Despite advances in the early diagnosis and treatment of breast cancer, it still remains a significant public-health concern: There are more than one million new cases diagnosed annually, resulting in more than 450,000 deaths worldwide.1 Worldwide, the incidence of breast cancer is estimated at 23% based upon 2008 statistics.2 In the United States, over 40,000 women die from breast cancer annually.3

Approximately 25% to 30% of breast cancers are the result of the overexpression of the human epidermal growth factor receptor 2 (HER2) gene, a potent mediator of cell growth and proliferation, and the corresponding overexpression of the HER2 receptor.4 In a case-only incidence analysis of female breast-cancer patient cases, HER2 was found present in 35% of both locally advanced and metastatic tumors, and 40%–43% of inflammatory breast cancer.5 Women with HER2-receptor positive breast cancer have an aggressive form of the disease and are more likely to have shortened disease-free survival and overall survival. 4 

The dual targeting of HER2-receptor positive tumors by both trastuzumab (Herceptin, Genentech) and lapatinib (Tykerb, GlaxoSmithKline) is being explored because of primary and acquired resistance to both drugs, their slightly different mechanisms of action, and the established synergistic interactions between both drugs in HER2-positive breast-cancer models.6 Trastuzumab works by inhibiting the ligand-independent HER2 and HER3 signaling and by triggering antibody-dependent cellular cytotoxicity.7,8  Lapatinib, in contrast, works by blocking ligand-induced heterodimer signaling and preventing signaling by a frequently expressed truncated version of the HER2 receptor that could make cells resistant to trastuzumab. Also, lapatinib causes an accumulation of HER2 at the cell surface that can enhance immune-mediated trastuzumab-dependent cellular toxicity.8

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Trastuzumab primarily induces a pro-apoptotic effect, and lapatinib inhibits cell proliferation, thus allowing the tumor to be targeted from two fronts.9,10 Evidence supports the use of dual HER2-receptor blockade. Blackwell and colleagues reported that the use of trastuzumab plus lapatinib in women with trastuzumab-refractory metastatic breast cancer demonstrated significant improvement in progression free-survival when compared to lapatinib alone (HR=0.73; 95% CI, 0.57–0.93; P=0.008).11