Comprehensive genomic profiling of circulating cell-free DNA (cfDNA) distinguishes focal amplification (amp) from aneuploidy among MET amps in diverse advanced cancer types.

Abstract

3046 Background: MET amps can occur from focal gene copy number gain (e.g. MET-driven) or gain of chromosome 7 (e.g. aneuploidy); however, the contribution of each to MET amp is not well established. MET inhibitor-sensitive lung cancers harboring high-level MET amp have been reported in the absence of other sensitizing MET alterations (alts), e.g. exon 14 skipping, particularly among those with higher MET to chromosome 7 ratios. Methods: 3,114 samples from 2,902 Asian patients with advanced solid tumors were tested with a comprehensive cfDNA NGS panel (Guardant360) between Oct 2015-Dec 2018. This 70-73 gene assay evaluates single nucleotide variants (SNV), selected insertion-deletions (indels), fusions, and copy number gains. Focal amp was determined bioinformatically as having statistically higher copy number relative to other genes, such as BRAF, or CDK6, in the same chromosome arm. Results: MET alts associated with aberrant signaling were found in 223 pts (7.7%) with 18 different cancer types, most commonly lung (128/1,678), colorectal (36/349), and prostate (11/48). Among 223 pts, 189 pts (84.8%) had amps, 38(17.0%) had exon 14 skipping, and 8 (3.6%) had activating SNVs. 39.7% of MET amp was focal but differed by cancer type; highest prevalence was in gastroesophageal (80%) and lowest in prostate cancers (9%). Samples with focal MET amp had higher plasma copy number compared to those with non-focal MET amp (mean 5.8 vs. 2.5; p < 0.0001) and lower total number of alts per sample (8.8 vs. 11; p = 0.0122). Focal MET amp was more common than non-focal MET amp among 419 EGFR mutated samples (6.9% vs. 3.8%, p = 0.05) suggesting focal MET amp may be biologically more relevant as a mechanism of EGFR TKI resistance. Conclusions: This is the first study to use cfDNA to examine focal vs. non-focal MET amp. Focal MET amp accounted for ~40% of all MET amps, was found in 2.6% of pts with diverse cancers, was associated with higher plasma copy number, and found in a higher proportion of EGFR mutated lung cancer samples. The ability to differentiate may be clinically relevant given higher MET to chromosome 7 ratios have been associated with improved therapeutic response.