Clinical Experience with Lapatinib in Patients with ErbB2-Overexpressing Metastatic Breast Cancer

mic ATP-binding site of the receptor TK, lapatinib blocks receptor phosphorylation and prevents subsequent downstream signaling. This is in contrast to trastuzumab which acts primarily by stimulating antibody-dependent cellular cytotoxicity (ADCC) [8, 9]. The rationale for the development of a dual inhibitor is threefold: Firstly, the combined blockage of two receptors involved in tumor proliferation may result in a synergistic inhibition of tumor cell growth [10]. Secondly, the simultaneous inhibition of ErbB1 and ErbB2 is thought to be more effective at preventing the formation of heterodimers containing ErbB1 and ErbB2 [11]. Finally, this may result in a more complete inhibition of different signal transduction pathways of the partly redundant intracellular signaling network [12]. Lapatinib may overcome trastuzumab resistance linked to the overexpression of a truncated form of ErbB2 (p95) which can be detected in an estimated 9% of breast cancer cells [13]. This truncated version lacks the extracellular receptor domain so that trastuzumab is unable to bind to the cancer cells. The membrane-associated p95 fragment shows high kinase activity in vitro and is characterized by an increased transforming potency and a worse outcome [5, 13, 14]. Another mechanism conferring resistance to trastuzumab therapy is loss of the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10), which occurs in about 50% of all breast cancers and correlates with a high potential of invasion and poorer prognosis. Significant loss of PTEN expression is seen in some 20–25% of HER2-positive breast cancers [15–18]. Activating mutations in PIK3CA have also been found in approximately 25% of primary breast cancers, and these mutations occur almost exclusively in PTEN-positive samples [17, 18]. Since both the loss of PTEN and oncogenic mutations in PIK3CA lead to activation of PI3K/AKT signaling [19], one would expect that both genes can contribute to the prediction of response to trastuzumab. Trastuzumab partially works by activating The ErbB Family – a New Target for Breast Cancer Therapy