Evaluation of pro-apoptotic BIM gene loss of function on lapatinib efficacy in patients with metastatic breast cancer (MBC) and in HER2-amplified cell lines.

Abstract

e11590 Background: BIM is a pro-apoptotic Bcl-2 protein. Cellular BIM levels are upregulated by tyrosine kinase inhibitors (TKI) and BIM expression is correlated with TKI-induced cancer cell apoptosis. Limited studies suggest lapatinib response is correlated with BIM expression in HER2-amplified cell lines and in tumor samples from a small cohort of MBC patients. A common germline deletion polymorphism in BIM confers loss of function and has been reported to mediate resistance to TKI therapy in patients with NSCLC or CML. Methods: Using blood sample germline DNA collected from patients with HER2 positive MBC during the clinical study EGF104535 (NCT00281658), we investigated the effect of the BIM deletion polymorphism on response to lapatinib, when administered in combination with paclitaxel. In addition, the effect of BIM siRNA knockdown on lapatinib anti-proliferative activity was evaluated in three HER2-amplified breast cancer cell lines (BT474, SrBr3, and HCC1954). Results: DNA was collected from 279 of the 444 randomized patients. Consistent with published data, BIM deletion was only observed among the 238 Asian patients. The deletion polymorphism was identified in 13 patients (11 heterozygous, 2 homozygous) randomized to lapatinib plus paclitaxel (n=120) and in 20 patients (19 heterozygous, 1 homozygous) receiving paclitaxel alone (n=118), providing 80% power to identify moderate genetic effects (hazard ratio>2, one-sided test; p<0.05). There was a clear PFS response distinction between treatments (lapatinib plus paclitaxel being favorable), however, there was no PFS distinction between BIM deletion carriers versus non-carriers in either treatment arm. No differences were observed in lapatinib IC50 values when cell lines were exposed to BIM-specific or scrambled siRNA. Conclusions: In these limited studies, reductions in BIM function, conferred by the BIM deletion polymorphism in HER2 positive, lapatinib plus paclitaxel-treated MBC patients, or by BIM-specific siRNA treatment of HER2-amplified cell lines did not influence lapatinib efficacy. Further evaluation of the genetics and expression of BIM and other Bcl-2 proteins is warranted. Clinical trial information: NCT00281658.