P1-09-06: Single Nucleotide Polymorphisms in the BRMS1 and SIPA1 Metastasis Suppressor Genes as Prognostic Markers in Breast Cancer Patients.

Introduction: Single nucleotide polymorphisms (SNPs) in the metastasis suppressors BRMS1 and SIPA1 may affect metastatic efficiency. BRMS1 affects apoptosis, colonization, cell adhesion, and invasive potential. Loss of BRMS1 expression has been correlated with younger age at diagnosis and reduced survival time in patients with progesterone-receptor (PR) negative, HER2−positive tumors. SIPA1 affects extracellular matrix gene expression and cell adhesion, and while SNPs have been associated with node positive, estrogen-receptor (ER)/PR negative tumors, evidence for a relationship with survival has been conflicting. Identifying SNPs that affect risk of recurrence and survival may improve the ascertainment of patients who require aggressive adjuvant therapy following a diagnosis of breast cancer. We evaluated associations between seven BRMS1 and SIPA1 SNPs and recurrence and survival in patients with primary breast cancer. Methods: We identified 1,015 incident breast cancer patients who received surgery at Roswell Park Cancer Institute (RPCI) and participated in the DataBank and BioRepository (DBBR) resource. Participants completed an epidemiologic questionnaire and provided a blood sample prior to surgery or other treatment. Clinical and pathologic data were linked to de-identified participant data in the DBBR database. SNPs in BRMS1 (rs11537993, rs3116068, and rs1052566) and SIPA1 (rs75894763, rs746429, rs3741378, and rs2306364) were genotyped by RPCI9s Genomics facility using Sequenom® iPLEX Gold and Taqman® real-time PCR assays. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals. Results: The median follow-up time was 33 months, and 49 deaths and 42 recurrences occurred. Tumors were more likely to be larger, node positive, ER/PR negative, and high grade among patients who experienced a recurrence or death. Recurrence was less likely in older patients and those with higher body mass index, although the latter association was nonsignificant (p=0.06). Patients with at least one variant allele of the BRMS1 rs3116068 genotype experienced shorter overall survival compared to patients with the homozygous common genotype (HR=2.05, 95% CI 1.15−3.63, rs3116068 AG+AA compared to GG). The remaining SNPs were not associated with overall survival, and none of the SNPs were associated with recurrence. Conclusions: In our data, the variant allele of rs3116068 was more common among women whose breast cancer was node negative and HER2−positive, compared to those with the common rs3116068 allele. The rs3116068 variant allele is also associated with poorer survival. While our findings do not support a role for common SNPs in the SIPA1 gene in breast cancer prognosis, BRMS1 rs3116068 may be a useful prognostic biomarker. Future goals are to examine additional SNPs in BRMS1 and other metastasis-related genes in a larger, racially diverse population. Funding: This research was supported by a gift from the Jayne and Phil Hubbell Family. The DBBR and Genomics Facility are RPCI Cancer Center Support Grant shared resources, supported by P30 CA016056-32. Ms. Roberts is a DOD Predoctoral Award recipient (BC10068) and Dr. Ambrosone is funded by the Breast Cancer Research Foundation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-09-06.