HER2 (ERBB2) has emerged as a clinically actionable molecular alteration in metastatic colorectal cancer (mCRC). While HER2 was previously framed primarily as a mechanism of resistance to anti-EGFR therapies, contemporary data position HER2 as a therapeutic target in its own right, particularly among patients with RAS wild-type tumors that demonstrate strong HER2 protein overexpression or ERBB2 gene amplification. The reviewed literature frames HER2-positive mCRC as a distinct subgroup for which targeted interventions can yield meaningful clinical activity in treatment-refractory settings.
The review emphasizes colorectal cancer–specific diagnostic strategies for identifying HER2 alterations. Both tissue-based assays (immunohistochemistry and genomic testing for ERBB2 amplification) and circulating tumor DNA (ctDNA) have complementary roles. ctDNA can facilitate initial screening, detection of ERBB2 amplification in patients for whom fresh tissue is unavailable, and repeat molecular assessment at progression. The authors support integrating tissue and ctDNA testing into routine practice to enable early identification of candidates for HER2-directed therapy and to monitor for emerging resistance.
Dual HER2 blockade using trastuzumab-based combinations represents an established approach with demonstrated activity in patients with HER2-overexpressing or ERBB2-amplified mCRC. The review summarizes evidence that trastuzumab-containing doublets have produced clinically meaningful responses in treatment-refractory disease. Specific comparative efficacy details, numeric outcomes, and regimen-level toxicities are discussed in the full review; the abstract underscores that these combinations are a key component of current HER2-directed care for selected patients.
Antibody–drug conjugates (ADCs) have become an important class in the HER2-targeted armamentarium for mCRC. Trastuzumab deruxtecan is highlighted as having shown clinically meaningful activity in this population. The review also notes emerging phase III data for trastuzumab rezetecan, which further support the concept of HER2-directed therapy, while observing that peer-reviewed publication, regulatory approval, and regional availability vary and should be considered when planning treatment.
Treatment selection for HER2-directed therapy should be individualized. Important considerations include RAS/BRAF mutation status, the level of HER2 expression or ERBB2 amplification, prior exposure to anti-EGFR agents, patient comorbidities, anticipated toxicity risks, and local availability of drugs or clinical trials. The review stresses that HER2 testing should be prioritized in appropriate clinical contexts to identify candidates who may derive benefit from dual blockade or ADC approaches.
A major practical question is the optimal sequencing of dual HER2 blockade versus ADC therapy. The review indicates that sequencing remains uncertain and that prospective evaluation is required. The authors propose a clinician-oriented framework intended to guide early identification of HER2-positive patients, to help determine when to use trastuzumab-based combinations versus ADCs, and to incorporate real-world constraints such as access and toxicity. However, definitive sequencing algorithms are not established within the source.
Repeat molecular assessment at progression is recommended to characterize mechanisms of resistance and to inform subsequent treatment choices. The review highlights the complementary utility of tissue rebiopsy and serial ctDNA analysis for detecting evolving genomic changes, including loss or gain of HER2 alterations or emergence of alternative driver mutations that may influence responsiveness to further HER2-directed therapy.
The review notes that some promising HER2-directed agents and data (for example, ADCs beyond trastuzumab deruxtecan) have emerging phase III evidence but may have variable peer-reviewed publication status, regulatory approval, and regional availability. These factors are important practical constraints when integrating HER2-targeted options into management plans.
The review concludes that HER2 testing and HER2-directed therapy should be integrated into precision oncology care pathways for mCRC, with careful patient selection and serial molecular monitoring. While dual trastuzumab-based blockade and ADCs have transformed options for HER2-positive mCRC, optimal sequencing and long-term strategies to address resistance require further prospective study.
Conflict of interest disclosures in the source note that the lead author has received lecture fees from pharmaceutical companies; coauthors declared no competing interests. The abstract and review focus on practical implementation rather than presenting new trial data; where specific numerical outcomes, trial names, or detailed regimen schedules are not reported in the abstract, those details were not provided in the summarized source.