Cancer Research • 2024-04-07

Improved survival and unique mutational signatures in small cell lung cancer arising in patients with limited tobacco use

Authors

K. Concannon¹, M. Sahu², W. Lewis¹, H. Tran¹, L. Diao¹, Y. Xi¹, B. Morris¹, S. Heeke¹, X. Tang¹, J. Stewart¹, I. Valiev³, G. Raso¹, J. Wang¹, K. Sasaki¹, C. Gay¹, J. Heymach¹, L. Byers¹
  1. The University of Texas MD Anderson Cancer Center, Houston, TX, US
  2. The University of Texas Health San Antonio Long School of Medicine, San Antonio, TX, US
  3. BostonGene, Corp., Waltham, MA, US

Abstract

Small-cell lung cancer (SCLC) remains the deadliest histologic lung cancer subtype with a median survival of only 12.3 months among trial-eligible patients with extensive-stage (ES-SCLC) disease, as demonstrated in the IMPower133 trial. Heavy tobacco use, >40 pack-years, is strongly associated with developing SCLC, which near universally harbors RB1 and TP53 co-mutations. However, there is a paucity of information regarding SCLC tumors that occur 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 >20%. To address this, we clinically characterized the treatments and outcomes of a 164 SCLC patient cohort with ≤10 pack year smoking histories treated at the University of Texas MD Anderson Cancer Center; 22 of which underwent whole-exome sequencing (WES). The overall survival of limited-stage (LS-SCLC) and extensive-stage (ES-SCLC) disease in the low pack-year cohort were 33.6 and 16.6 months, respectively (P=0.003); superior to historic medians of roughly 17.0 and 12.3 months, respectively. Among those with ES-SCLC, those who reported 1-10 pack-years had significantly improved median overall survival as compared to never-smokers; 19.5 vs 15.8 months, respectively (P=0.02). This trend was observed in LS-SCLC as well with 1-10 pack-year and never-smokers demonstrating median overall survivals of 88.6 vs 26.2 months, respectively (P=0.2). Demographic differences including age were similar across these cohorts. WES of tumors from 22 patients demonstrated significantly fewer mutations in RB1 and TP53 than was observed in previously reported cohorts of SCLC from smokers. Among the low-pack year cohort, 7/22 (32% vs 98.2%:P<0.001) harbored an RB1 alteration, 7/22 (32% vs 90.9%: P<0.001) harbored a TP53 mutation, and 4/22 (18% vs 90.9%: P<0.001) had co-occurring RB1/TP53 mutations. No patients harbored mutations in EGFR, HER2, or RET. Mutations in potentially targetable pathways were observed throughout the cohort including the DNA-damage repair pathways, RTK/RAS, and PI3K. Taken together, these data demonstrate that patients with low pack-year SCLC have improved overall survival compared to historic averages for SCLC patients with a history of heavy tobacco use. Paradoxically, however, light-smokers with SCLC live longer than never-smokers, and these patients may harbor a higher frequency of targetable alterations than typical SCLC patients, highlighting the importance of molecular profiling in SCLC patients with minimal tobacco use.
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