Originally published as JCO Early Release 10.1200/JCO.2006.05.9923 on November 20 2006

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Polymorphisms in XRCC1, XRCC3, and CCND1 and Survival After Treatment for Metastatic Breast Cancer

Mary A. Bewick, Michael S.C. Conlon, Robert M. Lafrenie

From the Sudbury Regional Hospital, Regional Cancer Center; and the Northern Ontario School of Medicine, Sudbury, Ontario, Canada

Address reprint requests to Mary A. Bewick, Sudbury Regional Hospital, Regional Cancer Center, 41 Ramsey Lake Rd, Sudbury, Ontario, Canada, P3E 5J1; e-mail: mbewick{at}hrsrh.on.ca

PURPOSE: Single nucleotide polymorphisms (SNPs) in DNA repair and cell cycle control genes may alter protein function and therefore the efficacy of DNA damaging chemotherapy. We retrospectively evaluated the association of SNPs in DNA repair genes, XRCC1-01 (Arg399Gln) and XRCC3-01 (Thr241Met), and a cell cycle control gene, CCND1-02 (A870G), with progression-free survival (PFS) and breast cancer specific survival (BCSS) in patients with metastatic breast cancer (MBC).

PATIENTS AND METHODS: SNPs in 95 patients with MBC enrolled onto one of five prospective clinical trials of high-dose chemotherapy and autologous stem-cell transplantation were evaluated using genotyping assays.

RESULTS: For XRCC1-01, the hazard ratio (HR) for BCSS was 2.8 (95% CI, 1.60 to 5.00) and the HR for PFS was 2.0 (95%CI, 1.12 to 3.43). For XRCC3-01, the HR for BCSS was 2.0 (95%CI, 1.12 to 3.70) and the HR for PFS was 2.0 (95%CI, 1.09 to 3.59). For CCND1-02, the HR for BCSS was 1.8 (95%CI, 1.12 to 2.78) and the HR for PFS was 1.8 (95%CI, 1.15 to 2.85). Patients carrying one variant genotype (HR, 1.7; 95%CI, 1.07 to 2.82) or combinations of any two variant genotypes (HR, 4.7; 95% CI, 2.41 to 8.94) had significantly poorer BCSS compared with patients carrying zero variants. In multivariable analysis, XRCC1-01, presence of liver metastases, and bone metastases independently predicted BCSS. Combinations of any two variant genotypes were stronger independent predictors of BCSS and PFS than the presence of liver or bone metastases.

CONCLUSION: XRCC1-01, XRCC3-01, and CCND1-01 may be predictive of survival outcome in patients with MBC treated with DNA damaging chemotherapy.

published online ahead of print at www.jco.org on November 20, 2006.

Supported by the Northern Cancer Research Foundation, Sudbury, Ontario, Canada.

Presented in poster format at the American Association for Cancer Research special conference on New Developments in the Epidemiology of Cancer Prognosis: Traditional and Molecular Predictors of Treatment Response and Survival, Charleston, SC, January 11-15, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.