Hyunjae R. Kim

Abstract Tumor genetic testing is standard of care for patients with advanced lung adenocarcinoma, but the fraction of patients who derive clinical benefit remains undefined. Here, we report the experience of 860 patients with metastatic lung adenocarcinoma analyzed prospectively for mutations in >300 cancer-associated genes. Potentially actionable genetic events were stratified into one of four levels based upon published clinical or laboratory evidence that the mutation in question confers increased sensitivity to standard or investigational therapies. Overall, 37.1% (319/860) of patients received a matched therapy guided by their tumor molecular profile. Excluding alterations associated with standard-of-care therapy, 14.4% (69/478) received matched therapy, with a clinical benefit of 52%. Use of matched therapy was strongly influenced by the level of preexistent clinical evidence that the mutation identified predicts for drug response. Analysis of genes mutated significantly more often in tumors without known actionable mutations nominated STK11 and KEAP1 as possible targetable mitogenic drivers. Significance: An increasing number of therapies that target molecular alterations required for tumor maintenance and progression have demonstrated clinical activity in patients with lung adenocarcinoma. The data reported here suggest that broader, early testing for molecular alterations that have not yet been recognized as standard-of-care predictive biomarkers of drug response could accelerate the development of targeted agents for rare mutational events and could result in improved clinical outcomes. Cancer Discov; 7(6); 596–609. ©2017 AACR. See related commentary by Liu et al., p. 555. This article is highlighted in the In This Issue feature, p. 539

Abstract Purpose: KRAS mutations occur in approximately 25% of patients with non–small cell lung cancer (NSCLC). Despite the uniform presence of KRAS mutations, patients with KRAS-mutant NSCLC can have a heterogeneous clinical course. As the pattern of co-occurring mutations may describe different biological subsets of patients with KRAS-mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy. Experimental Design: We identified patients with advanced KRAS-mutant NSCLC and evaluated the most common co-occurring genomic alterations. Multivariate analyses were performed incorporating the most frequent co-mutations and clinical characteristics to evaluate association with overall survival as well as response to platinum–pemetrexed chemotherapy and immune checkpoint inhibitors. Results: Among 330 patients with advanced KRAS-mutant lung cancers, the most frequent co-mutations were found in TP53 (42%), STK11 (29%), and KEAP1/NFE2L2 (27%). In a multivariate analysis, there was a significantly shorter survival in patients with co-mutations in KEAP1/NFE2L2 [HR, 1.96; 95% confidence interval (CI), 1.33–2.92; P ≤ 0.001]. STK11 (HR, 1.3; P = 0.22) and TP53 (HR 1.11, P = 0.58) co-mutation statuses were not associated with survival. Co-mutation in KEAP1/NFE2L2 was also associated with shorter duration of initial chemotherapy (HR, 1.64; 95% CI, 1.04–2.59; P = 0.03) and shorter overall survival from initiation of immune therapy (HR, 3.54; 95% CI, 1.55–8.11; P = 0.003). Conclusions: Among people with KRAS-mutant advanced NSCLC, TP53, STK11, and KEAP1/NFE2L2 are the most commonly co-occurring somatic genomic alterations. Co-mutation of KRAS and KEAP1/ NFE2L2 is an independent prognostic factor, predicting shorter survival, duration of response to initial platinum-based chemotherapy, and survival from the start of immune therapy. Clin Cancer Res; 24(2); 334–40. ©2017 AACR.

PURPOSE: Microsatellite instability (MSI)/mismatch repair (MMR) status is increasingly important in the management of patients with cancer to predict response to immune checkpoint inhibitors. We determined MSI status from large-panel clinical targeted next-generation sequencing (NGS) data across various solid cancer types. METHODS: The MSI statuses of 12,288 advanced solid cancers consecutively sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets clinical NGS assay were inferred by using MSIsensor, a program that reports the percentage of unstable microsatellites as a score. Cutoff score determination and sensitivity/specificity were based on MSI polymerase chain reaction (PCR) and MMR immunohistochemistry. RESULTS: By using an MSIsensor score ≥ 10 to define MSI high (MSI-H), 83 (8%) of 996 colorectal cancers (CRCs) and 42 (16%) of 260 uterine endometrioid cancers (UECs) were MSI-H. Validation against MSI PCR and/or MMR immunohistochemistry performed for 138 (24 MSI-H, 114 microsatellite stable [MSS]) CRCs, and 40 (15 MSI-H, 25 MSS) UECs showed a concordance of 99.4%. MSIsensor also identified 68 MSI-H/MMR-deficient (MMR-D) non-CRC/UECs. Of 9,591 non-CRC/UEC tumors with MSS MSIsensor status, 456 (4.8%) had slightly elevated scores(≥3 and <10) of which 96.6% with available material were confirmed to be MSS by MSI PCR. MSI-H was also detected and confirmed in three non-CRC/UECs with low exonic mutation burden (< 20). MSIsensor correctly scored all 15 polymerase ε ultra-mutated cancers as negative for MSI. CONCLUSION: MSI status can be reliably inferred by MSIsensor from large-panel targeted NGS data. Concurrent MSI testing by NGS is resource efficient, is potentially more sensitive for MMR-D than MSI PCR, and allows identification of MSI-H across various cancers not typically screened, as highlighted by the finding that 35% (68 of 193) of all MSI-H tumors were non-CRC/ UEC.

BACKGROUND: Heritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to transforming growth factor (TGF) beta signaling, including bone morphogenetic protein receptor type 2, activin receptor-like kinase 1, endoglin, and mothers against decapentaplegic 9. Approximately 25% of heritable cases lack identifiable mutations in any of these genes. METHODS AND RESULTS: We used whole exome sequencing to study a 3-generation family with multiple affected family members with PAH, but no identifiable TGF beta mutation. We identified a frameshift mutation in caveolin-1 (CAV1), which encodes a membrane protein of caveolae abundant in the endothelium and other cells of the lung. An independent de novo frameshift mutation was identified in a child with idiopathic PAH. Western blot analysis demonstrated a reduction in caveolin-1 protein, while lung tissue immunostaining studies demonstrated a reduction in normal caveolin-1 density within the endothelial cell layer of small arteries. CONCLUSIONS: Our study represents successful elucidation of a dominant Mendelian disorder using whole exome sequencing. Mutations in CAV1 are associated in rare cases with PAH. This may have important implications for pulmonary vascular biology, as well as PAH-directed therapeutic development.