PGx6710: Exploratory evaluation of a 2.9KB deletion in BIM gene with efficacy in lapatinib treated Asian subjects from EGF104535

Trial description: GlaxoSmithKline (GSK) is developing lapatinib (GW572016), a small molecule ErbB1/ErbB2 tyrosine kinase inhibitor (TKI), for the treatment of a variety of cancers, including breast cancer. Lapatinib was approved by the Food and Drug Administration (FDA) in the US on March 13, 2007 in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer (MBC) whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. In January 2010, lapatinib was approved in combination with letrozole for treatment of postmenopausal women with hormone positive metastatic breast cancer that overexpress HER2 receptor for whom hormonal therapy is indicated. BIM encodes a BH3-only protein and is a BCL2 family member. Up-regulation of BIM is required for TKIs to induce apoptosis. The common germline deletion in BIM reported in the Ng, KP et al., 2012 Nature Medicine paper is a 2,903 base pair deletion in intron two of the gene. They report that the deletion results in preferential splicing of exon 3 over exon 4 by at least five-fold. The pro-apoptotic BH3 domain is encoded exclusively by exon 4 of BIM and is required for apoptotic function, suggesting a novel mechanism of TKI resistance. In their report, they screened 2597 health individuals and found the deletion to be carried in 12.3% of individuals from East Asia, but no individuals from African or European populations. These findings are corroborated by public data available for The 1000 Genomes Project , 2010 where this common deletion is carried in 12.6% of Asians and is not observed in any other ethnic groups.This experiment is being conducted to determine if the previously identified germline BIM deletion is associated with response to lapatinib, in combination with paclitaxel, in EGF104535 self-reported Asian patients receiving treatment for metastatic breast cancer.