epidemiological evidence suggests that gender impacts most facets of the lung cancer experience, including the incidence, susceptibility, severity, and molecular basis of the disease. However, there is a lack of consensus on both the magnitude and etiology of these gender-based differences. The aim of this currently ongoing systematic literature review is to more precisely define this gender disparity among non-small cell lung cancer (NSCLC) patients worldwide and summarize current opinions about the molecular basis for these observations.

Methods:
A preliminary rapid review was launched to outline gender disparity among NSCLC patients in North America, Europe and South Asia. Independent studies were utilized from Medline; Embase; Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for the period between 1996 and 2016. Based on these results, a systematic literature review was carried out for the period between 1996 and 2016 using Medline and Embase databases worldwide. The main outcome measures are incidence and factors influencing NSCLC between the genders. A validated scoring system was used to appraise eligible studies for methodological quality and level of evidence.

Results:
The preliminary rapid search identified 17 eligible articles for review. Analysis suggests that females are more susceptible to tobacco related carcinogens, have a younger age at diagnosis and higher survival rates. We also observed an increase in the inclusion of female patients in the clinical studies over this period. Based on pre-specified selection criteria, the systematic review generated a total of 367 studies which have been retrieved and considered for further analysis. We will determine gender differences in NSCLC incidence and its molecular aberration utilizing data from independent studies based on rapid analysis of observational studies published globally.

Conclusion:
Our systematic literature review will help validate our preliminary findings that gender disparities in lung cancer do exist. Our findings will provide a platform for policy makers, researchers and clinicians to design clinical trials and interventions that account for these disparities.

Background:
The epidemiologic profile of lung cancer mortality in the U.S. is highly unusual. Mortality in males began to rise rapidly early in the 1920s and continued to increase through the 1990s before leveling off. Mortality in women did not begin to rise until decades later and did not approximate mortality in men until the early years of the twenty first century. This unusual pattern of disease can be explained by review of tobacco industry documents and court records.

Methods:
A search was conducted in the Legacy Tobacco Documents library at the University of California, San Francisco, as well as review of testimony and legal reports from state and federal court decisions.

Results:
The beginning of the epidemic of lung cancer in women in the U.S. can be reliably traced back to Easter Sunday in 1929. On that date, a publicity stunt crafted by Edward Bernays was reported in the New York Times as the "parade of torches" supposedly representing an expression of freedom by American women who would henceforward not be constrained from smoking in public. The public relations effort was supplemented by an advertising campaign orchestrated by Chicago marketing expert Albert Lasker. Female smoking rates began to rise after this date, culminating over the succeeding decades in a sharp increase in lung cancer cases and deaths among women. A second phase of marketing of cigarettes to women and girls in the U.S. began in the 1970s as Philip Morris executive Joseph Cullman collaborated with tennis star Billie Jean King to market a new "slim" cigarette to young women via the Virginia Slims tennis tournament under the slogan "You've come a long way baby." A further contribution to the lung cancer mortality arose out of the efforts of the Council for Tobacco Research (CTR) and the Council for Indoor Air Research (CIAR) to manufacture controversy regarding the danger of smoking as well as involuntary second hand smoking to provide cover for legislators voting against tobacco control legislation. As a direct result, many thousands of non-smoking women have had major involuntary exposure to tobacco carcinogens in the workplace causing lung cancer.

Conclusion:
Lung cancer cases presenting today originated in deliberate campaigns by tobacco executives, marketers and public relations experts to convince women and girls to smoke, despite their clear understanding that the products they were aggressively marketing would inevitably result in hundreds of thousands of deaths.

Background:
Female lung and breast cancers are two distinct disease entities in East Asia. Although studies on second primary cancers following the first breast cancer event have been carried out, no in-depth survey on double primary breast and lung cancers has been done. This study analyzed the association between these two distinct cancer types.

Methods:
In the exploratory cohort study, the data were obtained from the Taiwan National Health Insurance Research Database, which contained information on approximately 24.7 million insured individuals. The Taiwan Population Census and National Cancer Registry Databases were used to identify patients with breast and lung cancers. The cohort included individuals with newly diagnosed primary breast cancer between 2000 and 2011. An age- and sex-matched systematic random-sampling method was used for subject selection in the reference non-breast cancer cohort. Multivariate Cox proportional hazard regression analysis was used to determine the effects of breast cancer on the risk of lung cancer, as shown by hazard ratios (HRs) with 95% CIs. Detailed medical record and pathological reviews were done on the National Taiwan University Hospital (NTUH) patient cohort to validate the national cohort study results. The national lung cancer incidence rate was used as reference incidence rate in the validation cohort.

Results:
A total of 88,439 patients were diagnosed with female breast cancer between 2000-2011 in the national cohort. The HR for subsequent lung cancer was 1.27 (95% CI, 1.09-1.48). When stratified by age, the HR was 5.29 (95% CI, 2.26-12.4) in the patients aged less than 40 years, 1.67 (95% CI, 1.18-2.30) in the group aged 40-49, 1.27 (95% CI, 0.97-1.67) in the group aged 50-59, 1.09 (95% CI, 0.81-1.49) in the group aged 60-69, and 0.70 (95% CI, 0.48-1.02) in the group older than 70 years. A total of 13,517 primary female breast cancer patients were identified in the NTUH electronic medical record system between 2006-2015. The incidence rate ratio for second primary lung cancer was 16.08 in the patients whose primary breast cancer was diagnosed at age younger than 50 years and 1.43 for those diagnosed at age older than 50 years. These results supported the national cohort study findings that early-onset female breast cancer patients bear a relative high risk for second primary lung cancer.

Conclusion:
Our findings suggest a relative high risk for second primary lung cancer among patients whose primary female breast cancer is diagnosed at age less than 50 years.

Abstract not provided

Background:
NLST was the first RPT to demonstrate a significant LC mortality reduction, when comparing CT to CXR-screening. Consequently, CT-screening is now being incorporated into clinical practice. Nonetheless, questions about the value of CT-screening remain given costs of CT and workup of false-positives. A prior cost-effectiveness analysis of CT-screening using NLST data concluded that CT was generally cost-effective (NEJM:371,1793,2014). That analysis was performed under the assumption that CXR-screening only added costs without benefit. In an independent analysis of PLCO comparing CXR to no screening, we found that CXR-screening is associated with a highly significant LC survival advantage. This benefit was unrelated to conventional screening biases, including overdiagnosis. As CXR is less expensive than CT with a lower false-positive rate, its cost-effectiveness relative to CT should be assessed. Data from PLCO and NLST allows comparison of no screening, CXR, and CT.

Methods:
Costs of screening, diagnostic studies, and LC treatment were calculated based on original PLCO and NLST trial data obtained from NCI. These were estimated in 2015 US dollars from the Medicare perspective. Outpatient costs were calculated using the Medicare-2015B fee schedule. Inpatient costs were calculated using a national payment average by assigning a DRG based on procedures performed. Survival data was generated using the Kaplan-Meier method for each study and mean survival was calculated using available data. These estimates were used to calculate incremental cost per life-year gained The NLST-eligible subset of PLCO was also used to facilitate comparison of no screening, CXR, and CT.

Results:
Analysis of PLCO data demonstrate that CXR compared to no screening was associated with a gain of 0.0152 life-years per person at an additional cost of $244 per-person for a cost per-life-year gained of $19,175. In the NLST-eligible subset of PLCO, CXR cost an additional $350 with a gain of 0.0262 life-years per-person for a cost-per-life-year gained of $13,377. In NLST, CT compared to CXR cost an additional $1,181 per-person and with a gain of 0.0157 life-years per-person, or $75,180 per-life-year gained. Using the NLST-eligible subset of PLCO for comparison, the ratio for CT compared to no screening was $36,552.

Conclusion:
CT-screening is both effective and cost-effective and represents the optimal method of screening for LC. However, the survival advantage associated with CXR-screening in comparison to no screening and relatively low cost make CXR a reasonable alternative to CT-screening, particularly in regions of the world where cost and availability limit access to CT-screening.

Background:
The National Lung Screening trial (NLST) showed that screening with low-dose computed tomography (CT) compared with chest radiography reduced lung-cancer mortality. There is very few data's on subjects with occupational abestos exposure. We examined the cost-effectiveness of CT lung cancer screening in a french cohort of abestos post professional exposure subjets (APEXS cohort).

Methods:
We estimated mean lif-years, costs and incremental cost-effectiveness ration (ICER) for screening with low-dose CT compare to no screening in this population of abestose exposed subjects. Estimations of life-years gained were based on the efficacy of NLST trial aplpied to APEXS cohort, adjusted to sex and age. Costs were limited to directs costs, from the payer perspective. We also performed sensitiviy analysis based on several assumptions of screening program efficacy.

Results:
Compared with no screening, screening with low-dose CT, over a period of 2 years, will cost, for 1000 subjects of APEXS cohort 312 645 €, will provide 9.4 additional life-years. The corresponding ICER was 33 102 € per life-gained. Sensitiviyt analysis showed that this result is sensitive to screening program efficacy (number, stage, and survival diagnosed by the program).

Conclusion:
ICER of low-dose CT lung cancer program in a cohort of abestos post occupational exposure population appears as acceptable from the French health system.

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Background:
Cancer-related mortality can be measured by two disparate methods: relative survival (RSR, observed survival of cancer patients versus expected survival of a matched population), and cause-specific survival (CSS, based on lung-cancer-specific mortality among cancer patients). Both are vulnerable to biases: RSR depends on a comparable reference population, while CSS relies on accurate cause-of-death coding. Regardless, RSR is more common in population-based studies as the cause of death is uninvolved. We apply both methods to the same dataset to assess their implications among early-stage NSCLC.

Methods:
Outcomes of patients diagnosed with stage I/II NSCLC (2000-2013) were obtained from the SEER registry. Five-year cumulative incidence of death (CID) is estimated by competing risk approach. Population-level mortality was extracted from the National Center for Health Statistics. The actuarial survival were summarized as RSR (Ederer II) and CSS, stratified by age at diagnosis and stage. In addition, the sensitivity of the methods is assessed by including patients with unknown cause of death in CSS (CSS-2).

Results:
Analyses included 15792 age <60 and 70789 age 60+ patients, with stage I (81%) or II NSCLC. Death with unknown cause was 5% of all deaths; 5-year CID for lung-cancer, other-known and other-unknown deaths were 43%, 14% and 2%. Lung-cancer 5-year CID increased with age, from 22% (age <44) to 47% (age 75+) among stage I, and 44% to 68% among stage II. CSS were greater than RSR in all cases. Although the bias was negligible for 1-year follow-up, the deviation increases with increasing age and years of follow-up. The estimated CSS-2s were always between RSR and CSS, suggesting that RSR underestimates the true lung-cancer-survival.

Conclusion:
In practice, RSR is appropriate for short follow-up and aggregate summaries, while caution is advised when reporting RSR by age groups for longer follow-up. Accurate assessment of the causes of death may alleviate such biases.Figure 1

Background:
United States Preventive Services Task Force (USPSTF) and Centers for Medicare & Medicaid Services (CMS) recommendations for annual screening for lung cancer with low dose CT (LDCT) scans rely on age and smoking history to identify those at high risk for lung cancer. The Tammemagi et al. six year lung cancer risk prediction model, PLCOm2012, developed and validated in large lung cancer screening clinical trials, demonstrated good predictive performance in study participants. A 1.51% PLCOm2012 risk threshold has been reported to outperform CMS/USPSTF entry criteria. This is the first time the model predictive performance has been evaluated in clinical practice.

Methods:
Predictive performance of a reparameterized (no education predictor variable) six year lung cancer risk prediction model, PLCOm2012noEd, was retrospectively assessed in 2297 consecutive individuals that underwent clinical CT lung screening between January 1, 2012 and November 30, 2015. All patients met the National Comprehensive Cancer Network (NCCN) Lung Cancer Screening Guidelines Group 1 or Group 2 high-risk criteria.

Results:
79 cancers were detected in the 2297 screened individuals with a mean follow-up of 2.12 years (75.9% (60/79) – NCCN Group 1). The model six year mean risk for lung cancer was higher for participants with lung cancer, 4.71%, as compared to those without lung cancer, 3.54% (p=0.008). Area under the curve (AUC) of the receiver operator characteristics (ROC) was 0.635 (95% CI 0.577 – 0.693). At the 1.51% predicted risk recommended screening threshold overall sensitivity = 86.1%, specificity = 29.8%, and PPV = 4.2%. For NCCN Group 1 (similar to CMS/USPSTF entry criteria), sensitivity = 91.7%, specificity = 20.7% and PPV = 4.04%. For NCCN Group 2 (younger, lighter smoking history, no limit on time quit with one additional risk factor) mean predicted risk for participants with lung cancer was 2.35% as compared to 1.83% for those without lung cancer but the difference was not statistically significant; p=0.2374. As the incidence of lung cancer was the same in NCCN Group 2 and NCCN Group 1 (3.24% vs 3.51%; p=0.8566) the sensitivity of the model for NCCN Group 2 at the recommended 1.51% screening threshold was reduced to 68.4% with a specificity of 56.3%.

Conclusion:
Lung cancer risk prediction model, PLCOm2012noEd demonstrated reduced sensitivity in individuals meeting NCCN Group 2 high-risk criteria undergoing clinical CT lung screening and may not be appropriate to adequately assess risk of lung cancer in this population.

Background:
Evidence from a variety of settings indicates the presence of socioeconomic differences not only in the risk of developing cancer, but also in management and outcomes. We examined the influence of educational level on stage at presentation, management and mortality in patients with non-small cell lung cancer (NSCLC) in Sweden, a country with a National Health System aiming to provide medical care on equal terms to all residents.

Methods:
We identified 24,385 patients with a NSCLC diagnosis 2002-2011 in Lung Cancer Data Base Sweden, a research database generated by record linkage between the Swedish National Lung Cancer Register and several other population-based registers. In analyses adjusted for comorbidity and other prognostic factors, ORs and HRs were estimated to examine associations between patients´ educational level and aspects of management and mortality.

Results:
Diagnostic intensity CT Thorax, CT upper abdomen and transthoracal biopsy were more commonly performed in patients with high education. In multivariable analysis, the likelihood to undergo PET scan and EGFR testing was significantly higher in patients with high compared to low education OR 1.39 (95% CI 1.23-1.57) and 1.28 (95% CI 1.05-1.55), respectively. No social gradients in EGFR testing was observed in an analysis restricted to non-smoking patients with adenocarcinoma. Stage and histopathology Stage at diagnosis did not differ between educational groups. Adenocarcinomas were proportionally more common in patients with high compared to low education, both in all patients (61.9% vs 53.9%) and among non-smokers (50.7% vs 46.7%). Waiting times There were no differences in waiting times between dates of referral and diagnosis, or between dates of diagnosis and start of treatment. Multidisciplinary conference and treatment intensity The odds for treatment decisions being made in a multidisciplinary setting was higher for patients with high compared to low education (OR 1.26; 95% CI 1.04-1.51). In stage IA-IIB disease, the likelihood to undergo surgery was non-significantly elevated in patients with high education (OR 1.26; 95% CI 0.98-1.63). Mortality In early stage disease, high education was associated with lower all-cause (HR 0.79; 95% CI 0.70-0.89) and cause-specific mortality (HR 0.76; 95% CI 0.66-0.88) after adjustment for treatment, sex, age, region, year, comorbidity, smoking, stage, histology and performance status.

Conclusion:
We found evidence of social gradients in diagnostic and treatment intensity in patients with NSCLC. While there were no difference in stage at diagnosis between educational groups, a lower mortality in early stage NSCLC was observed in patients with high education.

Abstract not provided

Background:
Amplification of ERBB2 in EGFR-mutant lung cancers is a reported mechanism of acquired resistance to tyrosine kinase inhibitor (TKI) therapy. Comprehensive genomic profiling (CGP) of NSCLC tumors shows mutation of ERBB2, most often affecting the encoded HER2 receptor at residue S310, is also prevalent, particularly in the context of EGFR L858R.

Methods:
CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes plus select introns from 28 genes frequently rearranged in cancer on 14,887 consecutive cases of lung cancer. All classes of genomic alterations (GA) were assessed simultaneously, including base substitutions, indels, rearrangements/fusions, and copy number changes. Short variants (SV) include base substitutions or indels.

Results:
A total of 2,516 (16.9%) samples featured EGFR alterations, including amplification (amp) and SV. Of these, 2.9% (73/2,516) harbored alterations in ERBB2 (amp and/or SV). 18 samples (0.7%) harbored SV alterations in ERBB2, 14 of which were mutations at S310. ERBB2 S310 mutations were most often found with EGFR L858R. The ratio of observed to expected mutation at HER2 S310 in EGFR-mutated lung cancers was 2.12, and the ratio for HER2 S310 in combination with EGFR L858R was 5.03. The co-occurrence of HER2 S310 and EGFR L858R was highly significant (p<0.00005). The combination of EGFR and ERBB2 alterations was more common in women. The ratio of male:female patients with any lung cancer in this dataset was 1:1.1, whereas the ratio of male:female with any EGFR alteration was 1:1.7 and for both EGFR and ERBB2 alterations (amp or SV) was 1:3.4. Patients with a combination of EGFR and ERBB2 alterations have been shown to respond to treatment with the pan-ERBB inhibitor afatinib, or combinations of afatinib with the HER2-targeted therapy trastuzumab.

Conclusion:
Short variant alterations in ERBB2 may be an additional mechanism for tumors to acquire resistance to treatment with EGFR-targeted TKIs. Mutations at residue S310, in the extracellular domain of HER2, are the most common ERBB2 SV observed in EGFR-mutant lung cancer, and are significantly associated with EGFR L858R. The co-occurence of alterations in ERBB2 and EGFR is far more common in women than in men. Treatment with the pan-ERBB inhibitor afatinib, alone or in combination with agents targeting HER2, has been shown to benefit patients with lung cancer harboring mutations in both EGFR and ERBB2.

Background:
Combined inhibition of HER2 and mTOR is synergistic in models of HER2 (or ERBB2)-mutant lung cancers. PUMA-NER-4201 is an adaptive, multinational, randomized phase II study comparing the pan-HER inhibitor neratinib (Puma Biotechnology) ± the mTOR inhibitor temsirolimus in patients with advanced HER2-mutant lung cancers. In stage 1 of the study, neratinib + temsirolimus met predefined criteria for expansion into stage 2 [Besse et al. ESMO 2014].

Methods:
Patients with stage IIIB/IV locally determined HER2-mutant cancers were randomized to receive oral neratinib 240 mg once daily ± intravenous temsirolimus 8 mg once weekly (escalated to 15 mg/week after a 3-week cycle if tolerated) with loperamide prophylaxis. Primary endpoint: overall response rate (RECIST v1.1). Secondary endpoints: duration of response, progression‑free survival, overall survival, toxicity assessments (NCI-CTCAE, v4.0). ClinicalTrials.gov: NCT01827267.

Results:
Of 62 randomized patients, 60 received ≥1 dose of neratinib: neratinib alone (n=17); neratinib + temsirolimus (n=43). Baseline characteristics: male/female 32%/68%; median age 66 years; never smokers 60%; adenocarcinoma 98%. HER2 (or ERBB2) mutation type: exon 20 insertions 93.5%; missense substitutions 3.2%; unspecified 3.2%. The most common HER2 allelic variant was A775_G776insYVMA. Exploratory biomarker analysis from available tumor and plasma samples will be presented at the meeting. Efficacy and safety results are shown in the table. With loperamide prophylaxis, the incidence of grade 3 diarrhea was 12% with neratinib and 14% with neratinib + temsirolimus, which lasted for a median duration of 1.5 (interquartile range, 1.0‒2.0) days and 4.0 (interquartile range, 2.0‒16.0) days, respectively. Figure 1



Conclusion:
Neratinib (240 mg/day) + temsirolimus (8 or 15 mg/week) produced responses lasting 2 to 18+ months in 19% of patients with HER2‑mutant lung cancers. Correlative data will be presented at the meeting. Diarrhea was manageable with loperamide prophylaxis.

Background:
There is still an unmet need for targeted drugs in non small cell lung cancer (NSCLC) patients with HER2 mutation. Pyrotinib is an oral tyrosine kinase inhibitor targeting both HER-1 and HER-2 receptors. This phase II trial is designed to evaluate the safety and efficacy of pyrotinib in patients with HER2 mutant advanced NSCLC.

Methods:
A single arm prospective phase II trial was undergone to evaluate the efficacy and safety of Pyrotinib in patients with HER2 mutant advanced NSCLC in a single center of Shanghai Pulmonary Hospital, Tongji University(NCT 02535507). Pyrotinib was administrated 320mg or 400mg orally once a day. Next generation sequencing or ARMS was used to identify the patients with HER2 mutation. The primary endpoint was objective response rate and the secondary endpoints were side effect, progression free survival and overall survival.

Results:
From Jul 15 2015 to Jul 21, 2016, 11 patients with her2 mutated advanced NSCLC were enrolled into this study. Among them, the median age was 58 years old, 6 were male, 4 were smoker, ECOG PS 0/1/2 were 5/6 and all of them were adenocarcinoma. None of them received pyrotinib as the first line therapy and the median previous anti-cancer regimen was 2. 9 patients had the details variants of HER2 mutation including 7 with exon 20 776YVMA, 1 with exon 20 770AYVM and 1 with 2326G>ATTT. All of them evaluated the response, including 54.5% with partial response(6/11), 27.3% with stable disease(3/11) and 18.2% with progressive disease(2/11). 1 patient got response to pyrotinib after progressed from afatinib. 5 patients were still on the study and the median PFS was 6.2 months. Side effects were mild including 4 with grade I/II diarrhea, 2 with grade II fatigue, 2 with grade I rash and 1 with dispnea.

Conclusion:
Pyrotinib showed promising results about the ORR and PFS together with mild toxicity in patients with HER2 mutant advanced NSCLC, further multicenter large scale phase II study is initiated to validate the results in this study.

Abstract not provided

Background:
P53 mutations are common in lung cancer, and have also been described in EGFR mutated patients The impact of p53 mutations in EGFR M+ patients is controversial, especially if classified as “disruptive” and “non-disruptive” according to their functional effect on the p53 protein as proposed by Poeta and colleagues. The aim of the study was therefore to systematically analyze EGFR and p53 mutations within a cohort of patients with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and to investigate a potential impact of p53 mutations on treatment outcome.

Methods:
484 patients diagnosed with lung cancer stage IV were studied for the presence of EGFR as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing, hybrid cage next generation sequencing. P53 mutations were detected by Sanger Sequencing and either Miseq or hybrid cage NGS. Clinical characteristics including smoking status were available for more than 97%.

Results:
484 consecutive patients were studied. The overall EGFR M+ rate was 17.8% (86/484) in all patients, 84.9% (73/86) showing common mutations of exon 19 or 21. In 21/86 (24.4%) patients’ p53 analysis was not successful. P53 disruptive mutations were demonstrated in 24.6% (16/65) of successfully tested patients, and p53 non-disruptive mutation occurred in 27.7% (18/65) whereas p53 WT configuration was found in 47.7% (31/65). Median OS was 28 months in p53 disruptive mutation and 44 month in p53 WT compared to 23 months in p53 non-disruptive mutation (p<0.023). PFS on 1[st] line TKI therapy was 14 months in p53 disruptive mutation, 27 months in p53 WT and 10 months in p53 non-disruptive mutation (p<0.040). Similar results were shown in the EGFR common mutation subgroup. 11/16 (68.8%) patients with a disruptive p53 M+ and 25/29 (86.2%) patients with a p53 WT constellation achieved an objective response on the 1[st] line TKI therapy compared to 7/13 (53.8%) patients with a non-disruptive p53 status. The patients with an unknown p53 status achieved an objective response on the 1[st] line TKI therapy of 82.4.8% (14/17).

Conclusion:
Significant differences in PFS and OS in EGFR M+ patients were observed depending on p53 M+ status. P53 mutational status is predictive when disruptive and non-disruptive p53 M+ are differentiated. A p53 WT constellation has a positive effect on OS and PFS. P53 should be tested prospectively in EGFR M+ patients as management of patients on 1st line TKI may be different.

Background:
KRAS is the most frequently mutated oncogene in Non-Small Cell Lung Cancer (NSCLC) and its role as prognostic and predictive biomarker remains widely debated. Unfortunately, KRAS direct targeting strategies have been unsuccessful and no approved target therapy exists for KRAS-mutant-NSCLC. This pilot study evaluated the activated signaling architecture of advanced NSCLC harbouring a KRAS mutation to better characterize the signaling network driving this subgroup of pulmonary malignancies.

Methods:
Twenty Stage IV Formalin-fixed, paraffin-embedded (FFPE) NSCLCs were collected from chemo-naïve patients at S. Maria della Misericordia Hospital (Perugia, Italy). Ten tumors were KRAS-wild-type (KRAS-WT) and ten were KRAS-Mutant (KRAS-MUT). Whole-tissue lysates were obtained for all samples. Signaling network analysis was performed using the Reverse Phase Protein Array (RPPA) platform to quantitatively evaluate the expression/activation of 148 key proteins and phosphoproteins involved in cellular growth, survival, proliferation, apoptosis, autophagy, inflammation, invasion and cell motility. Wilcoxon Rank-Sum Test was used to compare the signaling architecture of KRAS-MUT and KRAS-WT tumours. All p-values <0.05 were considered significant. Non-parametric correlation analysis was performed to explore the signaling interconnection within each group of patients. Only correlations with p<0.0001 were considered significant.

Results:
This preliminary analysis revealed a statistically significant different activation level of 20 proteins between the KRAS-MUT and KRAS-WT samples. Five of the proteins that were statistically different in the KRAS-MUT group are involved in the inflammatory immunoresponse (ASK1 S83 p<0.01, Axl Y702 p=0.01, Stat2 Y690 p<0.01, Tyk2 Y1054/Y1055 p=0.01 and Twist p<0.01) and six in cell cycle control and DNA repair (ATM S1981 p=0.01; Bcl-xL p=0.03; Cleaved Caspase 3 D175 p=0.02; Histone H3 S10 p<0.01; p53 S15 p<0.01; p27 T187 p=0.04). The analytes that were statistically significant were all lower in the KRAS-MUT group compared to the WT (except for p27 T187 which decreased in the KRAS-MUT group compared to KRAS-WT). Pair-wise correlation analysis of the signaling proteins showed an overall more complex protein-protein interaction network and pathway activation (included AKT/mTOR signaling pathway) in the KRAS-MUT population with high number of statistically significant correlations compared to the KRAS-WT group.

Conclusion:
This pilot study indicated that the effect of KRAS mutation status on protein signaling in NSCLC was an alteration of the immunoresponse axis and DNA repair network. If validated in a larger cohort of patients, these results could have important clinical implications for stratification KRAS-MUT advanced NSCLC patients towards more efficacious targeted treatment and to identify new therapeutic targets based on multi-targets/multi-pathways KRAS inhibitory approach. (AIRC-supported study).

Background:
Activating mutations in the KRAS proto-oncogene define a prevalent and clinically heterogeneous molecular subset of lung adenocarcinoma (LUAC). We previously identified three major subgroups of KRAS-mutant LUAC on the basis of co-occurring genetic events in TP53 (KP), STK11/LKB1 (KL) and CDKN2A/B (KC) and reported that LKB1-deficient tumors exhibit a “cold” tumor immune microenvironment, with reduced expression of several immune checkpoint effector/mediator molecules, including PD-L1 (CD274). Here, we extend these findings and examine the clinical outcome of co-mutation defined KRAS subgroups to therapy with immune checkpoint inhibitors.

Methods:
We conducted a single-institution analysis of clinical and molecular data (PCR-based next generation sequencing of panels of 50, 134 or 409 genes) prospectively collected from patients enrolled into the MD Anderson Lung Cancer Moon Shot GEMINI database. KRAS-mutant LUAC were separated into KP, KL and K (wild-type for TP53 and STK11) groups. The log- rank test and Fisher’s exact test were used for comparison of progression-free survival (PFS) and objective response rate (ORR) respectively between the groups. In addition, automated IF-based enumeration of lymphocyte subsets was performed in 40 surgically resected LUAC (PROSPECT cohort) with available whole exome sequencing data.

Results:
Among 229 patients with KRAS-mutant LUAC who consented to the protocol we identified 35 patients with metastatic disease (17 KP, 6 KL, 12 K) that received immunotherapy with nivolumab (N=29), pembrolizumab (N=3), nivolumab/urelumab (N=1) and durvalumab/tremelimumab (N=2) and had robust clinical outcome data. There was no impact of different KRAS alleles (G12C/G12V/G12D) on PFS (P=0.6149, log-rank test) or ORR to immune checkpoint inhibitors (P=0.88, Fisher’s exact test, 2x3 contingency table). In contrast, co-mutation defined KRAS subgroups exhibited significantly different median PFS to immunotherapy (KP: 18 weeks, KL: 6 weeks, K: 16 weeks, P=0.0014, log-rank test). Objective responses were observed in 9/17 (52.9%) KP and 3/12 (25%) K tumors compared to 0/6 (0%) KL tumors (P=0.049, Fisher’s exact test, 2x3 contingency table). In the PROSPECT cohort of surgically resected LUACs with available whole exome sequencing data, somatic mutation in STK11 was associated with reduced intra-tumoral densities of CD3+ (P=0.0016), CD8+ (P=0.0125) and CD4+ (P=0.0036) lymphocytes.

Conclusion:
Mutations in STK11/LKB1 are associated with an inert tumor immune microenvironment and poor clinical response of KRAS-mutant LUAC to immune checkpoint blockade. The mechanism that underlies this phenotype and strategies to overcome it are under investigation. The impact of additional co-mutations on the immune profile and response of KRAS-mutant LUAC to immunotherapy is also being explored.

Abstract not provided

Background:
Comprehensive genomic profiling (CGP) can discover novel therapy targets in NSCLC. Amplification of RICTOR, encoding a component of the MTORC2 complex, has recently been identified as a targetable alteration leading to clinical benefit.

Methods:
CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes plus select introns from 28 genes frequently rearranged in cancer on 14,698 consecutive cases of NSCLC, comprising lung adenocarcinoma, squamous cell carcinoma (SCC) or NSCLC not otherwise specified (NOS). Tumor mutational burden (TMB) was determined on 1.1 Mb of sequenced DNA. All classes of genomic alterations (GA) were assessed simultaneously, including base substitutions, indels, rearrangements/fusions, and copy number changes.

Results:
747 (5.0%) NSCLC featured RICTOR amplification (amp). There were 380 (51%) male and 367 (49%) female patients with a mean age of 64.1 years (range 18-88 years). The primary tumor was analyzed in 333 (45%) cases and a metastasis biopsy in 414 (55%) cases. Genes most frequently co-altered with RICTOR amp included TP53 (79.5%) and FGF10 (64.6%), which is located close to RICTOR on chromosome 5 and is frequently co-amplified. Several known oncogenes in NSCLC were mutated at significantly higher rates in tumors with RICTOR amp, including EGFR (22%), MET (8.4%), ERBB2 (7%), as well as FGFR1 (5%), FGFR3 (1.4%), and FGFR4 (1.6%). 42.2% of tumors with RICTOR amp did not harbor additional alterations in KRAS or genes indicated in the NCCN guidelines. KRAS GA were identified in 19.6% of RICTOR amp tumors, compared with 29.8% of all NSCLC, but this difference was not statistically significant. Mean TMB in RICTOR amp tumors was intermediate (14.9 mut/Mb), and is higher than the overall average for NSCLC (9.2 mut/Mb). The number of RICTOR-amplified tumors with high TMB (>20 mut/Mb) was 23%, higher than the rate for non-RICTOR amp NSCLC (12.9%). Examples of patients with RICTOR amplification within late stage NSCLC responding to MTOR inhibitors will be presented.

Conclusion:
RICTOR amplification, when compared to other non-EGFR known drivers of NSCLC, is a relatively frequent clinically relevant GA that has been shown to respond to MTOR inhibitors. The co-occurrence of RICTOR amplification with mutation of known oncogenic drivers suggests a possible mechanism of acquired resistance to therapy that should be explored further. Tumors with RICTOR amp more often have higher levels of TMB than other NSCLC. Further study of RICTOR amp as a therapy target NSCLC in a clinical trial setting appears warranted.

Background:
Lung cancer is the leading cause of death among cancers. There is broad evidence that immune cells are involved in the growth and development of these malignancies. CD26/DPP4 (dipeptidyl peptidase 4) is a transmembrane glycoprotein, that is constitutively expressed on hematopoetic cells, but also found on lung epithelial and endothelial cells. We found previously that the activity of CD26/DPP4 of lung cancer patients at early stages is four times higher than in normal tissue. Here, we tested if CD26/DPP4-inhibition is able to modulate lung cancer growth in mice.

Methods:
An orthotopic lung tumor model was employed by sc. injections of the mouse lung cancer (Lewis Lung Carcinoma (LLC)) and a human lung adenocarcinoma cell line (H460). These were developed in mice C57BL6 (n=18) and CD1-nude mice (n=20) respectively. The CD26/DPP4-inhibitor Vildagliptin was given in drinking water of 50mg/kg daily dose. Tumor growth was evaluated by wet weight of tumor mass at 2 weeks. Histological assessments included TUNEL, immunohistochemistry (IHC) of CD3, B220, F4/80 and NKp46. IL-10, Arginase, IL-12, NKp46, NK1.1, IFN-g, Granzyme, and Perforin 1 were analyzed by RT-PCR. In vitro analysis of surfactant protein (SP) expression in LLC and H460 were performed by western blotting. For a proof of concept, macrophage ablation was performed by clodronate-liposome during Vildagliptin treatment.

Results:
Vildagliptin treatment significantly reduced the tumor growth of both, LLC and H460 in mice. IHC showed macrophages (F4/80+) and NK cells (NKp46+) to be significantly increased by Vildagliptin within tumors, while TUNEL stain and IHC of T- and B cell infiltration did not show any difference. Gene expression levels of anti-inflammatory markers (IL-10, and Arginase) were unchanged, while the pro-inflammatory cytokine IL-12 was significantly elevated. The NK cell markers NKp46, NK1.1, IFN-g, Granzyme and Perforin 1 were significantly upregulated within the tumor by Vildagliptin, indicating that inhibition of CD26/DPP4 recruits NK cells into the tumor. Furthermore, we found enhanced SP expressions in lung cancer cell lines by Vildagliptin treatment in vitro. Macrophage ablation with clodronate-liposome in Vildagliptin treated mice reversed the tumor size significantly.

Conclusion:
The Inhibition of CD26/DPP4 decreased lung cancer growth in primary models of mouse and human lung cancer and increased inflammatory macrophages and NK cell cytotoxicity within those tumors. Furthermore, an increased expression of SP by Vildagliptin treatment in lung cancer cell lines suggests that surfactant production in lung cancer activates macrophages to fight against lung cancer via the recruitment of macrophages and NK cells.

Background:
Our laboratory has translated (NCT02414269, NCT02792114) mesothelin (MSLN), a cancer-antigen, targeted chimeric antigen receptor (CAR) T-cell therapy to solid tumors including for lung adenocarcinoma (ADC) patients. The goal of this study is to investigate the anti-tumor efficacy of MSLN CAR T cells against lung ADC with heterogenous MSLN expression, and further develop mechanistic insights to potentiate the therapy.

Methods:
Human CAR T cells transduced with M28z, MSLN CAR with CD28 costimulation, were tested in vitro (cytotoxicity by [51]Cr release assay, proliferation, cytokine secretion, LFA-1/ICAM-1 [lymphocyte function associated antigen-1/intercellular adhesion molecule 1] adhesion assay, and flow cytometry) and in vivo (tumor and T-cell bioluminescence imaging [BLI], survival) against low-, high- or a mixture (50:50 or 70:30) of MSLN-expressing A549 human lung ADC.

Results:
MSLN CAR T cells demonstrate antigen-intensity dependant cytotoxicity against both low- and high- MSLN-expressing A549 cells with additive bystander cytotoxicity against [51]Cr-labelled low-MSLN A549 cells in the mixture both in vitro (Figure Panel A) and in vivo (22 days delay in tumor progression by low-MSLN A549 cells). Flow cytometry demonstrated ICAM-1 overexpression on low-MSLN A549 cells when treated with effector cytokine-rich supernatant collected by exposure of CAR T cells to high-MSLN A549 cells (Panel B), LFA-1 expression by MSLN-activated CAR T cells (Panel B). Activated CAR T cells adherence to ICAM-Fc coated plates compared to controls (Panel C). LFA-1/ICAM-1 expression promoted adherence of antigen-activated CAR T cells to low antigen-expressing tumor cells (Panel D), which is inhibited in the presence of LFA-1 blocking antibody (Panel E). Figure 1



Conclusion:
We provide a mechanistic reason for the antigen-specific, bystander efficacy of CAR T cells against low-antigen expressing lung cancer cells. Strategies to augment LFA-ICAM interactions between CAR T cells and cancer cells can effectively translate mesothelin-targeted CAR T-cell therapy against heterogenous antigen-expressing solid tumor, lung cancer.

Abstract not provided

Background:
Non-invasive genotyping of NSCLC patients by circulating tumor (ct)DNA is a promising alternative to tissue biopsies. However, ctDNA EGFR analysis remains challenging in patients with intrathoracic disease, with a reported 26-57% T790M mutation detection rate in plasma (Karlovich et al., Clin Cancer Res 2016; Wakelee et al., ASCO 2016). We investigated whether a mutation enrichment NGS could improve mutation detection in plasma and urine from TIGER-X, a phase 1/2 study of rociletinib in patients with EGFR mutation-positive advanced NSCLC.

Methods:
The therascreen (Qiagen) or cobas (Roche) EGFR test was used for EGFR T790M analysis in tumor biopsies. Urine and plasma were analyzed by trovera mutation enrichment NGS assay (Trovagene).

Results:
Of 174 matched tissue, plasma and urine specimens, 145 (83.3%) were T790M+ by central tissue testing, 142 (81.6%) were T790M+ by plasma, and 139 (79.9%) were T790M+ by urine. Urine and plasma combined identified 165 cases (94.8%) as T790M+. Of 25 cases positive by ctDNA but negative/inadequate by tissue, 16 were double-positive in plasma and urine, unlikely to be false positive (Figure 1). T790M detection rate was higher for extrathoracic (n=119) vs intrathoracic (n=55) disease in plasma (87.4% vs 69.1%, p=0.006) but not urine (81.5% vs 76.4%, p=0.42). Combination of urine and plasma identified T790M in 92.7% of intrathoracic and 95.8% of extrathoracic cases (p=0.47). In T790M+ patients, objective response rate was similar whether T790M mutation was identified by tissue, plasma or urine: 37.4%, 33.1% and 36.6%, respectively. 4 of 9 patients T790M+ by urine but negative by tissue responded, and 2 of 8 patients T790M+ by plasma but negative by tissue responded.

Conclusion:
Mutation enrichment NGS testing by urine and plasma combined identified 94.8% of T790M+ cases. Combination of urine and plasma may be considered before tissue testing in EGFR TKI resistant NSCLC, including patients without extrathoracic metastases. Figure 1

Background:
Treatment in non-small cell lung cancer is quickly evolving and new agents make it to the routine practice at a rapid pace. Whether outcome and PRO data generated in clinical trials with often narrow inclusion and exclusion criteria will hold up in the routine practice is of high interest, especially due to the increasing costs of new drugs. Therefore registry data are of ever increasing importance to patients, physicians and reimbursement institutions.

Methods:
Therefore, we have started a prospective, clinical registry for patients with metastatic non-small cell lung cancer. The purpose of CRISP is to set up a national clinical research platform to document representative data on molecular testing, sequences of systemic therapies and other treatment modalities, course of disease in patients with advanced or metastatic NSCLC in Germany not amenable to curative treatment. A particular focus is on molecular biomarker testing of patients before the start of first-line treatment. The data shall be used to assess the current state of care and to develop recommendations concerning topics that could be improved. PRO assessment will provide large-scale data on quality of life and anxiety/depression for real-life patients in routine practice. In addition, two questionnaires (concerning individual quality of life and patient-caregiver communication) will be validated in German patients with metastatic NSCLC. Furthermore CRISP will set up a decentral tissue annotation for future collaborative, investigational scientific biomarker testing.

Results:
This study will be carried out in up to 150 representative cancer centers in all therapeutic sectors in Germany. More than 8000 patients will be recruited and followed up to a maximum of 3 years, respectively until death. The first patients have been included as of December 2015. As of yet, 82 centers have been initiated, 211 patients have been recruited. Preliminary data will be presented at the meeting in terms of molecular test rates, demographic data as well as treatment stratification in the 1[st] line setting.

Conclusion:
The registry CRISP will be the first to present representative real life data, covering all treatment settings of patients with NSCLC in Germany. ClinicalTrials.gov Identifier: NCT02622581 CRISP is supported by Grants from AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, and Pfizer Pharma GmbH.

Background:
AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib, a T790M directed EGFR-TKI, vs platinum-based doublet chemotherapy in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on previous EGFR-TKI therapy. Concordance between plasma and tissue testing, and efficacy outcomes by baseline plasma T790M status, were evaluated.

Methods:
Eligible patients were randomised 2:1 to osimertinib 80 mg orally once daily or platinum-pemetrexed (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5) every three weeks for up to six cycles. Patients were tumour tissue T790M-positive (by cobas[®] EGFR Mutation Test v2) from a biopsy after disease progression prior to study entry. Blood samples were taken at baseline for retrospective analysis of T790M mutation status by plasma ctDNA using the cobas[®] EGFR Mutation Test v2.

Results:
Concordance data are reported in the table. Within the intent-to-treat (ITT) population (n=419), patients plasma T790M-positive and randomised to treatment (n=172) had markedly improved progression-free survival (PFS) by investigator assessment (IA) with osimertinib vs platinum-pemetrexed: hazard ratio 0.42 (95% CI: 0.29, 0.61); median 8.2 vs 4.2 months. Objective response rate (ORR) by IA was also distinctly improved with osimertinib vs platinum-pemetrexed: 77% vs 39% (odds ratio 4.96 [95% CI: 2.49, 10.15]; p<0.001). This is consistent with the ITT population: PFS hazard ratio 0.30 (95% CI: 0.23, 0.41); p<0.001 (median 10.1 vs 4.4 months); ORR 71% vs 31% (odds ratio 5.39 [95% CI: 3.47, 8.48]; p<0.001). Figure 1



Conclusion:
In plasma T790M-positive patients the clinical benefit of osimertinib was superior to platinum-pemetrexed, consistent with the ITT T790M-positive population selected by tumour tissue test. PFS with osimertinib was similar regardless of selection by tissue or plasma T790M-positive status. Based on these, and AURA Phase II data, routine biopsy testing is recommended for patients with a plasma T790M-negative test where feasible.

Abstract not provided

Background:
The association between depth of response to EGFR TKI and prognosis of EGFR-mutated NSCLC remains unclear. We aimed to assess the correlation between maximal tumor shrinkage and survival in patients treated with gefitinib and afatinib.

Methods:
Patients with advanced EGFR-mutated NSCLC enrolled in first-line gefitinib and afatinib clinical trials between 2005 and 2014 at the National Taiwan University Hospital were reviewed. Patients who had at least one measurable target lesion that shrank during treatment were included. Overall survival (OS) was defined as time from date of enrollment to death or May 30[th], 2016. Correlation between tumor shrinkage and OS was analyzed by Pearson correlation coefficient and Kaplan-Meier method. The influence of high maximal tumor shrinkage (defined as ≥50% tumor shrinkage), age, gender, types of EGFR mutation, central nervous system (CNS) involvement at diagnosis, CNS as site of progression, first-line EGFR TKI (gefitinib or afatinib), and subsequent treatments (chemotherapy, third-generation TKI) on OS was evaluated by a multivariate Cox proportional hazard model.

Results:
A total of 189 trial patients were screened and 91 patients were eligible for analysis (gefitinib n=42, afatinib n=49). The median maximal tumor shrinkage during first-line EGFR TKI treatment was 53% (interquartile range 30.5%). Maximal tumor shrinkage did not correlate with OS in all patients (R[2]=0.0225, p=0.169), and either the gefitinib (R[2]=0.0036, p=0.689) or afatinib (R[2]=0.0625, p=0.085) group (Fig.1A). High maximal tumor shrinkage also did not significantly affect OS (HR 0.86, 95% CI 0.54-1.40, p=0.564) (Fig. 1B). In multivariate analysis, CNS as site of progression (HR 2.96, 95% CI 1.39-6.29, p=0.005) and first-line afatinib (HR 0.51, 95% CI 0.29-0.91, p=0.022) were the only factors that significantly influenced OS.Figure 1



Conclusion:
The depth of response to first-line gefitinib and afatinib was not predictive of OS in patients with EGFR-mutated NSCLC.

Background:
DpR, defined as maximum tumor shrinkage, has emerged as a potential predictor for long-term treatment outcome across multiple tumors, including NSCLC treated with immunotherapy or targeted therapy. This exploratory analysis evaluated whether DpR correlated with survival in patients with advanced NSCLC treated with platinum-doublet chemotherapy in a phase III randomized clinical trial.

Methods:
Patients received first-line nab-paclitaxel 100 mg/m[2] weekly or paclitaxel 200 mg/m[2] q3w, both + carboplatin AUC 6 q3w. The current analysis evaluated DpR as best percent change from baseline in total target lesion length during treatment. For patients with tumor shrinkage, data were grouped into quartiles based on maximum percent shrinkage from baseline (Q1: > 0%-≤ 25%; Q2: > 25%-≤ 50%; Q3: > 50%-≤ 75%, Q4: > 75%) and compared with data from patients with no change or tumor growth (NC/G).

Results:
Tumor measurement by independent review (baseline and postbaseline) was evaluable in 959 patients pooled across treatments. The median (Figure) and 1-year OS increased with each quartile vs NC/G (NC/G: 4.8 months and 17%; Q1: 10.4 months and 44%; Q2: 14.5 months and 62%; Q3: 19.3 months and 71%; Q4: 23.5 months and 70%) with HRs for OS vs NC/G of 0.42 for Q1 (95% CI, 0.33-0.53; P < 0.0001), 0.28 for Q2 (0.22-0.36; P < 0.0001), 0.23 for Q3 (0.16-0.31; P < 0.0001), and 0.19 for Q4 (0.11-0.33; P < 0.0001), respectively. Similar findings were observed for all quartiles vs NC/G for age (≥ 70 and < 70 years) and histology (squamous and nonsquamous) in subset analyses (P < 0.05 for all comparisons).

Conclusion:
DpR was associated with increased OS in patients with advanced NSCLC receiving first-line platinum-based doublet chemotherapy, regardless of age or histology. These findings underscore the importance of evaluating quality of treatment response in this patient population.Figure 1

Background:
Circulating tumor cells (CTCs) have been reported prognostic and predictive in non-small cell lung cancer (NSCLC) and a few of other cancer types. In 1[st] line setting, whether EPCAM[+]CK[+]CD45[-] CTC and/or stem cell-like cKIT[+]EPCAM[+ ]CK[+]CD45[-] CTC enumeration and dynamic changes can be prognostic and/or predictive to standard chemotherapy need further investigation in Chinese patients with NSCLC.

Methods:
A prospective study on the CTC enumeration in advanced NSCLC with 1st line chemotherapy (POLICE) was started by China Thoracic Oncology Group (CTONG). Patients with NSCLC naïve for systemic regimens were enrolled since August 2013. CTCs were detected by Cell Search Platform and identified as positive for EPCAM[+]CK[+]CD45[-] phenotype. CD117 (cKIT) marker was added to test the frequency of stem cell-like cKIT[+]EPCAM[+]CK[+]CD45[- ]CTCs. Primary endpoints were CTC counts and its correlation with first line therapy.

Results:
Totally 180 patients were enrolled. In 174 case total CTC and cKIT[+]CTC positive (cutoff >=1) rates were 38.5% (67/172) vs 14.3% (24/168), 21.8% (31/142) vs 6.3% (9/142), 13.7% (13/95) vs 6.4% (6/94) and 40.4% (38/94) vs 15.0% (13/93) at time-points of baseline, after first-cycle-chemo, after four-cycles-chemo and disease progression. At time immediately after first-cycle-chemo, patients in CTC=0 group got statistically higher ORR (29.0% VS 7.1%, P=0.017) and DCR (74.2% VS 42.9%, P=0.002) than in CTC>=1 group. At time after four-cycles-chemo, patients in CTC=0 group got statistically higher DCR (88.3% VS 58.3%, P=0.026) than in CTC>=1 group. At time either after first-cycle-chemo or after four-cycles-chemo, patients in CTC>=1 group got worse PFS (5.7m VS 4.0m, P=0.025; 6.3m VS 4.0m, P=0.001 ) than in CTC=0 group. At time after first-cycle-chemo, patients in groups cKIT[+]CTC>=1 and cKIT[-]CTC>=1 got worse PFSs (3.1m vs 4.0m vs 5.7m, P=0.001) and worse DCRs (44.4% vs 42.1% vs 73.9%, P=0.009) than in CTC=0 group. For 142 patients categorized into three groups of dynamic CTC decrease (17), CTC unchanged (82), and CTC increase (43), there were significant differences in terms of DCR (71.8% vs 71.6% vs 33.3%, P=0.018) and PFS (5.2m vs 5.6m vs 3.1m, P=0.037).

Conclusion:
In first line setting of advanced NSCLC, at time-points after first-cycle-chemo other than baseline, total CTC or cKIT[+]CTC counts could be predictive for worse DCR or PFS. CTC increase from baseline to after-first-cycle-chemo might be a strong signal for the inefficacy of first line chemotherapy in the NSCLC patients.

Abstract not provided

Background:
Genotyping cell free circulating DNA (cfDNA) is a non-invasive method of detecting EGFR mutations (EGFRmu) in plasma and may provide an option to identify patients who progress while treated with EGFR TKIs. The aim of our study was to monitor plasma EGFRmu and identify dynamic case specific changes in plasma EGFRmu during routine treatment of advanced EGFRmu NSCLC patients.

Methods:
Plasma was collected from patients with advanced EGFRmu NSCLC treated with first- or second-generation EGFR TKIs. Plasma EGFRmu were dynamically monitored consecutively at every scheduled visit. Cobas EGFR Mutation Test v1 and v2 (Roche, USA) was used to detect 42 mutations at EGFR gene in exons 18 to 21. Liquid biopsy progression (LBP) was determined as reappearance of EGFRmu in plasma after negativisation during treatment or increase of EGFRmu levels expressed by semi-quantitative index (SQI). Radiologic progression was determined in accordance with RECIST1.1 criteria.

Results:
From May 2014, 23 patients were treated with EGFR TKIs for advanced EGFRmu NSCLC; 20/23 had detectable activating mutations in plasma before any treatment and were therefore included in our analysis. Dynamic changes of plasma EGFRmu during 1[st] line EGFR TKI treatment are shown in Figure 1. Eight patients (40%) experienced RECIST 1.1 progression while on treatment, whereas one patient was inevaluable. In 4/8 patients (50%) LBP appeared at the same time as radiologic progression, in 3/8 patients (37%) LBP appeared before radiologic progression (8w, 14w, 20w before, respectively) and in 1 patient (12%) radiologic progression appeared 6w before LBP. Among patients who did not experience radiologic progression yet, some dynamic changes in cfDNA were also observed, but alterations in the SQI values were much smaller. Figure 1



Conclusion:
Monitoring EGFR mutations in plasma is a feasible and less invasive method in routine clinical practice and could be used as a predictive marker of progression on treatment with EGFR TKIs.

Background:
NSCLC patients with activating mutations of the EGFR initially respond well to TKIs, but about half such patients develop TKI resistance through acquisition of a secondary T790M mutation. Whereas next-generation EGFR-TKIs have been developed to overcome T790M-mediated resistance, performance of a second tumor biopsy to assess T790M mutation status can be problematic.

Methods:
We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation–positive patients with acquired EGFR-TKI resistance.

Results:
A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M.

Conclusion:
Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.

Background:
EGFR T790M mutation occurs in about half of EGFR mutated NSCLC patients with acquired EGFR-TKI resistance. It is currently unknown if switching therapy to a third generation anti-EGFR TKI based on circulating tumor DNA at first detection with urine is superior to switching therapy based on radiographic progression. Herein we demonstrate the identification of T790M in urine months before radiographic progression, patient responses when treated with an anti-EGFR third generation TKIs, clinical cutoffs that may be predictive of benefit, and a novel clinical trial to consider for treatment selection.

Methods:
From 2014 to 2016 a total of 42 patients with EGFR activating mutations were followed at UCSD Moores Cancer Center through multiple lines of therapy. 34 patients had serial urine collection every 4-6wks from time of first visit. Clinical progression was assessed with CT imaging performed every two months.

Results:
Among the 42 patients, 35 patients had metastatic disease (6 with intrathoracic M1a disease and 29 with distant metastasis M1b). Urine volume ranged from 30-100ml. Average time from first line TKI start to urine T790M was 15.7mos (CI 9.6-25.6), time from TKI start to radiographic progression was 21.9mos (CI 10.7-27.0), and time from urine T790M to radiographic progression was 3.6mos (CI 0.9-6.8). All patients with >30 copies/10[5] genome equivalents (GEq) of urine T790M had response to third generation TKIs. In patients who had urine EGFR T790M from 10-30 copies/10[5] GEq, three serial measurements in the 10-30 range predicted response. EGFR T790M copies of less than 10 copies/10[5] GEq did not predict response to third generation inhibitors.

Conclusion:
EGFR T790M can be identified in urine before radiographic progression and quantitative cut-offs can be predictive of response. We are testing this prospectively in a clinical trial with serial ctDNA analyses obtained for resistance monitoring for up to 24 months on first line TKI therapy. Patients who have urine detection of T790M (>30 copies or three serial collections with 10-30 copies/10[5] GEq) at 12 months and before progression are randomized to second line third generation TKI therapy or continuation of the first line therapy until progression. Patients with undetectable urinary T790M or <10 copies/10[5] GEq will continue on the first line therapy past 12 months until progression. Overall survival, progression free survival, and time to progression will be compared between cohorts to validate the early detection of T790M by urine ctDNA and understand the impact of an early switch in therapy based on ctDNA analyses.

Abstract not provided

Abstract:
The demonstration that therapies directed at the programmed death-1 (PD-1) receptor or its ligand (PD-L1) result in durable responses and improved survival in a number of solid tumours including non-small cell lung cancer has awakened interest in cancer immunotherapy. The activity of PD-1/PD-L1 therapy in NSCLC implies that endogenous T-cells can recognize antigens on tumour cells and eliminate those cancer cells. The success of checkpoint inhibitor therapy in the metastatic setting has led to a immunotherapy trials in early stage (adjuvant) and stage lll NSCLC. This session will provide perspective on the current state and challenges facing immunotherapy in these settings. Current perspectives: The concept of using immunotherapy to prevent recurrence of NSCLC after resection of early stage NSCLC is not new. More recently, two randomized phase lll trials of therapeutic cancer vaccine strategies have been completed in resected, early stage NSCLC (MAGRIT) or after chemoradiation in stage lll disease (START). The MAGRIT trial (1) assessed the efficacy of an active, specific cancer immunotherapy (ASCI) against the MAGE-A3 cancer testis antigen in completely resected stage IB-IIIA NSCLC. Tumors from more than 13,000 patients were screened for MAGE-A3 expression and 2312 patients whose tumours expressed MAGE A3 were randomized 2:1 to MAGE-A3 (ASCI) or placebo. The MAGRIT trial failed to meet its primary end-point of improvement in disease free survival with MAGE-A3 ASCI. The START trial(2) assessed a MUC1 vaccine in stage III NSCLC patients who had response or stable disease after standard chemoradiation. The chemoradiation could have been delivered concurrently or sequentially. The modified intention to treat population included 1239 patients. The primary end-point was not met (adj. HRO .88, 95% CI 0.75 -103, p=0.123). Further development of this agent has been abandoned. The failure of these two large global phase III studies raises doubt about vaccine strategies used in isolation in early stage NSCLC. There are a number of possible explanations for these negative results (3). One of the primary reasons is that cancer vaccines , when used alone, fail to address the many immunosuppressive factors operating in the tumour microenvironment (TME). Clinical trials evaluating anti PD-1/PD-L1 therapy in early stage or locally advanced NSCLC have not yet reported results. The PACIFIC trial (NCT 20125461) is a randomized phase III trial of MEDI4736 versus placebo following concurrent chemoradiation in patients with stage III NSCLC. The primary outcome measures are OS and PFS. This trial completed accrual in April 2016 and has randomized more than 700 patients. In addition to the important efficacy outcomes, a number of exploratory objectives will assess tissue and blood for potential biomarkers. The Canadian Cancer Clinical Trials Group is assessing MEDI 4736 versus placebo in completely resected stage IB-IIIA NSCLC (NCT 02273375). This trial will randomize 1100 patients with the primary outcome measure being DFS in PD-L1 positive patients. PD-L1 positive is defined as > % positive tumour cells. Immune Based Prognostic Markers: The TME consists of stromal cells including endothelial cells and fibroblasts and a number of immune cell types. Tumours may escape immune recognition in large part by modulating the recruitment and function of various immune cells into the TME (4). A comprehensive review of the prognostic value of different immune cells in NSCLC has been reported (5). Two recent studies have separately assessed tumour lymphocytic infiltration (TLI) (6) or stromal CD8+ T-cell density (7) as potential prognostic markers in early stage NSCLC. Using the large, relatively homogenous population of curative resected NSCLC patients from the LACE-Bio collaboration, Brambilla et al examine the prognostic and predictive value of TLI. Patients were separated into discovery and validation sets. An intense TLI (>50% stromal lymphocytes in tumour bulk) was strongly prognostic of favourable overall survival and disease free survival. Based on previous work, Donner et al selected stromal CD8+ tumour infiltrating lymphocyte as the most promising immuno-based prognostic marker. Using four separate cohorts of curatively resected stage I-III patients, they established training and validation sets. Tissue microarrays were scored for stromal CD8 TLI's; stromal CD8 TIL density was found to be an independent prognostic factor and retained significant prognostic impact within each stage. The value of PD-L1 as a biomarker in NSCLC has been investigated primarily in advanced disease and focused on prediction of response and/or survival. Studies investigating the value of PD-L1 as a prognostic marker in early stage NSCLC have many limitations. These studies are small, include heterogenous populations, assess PD-L1 using different antibodies and scoring systems and included PD-L1 on tumour cells only or tumour cells and TLI's. It is not surprising that these studies show conflicting results. Based on the available evidence, the prognostic value of PD-L1 expression in early stage NSCLC remains uncertain. The adjuvant trials of anti-PD1/PD-L1 therapy currently being conducted may clarify the value of PD-L1 as both prognostic and predictive biomarkers in this setting. Challenges One of the fundamental challenges to developing effective cancer immunotherapies is our limited understanding of the human immune system in steady state and its response to stress. Animal models do not necessarily translate to humans. The Human Vaccines Project (8) is a global initiative that has as one of its primary objectives the decoding of the human immune system and providing a map of the human “immunome”. This private-public partnership uses state-of-the-art machine learning and technologies to elucidate the principles of immunogenicity to accelerate the development of new immunotherapies against infectious diseases and cancer. A second challenge is how best to target micrometastases in the adjuvant and locally advanced setting. While the primary tumor and metastatic lesions have many mutations in common, metastatic tumors possess mutations that are distinct from the primary. Do adjuvant therapies need to target the metastatic cascade and if so, which steps are the most susceptible to intervention? (9) The complex of the TME would predict that focusing on TIL’s or PD-L1 is likely to result in only modest improvements in outcome. Blank et al (10) argue that it will take a combination of biomarkers, the “cancer immunogram” , to determine the best approach in individual patients. References: Lancet Oncol 2016. 17;(8): 22-35 Lancet Oncol 2014; 15 : 59-68 Ann Oncol 2015; 26: 2213-2220 Nat Rev Immunology, 2015; 15: 73-86 Clin Cancer Res 2011; 17(16): 5247-56 J Clin Oncol 2016; 34:1223-30 Clin Cancer Res 2015; 21(11): 2635-43 Science Translational Medicine 2016; 8(334): 334-339 Nature Reviews Cancer 2015; 16: 201-218 Science 2016; 352(6286):658-660

Abstract:
Implementation of Precision Medicine in Routine Practice: The Latin American Experience – Part 2 Technology for molecular testing in lung cancer is a highly demanding aspect to tackle in the LATAM countries. Molecular testing requires incorporation of new technologies usually involving expensive equipment, reagents and supplies. Moreover, these items are commonly imported from other countries and are subjected to custom regulation and heavy taxes. Therefore, LATAM labs commonly face unpredictable delays in the legal processing of purchase orders, are constantly adjusting to changes in regulations and in the country’s financial status, and suffer from slow and sometimes poor support from companies that do not see them as preferred clients. As an example of consequences of some of this points, in Argentina the agents Nivolumab and Pembrolizumab were approved by government agencies for immunotherapy for NSCLC before the molecular testing laboratories had conditions to purchase the DAKO platform and the CDx antibodies for appropriate IHC testing. Some technical devices such as automated IHC platforms are more widely available. They were initially integrated onto large pathology labs in the main cities of several countries but smaller automated platforms are currently available in a number of other cities. There are laboratories equipped for fluorescence in situ hybridization (FISH) and for DNA sequencing in most countries. Sanger sequencing is still commonly used, but the main laboratories already incorporated newer technologies such as RT-PCR allele-specific technology (usually Cobas platform) and tailored panels of next generation sequencing (NGS) or have them in the short list for implementation. Additionally to the challenges in the laboratories organization, two other main issues obstruct the implementation of lung cancer molecular testing in the LATAM countries: the lack of a stable logistic infra-structure necessary to ship biological samples to the molecular laboratories in a cheap, reliable and rapid way, and the hurdle of cost reimbursement for the tests. In the past 10 years, expenses and logistics for transfer of biological specimens and reimbursement for molecular test costs, in most countries such as Mexico, Brazil and Argentina, were sponsored by pharmaceutical companies. Companies such as AstraZeneca, Roche, Boehringer Ingelheim, and Pfizer have acted through clinical trials or special access programs. In a smaller scale, molecular tests have been supported by governmental health agencies or covered by private health care insurance companies. A restricted number of patients are paying the tests out of the pocket, mostly sending to US laboratories. Least but not least, the implementation of lung cancer molecular testing relies in the adequate quantity and, most importantly, in the good quality of the available biological sample. Subsequent to the intense interdisciplinary work by the laboratory personnel, significant progress has been detected in the last years in the amount of tumor cells present in the testing specimens. However, proper quality is only achieved in a fraction of specimens. Most LATAM countries do not have local regulations for quality control (QC) of pathology laboratories, and a limited number of those laboratories are taken external QC certification. Moreover, there is no financial support for the adequate validation of the assays at their implementation and for the competency checking periodically thereafter. In consequence, the risk of having laboratories testing in substandard quality conditions is high. Institutions that are well-structured administratively, technically and scientifically and that handle large volumes of clinical specimens usually participate in external QC for molecular tests. They engage in accredited proficiency testing activities or, at least, send material to reference laboratories for investigation of reproducibility of results. Unfortunately, this does not occur in the majority of the LATAM laboratories. Therefore, it is critical to reach potential sponsors to assist the LATAM molecular testing laboratories in overcoming these challenges and rapidly jump to the future. Efforts leading to improve tissue quality, to facilitate local optimization of assays and to ensure assay validation by international standards are needed. A group of regional laboratories have been trying to organize a collaborative project to face these issues and also to come up with an affordable strategy to ensure good quality in pathology and molecular laboratories. Multiple barriers are making it difficult to succeed in this effort. The patient advocate groups have proved effective in sensitizing governments and regulatory agencies in the USA, but those groups are still very under-represented in LATAM. Professional institutions such as the IASLC are specially tailored to help. IASLC congregates internationally conscious personnel and lung cancer experts and would excel, for instance, in matching experts with laboratories requesting specific assistance and in coordinating a regional consortium of laboratories interested in rounds of specimen exchange for proficiency testing and in validated sets of control specimens for implementation of new tests. Data from at least 15 of the highest populated LATAM countries regarding their lung cancer test menu, the technical platforms used, and efforts for investigation of the assay performance characteristics have been surveyed and results will be discussed.

Abstract:
Implementation of Precision Medicine in Routine Practice: The Latin American Experience – Part 1 Marileila Varella-Garcia, PhD The increasing application of the concept of precision medicine (PM) in the last decade has revolutionized health care. Under this concept, the approach to disease treatment and prevention takes into account individual variability in genes, environment, and lifestyle to more accurately predict treatment and prevention strategies for a particular disease in specific patient subsets. PM has been progressing faster among infectious diseases and neoplasia, with emphasis in non-small cell lung cancer (NSCLC) among the solid tumors. However, we are still far away from a stable scenario to which we should adjust. The field is in continuous evolution with constant new discoveries and proposals. The implementation of PM for lung cancer has dramatically impacted several medical areas mainly in two basic aspects: the molecular diagnosis and the therapy regimen. The first involves questions such as how to collect and process specimen for testing, which tests to apply and in which level, how to define scoring criteria and cut-offs for variables with continuous distribution in the population, how to interpret and validate clinical assays, and how to properly communicate with the multidisciplinary team. The second involves questions pertinent to understanding the molecular diagnostic, access to and cost of new and old drugs, evaluation of side effects, selection of combination or sequential regimens, definition of clinical progression and resistance, and proper communication with the multidisciplinary team. Our discussion will primarily address molecular testing in lung cancer in Latin America countries (LATAM). One of the medical areas most largely affected by the changes accompanying PM is Pathology. The new specialty of Molecular Pathology has emerged to focus on the sub-microscopic aspects of disease by examination of molecules within tissues and bodily fluids. Molecular Pathology encompasses aspects of anatomic and clinical pathology as well as molecular biology, biochemistry, genetics, and bioinformatics. Molecular lung cancer testing in LATAM is centralized in the main cities of several countries and usually performed in laboratories of few large, private or public hospitals, mostly belonging to academic institutions. Examples of those laboratories are located in the Hospital Italiano and Hospital Roffo in Buenos Aires, Argentina; in the Instituto Nacional do Cancer in Rio de Janeiro and Instituto AC Camargo in Sao Paulo, Brazil; in the Universidad Catolica de Chile; in the Fundacion Santa Fe de Bogota and Fundacion Valle de Lili in Colombia, and in the Instituto Nacional de Cancerologia in Mexico City. There are also few commercial laboratories that offer standard tests under good laboratory practices. Examples are the laboratories Hermes Pardini and Consultoria em Patologia in Brazil, Argenomics and Biomarkers in Argentina, and ROE in Peru. The implementation of molecular testing poses important challenges to pathology practices in commercial and academic institutions, and efforts to overcome them have been extensively discussed. It is well recognized that changes in two organizational levels are required, one related to personnel and another related to equipment and technology. In terms of personnel, there is a need to increase multi-disciplinary communication affecting all areas including oncologists or surgeons requesting the tests, professionals (surgeons, pulmonologists, interventionists) collecting the specimens, technologists processing and handling the specimens, pathologists performing histology diagnosis and molecular testing interpretation, lab scientists (biologists, biotechnologists, biochemists) executing assays and interpreting the results, and bioinformaticians handling computer-generated data. The interdisciplinary work in the anatomic and clinical pathology laboratory must be intensified and personnel with distinct expertise and no clinical experience must be added and integrated to the team. The role of the pathologist in the communication and integration among team members (clinical/medical and laboratory group) is crucial. Interestingly, the work environment in a complex molecular testing laboratory has changed to demand personnel not only with excellent hard technical skills but also with soft skills such as active listening, coordination, adaptability, punctuality, problem solving, and friendly personality. The lab success relies in that each team member clearly understands his/her role and the value of efficient communication among team members, which is mainly modulated by the pathologists. Most of the LATAM laboratories already performing molecular testing have increased and strengthened this interdisciplinary work using biologists and biotechnologists originally trained in research fields. Nevertheless, the continuous update with the evolving field required from the pathologists, the scarceness of trained bioinformaticians for data sequencing analysis, and the vigorous integration of the entire professional team are still challenging personnel issues to be addressed. Data from at least 15 of the highest populated LATAM countries regarding their efforts in initiating and expanding molecular testing for lung cancer and the strengths and challenges faced have been surveyed and results will be discussed.

Abstract:
The importance of mediastinal downstaging during induction therapy of N2 disease P. De Leyn*, H. Decaluwe*, C. Dooms** and J. Vansteenkiste**. Department of Thoracic Surgery*, Department of Pneumology**, University Hospitals Leuven, Belgium Patients with preoperative pathological proven N2 disease have a dismal prognosis after surgery. Neoadjuvant chemotherapy or chemoradiotherapy is a therapeutic option that is used in patients with baseline resectable stage IIIA-N2 non-small cell lung cancer. Mediastinal downstaging is an important prognostic factor for long term survival. Different restaging techniques are available. The mediastinum can be restaged by CT scan, remediastinoscopy, VATS, PET-CT and EBUS-EUS fine needle aspiration. In primary staging, CT scan has proved to have a low accuracy. It is not surprising that the accuracy of CT scan in restaging the mediastinum is also low. In a Spanish study of 24 patients who underwent neoadjuvant chemotherapy for N2 non-small cell lung cancer, staging was performed by CT scan and remediastinoscopy (1). CT scan had a sensitivity of 41%, a specificity of 75% and an accuracy of 58%. In a prospective study of 93 patients who were restaged by integrated PET-CT after induction chemoradiotherapy, repeat PET-CT was found to be more accurate than CT alone for pathological stages. However, there were 20 false negative and 25 % false positive cases. So, in case of suspicion of residual mediastinal disease, nodal biopsies are still required (2). We evaluated in a prospective single center study repeat mediastinoscopy and PET-CT after induction chemotherapy for N2 disease. PET-CT had a sensitivity of 77% and a specificity of 88% (3). Repeat mediastinoscopy, technically much more difficult than the first procedure, offers the advantage of providing histological evidence of response after induction therapy. Although some centers obtain good results (4), most surgeons will accept that remediastinoscopy is technically difficult and often incomplete. We performed a prospective study to evaluate the accuracy of remediastinoscopy and PET-CT in restaging the mediastinum after mediastinoscopy proven N2 disease (3). The first mediastinoscopy was thoroughly performed with a mean lymph node level of 3.6 per patient biopsied. In our experience, remediastinoscopy was technically feasible, but inaccurate due to severe adhesions and fibrosis. The sensitivity to detect residual mediastinal lymph nodes was only 28,6% with an accuracy of 58,3%. Minimally invasive endoscopic technique EUS and EBUS also obtain histological diagnosis. Their accuracy is very good in baseline mediastinal staging. In the study Herth et al (5) EBUS-FNA was performed for restaging after induction chemotherapy or chemoradiotherapy for N2 disease in 124 patients. The sensitivity was 76% but the negative predictive value was as low as 20%. The largest series in the literature is reported by Szlubowski (6). They combined EBUS-EUS FNA for restaging N2 disease in 106 patients. Sensitivity was 67% with a negative predictive value of 73%. Some recent smaller studies showed better results for EBUS-EUS to prove persistent nodal disease. Most of the new lesions that appear after induction chemotherapy on PET-CT are not malignant (7). We know that some patients with minimal persistent N2 disease (mainly single level) can have a good prognosis after surgical resection (8). In a study published by Dooms et al (9) patients with less than 10% viable tumor cells in mediastinal lymph node sampled at mediastinoscopy and s with more than 60% decrease of SUV~max~ of primary tumor had a five year survival of over 60%. Therefore, we believe that a new staging algorithm could be used to select patients for radical therapy after induction chemotherapy for N2 disease. At baseline staging, pathological N2 disease should be proved by EBUS-EUS fine needle aspiration. PET-CT should be done to exclude distant metastasis and to evaluate SUV~max~ of the primary tumor. At restaging, mediastinoscopy with nodal dissection should be performed. Also repeat PET-CT should be done. In patients with major pathological response in lymph nodes and a major SUV drop of the primary tumor, surgery can be performed with good outcome. References (1)Mateu-Navarro M, Rami-Porta R, Bastus-Oiulats R, Cirera-Noqueras L, Gonzalez-Pont G. Remediastinoscopy after induction chemotherapy in non-small cell lung cancer. Ann Thorac Surg 2000;70:391-5. (2)Cerfolio R, Bryant A, Ojha B. Restaging patients with N2 (stage IIIa) non-small cell lung cancer after neoadjuvant chemoradiotherapy: a prospective study. J Thorac Cardiovasc Surg 2006;131(6):1229-1235. (3)De Leyn P, Stoobants S, Vansteenkiste J, Dewever W, Lerut A.. Prospective study of accuracy of redo videomediastinoscopy and PET-CT in detecting residual mediastinal disease after induction chemotherapy for NSCLC. Lung Cancer 2005;49 Suppl 2 : S3. (4)Rami-Porta R, Call S. Invasive staging of mediastinal lymph nodes: mediastinoscopy and remediastinoscopy. Thorac Surg Clin 2012: 22:177-89. (5)Herth F, Annema J, Eberhardt R, Yasufuku K, Ernst A, Krasnik M, Rintoul R. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer. J Clin Oncol 2008;26(20):3346-3350. (6)Szlubowski A, Zielinski M, Soja J, Filarecka A, Orzechowski S, Pankowski J, Obrochta A, Jakubiak M, Wegrzyn J, Cmiel A. Accurate and safe mediastinal restaging by combined endobronchial and endoscopic ultrasound-guided needle aspiration performed by single ultrasound bronchoscope. Eur J Cardiothor Surg 2014;46:262-266. (7)Collaud S, Lardinois D, Tischler V, Steinert H, Stahel R, Weder W. Significance of a new fluorodeoxyglucose-positive lesion on restaging positron emission tomography/computed tomography after induction therapy for non-small-cell lung cancer. Eur J Cardiothorac Surg 2012;41:612-616. (8)H. Decaluwé, P. De Leyn, J. Vansteenkiste, C. Dooms, D. Van Raemdonck, P. Nafteux, W. Coosemans, T. Lerut. Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothoracic Surg 2009 ;36 :433-9. (9)Dooms C, Verbeken E, Stroobants S, Nackaerts K, De Leyn P, Vansteenkiste J. Prognostic stratification of stage IIIA-N2 non-small-cell lung cancer after induction chemotherapy: a model based on the combination of morphometric-pathologic response in mediastinal nodes and primary tumor response on serial 18-fluoro-2-deoxy-glucose positron emission tomography. J Clin Oncol 2008;26(7):1128-1134.

Abstract:
Approximately 30% of patients with non-small cell lung cancer (NSCLC) are found to have locally advanced stage III tumours at initial diagnosis. For these patients the curative therapeutic options include definitive high-dose radiotherapy with concurrent chemotherapy or, alternatively, induction treatment followed by surgery. Preoperative chemotherapy or combined radiochemotherapy protocols followed by resection result in cure rates of 25-35 percent at 3 years for locally advanced NSCLC. However, surgical resection in patients with stage IIIa N2 remains an issue of controversy depending on the extent of lymph node involvement. Neoadjuvant chemo- or radiochemotherapy is being used to reduce disease burden in the mediastinum before surgery since patients who are downstaged via neoadjuvant therapy and then undergo resection experience a significantly longer 5-year survival of 40% to 50% than those who are found to have residual N2 disease at the time of surgery. Thus, identification of patients who are N2 negative after completion of their neoadjuvant therapy is a critical component for patient selection for thoracotomy. However, clinical restaging in these patients often is challenging. Endoscopic ultrasound guided biopsies (EUS/EBUS-FNA) have increasingly become available and are currently preferred procedures for staging and restaging before surgery due to their high diagnostic accuracy.(1) Serial PET-CT imaging captures anatomical changes and additionally offers semiquantitative information about morphometric and metabolic tissue changes during induction treatment. Issues of PET-CT performance and quality assurance concerning standardization have been clarified during recent years and the validity of repeated measurements has been approved.(2) Successful induction treatment regimes have been frequently found to reduce 18F-FDG uptake and thus PET-CT allows to assess the therapeutic response. Reduction in FDG-uptake of mediastinal lymph nodes after induction therapy has been shown to correlate well with histopathologic response (3), while postinduction PET avidity taken alone was not consistently found to be associated with pathological N2 involvement (4). In the direct comparison of EUS-FNA with PET-CT for restaging after induction chemoradiotherapy, concordance between findings of restaging EUS-FNA and metabolic response of lymph node metastases was observed in 63% patients treated within a prospective study but the diagnostic accuracy of PET-CT was limited.(5) Nevertheless, serial FDG-uptake measurements seem to provide prognostic information during induction therapy. Data collected in prospective trials suggest that a decrease in SUV~max~ between 45% to 60% optimally separates between responders and non-responders (6-9). In a recent large retrospective analysis, a decrease in SUV~max~ greater than 60% in the involved mediastinal nodes was the best predictor of overall survival, better than changes seen in the primary tumour site. (10) An analysis of a randomized trial in potentially resectable stage III NSCLC of induction treatment (including a hyperfractionated accelerated radiotherapy phase) and definitive radiochemotherapy compared with induction treatment followed by surgery confirmed that as early as after two cycles of cisplatin-based induction chemotherapy percentage of SUV~max~ remaining represents a significant prognostic parameter.(9) PET-response was of higher importance than all other clinical factors. Cut-off levels between 0.45 and 0.55 were predictive for freedom from extracerebral progression in all randomized patients. No important differences in the predictive value were observed comparing resection versus definitive radiochemotherapy. PET-response was closely related to extracerebral distant metastases but not to local recurrences, independent of treatment. One might conclude that less PET-responsive tumors are successfully controlled by intensified hyperfractionated accelerated radiochemotherapy or neoadjuvant radiochemotherapy and resection at loco-regional sites so that the highest risk of relapse remains at extracerebral distant sites. Therefore, a selection or intensification of the local therapy according to SUV-decrease is not warranted by these data. Functional imaging has not yet been fully established for treatment guidance but prospective evaluation is underway. In the group of poor-responding patients, treatment intensification by independent systemic options such as targeted therapy or immunomodulating therapy may become emerging new treatment options within clinical trials. References: 1) De Leyn EJCTS 2014, 2) Young, EJC 1999, 3) Pöttgen CCR 2006, 4) Ripley JTCS 2016, 5) Stigt, Lung Cancer 2009, 6) Hoekstra, JCO 2005, 7) Eschmann, Lung Cancer 2007, 8) Dooms, JCO 2008, 9) Pöttgen, JCO 2016, 10) Barnett ATS 2016

Abstract not provided

Abstract:
Rationale for restaging after induction therapy Persistent mediastinal nodal involvement after induction therapy is an independent prognostic factor associated with poor prognosis [1]. Based on the results of two phase III clinical trials on multimodality treatment for pathologically proven N2 non-small cell lung cancer (NSCLC) [2,3], patients with persistent mediastinal involvement do not benefit from surgical resection in terms of survival. The assessment of an objective response after induction therapy continues to be a diagnostic challenge. For this reason, the use of ‘mediastinal downstaging’ as a criterium to select patients for surgery requires a reliable restaging method to predict pathologic stage before lung resection. Algorithm for mediastinal restaging The European Society of Thoracic Surgeons guidelines for preoperative lymph node staging for NSCLC recommend histological confirmation of objective response after induction therapy. This confirmation can be done with ultrasound-guided endoscopic techniques. However, the use of an invasive surgical technique is still recommended when the results of endoscopic procedures are negative [4]. The role of mediastinoscopy Mediastinoscopy in restaging can be performed in the following situations: 1) after induction therapy with no pretherapeutic invasive diagnosis; 2) after induction therapy with mediastinal histological confirmation by endoscopic techniques; 3) after induction therapy preceded by staging mediastinoscopy. In this case, mediastinoscopy is a reoperation: a remediastinoscopy. The use of first mediastinoscopy for restaging is addressed in a small series [5]. In this article, a negative predictive value (NPV) of 90% with a prevalence of ypN2 of 46% were reported. Theoretically, this approach could be a good strategy to perform an easier and safe mediastinoscopy due to the absence of adhesions in the mediastinum. Remediastinoscopy (reMS) is a technique that does not differ much from a conventional mediastinoscopy. However, reMS is technically more demanding because of peritracheal adhesions, resulting in a lower accuracy in comparison with the first procedure. The main goal of this procedure is to take new biopsies of those nodes that had been positive at first mediastinoscopy. Moreover, if it is technically feasible, other nodal stations should be reached to rule out subclinical progression of the disease. Although reMS is not a common procedure, several authors have reported its feasibility and consistent results (see table 1). In addition, its results do not seem to depend on the type of the induction therapy (chemotherapy or chemoradiation) or on the level of thoroughness of the initial mediastinoscopy [6]. Morbidity rate ranges from 0% to 4%, and complications are not specific of reMS because they can also occur at first mediastinoscopy [1,6-8]. Regarding mortality, only one death has been reported. Based on the four largest published series, this intraoperative death represents a mortality rate of 0.2% [1,6-8]. The role of transcervical lymphadenectomies During the last decade, two new surgical staging procedures were developed: videoassisted mediastinoscopic lymphadenectomy (VAMLA) and transcervical extended mediastinal lymphadenectomy (TEMLA). The main difference between these procedures is that VAMLA is an endoscopic technique performed through a videomediastinoscope, and TEMLA is an open procedure assisted by a videomediastinoscope or a videothoracoscope, depending on the nodal station dissected. Both techniques imply the removal of all the lymph nodes of the explored nodal stations, allowing the identification of minimal nodal disease that is not identified on computed tomography (CT) or positron emission tomography (PET). Therefore, after a properly performed transcervical lymphadenectomy, the restaging of the mediastinum is unnecessary because there is no material left for a new biopsy. Focusing on the use of these procedures for restaging after induction therapy, only TEMLA has been validated on two retrospective studies conducted in the same institution. In the first series with 63 patients, the diagnosis of N2-3 disease before induction treatment was confirmed with invasive techniques in 27 patients (20 with endosonography and 7 with mediastinoscopy), and with CT in 36. Sensitivity, specificity and accuracy of restaging TEMLA were 95.5%, 100% and 98.3%, respectively [9]. In the second series with 176 patients treated with chemo- or chemotherapy, the restaging values of endobronchial endosonography (EBUS) and/or esophageal ultrasonograpy (EUS) (88 patients) were compared with those of TEMLA (78 patients). There was a significant difference between EBUS/EUS and TEMLA for sensitivity (64.3% and 100%; p < 0.01) and NPV (82.1% and 100%; p < 0.01) in favor of TEMLA [10]. Regarding their use for primary staging, VAMLA and TEMLA represent a new paradigm. Firstly, transcervical lymphadenectomies could also be considered part of the induction treatment because the mediastinum is staged and downstaged by these operations. Secondly, due to the fact that nodal restaging is unnecessary, new parameters should be used to select patients for lung resection after induction such as the stability of the primary tumor and the absence of extrathoracic disease based on the results of postinduction CT or PET. Finally, intraoperative pathologic study of the remaining lymph nodes should confirm the absence of nodal involvement before proceeding with lung resection, especially if pneumonectomy is required. Conclusions In multimodality treatments for patients with stage IIIA(N2) tumors, pathologic restaging after induction therapy is essential to decide on subsequent treatment. ReMS is a useful procedure regardless of the induction treatment used or the intensity of the first mediastinoscopy. The role of transcervical lymphadenectomies in staging and restaging should be implemented in clinical practice and validated in future clinical trials. References 1. De Waele M, Serra-Mitjans M, Hendriks J, et al. Accuracy and survival of repeat mediastinoscopy after induction therapy for non-small cell lung cancer in a combined series of 104 patients. Eur J Cardiothorac Surg 2008;33:824-8. 2. Van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007;99:442-50. 3. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non- small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009;374:379-86. 4. De Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 2014;45:787–98. 5. Lardinois D, Schallberger A, Betticher D, et al. Postinduction video-mediastinoscopy is as accurate and safe as video-mediastinoscopy in patients without pretreatment for potentially operable non-small cell lung cancer. Ann Thorac Surg 2003;75:1102–6. 6. Call S, Rami-Porta R, Obiols C, et al. Repeat mediastinoscopy in all its indications: experience with 96 patients and 101 procedures. Eur J Cardiothorac Surg 2011; 39:1022-7. 7. Stamatis G, Fechner S, Hillejan L, et al. Repeat mediastinoscopy as a restaging procedure. Pneumologie 2005;59:862-6. 8. Marra A, Hillejan L, Fechner S, et al. Remediastinoscopy in restaging of lung cancer after induction therapy. J Thorac Cardiovasc Surg 2008;135:843-9.
 9. Zieliński M, Hauer L, Hauer J, et al. Non-small-cell lung cancer restaging with transcervical extended mediastinal lymphadenectomy. Eur J Cardiothorac Surg 2010;37:776–80. 10. Zielinski M, Szlubowski A, Kołodziej M, et al. Comparison of endobronchial ultrasound and/or endoesophageal ultrasound with transcervical extended mediastinal lymphadenectomy for staging and restaging of non-small-cell lung cancer. J Thorac Oncol 2013;8:630-6. Table 1. Staging values of the largest published series of remediastinoscopies for restaging after induction therapy.

Abstract:
The optimal strategy for patients with stage III non-small cell lung cancer (NSCLC) is not well-established and significant variation in practice exists across the United States and Europe. In the U.S., the majority of National Comprehensive Cancer Network (NCCN) member institutions consider surgery to be indicated in stage IIIA patients with involvement of a single N2 lymph node station smaller than 3 cm who have undergone induction chemotherapy. However, there is no agreement among institutions regarding treatment for other manifestations of stage IIIA-N2 involvement (e.g., multi-station or bulky disease) and both NCCN and European Society of Medical Oncology (ESMO) guidelines recommend that the role of surgery be discussed in a multidisciplinary tumor board setting. The use of induction chemotherapy vs induction chemoradiotherapy is currently of great interest worldwide, and the use of the latter is still common despite the results of numerous clinical trials and meta-analysis. The lack of consensus regarding treatment strategies for stage III NSCLC is in part due to the relatively low number of randomized studies available to guide decision-making, as well as institutional biases despite evidence. One important issue is the role and methods of restaging after induction therapy for patients with potentially resectable Stage IIIA (N2) disease. While all would agree that pathologic confirmation of N2 disease prior to induction chemotherapy is mandatory, using EBUS or mediastinoscopy, not all surgeons believe that restaging after induction therapy to confirm response to chemotherapy is necessary, despite evidence that the overall and cancer-specific survival of non-responders is quite low. There are 2 dominant strategies for staging and restaging patients with N2 disease: EBUS prior to induction therapy and restaging with videomediastinoscopy or mediastinoscopy prior to induction therapy and restaging with thoracoscopy or repeat mediastinoscopy. There may be a role for each strategy depending on individual patient characteristics. Advantages of thoracoscopic restaging after induction therapy include the ability to resect all ipsilateral nodes to most accurately assess response and the resection of nodal tissue at thoracoscopy is the first step in thoracoscopic resection and thus greatly facilitates the procedure. The role of thoracoscopic restaging after induction therapy will be reviewed, and the technical aspects for successful restaging and thoracoscopic lobectomy after induction therapy are demonstrated in videos. References 1. Martins RG, D'Amico TA, Loo BW, Jr., et al. The management of patients with stage IIIA non-small cell lung cancer with N2 mediastinal node involvement. Journal of the National Comprehensive Cancer Network : JNCCN. 2012;10(5):599-613. 2. Vansteenkiste J, De Ruysscher, D, Eberhardt WEE, Lim E, Senan S, Felip E, Peters s. Early-Stage and Locally Advanced (non-metastatic) Non-Small-Cell Lung Cancer: ESMO Clinical Practice Guidelines. Annals of Oncology. 2013;24((suppl 6)):vi 89-98. 3. Ettinger DS, Wood DE, Akerley W, et al. Non-small cell lung cancer, version 6.2015. Journal of the National Comprehensive Cancer Network : JNCCN. 2015;13(5):515-524. 4. Weeks JC, Uno H, Taback N, et al. Interinstitutional variation in management decisions for treatment of 4 common types of cancer: A multi-institutional cohort study. Annals of internal medicine. 2014;161(1):20-30. 5. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet. 2015;386(9998):1049-1056. 6. Katakami N, Tada H, Mitsudomi T, et al. A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903). Cancer. 2012;118(24):6126-6135. 7. Girard N, Mornex F, Douillard JY, et al. Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial. Lung Cancer. 2010;69(1):86-93. 8 Jaklitsch MT, Gu L, Harpole DH, D'Amico TA, et al. Prospective phase II trial of pre-resection thoracoscopic restaging following neoadjuvant therapy for IIIA(N2) non-small cell lung cancer: Results of CALGB 39803. J Thorac Cardiovasc Surg 2013;146: 9-16 9. Yang CF, Gulack BC, Gu L, et al. Adding radiation to induction chemotherapy does not improve survival of patients with operable clinical N2 non-small cell lung cancer. The Journal of thoracic and cardiovascular surgery. 2015;150(6):1484-1492; discussion 1492-1483. 10. Shah AA, Berry MF, Tzao C, et al. Induction chemoradiation is not superior to induction chemotherapy alone in stage IIIA lung cancer. Ann Thorac Surg. 2012;93(6):1807-1812.