HER2-Targeted Therapy for Metastatic Colorectal Cancer: Current Evidence, Patient Selection, and Practical Treatment Sequencing.

HER2 has emerged as an actionable molecular alteration in metastatic colorectal cancer (mCRC), particularly in patients with RAS wild-type disease and tumors with strong HER2 overexpression or ERBB2 amplification. Once recognized mainly as a mechanism of resistance to anti-EGFR therapy, HER2 now defines a therapeutically relevant subgroup. Dual HER2 blockade with trastuzumab-based combinations and antibody-drug conjugates, particularly trastuzumab deruxtecan, have demonstrated clinically meaningful activity in treatment-refractory disease. Emerging phase III data with trastuzumab rezetecan further support HER2-directed therapy, although peer-reviewed publication, regulatory status, and regional availability remain important considerations. This narrative review focuses on the practical integration of HER2 testing and HER2-directed treatment into mCRC care. We summarize colorectal cancer-specific diagnostic approaches, evidence for established and emerging regimens, and treatment-selection considerations according to RAS/BRAF status, HER2 expression level, prior anti-EGFR exposure, comorbidities, toxicity risk, and local access. We also discuss the complementary roles of tissue testing and circulating tumor DNA, including repeat molecular assessment at progression. Finally, we propose a clinician-oriented framework for early patient identification, treatment sequencing, and resistance assessment. Optimal sequencing between dual HER2 blockade and antibody-drug conjugates remains uncertain and requires prospective evaluation.