Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

T h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 359;13 www.nejm.org september 25, 2008

is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that (KL) or (KP) comutations define distinct subgroups of -mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups ( < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with -mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free ( < 0.001) and overall ( = 0.0015) survival compared with ; LUAC. Among 924 LUACs, alterations were the only marker significantly associated with PD-L1 negativity in TMB LUAC. The impact of alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1-positive non-small cell lung cancer. In-mutant murine LUAC models, loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify alterations as a major driver of primary resistance to PD-1 blockade in -mutant LUAC. This work identifies alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. .

Small cell lung cancer (SCLC) is an exceptionally lethal malignancy for which more effective therapies are urgently needed. Several lines of evidence, from SCLC primary human tumours, patient-derived xenografts, cancer cell lines and genetically engineered mouse models, appear to be converging on a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). In this Perspective, we review and synthesize these recent lines of evidence and propose a working nomenclature for SCLC subtypes defined by relative expression of these four factors. Defining the unique therapeutic vulnerabilities of these subtypes of SCLC should help to focus and accelerate therapeutic research, leading to rationally targeted approaches that may ultimately improve clinical outcomes for patients with this disease. 'Omic' profiling Genomics. Key genomic profiling studies of human SCLC, including comprehensive whole-exome and whole-genome analyses, were published in 2012 and 2015 (REFS 11-13); the key findings of Rudin et al.

Purpose EMT has been associated with metastatic spread and EGFR inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using NSCLC cell lines and patients treated in the BATTLE study. Methods We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from NSCLC patients. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination) study, and potential therapeutic targets associated with EMT were identified. Results Compared with epithelial cells, mesenchymal cells demonstrated significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend towards greater sensitivity to the Axl inhibitor SGI-7079, while the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In NSCLC patients, the EMT signature predicted 8-week disease control in patients receiving erlotinib, but not other therapies. Conclusion We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype

Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intra-tumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multi-region whole exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20/21 known cancer gene mutations were identified in all regions of individual tumors suggesting single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months post-surgery, 3 patients have relapsed and all 3 patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas.

Summary Background Retrospective evidence indicates that disease progression after first-line chemotherapy for metastatic non-small cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential benefit of aggressive local consolidative therapy (LCT) on progression-free survival (PFS) for patients with oligometastatic NSCLC is unknown. Methods We conducted a multicenter randomized study (NCT01725165; currently ongoing but not recruiting participants) to assess the effect of LCT on progression-free survival ((PFS). Eligible patients hadwere (1) histologic confirmation of (2) stage IV NSCLC, (3) ≤3 disease sites after systemic therapy, and (4) no disease progression before randomization. Front line therapy was ≥4 cycles of platinum doublet therapy or ≥3 months of inhibitors of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) for patients with EGFR mutations or ALK rearrangements. Patients were randomized to either LCT ([chemo]radiation or resection of all lesions) +/− maintenance therapy versus maintenance therapy/observation only. Maintenance therapy was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic therapy. Randomization was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, central nervous system metastases, intrathoracic nodal status, and EGFR/ALK status. The primary endpoint was PFS, powered to detect an increase from 4 months to 7 months (hazard ratio [HR}=0.57) using intent-to-treat analysis. The plan was to study 94 randomized patients, with an interim analysis at 44 events. PFS, overall survival (OS), and time to develop a new lesion were compared between arms with log-rank tests. Results The study was terminated early after treatment of 49 patients (25 LCT, 24 control), when at a median follow-up time for PFS of 18.7 months, the median PFS time in the LCT group was 11.9 months (90% confidence interval [CI] 5.72 ,20.90) versus 3.9 months (90% CI 2.30, 6.64) in the maintenance group (HR=0.35, 90% CI 0.18,0.66, log rank p=0.005). Toxicity was similar between groups, with no grade 4–5 events. Grade 3 or higher adverse events in the maintenance therapy arm were fatigue (n=1) and anemia (n=1). In the LCT arm, Grade 3 events were: esophagitis (n=2), anemia (n=1), pneumothorax (n=1), and abdominal pain (n=1). Overall survival data are immature, with only 14 deaths recorded. Interpretation LCT +/− maintenance therapy for patients with ≤3 metastases from NSCLC that did not progress after initial systemic therapy improved PFS relative to maintenance therapy alone. These findings imply that aggressive local therapy should be further explored in phase III trials as a standard treatment option in this clinical scenario.

Immunosuppression of tumor-infiltrating lymphocytes (TIL) is a common feature of advanced cancer, but its biological basis has remained obscure. We demonstrate here a molecular link between epithelial-to-mesenchymal transition (EMT) and CD8+ TIL immunosuppression, two key drivers of cancer progression. We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumor cells, leading to CD8+ T cell immunosuppression and metastasis. These findings are supported by robust correlations between the EMT score, miR-200 levels and PD-L1 expression in multiple human lung cancer datasets. In addition to revealing a link between EMT and T cell dysfunction, these findings also show that ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and suggest that subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists.