Validation of Amplification as a Predictive Biomarker for Anti-Epidermal Growth Factor Receptor Antibody Therapy in Metastatic Colorectal Cancer.

Purpose: amplification has been implicated in resistance to therapy with anti-epidermal growth factor receptor antibodies (anti-EGFRabs) in metastatic colorectal cancer (mCRC). The purpose of the study was to validate the predictive impact of amplification in mCRC.

Patients And Methods: We analyzed patients with wild-type mCRC across two distinct cohorts. In cohort 1 (n = 98), amplification was tested in tumor tissue using dual in situ hybridization ( amplification: ratio, 2.0 or greater). Cohort 2 (n = 70) included 16 patients with amplification and 54 nonamplified controls identified by next-generation sequencing ( amplification: four or more copies) who had received prior anti-EGFRabs. The primary end point was progression-free survival (PFS) on treatment with anti-EGFRab therapy, which was estimated and compared using the Kaplan-Meier method and log-rank test.

Results: Median PFS in cohort 1 on anti-EGFRab-based therapy was significantly shorter in patients with amplification compared with nonamplified patients (2.8 8.1 months, respectively; hazard ratio [HR], 7.05; 95% CI, 3.4 to 14.9; < .001). These findings were validated in cohort 2 (median PFS for amplified nonamplified: 2.8 9.3 months, respectively; HR, 10.66; 95% CI, 4.5 to 25.1; < .001). The median PFS on therapy without anti-EGFRabs was similar among -amplified and nonamplified patients in both cohort 1 (9.7 11.1 months, respectively; HR, 1.01; 95% CI, 0.4 to 2.4; = .97) and cohort 2 (9.6 11.3 months, respectively; HR, 1.21; 95% CI, 0.5 to 3.1; = .66). In multivariable analyses, amplification emerged as a single independent predictor of poor PFS on anti-EGFRab therapy in both cohort 1 (HR, 6.48; 95% CI, 3.1 to 13.6; < .001) and cohort 2 (HR, 10.1; 95% CI, 4.3 to 23.9; < .001).

Conclusion: amplification in wild-type mCRC seems to be a predictive biomarker for lack of efficacy of anti-EGFRab therapy. Screening patients with wild-type mCRC for amplification should be considered before anti-EGFRab treatment to guide therapy and to identify patients for early referral to clinical trials.