Dual Blockade of HER-2 Provides a Greater Magnitude of Benefit in Patients With Hormone-Negative Versus Hormone-Positive Breast Cancer

The dual small molecule tyrosine kinase inhibitor lapatinib blocks both human epidermal growth factor receptor (HER-1) and human epidermal growth factor receptor 2 (HER-2) tyrosine kinase activity by binding reversibly to the ATP-binding site of the receptor's intracellular domain. Lapatinib, in combination with capecitabine, has been approved in 2007 for the treatment of patients with advanced HER-2+ breast cancer upon progressive disease following standard chemotherapy. Approval was also extended to the treatment of postmenopausal women with advanced hormone receptor (HR)-positive and HER-2-positive breast cancer in 2010. More recently, clinical trials that have investigated the efficacy of dual HER-2 blockade in both the metastatic and neoadjuvant breast cancer settings. For example, in 2013 the European Medicines Agency approved the combination of lapatinib and trastuzumab in HER-2+/HR− patients. We review the efficacy results from dual HER-2 blockade studies and present new post hoc analysis efficacy data according to HR status. We show that dual blockade of HER-2 appears to provide a greater magnitude of benefit in the HR− versus the HR+ subgroup of patients. Finally, we examine the potential of molecularly subtyping HER-2+ tumors using the PAM50 test as a predictor of response to treatment with the combination of trastuzumab and lapatinib.