HER2-positive Colorectal Cancer: Molecular Biology, Clinical Significance, and Therapeutic Implications with an Emphasis on Metastatic Disease

Human epidermal growth factor receptor 2 (HER2), the protein product of the ERBB2 gene, is an emerging therapeutic target in colorectal cancer (CRC).Although HER2 alterations occur in a small proportion of CRCs, advances in molecular characterization and HER2-directed therapies have increased the clinical importance of this biomarker.HER2-positive CRC is biologically heterogeneous, and its clinical significance depends on the type of ERBB2 alteration (amplification or mutation), the level of HER2 protein expression, coexisting molecular features, and disease setting.ERBB2 amplification and HER2 overexpression activate oncogenic pathways, including mitogen-activated protein kinase and phosphoinositide 3-kinase-protein kinase B signaling, and may contribute to resistance to anti-epidermal growth factor receptor (EGFR) therapy.HER2-positive CRC is enriched in KRAS/NRAS/rapidly accelerated fibrosarcoma B-type kinase (BRAF) [rat sarcoma GTPase (RAS)/BRAF] wild-type, left-sided, and microsatellite-stable tumors.HER2 overexpression, ERBB2 amplification, and ERBB2 mutation are biologically distinct alterations.Accurate biomarker assessment is therefore essential, although HER2 testing criteria in CRC remain less standardized than those in breast and gastric cancers.HER2-directed therapy has become an established strategy for selected patients with previously treated metastatic CRC.Trastuzumab-based dual HER2 blockade, including tucatinib plus trastuzumab, has demonstrated meaningful and durable responses, particularly in HER2positive, RAS wild-type tumors.Trastuzumab deruxtecan has further expanded treatment options and shown activity in HER2-positive tumors, including RASmutant disease, with the greatest benefit observed in immunohistochemistry 3+ tumors.Emerging HER2-targeted antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates may further broaden therapeutic options, although optimal sequencing and mechanisms of resistance remain uncertain.HER2 has evolved from a biomarker associated with anti-EGFR resistance into an actionable therapeutic target in CRC.Given the rapid expansion of HER2directed treatment options and testing approaches, this review synthesizes current evidence on HER2 biology, testing, therapeutic strategies, and resistance mechanisms in CRC, with particular emphasis on metastatic disease, to provide an updated, clinically oriented reference for the field.