Abstract 931: Comprehensive analysis of 3,600 small cell lung cancer cases reveals rare genetic subtypes and multiple mechanisms of histological transformation
Authors: Sivakumar Smruthy , Moore Jay A. , Montesion Meagan , Lin Douglas I. , Fleischmann Zoe , Ebot Ericka M. , Newberg Justin , Mills Jennifer M. , Hegde Priti S. , Frampton Garrett M. , Sage Julien , Lovly Christine M. 
Published: April 2023

Abstract
Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with limited treatment options and extremely poor survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied and lack of access to longitudinal samples to understand tumor evolution.
Methods: Here we provide a comprehensive analysis of 3,600 patients with SCLC who underwent targeted genomic profiling of at least 324 cancer-related genes as part of routine clinical care, including 678 cases with additional clinical and treatment information obtained from a US-based de-identified SCLC clinico-genomic database that originated from approximately 280 US cancer clinics. This large cohort allowed us to examine for new genetic subtypes, ancestry-associated genomic alterations, biopsy site-specific patterns, survival trends and histological transformation of SCLC from non-small cell lung cancer (NSCLC).
Results: Consistent with prior studies, SCLCs were predominantly TP53/RB1 altered. Yet, 5.5% of the cases in our cohort were TP53/RB1 wild-type tumors. These tumors often lacked a tobacco mutational signature, exhibited alternate mechanisms of p53/Rb pathway inactivation (e.g., CDKN2A, CCND1, MDM2), and had a high fraction of human papillomavirus-positive cases (12.7%). Another rare subtype of SCLCs included STK11-altered tumors (1.7%), which were observed more frequently in patients of African ancestry, and were associated with a decreased overall survival (OS) compared with the STK11 wild-type cohort. In our cohort, gene amplifications on 4q12 (KDR, KIT, PDGFRA) were associated with increased OS while CCNE1 amplification was associated with decreased OS. Interestingly, alterations in PTEN were more common in brain metastases compared to lung biopsies and liver metastases, suggesting its potentially unique role in brain metastases of SCLCs. Profiling of over 100 putative transformed SCLCs demonstrated that lineage plasticity may occur at variable lengths of time from the original NSCLC diagnosis and include multiple distinct molecular cohorts of NSCLC, beyond EGFR-mutant NSCLC (e.g., kinase fusion+ tumors: RET, ALK, ROS1, NTRK1).
Conclusion: Our work underscores the existence of genetic subtypes in SCLC, including rare subtypes with potential clinical utility. Findings from this study provide an improved understanding of genetic subtypes in SCLC and better inform mechanisms of transformation to SCLC from NSCLC, that may further guide the development of personalized therapies for subsets of patients with this fatal tumor.
Citation Format: Smruthy Sivakumar, Jay A. Moore, Meagan Montesion, Douglas I. Lin, Zoe Fleischmann, Ericka M. Ebot, Justin Newberg, Jennifer M. Mills, Priti S. Hegde, Garrett M. Frampton, Julien Sage, Christine M. Lovly. Comprehensive analysis of 3,600 small cell lung cancer cases reveals rare genetic subtypes and multiple mechanisms of histological transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 931.