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Updated: Dec 16, 2025
Validated Immunochemical Assay for Comprehensive Determination of the Human Epidermal Growth Factor Receptor 2 Released from and Bound to Cells
Published on: May 9, 2025
Biomarkers for HER2-positive metastatic breast cancer: Beyond hormone receptors
Maria Vittoria Dieci1, Federica Miglietta2, Gaia Griguolo1
1Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Medical Oncology 2, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.
Abstract:
The overexpression of human epidermal growth factor receptor-2 (HER2) results in a biologically and clinically aggressive breast cancer (BC) subtype. Since the introduction of anti-HER2 targeted agents, survival rates of patients with HER2-positive metastatic BC have dramatically improved. Currently, although the treatment decision process in metastatic BC is primarily based on HER2 and hormone-receptor (HR) status, a rapidly growing body of data suggests that several other sources of biological heterogeneity may characterize HER2-positive metastatic BC. Moreover, pivotal clinical trials of new anti-HER2 antibody-drug conjugates showed encouraging results in HER2-low metastatic BC, thus leading to the possibility, in the near future, to expand the pool of patients suitable for HER2-targeted treatments. The present review summarizes and puts in perspective available evidence on biomarkers that hold the greatest promise to become potentially useful tools for optimizing HER2-positive metastatic BC patients' prognostic stratification and treatment in the next future. These biomarkers include HER2 levels and heterogeneity, HER3, intrinsic molecular subtypes by PAM50 analysis, DNA mutations, and immune-related factors. Molecular discordance between primary and metastatic tumors is also discussed.
Insights
New biomarkers are emerging to improve treatment for HER2-positive breast cancer (BC). Research is exploring factors beyond HER2 status to personalize care for metastatic BC patients.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- HER2-overexpressing breast cancer (BC) is aggressive, but anti-HER2 therapies have improved survival.
- Treatment decisions for metastatic BC currently rely on HER2 and hormone receptor (HR) status.
- Biological heterogeneity in HER2-positive metastatic BC is increasingly recognized.
Purpose of the Study:
- To review promising biomarkers for prognostic stratification and treatment optimization in HER2-positive metastatic BC.
- To discuss the potential expansion of HER2-targeted therapies to HER2-low metastatic BC.
- To explore molecular discordance between primary and metastatic tumors.
Main Methods:
- Literature review of current evidence on biomarkers in HER2-positive metastatic BC.
- Analysis of data from clinical trials involving new anti-HER2 antibody-drug conjugates.
- Discussion of established and emerging biomarkers including HER2 levels, HER3, PAM50 subtypes, DNA mutations, and immune factors.
Main Results:
- Anti-HER2 agents have significantly improved survival for HER2-positive metastatic BC.
- New antibody-drug conjugates show promise for HER2-low metastatic BC, potentially broadening treatment eligibility.
- Biomarkers like HER2 heterogeneity, HER3, PAM50, mutations, and immune factors may refine patient stratification.
Conclusions:
- Further research into novel biomarkers is crucial for optimizing treatment strategies in HER2-positive metastatic BC.
- Understanding molecular heterogeneity and discordance is key to personalized medicine.
- Emerging biomarkers may soon enable more precise prognostic stratification and targeted treatment selection.
