AUTHOR=Cardona Andrés F. , Rojas Leonardo , Zatarain-Barrón Zyanya Lucia , Ruiz-Patiño Alejandro , Ricaurte Luisa , Corrales Luis , Martín Claudio , Freitas Helano , Cordeiro de Lima Vladmir Cláudio , Rodriguez July , Avila Jenny , Bravo Melissa , Archila Pilar , Carranza Hernán , Vargas Carlos , Otero Jorge , Barrón Feliciano , Karachaliou Niki , Rosell Rafael , Arrieta Oscar 

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

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00254

DOI=10.3389/fonc.2019.00254

ISSN=2234-943X

ABSTRACT=<p><bold>Objectives:</bold> 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.</p><p><bold>Material and Methods:</bold> To further investigate the clinical and genetic characteristics of this patient subgroup, a cohort of small cell lung cancer patients was divided into smokers (<italic>n</italic> = 10) and never/ever-smokers (<italic>n</italic> = 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.</p><p><bold>Results:</bold> Median age was 63 years (46–81), 40% were men, and 90% had extended disease. Smoker patients had significantly more cerebral metastases (<italic>p</italic> = 0.04) and were older (<italic>p</italic> = 0.03) compared to their non-smoker counterparts. For never/ever smokers, the main genetic mutations were <italic>TP53</italic> (80%), <italic>RB1</italic> (40%), <italic>CYLD</italic> (30%), and <italic>EGFR</italic> (30%). Smoker patients had more <italic>RB1</italic> (80%, <italic>p</italic> = 0.04), <italic>CDKN2A</italic> (30%, <italic>p</italic> = 0.05), and <italic>CEBPA</italic> (30%, <italic>p</italic> = 0.05) mutations. Response rates to first-line therapy with etoposide plus cisplatin/carboplatin were 50% in smokers and 90% in never/ever smokers (<italic>p</italic> = 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]; <italic>p</italic> = 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.</p><p><bold>Conclusion:</bold> 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 <italic>EGFR, MET</italic>, and <italic>SMAD4</italic> mutations. Further studies are required to assess whether the differential mutation profile is a consequence of a diverse pathological mechanism for disease onset.</p>