Significant Effect of Polymorphisms in on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study.

CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, "endoxifen." There are still controversial reports questioning the association between genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of genotype on tamoxifen therapy. We enrolled 279 patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of on Ki-67 response, pathological response, and hot flushes. Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy ( = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response ( = 0.0076 and 0.0023, respectively). Although variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy ( = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele). This is the first prospective study evaluating the relationship between variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in is a key predictor for the response to tamoxifen in patients with breast cancer. .