Profiling of circulating free DNA using targeted and genome wide sequencing in patients with Small Cell Lung Cancer

Abstract Introduction Small cell lung cancer (SCLC) accounts for ∼250,000 deaths worldwide each year. Acquisition of adequate tumour biopsies is challenging and liquid biopsies present an alternative option for patient stratification and response monitoring. Methods We applied whole genome next-generation sequencing (NGS) to circulating-free DNA (cfDNA) from 39 patients with limited-stage (LS-SCLC) and 30 of patients with extensive-stage (ES-SCLC) to establish genome wide copy number aberrations (CNA) as well as targeted mutation analysis of 110 SCLC associated genes. Quantitative metrics were calculated for CNA including Percent Genome Amplified (PGA; percentage of genomic regions amplified), Z-score (measure of standard deviation) and Moran's I (measure of spatial autocorrelation). In addition CellSearch®, an epitope dependent enrichment platform was used to enumerate circulating tumour cells (CTCs) from a parallel blood sample. Results Genome-wide and targeted cfDNA sequencing data identified tumour related changes in 94% of patients with LS-SCLC and 100% of patients with ES-SCLC. Parallel analysis of CTCs based on ≥ 1 CTC/7.5ml blood increased tumour detection frequencies to 95% for LS-SCLC. Both CTC counts and cfDNA readouts correlated with disease stage and overall survival (OS). Conclusions We demonstrate that a simple cfDNA genome wide copy number approach provides an effective means of monitoring patients through treatment and show that targeted cfDNA sequencing identifies potential therapeutic targets in >50% of patients. We are now incorporating this approach in additional studies and trials of targeted therapies.