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Updated: Dec 9, 2025
Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Targeting HER2 heterogeneity in early-stage breast cancer
Sonia Pernas1, Sara M Tolaney2
1Department of Medical Oncology, Catalan Institute of Oncology (ICO)-H.U.Bellvitge-IDIBELL, Barcelona, Spain.
Purpose Of Review:
HER2-positive (HER2+) breast cancer is clinically and biologically a heterogenous disease and not all patients benefit to the same extent from current anti-HER2 therapies.
Recent Findings:
Among HER2+ breast cancer, molecular intrinsic subtypes, PIK3CA mutation status, levels of HER2 gene/protein, immune infiltration, or intratumor heterogeneity modulate HER2-treatment sensitivity. HER2-enriched carcinomas, with high levels of HER2 and tumor-infiltrating lymphocytes (TILs) are highly sensitive to anti-HER2 therapies, regardless of chemotherapy. Luminal A/B tumors are more estrogen receptor-dependent than HER2-dependent, harbor higher rates of PIK3CA mutations, and are less responsive to anti-HER2 treatment. HER2 intratumoral heterogeneity that exists in approximately 10% of HER2+ disease may also cause treatment resistance. Early changes occur during neoadjuvant anti-HER2 therapy that can predict response. Importantly, HER2 expression is not a binary but rather a continuous variable. Overall, 34-63% of HER2-negative breast cancers express HER2, and HER2-low tumors have become a new entity, for which novel targeted therapies may be effective.
Summary:
Although much of what is discussed currently remains investigational, it is clear that HER2+ breast cancer is a complex disease comprising different entities. Future strategies to escalate or de-escalate treatment in early-stage HER2+ disease should consider other biomarkers beyond HER2 and estrogen receptor status, including intrinsic subtype, HER2 levels, and TILs; and evaluate different treatment strategies among patients with estrogen receptor-positive/HER2+ and estrogen receptor-negative/HER2+ diseases.
Insights
HER2-positive breast cancer is diverse, with varying responses to anti-HER2 therapies. Biomarkers like HER2 levels and tumor subtypes influence treatment sensitivity, guiding personalized strategies for better outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- HER2-positive (HER2+) breast cancer exhibits significant clinical and biological heterogeneity.
- Not all patients achieve optimal benefit from current anti-HER2 therapies due to this diversity.
Purpose of the Study:
- To review the factors modulating HER2-treatment sensitivity in HER2+ breast cancer.
- To highlight the emerging understanding of HER2-low breast cancer and its therapeutic implications.
Main Methods:
- Review of current literature on HER2+ breast cancer heterogeneity and treatment response.
- Analysis of biomarkers including molecular subtypes, PIK3CA mutations, HER2 levels, and immune infiltration.
- Evaluation of intratumor heterogeneity and early treatment response predictors.
Main Results:
- HER2-enriched subtypes with high HER2 and tumor-infiltrating lymphocytes (TILs) show high sensitivity to anti-HER2 therapies.
- Luminal subtypes are less responsive to anti-HER2 treatment, often harboring PIK3CA mutations.
- HER2 intratumor heterogeneity can lead to treatment resistance; early neoadjuvant changes predict response.
- HER2 expression is continuous, with HER2-low breast cancers representing a new therapeutic target.
Conclusions:
- HER2+ breast cancer comprises distinct entities requiring tailored treatment strategies.
- Future treatment decisions should integrate biomarkers beyond HER2 and estrogen receptor status, including intrinsic subtype, HER2 levels, and TILs.
- Differentiated treatment approaches are needed for estrogen receptor-positive/HER2+ and estrogen receptor-negative/HER2+ breast cancers.
