Germline single nucleotide polymorphisms (SNPs) in XRCC3, XRCC1, and XPD, and survival outcomes after adjuvant chemotherapy (CT) in early breast cancer (EBC) patients (pts).

Abstract

619 Background: Specific DNA repair pathways are responsible for the different types of DNA damage, including those caused by CT. XRCC1, XRCC3, and XPD are involved in base-excision repair, double-strand break repair, and nucleotide excision repair, respectively. Certain SNPs in these genes are common in the general population and may result in different abilities to repair CT-related DNA insults. Methods: Peripheral blood samples for DNA extraction were collected from women considered for adjuvant CT for EBC between January 1990 and February 2004. XRCC1Arg399Gln, XRCC3Thr241Met and XPDLys751Gln SNPs were studied by RT-PCR genotyping using TaqMan probes. Demographics, clinical and treatment characteristics, disease free survival (DFS) and overall survival (OS) times were collected. Associations between these SNPs and survival outcomes were analysed using Kaplan-Meier method and Cox regression model. Results: 150 women (73% postmenopausal) were included, with a median age of 62 years (range 35-91). The commonest clinico-pathological characteristics were: ductal carcinoma (84%), grade 3 (44%), luminal subtype 64% (triple-negative 16%, HER2 11%), pT2 (54%), pN+ 56% (pN1 50%). 64% of pts received adjuvant anthracyclines, 15% taxanes, and 63% hormonotherapy. Median follow-up was 62 months (range 11-228). 5-years DFS and OS rates were 70% (CI95% 63-78) and 84% (CI95% 78-90), respectively. Overall, no SNP was associated with DFS. XRCC3Met241Met was associated with longer OS (p = 0.02) in the univariate analysis. In the pts subgroup receiving anthracylines (which induce single- and double-strand DNA breaks) XRCC1Arg399Arg was associated with longer DFS (HR 0.4, CI95% 0.2-0.9) and XRCC3Met241Met with improved OS (HR 0.15, CI95% 0.02-0.99). Conclusions: Germline SNPs in XRCC3 and XRCC1 genes are associated with different outcomes in our series, likely attributable to the differential abilities to repair anthracycline-induced DNA damage. These promising findings have pharmacogenomics implications in matching particular adjuvant CT for specific EBC pts. Prospective studies to validate the impact of these SNPs are awaited. No significant financial relationships to disclose.