Genomic Profile and Resistance to Anti-Epidermal Growth Factor Receptor Antibody in RAS-Amplified Colorectal Cancer: A Study Based on a Japanese Cancer Genome Database.

[PURPOSE] RAS mutation is a key biomarker of anti-epidermal growth factor receptor (EGFR) antibody resistance in colorectal cancer (CRC). However, the clinical impact of RAS amplification on the efficacy of anti-EGFR therapy remains unclear. This study aimed to characterize RAS-amplified CRC and evaluate the sensitivity of these tumors to anti-EGFR antibodies.

[METHODS] We conducted a retrospective observational study using the Center for Cancer Genomics and Advanced Therapeutics database in Japan, which includes clinical and genomic data from patients who underwent comprehensive genomic profiling. We analyzed the data from 9,135 patients with unresectable colorectal adenocarcinoma (CRA) who underwent FoundationOne CDx testing.

[RESULTS] RAS amplification was identified in 2.1% (188/9,135) of patients with CRA. Among 1,649 patients with RAS wild-type CRA who received first-line chemotherapy with anti-EGFR antibodies, those with RAS amplification had a lower overall response rate (ORR) and a shorter time to treatment failure (TTF) compared with those without RAS amplification (ORR, 37.5% [21/56] 52.9% [843/1,593]; median TTF, 195 days [95% CI, 129 to 224] 274 days [95% CI, 258 to 293]; = .023 and = .005, respectively). By contrast, among 4,858 patients treated with bevacizumab, no significant differences were observed in ORR (37.3% [31/83] 37.1% [1,772/4,775]; = .964) or TTF (median, 231 days [95% CI, 175 to 273] 259 days [95% CI, 252 to 270]; = .445).

[CONCLUSION] RAS amplification is a rare alteration that may confer resistance to anti-EGFR antibodies. Assessing RAS amplification status may help guide the appropriate use of anti-EGFR antibodies in clinical practice.