Current Approaches and Emerging Directions in HER2-resistant Breast Cancer
1Women's Cancer Center at Magee-Women's Hospital, University of Pittsburgh School of Medicine, Magee-Women's Hospital, Pittsburgh, PA, USA. ; Comprehensive Breast Cancer Center, University of Pittsburgh School of Medicine, Magee-Women's Hospital, Pittsburgh, PA, USA.
Abstract:
Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancers; HER2 overexpression is indicative of poor prognosis. Trastuzumab, an anti-HER2 monoclonal antibody, has led to improved outcomes in patients with HER2-positive breast cancer, including improved overall survival in adjuvant and first-line settings. However, a large proportion of patients with breast cancer have intrinsic resistance to HER2-targeted therapies, and nearly all become resistant to therapy after initial response. Elucidation of underlying mechanisms contributing to HER2 resistance has led to development of novel therapeutic strategies, including those targeting HER2 and downstream pathways, heat shock protein 90, telomerase, and vascular endothelial growth factor inhibitors. Numerous clinical trials are ongoing or completed, including phase 3 data for the mammalian target of rapamycin inhibitor everolimus in patients with HER2-resistant breast cancer. This review considers the molecular mechanisms associated with HER2 resistance and evaluates the evidence for use of evolving strategies in patients with HER2-resistant breast cancer.
Insights
Human epidermal growth factor receptor-2 (HER2) positive breast cancer often develops resistance to targeted therapies. This review explores resistance mechanisms and novel therapeutic strategies for HER2-resistant breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Human epidermal growth factor receptor-2 (HER2) overexpression occurs in up to 30% of breast cancers, predicting a poor prognosis.
- Anti-HER2 therapies like trastuzumab have improved survival in HER2-positive breast cancer.
- Intrinsic and acquired resistance to HER2-targeted therapies remain significant clinical challenges.
Purpose of the Study:
- To review the molecular mechanisms underlying resistance to HER2-targeted therapies in breast cancer.
- To evaluate emerging therapeutic strategies for patients with HER2-resistant breast cancer.
Main Methods:
- Review of preclinical and clinical studies on HER2 resistance mechanisms.
- Analysis of ongoing and completed clinical trials for novel HER2-resistant breast cancer treatments.
- Examination of data for targeted agents including mTOR inhibitors.
Main Results:
- Multiple molecular pathways contribute to intrinsic and acquired resistance to HER2-targeted therapies.
- Novel strategies targeting HER2, downstream signaling, HSP90, telomerase, and VEGF are under investigation.
- Phase 3 data for everolimus in HER2-resistant breast cancer demonstrate therapeutic potential.
Conclusions:
- Understanding HER2 resistance mechanisms is crucial for developing effective treatment strategies.
- A range of novel therapeutic agents and combinations are being evaluated to overcome HER2 resistance.
- Evolving treatment paradigms offer new hope for patients with advanced or resistant HER2-positive breast cancer.
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