HER2 amplification as a negative predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer.

Abstract

3517 Background: HER2 amplification (HERamp), seen in 5% of KRAS wildtype (WT) metastatic colorectal cancers (mCRC), is associated with resistance to anti-epidermal growth factor receptor antibodies (antiEGFRabs). The purpose of this study was to validate the predictive impact of HERamp in mCRC. Methods: We performed systematic analyses of RAS and BRAF WT mCRC patients (pts) across 2 distinct cohorts. We tested HERamp in cohort 1 (N = 97) using immunohistochemistry and dual in-situ hybridization (HERamp: HER2/CEP17 ≥ 2.2). We validated these findings in cohort 2 (N = 99), which comprised of 37 cases of HERamp mCRC pts identified by next-generation sequencing (HERamp: ≥ 4 copies) and 62 HER2 non-amplified (HER2NA) pts treated previously with antiEGFRabs who served as controls. The primary objective was to compare progression-free survival (PFS) in pts treated with antiEGFRabs. PFS and overall survival (OS) were estimated using Kaplan Meier method and compared using log rank test. Results: HERamp was seen in 14 (14 %) of RAS/BRAF WT pts in cohort 1. In this cohort, median OS (29.1 v 45.1 months (m), P = 0.78) and PFS on first line therapy without an antiEGFRab (PFS1) (9.7 v 8.4 m, P = 0.70) was similar between HERamp and HER2NA pts. A total of 66 pts in cohort 1 received antiEGFRab after first line therapy. Median PFS on antiEGFRab therapy (PFS2) was significantly shorter in pts with HERamp compared to HER2NA tumors (2.9 v 8.1 m, hazard ratio (HR) 5.0, P < 0.0001). These findings were confirmed in cohort 2, in which 69 pts received antiEGFRab after first line therapy and median PFS2 was significantly shorter for HERamp pts compared to HER2NA pts (2.8 v 9.3 m, HR 6.6, P < 0.0001) with a similar OS (P = 0.86) and PFS1 (P = 0.62). Conclusions: HER2 amplification in mCRC is a predictive biomarker for lack of efficacy of antiEGFRab therapy. This magnitude of effect is comparable to RAS mutations; the only other validated predictive biomarker for antiEGFRabs, and affects 1 in 8 patients currently receiving these agents. Patients with RAS/RAF WT mCRC should be screened for HER2 amplification prior to treatment with antiEGFRabs and should be considered for early referral to clinical trials.