Title: PS01.24: Clinical Outcomes of Patients with Pulmonary Large Cell Neuroendocrine Carcinoma Characterized by Next-Generation Sequencing
Abstract: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. Pathologically, LCNEC shares features with SCLC such as a neuroendocrine phenotype and high proliferation rate (Ki67), however, lacks the classic cytomorphology of SCLC. Clinically, LCNEC are associated with high rate of metastases and poor patient survival, however, remarkably broad survival ranges have been reported ranging from 15-60% at 5 years, suggesting that this may be a heterogeneous disease. In addition, highly variable results have been reported regarding the chemosensitivity of LCNEC to platinum/etoposide based regimens utilized for SCLC resulting in the lack of consensus on whether LCNEC should be clinically managed as SCLC versus NSCLC. In a recent study of resected LCNEC at our institution we found that genomic profiles segregated into 2 major subsets: SCLC-like characterized by TP53+RB1 co-mutation/loss and NSCLC-like characterized by the lack of co-altered TP53+RB1 (Rekhtman et al, Clin Cancer Res 2016). The goal of this study is to evaluate whether the 2 major subgroups of LCNEC display distinct clinical outcomes, such as treatment response and overall survival, by analyzing clinical features in patients with advanced stage IV LCNEC who underwent next-generation sequencing. Stage IV LCNEC (n = 32) tumor/normal pairs underwent targeted next-generation sequencing of 410 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Clinical information including treatment history, outcome, and overall survival are in the process of being analyzed. Commonly altered genes in stage IV LCNEC include TP53 (91%), RB1 (44%), KEAP1 (38%), STK11 (34%), and KRAS (28%). Genomic profiles again segregated into 2 major subsets: SCLC-like characterized by TP53+RB1 co-mutation/loss (14/32, 44%) and NSCLC-like characterized by the lack of co-altered TP53+RB1 (13/32,41%) and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1). We are currently analyzing clinical outcome data. Stage IV LCNEC is a biologically heterogenous disease, comprising distinct subsets with genomic signatures of SCLC and NSCLC. Pending clinical outcome analysis, recognition of these subsets may inform the classification, management and prognosis of patients.