Validation of HER2 Amplification as a Predictive Biomarker for Anti–Epidermal Growth Factor Receptor Antibody Therapy in Metastatic Colorectal Cancer
Abstract
Purpose: HER2 amplification has been implicated in resistance to therapy with anti–epidermal growth factor receptor antibodies (anti-EGFRabs) in metastatic colorectal cancer (mCRC). The purpose of the study was to validate the predictive impact of HER2 amplification in mCRC. Patients and Methods: We analyzed patients with RAS/BRAF wild-type mCRC across two distinct cohorts. In cohort 1 (n = 98), HER2 amplification was tested in tumor tissue using dual in situ hybridization ( HER2 amplification: HER2/CEP17 ratio, 2.0 or greater). Cohort 2 (n = 70) included 16 patients with HER2 amplification and 54 HER2 nonamplified controls identified by next-generation sequencing ( HER2 amplification: four or more copies) who had received prior anti-EGFRabs. The primary end point was progression-free survival (PFS) on treatment with anti-EGFRab therapy, which was estimated and compared using the Kaplan-Meier method and log-rank test. Results: Median PFS in cohort 1 on anti-EGFRab–based therapy was significantly shorter in patients with HER2 amplification compared with HER2 nonamplified patients (2.8 v 8.1 months, respectively; hazard ratio [HR], 7.05; 95% CI, 3.4 to 14.9; P < .001). These findings were validated in cohort 2 (median PFS for HER2 amplified v nonamplified: 2.8 v 9.3 months, respectively; HR, 10.66; 95% CI, 4.5 to 25.1; P < .001). The median PFS on therapy without anti-EGFRabs was similar among HER2-amplified and nonamplified patients in both cohort 1 (9.7 v 11.1 months, respectively; HR, 1.01; 95% CI, 0.4 to 2.4; P = .97) and cohort 2 (9.6 v 11.3 months, respectively; HR, 1.21; 95% CI, 0.5 to 3.1; P = .66). In multivariable analyses, HER2 amplification emerged as a single independent predictor of poor PFS on anti-EGFRab therapy in both cohort 1 (HR, 6.48; 95% CI, 3.1 to 13.6; P < .001) and cohort 2 (HR, 10.1; 95% CI, 4.3 to 23.9; P < .001). Conclusion: HER2 amplification in RAS/RAF wild-type mCRC seems to be a predictive biomarker for lack of efficacy of anti-EGFRab therapy. Screening patients with RAS/BRAF wild-type mCRC for HER2 amplification should be considered before anti-EGFRab treatment to guide therapy and to identify patients for early referral to clinical trials.
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The prognostic relevance of ERBB2 amplification itself in metastatic colorectal cancer remains controversial.
“the prognostic relevance of ERBB2 amplification itself in mCRC remains controversial.42 43 45”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [43]
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- Authors
- Raghav, K., Loree, J. M., Morris, J. S., Overman, M. J., Yu, R., Meric-Bernstam, F., Menter, D., Korphaisarn, K., Kee, B., Muranyi, A., Singh, S., Routbort, M., Chen, K., Shaw, K. R. M., Katkhuda, R., Shanmugam, K., Maru, D., Fakih, M., & Kopetz, S.
- Affiliations
- City Of Hope National Medical Center (US)
- Kanwal Raghav, Jonathan M. Loree, Jeffrey S. Morris, Michael J. Overman, Ruoxi Yu, Funda Meric-Bernstam, David Menter, Krittiya Korphaisarn, Brian Kee, Mark Routbort, Ken Chen, Kenna R.M. Shaw, Riham Katkhuda, Dipen Maru, and Scott Kopetz, The University of Texas MD Anderson Cancer Center, Houston, TX; Andrea Muranyi, Shalini Singh, and Kandavel Shanmugam, Ventana Medical Systems, Tucson, AZ; and Marwan Fakih, City of Hope Comprehensive Cancer Center, Duarte, CA.
- ORCID
- Venue
- JCO Precision Oncology
- Published
- 2019-12
- Volume
- 3
- Issue
- 3
- Pages
- 1-13
- ISSN
- 2473-4284 (ISSN-L)
- OpenAlex
- W2912216712
- Cited by
- 132
- References
- 31
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 24 · 2023: 20 · 2022: 20 · 2021: 9 · 2020: 8 · 2019: 15 · 2018: 3 · 2017: 5 · 2016: 1
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JCO Precision Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- HER2 amplification, metastatic colorectal cancer, anti-EGFR antibody therapy, predictive biomarkers, progression-free survival, RAS/BRAF wild-type, treatment resistance, HER2/CEP17 ratio, next-generation sequencing, anti-EGFR therapy, biomarker validation, prognostic factors
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