---
title: "HER2-Targeted Therapy in Metastatic Colorectal Cancer: Evidence, Testing, and Sequencing"
id: "pubmed-42663748"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42663748"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42663748/"
doi: "10.1007/s12029-026-01564-1"
published_at: "2026-08-28T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# HER2-Targeted Therapy in Metastatic Colorectal Cancer: Evidence, Testing, and Sequencing
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42663748
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42663748/)
- **DOI:** [10.1007/s12029-026-01564-1](https://doi.org/10.1007%2Fs12029-026-01564-1)
- **Published At:** 2026-08-28T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- **HER2 (ERBB2)** is an actionable molecular alteration in metastatic colorectal cancer (mCRC), especially in **RAS wild-type** tumors with strong HER2 overexpression or ERBB2 amplification. - Historically recognized as a mechanism of resistance to anti-EGFR therapy, HER2 now identifies a therapeutically relevant subgroup of mCRC. - Dual HER2 blockade using **trastuzumab-based combinations** has shown clinically meaningful activity in treatment-refractory mCRC. - **Antibody–drug conjugates (ADCs)**, particularly **trastuzumab deruxtecan**, have demonstrated important activity; additional ADCs such as **trastuzumab rezetecan** have emerging phase III data but variable publication, regulatory, and availability status. - The review emphasizes practical integration of **HER2 testing** into care, including colorectal-specific diagnostic approaches and the complementary use of **circulating tumor DNA (ctDNA)** alongside tissue testing. - Patient selection and treatment choice should account for **RAS/BRAF status**, HER2 expression/amplification level, prior anti-EGFR exposure, comorbidities, toxicity risk, and local drug access. - Repeat molecular assessment at progression, via tissue or ctDNA, is recommended to evaluate resistance mechanisms and inform sequencing. - The optimal sequencing between **dual HER2 blockade** and **ADCs** remains uncertain and requires prospective evaluation. - The authors propose a clinician-oriented framework for early identification, sequencing, and resistance assessment; details for implementation and definitive sequencing algorithms are not established in the source.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliations * 1 Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo-shi, 003-0804, Hokkaido, Japan. stamotsu@jk9.so-net.ne.jp. * 2 Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo-shi, 003-0804, Hokkaido, Japan. * PMID: **42663748** * DOI: [ 10.1007/s12029-026-01564-1 ](https://doi.org/10.1007/s12029-026-01564-1) Item in Clipboard Review # HER2-Targeted Therapy for Metastatic Colorectal Cancer: Current Evidence, Patient Selection, and Practical Treatment Sequencing Tamotsu Sagawa et al. J Gastrointest Cancer. 2026. Show details Display options Display options Format Abstract PubMed PMID J Gastrointest Cancer Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22J+Gastrointest+Cancer%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22J+Gastrointest+Cancer%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42663748/) . 2026 Aug 28;57(1):200. doi: 10.1007/s12029-026-01564-1. ### Authors [Tamotsu Sagawa](https://pubmed.ncbi.nlm.nih.gov/?term=Sagawa+T&cauthor_id=42663748)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42663748/#short-view-affiliation-1 "Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo-shi, 003-0804, Hokkaido, Japan. stamotsu@jk9.so-net.ne.jp."), [Hiroyuki Nagashima](https://pubmed.ncbi.nlm.nih.gov/?term=Nagashima+H&cauthor_id=42663748)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42663748/#short-view-affiliation-2 "Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo-shi, 003-0804, Hokkaido, Japan."), [Koshi Fujikawa](https://pubmed.ncbi.nlm.nih.gov/?term=Fujikawa+K&cauthor_id=42663748)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42663748/#short-view-affiliation-2 "Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo-shi, 003-0804, Hokkaido, Japan.") ### Affiliations * 1 Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo-shi, 003-0804, Hokkaido, Japan. stamotsu@jk9.so-net.ne.jp. * 2 Department of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, 3-54 Kikusui 4-jo 2-chome, Shiroishi-ku, Sapporo-shi, 003-0804, Hokkaido, Japan. * PMID: **42663748** * DOI: [ 10.1007/s12029-026-01564-1 ](https://doi.org/10.1007/s12029-026-01564-1) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract 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. **Keywords:** ERBB2; Circulating tumor DNA; Colorectal cancer; HER2; Metastatic colorectal cancer; Patient selection; Precision oncology; Trastuzumab; Trastuzumab deruxtecan; Trastuzumab rezetecan; Treatment sequencing; Tucatinib. © 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declarations. Ethics Approval and Consent to Participate: Not applicable. Competing interests: Tamotsu Sagawa has received lecture fees from pharmaceutical companies. Hiroyuki Nagashima and Koshi Fujikawa declare no competing interests. Consent for Publication: Not applicable. ## References 1. 1. Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:10–32. - [DOI](https://doi.org/10.1016/j.annonc.2022.10.003) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/36307056/) 2. 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 3.2024. 3. 1. Morris VK, Kennedy EB, Baxter NN, et al. Treatment of metastatic colorectal cancer: ASCO guideline. J Clin Oncol. 2023;41:678–700. - [DOI](https://doi.org/10.1200/jco.22.01690) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/36252154/) 4. 1. Watanabe J, Muro K, Shitara K, et al. Panitumumab vs bevacizumab added to standard first-line chemotherapy and overall survival among patients with RAS wild-type, left-sided metastatic colorectal cancer: the PARADIGM randomized clinical trial. JAMA. 2023;329:1271–82. - [DOI](https://doi.org/10.1001/jama.2023.4428) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/37071094/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/10114040/) 5. 1. Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA. 2017;317:2392–401. - [DOI](https://doi.org/10.1001/jama.2017.7105) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/28632865/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/5545896/) Show all 32 references ## Publication types * Review Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Review%22%5Bpt%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Review) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42663748/) ## MeSH terms * Antineoplastic Agents, Immunological / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Antineoplastic+Agents%2C+Immunological%2Fpharmacology%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Antineoplastic+Agents%2C+Immunological) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42663748/) * Antineoplastic Agents, Immunological / therapeutic use Actions * [ Search in PubMed 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