Inferring the evolution and progression of small-cell lung cancer by single-cell sequencing of circulating tumor cells

Purpose: Genomic analyses of small-cell lung cancer strated that patients with low CNA scores (<0) had signifi-(SCLC) are limited by the availability of tumor specimens. cantly prolonged progression-free survival (PFS) and overall This study aimed to investigate the suitability of single-cell survival (OS) after first-line chemotherapy in comparison with sequencing of circulating tumor cells (CTC) as a method of those with high scores (0; PFS: 212 days vs. 110.5 days, P ¼ inferring the evolution and progression of SCLCs. 0.0042; and OS: 223.5 days vs. 424 days, P ¼ 0.0006). The Experimental Design: Between July 1, 2011, and July 28, positive predictive value and negative predictive value of the 2014, 48 consecutively diagnosed patients with SCLC were CNA score for clinical subtype (refractory vs. sensitive) were recruited for this study. CTCs were captured from each patient 80.0% and 93.7%, respectively. By tracing allele-specific CNAs with CellSearch system. Somatic mutations and copy number in CTCs isolated at different time points during chemotherapy, alterations (CNA) were monitored by single-cell sequencing of we showed that CNA heterogeneity might result from allelic CTCs during chemotherapy. losses of initially consistent CNAs. Results: Single-cell sequencing of CTCs can provide a muta-Conclusions: Single CTC-based sequencing can be utilized tional atlas for SCLC. A 10-CNA score based on single CTCs to depict the genomic profiles and evolutionary history of was established as a classifier for outcomes of initial chemo-SCLC, thus offering the potential for clinical stratification of therapy in patients with SCLC. The survival analyses demon-patients with SCLC.