Search

Purpose: CYP2D6 is key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen”. We previously reported that reduced- or null-function alleles of CYP2D6 were significantly associated with poor clinical outcome of breast cancer patients treated with tamoxifen. However, there are still discrepant reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we carried out prospective multicenter studies to evaluate the value of CYP2D6 genotyping in tamoxifen therapy. Patients and Methods: We studied 279 patients with hormone receptor-positive and Her-2 negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 - 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker of response to tamoxifen. We investigated the effects of allelic variants of CYP2D6 on Ki-67 change in breast cancer tissues, histological response, breast conservative operation and hot flash. Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy for 14-28 days (P = 0.00000000024). Moreover, proportion of estrogen receptor positive cells in breast cancer tissues were significantly associated with Ki-67 change after tamoxifen therapy (P = 0.0099). CYP2D6 variants were not significantly associated with histological response, breast conservative operation and hot flash (P = 0.25, P = 0.28 and P = 0.34, respectively). However, CYP2D6 variants were significantly associated with Ki-67 decrease after the preoperative tamoxifen therapy (P = 0.000014; in patients with two variant alleles v patients carrying one or two wild-type alleles). Conclusion: Our result suggest that genetic variation in CYP2D6 is a key predictor for the prognosis of patients with breast cancer treated with tamoxifen. Citation Format: Hitoshi Zembutsu, Seigo Nakamura, Sadako Akashi-Tanaka, Takashi Kuwayama, Chie Watanabe, Tomoko Takamaru, Hiroyuki Takei, Kana Miyahara, Hiroshi Matsumoto, Yoshie Hasegawa, Goro Kutomi, Hiroaki Shima, Fukino Satomi, Hideki Maeda, Minoru Okazaki, Hisamitsu Zaha, Mai Onomura, Ayami Matsukata, Yasuaki Sagara, Shinichi Baba, Akimitsu Yamada, Kazuhiro Shimada, Daisuke Shimizu, Koichiro Tsugawa, Arata Shimo, Tan Ern Yu, Mikael Hartman, Chan Ching Wang, Soo Chin Lee, Yusuke Nakamura. Association between CYP2D6 genotype and response to tamoxifen in a prospective multicenter study in Japan. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2031.