Clinical effects of A4889G and T6235C polymorphisms in cytochrome P-450 CYP1A1 for breast cancer patients treated with tamoxifen: implications for tumor aggressiveness and patient survival.

Purpose: Individual differences in cytochrome P-450 efficiency partly explain their variations in resistance to tamoxifen and estrogen metabolism. Two polymorphisms of the CYP1A1 gene-A4889G and T6235C-are known to affect activation of estrone and estradiol and to deregulate concentration of highly active tamoxifen metabolites. However, the clinicopathologic implications of these findings have not yet been evaluated.

Objective: The objective of this study is to evaluate whether T6235C and A4889G gene polymorphisms are related to pathological presentations and clinical outcomes of ER+/PR+ breast cancer (BC) in women using tamoxifen.

Methods: We included 405 women with ER+/PR+ tumors, who used tamoxifen as their primary therapy, and for whom 5-year follow-up data were available. We evaluated associations within clinicopathologic features, including overall 5-year survival, with CYP1A1 gene status.

Results: Univariate analysis showed that a slightly higher proportion of women with AG/GG genotypes were of European descent (P = 0.05) and that TC/CC genotype was significantly associated with premenopausal status (P = 0.01); however, no significant association remained after multivariate adjustment. Women with CYP1A1 genotypes other than AA and TT were more prone to develop low-grade tumors; 85.9 % of tumors in AA and TT genotype groups were grade III, but only 76.1 % of tumors in carriers of the polymorphisms were grade III (adjusted P = 0.02; OR 0.51 for grade III disease; 95 % CI 0.28-0.93). After 60 months of follow-up, ~75 % of the women were alive. There was no significant difference in survival related to the CYP1A1 gene status.

Conclusions: Breast cancer patients carrying CYP1A1 gene polymorphisms developed less aggressive tumors, but showed no evidence of better prognoses.