Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy

Background: Paclitaxel and gemcitabine (PG) combination chemotherapy is effective as a maintenance chemotherapeutic regimen in metastatic breast cancer (MBC) patients because it increases progression-free survival (PFS), which increases overall survival (OS). The primary purpose of our study was to investigate the association between genetic polymorphisms in the genes involved in PG pathways and clinical outcomes in MBC patients treated with PG chemotherapy. Methods: A total of 324 MBC patients were enrolled in this prospective multicenter trial of PG as the first-line chemotherapy. Eighty-five of the 324 patients from two institutes were available for analysis of single nucleotide polymorphisms (SNPs). Germline DNA was extracted from peripheral blood mononuclear cells. Thirty-eight SNPs in 15 candidate genes selected from pathways that may influence the metabolism and transport of, or sensitivity, to PG were analysed. Results: The median PFS and OS of all 324 patients were 8.7 months (95% confidence interval [CI]: 7.5-9.6 months) and 26.9 months (95% CI: 23.6-30.1 months), respectively. An SNP in SLC28A3 (rs7867504, C/T) was associated with OS (CC or CT versus TT: 37 versus 21 months, p = 0.027, hazard ratio [HR] 2.6, 95% CI: 1.1-6.3). SLC29A1 GA haplotype had a significantly shorter OS (p = 0.030, HR 3.391, 95% CI: 1.13-10.19). RRM1 (ribonucleotide reductase large subunit M1) SNP (rs9937), and haplotypes ATAA and ATGA were significantly associated with neurotoxicity. Conclusion: Genetic polymorphisms in SLC28A3, SLC29A1 and RRM1 can influence the clinical outcome of MBC patients treated with PG chemotherapy. Further studies on the functional mechanisms relating to these germline polymorphisms in these genes are warranted. (C) 2013 Elsevier Ltd. All rights reserved.