Abstract 2266: Molecular and genomic characterization of SCLC
Authors: Stephen V. Liu, Edward S. Kim, Rebecca A. Feldman, Zoran Gatalica, Jeffrey Swensen, Hossein Borghaei, Alexander I. Spira, Gerold Bepler, Sandeep Reddy, Afshin Dowlati
Journal: Cancer Research (2016)

Abstract Introduction: Small cell lung cancer (SCLC), strongly tobacco-associated, has been described to have a heavy mutation burden, harboring high rates of TP53 and RB1 alterations. While initially responsive to radiation and chemotherapy, SCLC is characterized by eventual progression and resistance to traditional therapy. We retrospectively analyzed a molecular profiling (MP) database to identify potentially actionable alterations using a multi-platform approach which includes massively parallel sequencing. Experimental Procedures: SCLC patient samples were referred to a central CLIA laboratory (Caris Life Sciences, AZ) for MP (immunohistochemistry [IHC] and next generation sequencing [NGS]). Expression of PD1 (MRQ-22, ≥1+) on tumor infiltrating lymphocytes (TILs) and PDL1 (130021, SP142, ≥2+≥5%) in tumor cells was performed by IHC. Additional IHC (ERCC1, TOPO1) and NGS on 591 genes was performed on FFPE samples using the Illumina NextSeq platform in a subset of patient samples. All variants were detected with &amp;gt; 99% confidence. Variants are described as follows: pathogenic, presumed pathogenic, variants of unknown significance and unclassified variants (excluding SNPs). Results: 203 SCLC samples were identified, 48% were females (97) and 52% were males (106). Median age was 65 [range: 29-88]. Cancer cells expressed PDL1 in 2.5% of cases (5/203) and PD1+ TILs were detected in 38% (75/197). For comparison, internal PDL1+ in non-small cell lung carcinomas (NSCLC) was 31% (339/1098). Notable findings from IHC included ERCC1 negative status in 93% (14/15) and TOPO1 + in 70% (14/20). CNV and mutational analysis (NGS) was available for 10 and 22 patients, respectively. Amplifications were found in the following genes: CCND3, CRKL, FGF4, FGFR1 and NFKB1A (n = 1, respectively), and CCND1, CCNE1, CDKN2A and FGF3 (n = 2, respectively). As previously reported, the most frequently altered genes were TP53 (73%) and RB1 (68%). Clinically relevant pathogenic or presumed pathogenic variants included: EGFR (exon 19 deletion), BRAF (G469A), APC (T1556fs), NF1 (A1610fs, D699fs), NOTCH1 (E473fs, C332Y, G546X) and PTCH1 (N1351fs). It was thought the patient with EGFR mutation is a case of NSCLC transformation to SCLC. Variants with unknown significance or unclassified variants detected in genes with clinical relevance and of potential interest for targeted therapy in SCLC include: DDR2, cMET, RET, FGFR1/3, BRCA2, IGF1R, RICTOR and NTRK1. Conclusion: Genomic and molecular characterization of SCLC samples reveals a heterogeneous population. Several potentially actionable targets are identified by NGS. Early reported trial data suggests susceptibility of SCLC to immune checkpoint inhibitors. We observed higher levels of PD1+ TILs, however differences in antibody clones, thresholds or staining localization (tumor cells vs. stromal lymphocytes), may account for the observed overall low PD-L1 expression. Further efforts are needed to identify and validate new therapeutic targets in SCLC. Citation Format: Stephen V. Liu, Edward S. Kim, Rebecca A. Feldman, Zoran Gatalica, Jeffrey Swensen, Hossein Borghaei, Alexander I. Spira, Gerold Bepler, Sandeep Reddy, Afshin Dowlati. Molecular and genomic characterization of SCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2266.