Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with advanced non-small cell lung cancer (NSCLC).

Abstract

9025 Background: Tissue biopsy is the gold standard for detection of genomic alterations (GA) and selection of matched targeted therapies in NSCLC, but ctDNA assay provides a possible complementary approach for some pts. Methods: Hybrid-capture based genomic profiling of 62 genes using a ctDNA assay (FoundationACT™) was performed on blood samples from 1,019 consecutive NSCLC pts. The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Results: Pt characteristics: Median age 69 years (range 8-94); 54% were female. Histologies included adenocarcinoma (n = 720), NSCLC not otherwise specified (NSCLC NOS; n = 179), squamous cell (n = 57), LC NOS (n = 51), large cell (n = 6), and sarcomatoid (n = 6). ≥1 reportable GA was detected in 71% of all cases and in 83% of cases with evidence of ctDNA in the blood (MSAF > 0). For 22 pts with paired blood and tissue samples collected within 30 days and MSAF > 0, 33/64 (52%) GA detected in tissue were also detected in ctDNA. In 55 pts for whom tissue was insufficient for analysis, ≥1 GA was detected in ctDNA in 43 (78%) cases. For 856 cases with MSAF > 0, an average of 1.8 GA/sample were reported. GA were most frequently detected in TP53 (57%), EGFR (23%) and KRAS (17%). Comparative analysis with the tissue-based FoundationCORE™ database (n = 19,264) showed similar frequencies of GA per gene, although KRAS mutation was more frequent in tissue than ctDNA (27% vs 17%, P < 0.0001), and EGFR T790M was more frequent in ctDNA than tissue (7% vs 2%, P < 0.0001), likely reflecting use of liquid versus tissue biopsy after relapse on targeted therapy .Kinase fusions ( ALK, ROS1, RET, FGFR3, PDGFRA) were identified in 5% (39/856) of cases. Diverse and novel mechanisms of acquired resistance (AR) were detected in ctDNA including MET Y1230C and EGFR amplification post-crizotinib, FGFR3-TACC3 fusion post-EGFR inhibitor, and multiple EGFRAR mutations post-osimertinib. Conclusions: In this series, use of a rigorously validated capture-based assay revealed evidence of ctDNA in the blood in 84% of cases. Our results provide clinical support for use of this assay as a complementary technology to tissue-based genomic testing in a subset of pts with NSCLC.