Clinical and Genomic Characteristics of Small Cell Lung Cancer in Never Smokers: Results From a Retrospective Multicenter Cohort Study

Abstract

Background: Small cell lung cancer (SCLC) has the strongest association with smoking among lung cancers. The characteristics of never smokers with SCLC is not known.

Research question: Are the clinical characteristics, prognostic factors, survival, genomic alterations, and tumor mutational burdens of SCLC in patients who have never smoked different from those who have smoked?

Study design and methods: A retrospective multicenter cohort study of patients with clinician-confirmed SCLC was performed with the use of a longitudinal and nationally representative electronic medical records database. Smoking history was assessed through technology-enabled abstraction and confirmed for never smokers via chart review. Genomic characteristics of never smoker patients with SCLC were examined with the use of a next-generation sequencing-based gene panel and whole exome sequencing.

Results: One hundred of 5,632 patients (1.8%) with SCLC were never smokers. Relative to smokers, never smokers were more likely to be female (66.0% vs 52.4%; P = .009) and present with extensive stage (70.0% vs 62.2%; P = .028). Never smokers had a higher proportion of patients in age groups 35 to 49 years (7.0% vs 3.0%; P = .006) and ≥80 years (17.0% vs 8.2%; P = .006). Known risk factors for lung cancer were found in <20% of never smokers. There were no overall survival differences between never smokers and smokers. Among patients with available genomic data (n = 9), never smoker SCLC were characterized by lower tumor mutational burden, a lower frequency of TP53 mutations, and an absence of mutational signatures related to tobacco exposure.

Interpretation: The sex- and age-specific distribution of SCLC among never smokers, along with differences that were identified by genomic analyses, suggests a distinct biology of SCLC in never smokers compared with smokers.

Keywords: COSMIC signature 4; never smoker; small cell lung cancer; tumor mutation burden.

Figure 1

Never smoker SCLC cohort selection. ICD = International Classification of Diseases; SCLC = small cell lung cancer.

Figure 2

A-C, Overall survival of patients with small cell lung cancer who were never smokers and smokers: A, stratified by stage at diagnosis; B, stratified by serum sodium at diagnosis; and C, based on smoking status.

Figure 3

A-E, Genomic characterization and signatures in never smokers. A, Genomic characteristics and B, mutational signatures of NCI never smoker small cell lung cancer. C, Correlation between signature 4 and tumor mutation burden; D, heat map shows smoking status, key genetic alterations, and mutational signatures; E, distribution of tumor mutation burden; and F, RB1 and TP53 mutations among the dataset of George et al and the NCI never smoker SCLC. EGFR = epidermal growth factor receptor; NCI = National Cancer Institute. See Figure 1 legend for expansion of other abbreviation.