Abstract 610: Prospective genomic characterization of small cell lung cancer by targeted next generation sequencing
Authors: Helen H. Won, M. Catherine Pietanza, Lee M. Krug, Anna M. Varghese, Natasha Rekhtman, Lu Wang, William Travis, Paul K. Paik, Gregory J. Riely, Maureen F. Zakowski, Marc Ladanyi, Mark G. Kris, Charles M. Rudin, Michael F. Berger
Journal: Cancer Research (2015)

Abstract INTRODUCTION: Recent studies using next generation sequencing (NGS) technologies have provided insights into the molecular landscape of small cell lung cancer (SCLC), including frequent inactivation of TP53 and RB1. However, molecular profiling of SCLC has been impeded by lack of tissue. We performed prospective genomic profiling of patients with advanced SCLC, demonstrating the ability to test small biopsy specimens, and we report trends associated with clinical characteristics. METHODS: Formalin fixed paraffin embedded surgical resections, core biopsies, and fine needle aspirates from 50 patients with SCLC were subjected to FGFR1 FISH testing, PTEN immunohistochemistry (IHC), and deep-coverage targeted NGS (median 420x) to identify single nucleotide variants, indels, and copy number alterations in a common set of 222 cancer-associated genes. Demographic and clinical data were collected. Genotyping data were stratified by smoking status, stage, and response to therapy. RESULTS: Of the 50 patients with SCLC, 58% had extensive stage disease, and 30% were resistant to first line therapy. We observed diverse genetic profiles in SCLC, with alterations occurring in 202 of 222 targeted genes. The median number of non-synonymous somatic mutations was 7. Of 526 total non-synonymous mutations, 5% were hotspot COSMIC mutations, 25% were loss-of-function, and 47% were G-to-T transversions indicative of tobacco-induced carcinogenesis. Recurrent loss-of-function mutations in RB1 (96%) and TP53 (92%) were observed. Other frequent genomic events included alterations in SOX2 (26%), EPHA5 (22%), CDKN2C (20%), MYCL1 (20%), and PIK3CA (18%). Actionable point mutations in PIK3CA, amplifications of FGFR1, amplifications of MYC, and loss of PTEN were confirmed by independent clinically validated assays. The genotyping data showed differences based on disease stage, response to therapy, and smoking status. Patients with limited disease had a higher median number of mutations detected (9 mut/tumor) than patients with extensive disease (5 mut/tumor). Tumors refractory to chemotherapy were more likely to harbor homozygous deletions including on chromosome 3p, while tumors sensitive to chemotherapy had more diversified amplifications, deletions, and mutations. The median number of mutations detected for never smokers (0 pack years), moderate smokers (&amp;lt;20 pack years), and heavy smokers (20+ pack years) were 3, 4.5, and 8 mut/tumor, respectively (P&amp;lt;0.05). None of the mutations detected in tumors from never smokers were G-to-T transversions. CONCLUSION: Comprehensive molecular profiling is feasible on clinical SCLC specimens. Our study illustrates the molecular diversity and mutational patterns in SCLC. We confirmed previously reported recurring events, and further identified associations between genomic profiles and clinical features including stage, response, and smoking status. Citation Format: Helen H. Won, M. Catherine Pietanza, Lee M. Krug, Anna M. Varghese, Natasha Rekhtman, Lu Wang, William Travis, Paul K. Paik, Gregory J. Riely, Maureen F. Zakowski, Marc Ladanyi, Mark G. Kris, Charles M. Rudin, Michael F. Berger. Prospective genomic characterization of small cell lung cancer by targeted next generation sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 610. doi:10.1158/1538-7445.AM2015-610