Comparative genomic profiling of paired tissue and blood samples from advanced non-small cell lung cancer patients.

Abstract

e20521 Background: While tissue-based next generation sequencing (NGS) ushered in a new era of precision medicine, profiling of circulating tumor DNA (ctDNA) has also emerged as a minimally invasive alternative to inform clinical decisions. In non-small cell lung cancer (NSCLC), data describing comparison between mutational profiles of paired tissue and blood samples remained scarce. Methods: Matched formalin-fixed paraffin-embedded tissue and peripheral blood samples (≤14 days apart) were collected from treatment naïve advanced NSCLC patients. Genomic profiling was performed using whole exome sequencing (WES) for tissues and a 150-gene panel for ctDNA, with a mean sequencing depth of 239× and 3417× respectively. Tumor- and blood-based tumor mutational burdens (tTMB and bTMB) were defined as the sum of missense, stop-loss, in-frame and frameshift mutations in protein coding regions and the number of somatic single nucleotide variations and indels in targeted coding regions respectively. Maximum somatic allele frequency (MSAF) was also determined for each case as a measure of ctDNA quantity. Results: Matched tissue and blood samples from 48 patients were included for sequencing. A total of 410 mutations were identified, where 84 (20.5%) were covered in both sample types. Sixty-three (15.4%) alterations were only detected in tissues while 263 (64.1%) were exclusively seen in ctDNA. The most frequently altered genes were SMARCA2 (62.5%), TP53 (54.2%), and AR (47.9%) in ctDNA and were TP53 (37.5%) and EGFR (22.9%) in tissues. Aberrations in all genes, except for FAT1 and KRAS, occurred at a higher frequency in ctDNA. The median tTMB and bTMB were 75 and 7, respectively. bTMB displayed a moderate linear relationship with tTMB as indicated by a Spearman correlation of 0.62 (P < 0.01). Patients with bTMB ≥ 7 had significantly higher MSAF (Mann-Whitney P < 0.001), suggesting a positive correlation between bTMB and ctDNA fraction in blood. Conclusions: Mutational profiles as well as TMB levels were in general consistent between blood and tissue samples, further corroborating a role for ctDNA testing as a complementary approach to tissue testing in advanced NSCLC.