Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced non-small cell lung cancer.

INTRODUCTION: Genomic profiling informs selection of matched targeted therapies as part of routine clinical care in non-small cell lung cancer (NSCLC). Tissue biopsy is the gold standard; however, genomic profiling of blood-derived circulating tumor DNA (ctDNA) has emerged as a minimally invasive alternative.

METHODS: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 1,552 patients with NSCLC.

RESULTS: Evidence of ctDNA was detected in 80% of samples, and of these at least one reportable genomic alteration (GA) was detected in 86% of cases. Frequently altered genes were TP53 (59%), EGFR (25%), and KRAS (17%). Comparative analysis with a tissue genomic database (n = 21,500) showed similar frequencies of GA per gene, although KRAS mutation and EGFR T790M were more frequent in tissue and ctDNA, respectively (both P <0.0001), likely reflecting use of liquid versus tissue biopsy after relapse on targeted therapy. In temporally matched ctDNA and tissue samples from 33 patients with evidence of ctDNA in the blood, 64% of GA detected in tissue were also detected in ctDNA, including 78% (58/74) of short variants and 100% (4/4) of rearrangements, but only 16% (4/25) of amplifications.

CONCLUSIONS: Genomic profiling of ctDNA detected clinically relevant GAs in a significant subset of NSCLC cases. Most alterations detected in matched tissue were also detected in ctDNA. These results suggest utility of ctDNA testing in advanced NSCLC as a complementary approach to tissue testing. Blood-based ctDNA testing may be particularly useful at the time of progression on targeted therapy.