P1.14-46 Genomic Profiling of Large Cell Neuroendocrine Carcinomas of Lung: A Path Towards Individualized Treatment Options

Abstract

Listen

Translate article

Large cell neuroendocrine carcinomas of lung (LCNEC) are aggressive tumors which straddle the non-small cell / small cell lung carcinoma dichotomy. We performed comprehensive genomic profiling (CGP) to compare genomic alterations (GA) in LCNEC with those in small cell lung carcinoma (SCLC) and lung adenocarcinoma (LUAD). FFPE tissue from 657 LCNEC, 2232 SCLC, and 28,052 LUAD underwent hybrid-capture based CGP to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was calculated using 114 loci. Genomically, LCNEC’s tended to segregate towards either SCLC or LUAD (Table 1). RB1 and PTEN inactivation, hallmarks of SCLC, often co-occurred and were detected in 38% and 10% of LCNEC, respectively. These cases were also enriched for other “SCLC” alterations, including CCNE1, NOTCH1, SOX2, FGFR1. KRAS, STK11, and CDKN2A/B alterations, hallmarks of LUAD, often co-occurred and were each detected in 15% of LCNEC. These cases were enriched for other “LUAD” alterations, including SMARCA4, ATM, NKX2-1, KEAP1. Only 20 of 657 (3%) LCNEC had co-occurring RB1 and KRAS alterations. 20 of 657 (3%) LCNEC carried EGFR activating alterations. GA involved other receptor tyrosine kinases (ALK, ERBB2/3, FGFR1/2/3, KIT, MET, NTRK1/2/3, PDGFRA/B, RET, ROS1), and PI3K, MAPK, and CCND1 pathway genes. 17% and 49% of LCNEC had TMB of ≥20 and ≥10 mut/Mb, respectively. 0.2% of LCNEC were MSI-High, and 19.4% were PD-L1 positive. Treatment for LCNEC is not standardized and often requires choosing between “SCLC” or “NSCLC” chemotherapy regimens based on clinical impression and anecdotal evidence. CGP can help inform these crucial decisions. Identification of actionable GA will enable use of targeted agents as alternatives or adjuncts to chemotherapy (Table 2). Immunotherapy is an important option, as a significant proportion of LCNEC patients have high TMB or PD-L1 positive tumors.