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Updated: Sep 24, 2025
Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
Unusual Patterns of HER2 Expression in Breast Cancer: Insights and Perspectives
Dora Grassini1,2, Eliano Cascardi1,2, Ivana Sarotto1
1Pathology Unit, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy.
Abstract:
The biomarker human epidermal growth factor receptor-2 (HER2) has represented the best example of successful targeted therapy in breast cancer patients. Based on the concept of "oncogene addiction," we have learnt how to identify patients likely benefitting from anti-HER2 agents. Since HER2 gene amplification leads to marked overexpression of the HER2 receptors on the cell membrane, immunohistochemistry with clinically validated antibodies and scoring system based on intensity and completeness of the membranous expression constitute the screening method to separate negative (score 0/1+) and positive (score 3+) carcinomas and to identify those tumours with complete yet only moderate HER2 expression (score 2+, equivocal carcinomas), which need to be investigated further in terms of gene status to confirm the presence of a loop of oncogene addiction. This process has demanded quality controls and led to recommendations by Scientific Societies, which pathologists routinely need to follow to guarantee reproducibility. In this review, we will span from the description of classical HER2 evaluation to the discussion of those scenarios in which HER2 expression is unusual and/or difficult to define. We will dissect HER2 heterogeneity, HER2 conversion from primary to relapsed/metastatic breast cancer, and we will introduce the new category of HER2-low breast carcinomas.
Insights
This review details human epidermal growth factor receptor-2 (HER2) testing in breast cancer, explaining how to identify patients for targeted therapy. It covers standard evaluation, challenges, and emerging categories like HER2-low.
Area of Science:
- Oncology
- Pathology
- Molecular Biology
Background:
- Human epidermal growth factor receptor-2 (HER2) is a key biomarker for targeted therapy in breast cancer.
- The concept of "oncogene addiction" guides patient selection for anti-HER2 agents.
- HER2 gene amplification causes receptor overexpression, driving cancer growth.
Purpose of the Study:
- To review classical HER2 evaluation methods in breast cancer.
- To discuss challenges and unusual scenarios in HER2 expression assessment.
- To introduce the concept of HER2-low breast carcinomas.
Main Methods:
- Immunohistochemistry (IHC) with validated antibodies and scoring systems (0, 1+, 2+, 3+).
- Assessment of membranous HER2 receptor expression intensity and completeness.
- Further gene status investigation for equivocal (2+) cases.
Main Results:
- Standard IHC effectively categorizes HER2 status (negative/positive) and identifies equivocal cases requiring further testing.
- Pathological evaluation requires strict quality controls and adherence to scientific society recommendations for reproducibility.
- HER2 evaluation faces challenges including heterogeneity and conversion in metastatic disease.
Conclusions:
- Accurate HER2 assessment is crucial for effective targeted therapy in breast cancer.
- Understanding HER2 heterogeneity and conversion is vital for managing advanced disease.
- The emergence of HER2-low as a distinct category requires new diagnostic and therapeutic considerations.
