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.

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Keywords: HER2-positive, human epidermal growth factor receptor-2, HER2 therapy resistance


Up to 30% of invasive breast cancers overexpress human epidermal growth factor receptor-2 (HER2),1leading to stimulation of pathways involved in cell proliferation and survival, including the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and mitogen-activated protein kinase pathways.2

HER2 overexpression is correlated with age older than 50 years, higher T stage, and histological grade,3 and it is a marker of aggressive disease, including decreased recurrence-free survival, breast cancer–related survival, and overall survival (OS).3–7

Molecular profiling has led to the classification of breast cancers into distinct subtypes, including HER2-positive (HER2+) breast cancer. It is recommended that HER2 status be assessed for all invasive breast cancers, because it influences prognosis and selection of therapy;8–10 an immunohistochemistry staining result of 3 or more, a fluorescence in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus, or a FISH ratio greater than 2.2 is considered a positive HER2 result.11 Prognostic and predictive biomarker approaches for assessing HER2 status and better optimizing therapies are also under investigation.12,13

The identification of HER2 in breast cancer pathogenesis has led to the development of therapies targeting this receptor. Trastuzumab is a monoclonal antibody that has demonstrated improved survival in the first-line setting in combination with chemotherapy in patients with HER2+ advanced disease14,15 and improved disease-free survival and OS in patients with HER2+ early breast cancer when used in combination with or sequentially after adjuvant chemotherapy.16–18

Although the development of HER2-targeted therapy has transformed the treatment of patients with HER2+breast cancer, nearly 70% of patients with metastatic breast cancer have intrinsic resistance and nearly all become resistant to therapy after initial responsiveness.19,20

In addition, despite HER2-targeted therapy, many patients develop central nervous system (CNS) progression, which is a population of patients with limited therapeutic options.21 Development of novel treatment approaches for HER2+ breast cancer is clinically significant, particularly in the context of strategies to overcome resistance to HER2-targeted therapy.