Abstract
Approximately half of breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) also express hormone receptors (HRs). Although HR positivity predicts efficacy of endocrine agents, preclinical and clinical data suggest that HER2 overexpression confers intrinsic resistance to hormonal treatment. In addition, HER2 overexpression is an independent adverse prognostic factor regardless of the hormonal status of the tumor, indicating that patients with HR+/HER2+ breast tumors might not derive a benefit from single-agent hormonal therapy. These data provided a strong rationale for exploring the targeting of both HR and HER2 signaling pathways in HR+/HER2+ breast tumors to optimize hormonal therapy and overcome resistance to anti-estrogen therapy. Results from a randomized clinical trial that combined hormonal treatment with targeted anti-HER2 therapy in postmenopausal women with HR+/HER2+ advanced breast cancer indicate that this novel dual-targeting strategy significantly improves outcomes compared with endocrine treatment alone. Nonetheless, other data suggest that it might achieve an inferior outcome compared with anti-HER2 therapy plus chemotherapy. Therefore, targeting both the HR and HER2 signaling pathways upfront might not be the most-effective therapeutic strategy in the management of HR+/HER2+ breast cancer. We discuss the clinical implication of resistance to endocrine therapy, and describe new insights into the management of HR+/HER2+ advanced breast cancer.
Key Points
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Aromatase inhibitors are the most effective endocrine agents for the treatment of postmenopausal patients with breast tumors expressing hormonal receptors (HR+); however, not all HR-expressing tumors respond to endocrine therapies and those who respond eventually become resistant
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Several mechanisms for resistance to hormonal therapy have been proposed, including downregulation of HR expression, HR mutations, altered expression of coregulators, and ligand-independent activation of estrogen receptor and coactivators by overexpression and/or amplification of HER2
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HR+/HER2+ breast tumors are too aggressive to benefit from single-agent hormonal therapy; however, preclinical and recent clinical data indicate that such resistance might be overcome by inhibiting the HER2 pathway
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Anti-ER/HER2 concurrent treatment provides significantly better outcomes in HR+/HER2+ advanced breast cancer than hormone therapy alone, but clinical data indicate that it might achieve an inferior outcome compared with anti-HER2 therapy plus chemotherapy
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Combination chemotherapy with anti-HER2 therapy should be the first-line treatment option considered in patients with good performance status, visceral disease or rapidly progressing HR+/HER2+ breast tumors
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Whatever approach is chosen for the treatment of HER2+ breast cancer, it should be given upfront with anti-HER2 therapy
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Prat, A., Baselga, J. The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2. Nat Rev Clin Oncol 5, 531–542 (2008). https://doi.org/10.1038/ncponc1179
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DOI: https://doi.org/10.1038/ncponc1179
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