VEGF polymorphism may be associated with overall survival in lapatinib-treated breast cancer patients with brain metastases.

Abstract

10532 Background: Lapatinib is a dual HER2/EGFR tyrosine kinase inhibitor (TKI) approved in combination with capecitabine or letrozole for patients with HER2+ metastatic breast cancer (MBC). Consistent with TKI therapies, patient response is variable and suggestive of additional determinants of sensitivity and resistance. This exploratory pharmacogenetic study sought to identify germline genetic variants that associate with lapatinib treatment outcomes in HER2+ MBC patients. Methods: Fifty five functional single nucleotide polymorphisms (SNPs) in 24 candidate genes were evaluated in a subset of MBC patients participating in two clinical trials: EGF105084: lapatinib monotherapy in HER2+ MBC patients with recurrent brain metastases following trastuzumab and cranial radiotherapy (n=120) and EGF104900: lapatinib plus trastuzumab (n=92) and lapatinib monotherapy (n=103) in HER2+ MBC patients with disease progression following trastuzumab. Testing for associations of SNPs with progression free survival (PFS) and overall survival (OS) during lapatinib treatment was performed using Cox proportional hazards methods, with covariate adjustment. Markers were considered to be significantly associated if they achieved a predefined multiple testing threshold of p<0.0003. Results: No SNPs were significantly associated with PFS in either study. A SNP in VEGFA (rs3025039, 936C>T) was significantly associated with improved OS (p=0.0002) for the T allele carriers, with an allelic hazard ratio of 0.21 (0.08-0.52) in EGF105084. The association was not seen in EGF104900. This SNP is located in the 3’ UTR gene region, the T allele is associated with lower serum VEGFA levels and reduced breast cancer risk [Krippl et al, 2003, Int J Cancer 106: 468; Kataoka et al, 2006, Cancer Epidemiol Biomarkers Prev, 15:1148]. Conclusions: A germline variant in VEGFA may be associated with survival outcome in MBC patients with brain metastases who are treated with lapatinib. This may represent activation of VEGF angiogenic pathways to overcome HER2 inhibition in patients carrying the higher expression genotype. These associations are considered exploratory and require confirmation in an independent dataset.