SLCO1B1*5 polymorphism (rs4149056) is associated with chemotherapy-induced amenorrhea in premenopausal women with breast cancer: a prospective cohort study.

Toralf Reimer,Hans-Jürgen Thiesen,Steffi Hartmann,Bernd Gerber,Dirk Koczan,Sarah Kempert

doi:10.1186/s12885-016-2373-3

Toralf Reimer, Hans-Jürgen Thiesen + Show 4 more

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https://doi.org/10.1186/s12885-016-2373-3

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Journal: BMC Cancer	Publication Date: May 27, 2016
Citations: 44	License type: cc-by

Affiliation: Klinikum Südstadt Rostock, University of Rostock

Abstract

BackgroundBecause inheritance is recognized as playing a role in age at menarche and natural menopause, the development of chemotherapy-induced amenorrhea (CIA) might depend on inherited genetic factors; however, studies that explore such a correlation are few and have received scant attention. Given the importance of this topic we conducted a comprehensive genotype study in young women (≤45 years) with early-stage breast cancer.MethodsOur approach tested the effect of variant polymorphisms in drug metabolism enzymes (DMEs) using a predesigned pharmacogenomics panel (TaqMan® OpenArray®, Life Technologies GmbH, Darmstadt, Germany) in premenopausal women (n = 50). Patients received contemporary chemotherapy; in all cases a cyclophosphamide-based regimen with a dose of at least 500 mg/m2 for six cycles. CIA was considered to be present in women with no resumption of menstrual bleeding within 12 months after completion of chemotherapy or goserelin.ResultsTwenty-six patients (52 %) showed CIA during follow-up whereas 24 women (48 %) remained premenopausal. Of all the DMEs studied, only the SLCO1B1*5 (rs4149056) genotype was associated with the development of CIA (P = 0.017). Of the 26 patients who were homozygous for the T/T allele SLCO1B1*5, 18 (69.2 %) developed CIA compared with 8 (30.8 %) of the 22 patients who were heterozygous (C/T allele). The association of heterozygous SLCO1B1*5 allele (OR 0.038; 95%CI: 0.05–0.92) with a lower risk of developing CIA remained significant in a binary logistic regression analysis that include age, SLCO1B1*5 allele variants, and goserelin therapy.ConclusionsPatient age and SLCO1B1*5 allele variants predict the likelihood of young women with breast cancer developing CIA.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2373-3) contains supplementary material, which is available to authorized users.

Highlights

Because inheritance is recognized as playing a role in age at menarche and natural menopause, the development of chemotherapy-induced amenorrhea (CIA) might depend on inherited genetic factors; studies that explore such a correlation are few and have received scant attention
Our approach tested the effect of variant polymorphisms in drug metabolism enzymes (DMEs) using a predesigned pharmacogenomics panel in premenopausal women receiving contemporary chemotherapy
50 % (n = 25) of included patients were treated with the gonadotrophin-releasing hormone (GnRH) agonist goserelin, 3.6 mg subcutaneously every 4 weeks, in two different clinical situations: 1) concurrent treatment with chemotherapy in hormone-insensitive breast cancer according to the ZOladex Rescue of Ovarian function (ZORO) study protocol (n = 4) [24]; or 2) concurrent and/or sequential goserelin application for a maximum of 2 years in hormone receptor-positive disease (n = 21)

Summary

Introduction

Because inheritance is recognized as playing a role in age at menarche and natural menopause, the development of chemotherapy-induced amenorrhea (CIA) might depend on inherited genetic factors; studies that explore such a correlation are few and have received scant attention. Patients younger than 50 years of age, especially those with hormone-insensitive breast cancer, achieve significant benefit from adjuvant systemic chemotherapy in terms of prolonged disease-free and overall survival [2]. A considerable number of these young patients will suffer from chemotherapy-induced amenorrhea (CIA) thereafter, depending on age at diagnosis and type of chemotherapy used [3]. Premenopausal women in whom amenorrhea developed as a consequence of adjuvant breast cancer therapy had significantly better disease-free and overall survival than did women without amenorrhea, when the tumor was estrogen receptor (ER)-positive [4]. Apart from its impact on survival and the loss of fertility, CIA due to premature ovarian failure leads to subjective and objective menopausal symptoms, which can negatively affect short- and long-term quality of life [6, 7]

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