Multigene Mutation Profiling and Clinical Characteristics of Small-Cell Lung Cancer in Never-Smokers vs. Heavy Smokers (Geno1.3-CLICaP)

Abstract

<b>Objectives:</b> Lung cancer is a heterogeneous disease. Presentation and prognosis are known to vary according to several factors, such as genetic and demographic characteristics. Small-cell lung cancer incidence is increasing in never-smokers. However, the disease phenotype in this population is different compared with patients who have a smoking history. <b>Material and Methods:</b> To further investigate the clinical and genetic characteristics of this patient subgroup, a cohort of small cell lung cancer patients was divided into smokers (<i>n</i> = 10) and never/ever-smokers (<i>n</i> = 10). A somatic mutation profile was obtained using a comprehensive NGS assay. Clinical outcomes were compared using the Kaplan-Meier method and Cox proportional models. <b>Results:</b> Median age was 63 years (46-81), 40% were men, and 90% had extended disease. Smoker patients had significantly more cerebral metastases (<i>p</i> = 0.04) and were older (<i>p</i> = 0.03) compared to their non-smoker counterparts. For never/ever smokers, the main genetic mutations were <i>TP53</i> (80%), <i>RB1</i> (40%), <i>CYLD</i> (30%), and <i>EGFR</i> (30%). Smoker patients had more <i>RB1</i> (80%, <i>p</i> = 0.04), <i>CDKN2A</i> (30%, <i>p</i> = 0.05), and <i>CEBPA</i> (30%, <i>p</i> = 0.05) mutations. Response rates to first-line therapy with etoposide plus cisplatin/carboplatin were 50% in smokers and 90% in never/ever smokers (<i>p</i> = 0.141). Median overall survival was significantly longer in never smokers compared with smokers (29.1 months [23.5-34.6] vs. 17.3 months [4.8-29.7]; <i>p</i> = 0.0054). Never/ever smoking history (HR 0.543, 95% CI 0.41-0.80), limited-stage disease (HR 0.56, 95% CI 0.40-0.91) and response to first-line platinum-based chemotherapy (HR 0.63, 95% CI 0.60-0.92) were independently associated with good prognosis. <b>Conclusion:</b> Our data supports that never/ever smoker patients with small-cell lung cancer have better prognosis compared to their smoker counterparts. Further, patients with never/ever smoking history who present with small-cell lung cancer have a different mutation profile compared with smokers, including a high frequency of <i>EGFR, MET</i>, and <i>SMAD4</i> mutations. Further studies are required to assess whether the differential mutation profile is a consequence of a diverse pathological mechanism for disease onset.