Genomic characterization of circulating tumor DNA from Chinese advanced small-cell lung cancer to reveal potential therapeutic opportunities.

Abstract

e21111 Background: Molecular profiling via next-generation sequencing (NGS) has been applied to select patients benefiting from targeted therapy or immunotherapy. Sequencing of blood-derived circulating tumor DNA (ctDNA) presents an alternative for advanced cancers given the challenge of obtaining tumor biopsies. We identified potentially actionable genomic alterations (GAs) in Chinese advanced small-cell lung cancer (SCLC) patients using ctDNA testing. Methods: Blood samples from 119 patients with advanced SCLC were sequenced via target deep sequencing covering 150 or 189 cancer-related genes and 100 microsatellite loci. Blood tumor mutation burden (bTMB), defined as the number of somatic single-nucleotide variants, short insertions and deletions (SNV/Indels) in examined coding region, was calculated in 93 patients. High bTMB was set to 10 that ranks top 25% in all SCLC patients. Results: The total number of GAs was 1156 in 127 genes, with an average of 9.7 GAs per sample ranging from 1 to 31. All patients harbored at least one GA and 107/119 patients had at least one GA with clinical significance. TP53 (82.4%) was the commonly altered gene followed by RB1 (57.1%), LRP1B (41.2%), FAT1 (25.2%), FAM135B (23.5%), PIK3CA (21%). GAs were detected frequently in cell cycle pathway (83.2%), PI3K/AKT/mTOR pathway (33.6%), RTK-RAS-MAPK pathway (29.4%), and DDR pathway (10.1%). Overall, 54 (45.4%) patients had alterations with therapeutic relevance, including 2 high blood microsatellite instability and 23 high bTMB that might benefit from immune checkpoint inhibitors. Actionable SNV/Indels were identified, including EGFR mutation (3), KRAS/HRAS mutation (5), DNA damage repair (DDR) pathway (4; including ATM, BRCA1, BRCA2), and PI3K/AKT/mTOR pathway (10; including PIK3CA, PTEN) that might benefit from EGFR tyrosine kinase inhibitors, RAS inhibitors, PARP inhibitors and mTOR inhibitors, respectively. We also found amplification of HER2 (3), FGFR1 (14), and MET (3) that might benefit from anti-HER2 antibodies, FGFR1 inhibitors and MET inhibitors, respectively. Conclusions: To our knowledge, this is the first large-scale analysis of blood-derived ctDNA in Chinese advanced SCLC. Potentially actionable GAs were detected in 45.4% patients. Deep sequencing of ctDNA could provide molecular profiles and might optimize treatment decision in advanced SCLC.