Abstract 1398: Clinical and transcriptomic analysis demonstrates improved survival and unique gene expression signatures among SCLC arising in patients with minimal tobacco use
Authors: Concannon Kyle , Heeke Simon , Sahu Moushumi , Tang Ximing , Sasaki Koji , Patel Sonia , Raso Maria Gabriela , Tran Hai , Gay Carl , Byers Lauren 
Published: April 2023

Abstract
Small-cell lung cancer (SCLC) represents 15% of all lung cancers with roughly 30,000 new cases in the U.S. annually. SCLC remains the deadliest histologic subtype with a median survival of only 12.3 months among those with extensive-stage (ES-SCLC) disease as demonstrated in the IMPower133 trial. Recent research by our group (Gay et al, 2021) has demonstrated that SCLC is defined by four transcriptionally defined subtypes, characterized by the predominant expression of the three transcription factors ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and a fourth, inflamed subtype (SCLC-I). While SCLC is commonly associated with a history of heavy smoking, there is a paucity of information regarding tumors arising in patients with minimal tobacco use. This represents an unmet need given an increasing appreciation for low pack-year and never-smoker SCLC with some studies, like the CAPSTONE-1 trial, demonstrating an incidence of never-smoking SCLC &gt;20%. To address this disparity, we profiled a cohort of 113 SCLC patients with ≤10 pack-year smoking history (~12.9% of patients with SCLC seen over that time period) treated at the University of Texas MD Anderson Cancer Center. Clinical outcomes were analyzed, as was transcriptomic analysis in a subset of patients. The overall survival of limited-stage (LS-SCLC) and ES-SCLC in the low-pack year cohort was 26.9 and 16.5 months respectively (P=0.029); superior to historic medians of roughly 17.0 and 12.3 months respectively. Interestingly, TP53 and RB1 mutations were significantly less common in the low-pack year cohort compared to patients with higher smoking burdens as determined by George et al. who evaluated 110 SCLC samples using whole-genome sequencing. Clinically obtained mutational analysis of our cohort (N=49) demonstrated a TP53 mutational incidence of 51.0% vs 98.2% from George et al. (P&lt;0.001). Similarly, our RB1 mutational incidence was 26.5% vs 90.9% from George et al. (P&lt;0.001). Samples lacking TP53-RB1 coexisting mutations frequently demonstrated abnormalities in alternative DNA repair genes including STK11, POLE, PALB2, MUTYH, MSH2, MSH6, MLH1, MDM2, BRCA2, and ARID1A. Given these findings, we performed whole-transcriptome profiling on our low pack-year SCLC samples to determine the SCLC-subtypes and identify unique gene signatures which may drive oncogenesis via mechanisms distinct from loss of RB1 and TP53. These data demonstrate that SCLC arising from patients with minimal smoking histories confers a more favorable prognosis and harbors unique RNA signatures with potential therapeutic implications. We anticipate these results will shift the current clinical practice toward routine evaluation of non-RB1 or TP53-mediated drivers of oncogenesis among low pack-year patients with SCLC and promote further work in identifying novel therapies for this population.
Citation Format: Kyle Concannon, Simon Heeke, Moushumi Sahu, Ximing Tang, Koji Sasaki, Sonia Patel, Maria Gabriela Raso, Hai Tran, Carl Gay, Lauren Byers. Clinical and transcriptomic analysis demonstrates improved survival and unique gene expression signatures among SCLC arising in patients with minimal tobacco use [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 1398.