The Amount of Evidence Needed to Support ERBB2 as a Biomarker for Resistance to EGFR Inhibitors in Metastatic Colorectal Cancer

To the Editor Bregni et al¹ highlight the clinical benefit of anti-epidermal growth factor receptor (EGFR) therapy in ERBB2-amplified (referred to as “HER2-amplified” by the authors, but herein referred to as “ERBB2-amplified” [ERBB2-positive]) metastatic colorectal cancer (mCRC) using retrospective analyses of preenrollment treatment data for 26 patients on HERACLES trial. Based on consistent preclinical and clinical studies showing limited activity of anti-EGFR antibodies and promising activity of anti-ERBB2 therapies in patients with mCRC, there is emerging consensus for early tissue testing for ERBB2, and preferential treatment of patients with ERBB2-positive mCRC on anti-ERBB2 treatment trials.² Bregni et al¹ question this evidence, and argue instead for ctDNA-based testing of ERBB2-positive status after progression on anti-EGFR therapies. We do not believe that their analysis and other contemporary evidence support the conclusions.