Abstract 2825: Germline genetic variants in ANGPT1 & 2 and FGF2 are associated with pathologic complete response to bevacizumab in breast cancer patients
Authors: Makhoul Issam , Griffin Robert , Erickson Stephen , Dhakal Ishwori , Raj Venay R. , Graves Dorothy A. , Lee Jeannette Y. , Orloff Mohammed S. , Siegel Eric R. , Kadlubar Susan A. 
Published: May 2015

Purpose: Vascular endothelial growth factor (VEGF) is a central mediator of angiogenesis in cancer and may be targeted by the monoclonal antibody bevacizumab (B). We have conducted a prospective phase II study using neoadjuvant B and chemotherapy (CT) in breast cancer patients and showed improved pathologic complete response (pCR) with the combination compared to the expected pCR with CT alone (41% vs. 25%, p=0.029 one sided). We evaluated baseline serum levels of ten angiogenesis-related proteins (ANG1, ANG2, bFGF, IL-1a, MMP-9, PDGF-BB, PECAM-1, Tie-2, VEGF and VEGFR2) and found that baseline Tie-2 and bFGF serum levels were associated with pCR. The goal of the current study is to explore the association of germline single-nucleotide polymorphisms (SNPs) to pCR obtained with bevacizumab therapy.

Methods: Our original patient population consisted of 27 whites (EA) and 12 African Americans (AA) who received docetaxel/cyclophosphamide/bevacizumab and doxorubicin. Only 22 EA and 11 AA had buffy coat samples available for genotyping with the Illumina® HumanOmni2.5-8v1-1 BeadChip. We tested 555 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes.

Results: Univariate analysis revealed that 73% AA patients achieved pCR compared to 27% EA (p=0.012) and that 54% of the patients with ductal carcinomas achieved pCR compared to 11% with lobular or poorly differentiated tumors (p=0.021). We therefore included race and cancer type as covariates in a logistic regression model testing for association between pCR and each of the 555 SNPs. There were five SNPs in ANGPT1, five in ANGPT2, and four in FGF2 that were associated with pCR (p&lt;0.05). Because of the modest sample size, none of these SNPs reached levels of significance after adjusting for multiple comparisons.

Conclusion: ANGPT1, ANGPT2 and FGF2 are promising targets for future research. SNP analysis results support our hypothesis that the interaction of the host's angiogenic profile and the type of cancer explains differences in clinical response to VEGF inhibition. Specifically, our work showed that variants of the ANGPT1, ANGPT2, and FGF2 genes or their respective proteins might render certain tumors more susceptible to targeting of VEGF..

Citation Format: Issam Makhoul, Robert Griffin, Stephen Erickson, Ishwori Dhakal, Venay R. Raj, Dorothy A. Graves, Jeannette Y. Lee, Mohammed S. Orloff, Eric R. Siegel, Susan A. Kadlubar. Germline genetic variants in ANGPT1 & 2 and FGF2 are associated with pathologic complete response to bevacizumab in breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2825. doi:10.1158/1538-7445.AM2014-2825