Targeting HER2 in Metastatic Colorectal Cancer: Current Therapies, Biomarker Refinement, and Emerging Strategies

HER2 overexpression/amplification is a well-established oncogenic driver across several tumor types and has emerged as a therapeutically actionable biomarker in 3–5% of metastatic colon and rectal cancers (mCRCs). Based on increasing clinical evidence, several anti-HER2 therapeutic regimens have been incorporated into treatment guidelines. In this review, we provide a comprehensive overview of both established and emerging HER2-targeted strategies in mCRC, examining the mechanisms of action, toxicity profiles, and clinical efficacy of individual anti-HER2 drugs and their associations. As accurate and standardized HER2 testing remains critical, we also discuss current methodologies and challenges in HER2 screening for mCRC. In addition, we present an in-depth analysis of the relationship between HER2 amplification levels, co-occurring genomic alterations, and treatment outcomes across clinical trials, underscoring the importance of quantitative HER2 assessment and comprehensive tumor profiling. These data support the refinement of therapeutic strategies through more precise diagnostic approaches and improved patient selection, considering factors such as gene-dosage, toxicity, and coexisting mutations. Finally, the emerging role of anti-HER2 rechallenge strategies and the advent of novel HER2-directed therapies—including bispecific antibodies, novel tyrosine kinase inhibitors, antibody-drug conjugates, and immune-based therapies—are discussed as new opportunities to improve outcomes in this molecular subset of patients.