Abstract 248: Association of vitamin D related polymorphisms with hereditary breast cancer in 431 patients wild type forBRCA1andBRCA2mutations

Background: A high proportion of Breast Cancer (BC) patients with a positive family history is not explained by mutations in BRCA1 and BRCA2 genes and the biology and BC outcome are different compared to patients with BRCA mutations. Low serum 25-hydroxyvitamin D (25(OH)D) has been found to be associated with an increased cancer incidence and poorer prognosis. Single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genes (also called GC (Globulin Complex)), may contribute to final vitamin D activity. The aim of this study is to assess the role of 25(OH)D and VDBP serum levels, VDR and GC SNPs on BC recurrence and survival in a cohort of patients with positive family history, wild type (WT) for BRCA1 and BRCA2. Methods: VDR (ApaI, FokI, TaqI, BsmI) and GC (rs2282679, rs4588, rs7041) SNPs were analyzed, by TaqMan SNP Genotyping Assays (Thermo Fisher Scientific), for 431 WT patients. Serum levels of 25(OH)D and VDBP were measured using an electro-chemiluminescence immunoassay (Abbott) and Human Vitamin D BP Quantikine ELISA kit (R&D) respectively. Results: A cohort of 431 BC patients was followed from 2001 to 2015 (median follow-up 9 years). Women with the GC rs228679 variant had significantly lower levels of circulating VDBP and 25(OH)D compared to carriers of the major allele, whereas the GC rs7041 variant was associated with a greater level of VDBP and 25(OH)D. Multivariate Cox models showed that BsmI is significantly associated with BC outcome: patients with the major allele of BsmI (C) have half the risk of recurrence (CC vs. TT HR=0.43; 95%CI: 0.27-0.68; and CC vs. CT HR=0.66; 95%CI: 0.45-0.99). Finally, low serum VDBP concentrations are significantly associated with a higher risk of BC recurrence (VDBP<187 vs >321: HR=1.79; 95%CI: 1.03-3.13) and 25(OH)D>30 ng/ml in late summer/autumn vs <20 ng/ml in winter/spring is associated with a significant decrease risk of mortality (HR=0.44; 95%CI: 0.22-0.89). Conclusions: 25(OH)D and VDBP serum levels were related with survival and breast cancer recurrence and influenced by genetic variants of GC SNPs. An allele VDR dose-related decrease of breast cancer recurrence was achieved with the increasing number of allele C of BsmI rs1544410(C>T). Our study provides evidence for the pivotal role of vitamin D metabolism in breast cancer outcome of high risk patients with a positive family history, wild type for BRCA1 or BRCA2 genes. Citation Format: Valentina Aristarco, Davide Serrano, Monica Barile, Davide Bondavalli, Mariarosaria Calvello, Debora Macis, Harriet Johansson, Aliana Guerrieri Gonzaga, Irene Feroce, Valeria Pensotti, Sara Gandini, Bernardo Bonanni. Association of vitamin D related polymorphisms with hereditary breast cancer in 431 patients wild type for BRCA1 and BRCA2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 248.