Validation of <i>HER2</i> Amplification as a Predictive Biomarker for Anti-Epidermal Growth Factor Receptor Antibody Therapy in Metastatic Colorectal Cancer.

Abstract

<i>HER2</i> 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 <i>HER2</i> amplification in mCRC. We analyzed patients with <i>RAS/BRAF</i> wild-type mCRC across two distinct cohorts. In cohort 1 (n = 98), <i>HER2</i> amplification was tested in tumor tissue using dual in situ hybridization (<i>HER2</i> amplification: <i>HER2/CEP17</i> ratio, 2.0 or greater). Cohort 2 (n = 70) included 16 patients with <i>HER2</i> amplification and 54 <i>HER2</i> nonamplified controls identified by next-generation sequencing (<i>HER2</i> 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. Median PFS in cohort 1 on anti-EGFRab-based therapy was significantly shorter in patients with <i>HER2</i> amplification compared with <i>HER2</i> nonamplified patients (2.8 <i>v</i> 8.1 months, respectively; hazard ratio [HR], 7.05; 95% CI, 3.4 to 14.9; <i>P</i> < .001). These findings were validated in cohort 2 (median PFS for <i>HER2</i> amplified <i>v</i> nonamplified: 2.8 <i>v</i> 9.3 months, respectively; HR, 10.66; 95% CI, 4.5 to 25.1; <i>P</i> < .001). The median PFS on therapy without anti-EGFRabs was similar among <i>HER2</i>-amplified and nonamplified patients in both cohort 1 (9.7 <i>v</i> 11.1 months, respectively; HR, 1.01; 95% CI, 0.4 to 2.4; <i>P</i> = .97) and cohort 2 (9.6 <i>v</i> 11.3 months, respectively; HR, 1.21; 95% CI, 0.5 to 3.1; <i>P</i> = .66). In multivariable analyses, <i>HER2</i> 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; <i>P</i> < .001) and cohort 2 (HR, 10.1; 95% CI, 4.3 to 23.9; <i>P</i> < .001). <i>HER2</i> amplification in <i>RAS/RAF</i> wild-type mCRC seems to be a predictive biomarker for lack of efficacy of anti-EGFRab therapy. Screening patients with <i>RAS/BRAF</i> wild-type mCRC for <i>HER2</i> amplification should be considered before anti-EGFRab treatment to guide therapy and to identify patients for early referral to clinical trials.