Genomic Profiling of Circulating Tumor DNA from Patients with Extensive-Stage Small Cell Lung Cancer Identifies Potentially Actionable Alterations

Abstract

Comprehensive genomic profiling may help uncover potentially actionable alterations in small cell lung cancer (SCLC) patients who have progressed on standard chemotherapy. However, tissue procurement may be extremely challenging for extensive-stage patients. We aimed to investigate the possibility of genomic profiling and detecting actionable alterations from blood in Chinese SCLC patients. Blood samples collected from extensive-stage SCLC pateints were subjected to circulating tumor DNA (ctDNA) extraction and targeted-next generation sequencing (NGS) using a 150-gene panel. A total of 1,300 aberrations were detected in 128 genes and 89.2% (116/130) patients harbored at least one oncogenic alteration. The most frequently mutated genes included TP53 (82.3%), RB1 (56.2%), LRP1B (40.8%) etc. and 54.6% of the patients had concurrent TP53/RB1 mutations. The RTK/RAS/RAF axis was the most frequently mutated oncogenic pathway. Samples harboring alterations in the DNA damaging repair (DDR), Notch, PI3K/mTOR, RTK/RAS/RAF, and Wnt pathways exhibited significantly higher blood tumor mutational burden (bTMB) than their wildtype counterparts. Classification based on OncoKB criteria detected potentially actionable alterations in about 50% of the population, half of which were bTMB-H and bMSI-H, indicating response to immune checkpoint inhibitors. Alterations in the RTK/RAS/RAF, DDR, and PI3K/mTOR also suggested potential sensitivity to matched targeted therapies or emerging investigational agents. Blood-based panel NGS is promising for delineating genomic landscape of SCLC and may also shed some light on treatment selection for Chinese SCLC patients.