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Breast Cancer. 2019 Feb 7. doi: 10.1007/s12282-019-00952-9. [Epub ahead of print]

Pharmacogenomic-pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer.

Ishiguro H1,2, Ohno S3,4, Yamamoto Y5,4, Takao S6,4, Sato N7,4, Fujisawa T8,4, Kadoya T9,4, Kuroi K10,4, Bando H11,4, Teramura Y12,4, Iwata H13,4, Tanaka S14, Toi M15,4.

Author information

1
Department of Medical Oncology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi, 329-2763, Japan. hishiguro@iuhw.ac.jp.
2
Japan Breast Cancer Research Group (JBCRG), Tokyo, Japan. hishiguro@iuhw.ac.jp.
3
Center of Breast Oncology, The Cancer Institute Hospital of JFCR, Tokyo, Japan.
4
Japan Breast Cancer Research Group (JBCRG), Tokyo, Japan.
5
Department of Molecular-Targeting Therapy for Breast Cancer, Kumamoto University Hospital, Kumamoto, Japan.
6
Department of Breast Surgery, Hyogo Cancer Center, Akashi, Japan.
7
Department of Breast Surgery, Niigata Cancer Center Hospital, Niigata, Japan.
8
Department of Breast Oncology, Gunma Prefectural Cancer Center, Ohta, Japan.
9
Department of Surgical Oncology, Hiroshima University Hospital, Hiroshima, Japan.
10
Department of Breast Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
11
Breast and Endocrine Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
12
Department of Surgery, Hikone Municipal Hospital, Hikone, Japan.
13
Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
14
Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.
15
Department of Breast Surgery, Graduate School of Medicine Kyoto University, Kyoto, Japan.

Abstract

BACKGROUND:

An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers.

METHODS:

The pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for ≥ 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities.

RESULTS:

Fifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for ≥ 24 weeks.

CONCLUSION:

TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.

KEYWORDS:

Breast cancer; CYP2D6; Pharmacokinetics; Tamoxifen; Toremifene

PMID:
30734152
DOI:
10.1007/s12282-019-00952-9

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