title: Significant Effect of Polymorphisms inCYP2D6on Response to Tamoxifen Therapy for Breast Cancer: A Prospective Multicenter Study.
abstract: 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 betweenCYP2D6genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect ofCYP2D6genotype 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 ofCYP2D6on 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). AlthoughCYP2D6variants 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 betweenCYP2D6variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation inCYP2D6is a key predictor for the response to tamoxifen in patients with breast cancer.Clin Cancer Res; 23(8); 2019-26. ©2016 AACR.
authors: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan. hzenbuts@ncc.go.jp.
authors: Hitoshi
authors: H
authors: Zembutsu
authors: Department of Breast Surgery, Showa University, Tokyo, Japan.
authors: Seigo
authors: S
authors: Nakamura
authors: Department of Breast Surgery, Showa University, Tokyo, Japan.
authors: Sadako
authors: S
authors: Akashi-Tanaka
authors: Department of Breast Surgery, Showa University, Tokyo, Japan.
authors: Takashi
authors: T
authors: Kuwayama
authors: Department of Breast Surgery, Showa University, Tokyo, Japan.
authors: Chie
authors: C
authors: Watanabe
authors: Department of Breast Surgery, Showa University, Tokyo, Japan.
authors: Tomoko
authors: T
authors: Takamaru
authors: Department of Breast Surgery, Nippon Medical School, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Takei
authors: Department of Breast Surgery, Tokyo Medical University, Tokyo, Japan.
authors: Takashi
authors: T
authors: Ishikawa
authors: Department of Breast Surgery, Tokyo Medical University, Tokyo, Japan.
authors: Kana
authors: K
authors: Miyahara
authors: Department of Breast Surgery, Saitama Cancer Center, Saitama, Japan.
authors: Hiroshi
authors: H
authors: Matsumoto
authors: Department of Breast Surgery, Hirosaki Municipal Hospital, Hirosaki, Japan.
authors: Yoshie
authors: Y
authors: Hasegawa
authors: 1st Department of Surgery, Sapporo Medical University, Sapporo, Japan.
authors: Goro
authors: G
authors: Kutomi
authors: 1st Department of Surgery, Sapporo Medical University, Sapporo, Japan.
authors: Hiroaki
authors: H
authors: Shima
authors: 1st Department of Surgery, Sapporo Medical University, Sapporo, Japan.
authors: Fukino
authors: F
authors: Satomi
authors: Department of Breast Surgery, Sapporo Breast Surgical Clinic, Sapporo, Japan.
authors: Minoru
authors: M
authors: Okazaki
authors: Department of Breast Surgery, Nakagami Hospital, Okinawa, Japan.
authors: Hisamitsu
authors: H
authors: Zaha
authors: Department of Breast Surgery, Nakagami Hospital, Okinawa, Japan.
authors: Mai
authors: M
authors: Onomura
authors: Department of Breast Surgery, Sagara Hospital, Kagoshima, Japan.
authors: Ayami
authors: A
authors: Matsukata
authors: Department of Breast Surgery, Sagara Hospital, Kagoshima, Japan.
authors: Yasuaki
authors: Y
authors: Sagara
authors: Department of Breast Surgery, Sagara Hospital, Kagoshima, Japan.
authors: Shinichi
authors: S
authors: Baba
authors: Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Japan.
authors: Akimitsu
authors: A
authors: Yamada
authors: Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, Yokohama, Japan.
authors: Kazuhiro
authors: K
authors: Shimada
authors: Department of Breast Surgery, Yokohama Minato Red Cross Hospital, Yokohama, Japan.
authors: Daisuke
authors: D
authors: Shimizu
authors: Department of Breast and Endocrine Surgery, St. Marianna University School of Medicine Hospital, Kawasaki, Japan.
authors: Koichiro
authors: K
authors: Tsugawa
authors: Department of Breast and Endocrine Surgery, St. Marianna University School of Medicine Hospital, Kawasaki, Japan.
authors: Arata
authors: A
authors: Shimo
authors: Department of General Surgery, Tan Tock Seng Hospital, Singapore.
authors: Ern Yu
authors: EY
authors: Tan
authors: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore.
authors: Mikael
authors: M
authors: Hartman
authors: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore.
authors: Ching-Wan
authors: CW
authors: Chan
authors: Department of Hematology Oncology, National University Cancer Institute, National University Health System, Singapore.
authors: Soo Chin
authors: SC
authors: Lee
authors: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
authors: Yusuke
authors: Y
authors: Nakamura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D019394:Ki-67 Antigen; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6