Volume 11 Supplement 1

VIII Madrid Breast Cancer Conference: Latest Advances in Breast Cancer

Open Access

Molecular mechanisms of resistance to HER2-targeted therapy

  • FJ Esteva1
Breast Cancer Research200911(Suppl 1):S22

https://doi.org/10.1186/bcr2283

Published: 23 June 2009

The human epidermal growth factor receptor 2 (HER2, also known as ErbB-2) is amplified in 20 to 25% of invasive breast cancers. HER2 overexpression has been associated with poor survival rates [1]. Trastuzumab (Herceptin) is a monoclonal antibody directed against domain IV of the extracellular domain of HER2. Lapatinib (Tykerb) is a small-molecule tyrosine kinase inhibitor targeted against the intracellular domain of HER2 (ATP binding site). Both agents produce objective response rates in 20 to 30% of patients with HER2-positive metastatic breast cancer. Efficacy is improved when these targeted therapies are combined with chemotherapy or endocrine therapy. However, the majority of patients that respond to trastuzumab or lapatinib develop progressive disease within 1 year of treatment initiation. Trastuzumab has been shown to improve survival rates in women with early-stage breast cancer. Approximately 15% of patients develop metastatic breast cancer despite adjuvant trastuzumab, chemotherapy and endocrine therapy [2]. Potential molecular mechanisms of HER2-targeted therapy include increased signaling via the phosphatidylinositol 3-kinase/protein kinase B (PI3K) pathway through overexpression or cross-talk between HER2 and the insulin-like growth factor-I receptor or PTEN loss. Decreased interaction between trastuzumab and HER2 may be caused by steric hindrance of the HER2 receptor by MUC-4, or by the presence of a truncated HER2 protein, which may block inhibitory actions of trastuzumab [3]. One of the mechanisms of action of trastuzumab is the induction of antibody-dependent cellular cytotoxicity, which may play an important role in the adjuvant setting. In patients with metastatic breast cancer, continuation of trastuzumab beyond progression resulted in prolongation of the time to progression [4]. The mechanism of action of trastuzumab in this setting is not known. Novel therapies targeted against these aberrant molecular pathways are being studied in laboratory and clinical settings, and offer hope that the efficacy and duration of response to trastuzumab can be greatly improved. These include pertuzumab, a monoclonal antibody that targets domain II of the HER2 extracellular domain and prevents heterodimer formation between HER2 and HER3 or EGFR; trastuzumab-DM1, a potent antibody–drug conjugate that is effective in the setting of resistance to multiple lines of HER2-directed therapy; Hsp90 inhibitors that degrade the HER-2 protein (for example, 17-AAG); irreversible small molecule tyrosine kinase inhibitors (for example, HKI-272); and IGF-IR inhibitors. Indirect approaches include immunotherapy and anti-angiogenic therapy. Understanding mechanisms of resistance in vivo will help us identify what is the optimal treatment for individual patients.

Authors’ Affiliations

(1)
The University of Texas MD Anderson Cancer Center

References

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Copyright

© BioMed Central Ltd. 2009

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