Treatment of HER2-overexpressing metastatic breast cancer

Abstract

Metastatic breast cancer (MBC) overexpressing human epidermal growth factor receptor-2 (HER2) once had an overall worse prognosis, but therapies targeting HER2 have altered the natural course of HER2-positive disease. The initial success of trastuzumab in improving survival rates led to the clinical development of lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1). HER2 protein overexpression and/or gene amplification remains the most important predictive factor for response to HER2-targeted therapies. The optimal duration of chemotherapy (CT) is at least 4-6 months (or longer) and/or to the time of maximal response, depending on toxicity and the absence of progression. HER2-targeted therapy can continue until progression or unacceptable toxicity. For patients with estrogen receptor-positive/progesterone receptor-positive breast cancer who are not good candidates for CT or wish to avoid the toxicity of CT, initial therapy with hormone therapy in combination with HER2-targeted therapy is a reasonable option. However, because the addition of HER2 therapy to endocrine therapy does not improve overall survival (OS), patients with low-volume disease, a long disease-free interval, indolent disease, or significant comorbidities are also candidates for endocrine therapy alone. For patients who relapse and were previously treated with adjuvant anti-HER2 therapy, the resumption of systemic treatment that includes HER2 blockade is recommended. As in the first-line setting, multiple choices are available for second-and third-line therapy. Successful targeting of HER2 has improved outcomes in HER2-positive breast cancer, but treatment resistance and brain metastases remain a problem. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in HER2-positive tumors.