Weighing the Options for Human Epidermal Growth Factor Receptor 2–Directed Therapy in Metastatic Breast Cancer

Since the introduction of trastuzumab in the late 1990s, the treatment landscape for patients with metastatic human epidermal growth factor receptor 2 (HER2) –positive breast cancer has changed dramatically. In addition to trastuzumab, a series of novel HER2-directed therapies has gained regulatory approval, including lapatinib, pertuzumab, and ado-trastuzumab-emtansine (T-DM1). The result is that for many patients, the disease has been transformed from a rapidly lethal illness to one in which episodes of disease progression are punctuated by long periods of tumor control.1 Despite these advances, HER2-positive metastatic breast cancer is still not generally curable, and the vast majority of patients will eventually succumb to their disease. Furthermore, over time, up to half of patients will develop CNS metastases, and these can be a source of both substantial mor-bidity and mortality.1,2 The two articles that accompany this editorial3,4 directly ad-dress several related questions. First, is there a preferred anti-HER2 therapy for use in the first-line setting? Second, does the choice of anti-HER2 therapy affect the incidence of brain metastases? In addition, these studies raise important considerations regarding trial design moving forward. In the NCIC Clinical Trials Group MA.31 trial, Gelmon et al3 directly compared first-line trastuzumab versus lapatinib, each paired with a taxane, in patients with HER2-positive metastatic breast cancer. Among the 652 patients in the intent-to-treat population, although the objective response rates were similar, progression-free survival (PFS) was inferior in the lapatinib arm (median, 9.0 v 11.3 months; hazard ratio [HR], 1.37; P .001), and there was a trend for overall survival (OS) in favor of trastuzumab, which reached significance in the centrally confirmed HER2-positive subset (n 537; HR, 1.47; P .03). Patient-reported global quality of life, as assessed by the European Organisation for Research and Treatment of Cancer