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Supplementary Figure S1. 　ER status in breast cancer tissues was associated with Ki-67 response after tamoxifen therapy. (A) Ki-67 response was lower in the tissues in which the proportion of ER-positive cells was less than 2/3 than in the tissues in which the proportion of ER-positive cells was 2/3 or more. (B) In Allred score, a semi quantitative system, that takes into consideration the proportion of positive cells (scored on a scale of 0-5) and staining intensity (scored on a scale of 0-3), tissues with score of 7 or less showed lower Ki-67 response than those with score of 8. Supplementary Figure S2. Correlation between Ki-67 response and tumor response after tamoxifen therapy. No significant tumor response was observed by short-term pre-operative tamoxifen therapy. No correlation was also observed between the tumor response and Ki-67 response (Pearson correlation coefficient; R = -0.12). Tumor response was measured in bi-directional maximum dimension using ultrasound. Supplementary Figure S3. Relationship between Ki-67 response and pathological response after tamoxifen therapy. The breast cancer tissues with no pathological response (Grade 0) showed significantly lower Ki-67 response than those with Grade 1a or more pathological response. Supplementary Figure S4. Association between CYP2D6 genotypes and Ki-67 labeling index in pre-treatment tissue. CYP2D6 genotype was not associated with Ki-67 labeling index in pre-treatment tissue.

Supplementary Table S1 Association between all CYP2D6 genotype and ER status in pre-treatment tissue.

Purpose: 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 CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.Experimental Design: 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 CYP2D6 on Ki-67 response, pathological response, and hot flushes.Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor–positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019–26. ©2016 AACR.