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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

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

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

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

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; 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.

Methods

Our 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.

Results

Twenty-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.

Conclusions

Patient age and SLCO1B1*5 allele variants predict the likelihood of young women with breast cancer developing CIA.
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Literature
1.
Cancer in Germany 2007/2008. 8th edition. Robert-Koch Institute (ed.) and the Association of Population-based Cancer Registries in Germany (ed.), Berlin, 2012.
2.
Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–717.CrossRef
3.
Walshe JM, Denduluri N, Swain SM. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol. 2006;24:5769–79.CrossRefPubMed
4.
Swain SM, Jeong JH, Geyer Jr CE, Costantino JP, Pajon ER, Fehrenbacher L, et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010;362:2053–65.CrossRefPubMedPubMedCentral
5.
Swain SM, Jeong JH, Wolmark N. Amenorrhea from breast cancer therapy – not a matter of dose. N Engl J Med. 2010;363:2268–70.CrossRefPubMed
6.
Schover LR. Premature ovarian failure and its consequences: vasomotor symptoms, sexuality, and fertility. J Clin Oncol. 2008;26:753–8.CrossRefPubMed
7.
Yoo C, Yun MR, Ahn JH, Jung KH, Kim HJ, Kim JE, et al. Chemotherapy-induced amenorrhea, menopause-specific quality of life, and endocrine profiles in premenopausal women with breast cancer who received adjuvant anthracycline-based chemotherapy: a prospective cohort study. Cancer Chemother Pharmacol. 2013;72:565–75.CrossRefPubMed
8.
Abusief ME, Missmer SA, Ginsburg ES, Weeks JC, Partridge AH. Relationship between reproductive history, anthropometrics, lifestyle factors, and the likelihood of persistent chemotherapy-related amenorrhea in women with premenopausal breast cancer. Fertil Steril. 2012;97:154–9.CrossRefPubMedPubMedCentral
9.
Anderson RA, Rosendahl M, Kelsey TW, Cameron DA. Pretreatment anti-Müllerian hormone predicts for loss of ovarian function after chemotherapy for early breast cancer. Eur J Cancer. 2013;49:3404–11.CrossRefPubMedPubMedCentral
10.
Bozza C, Puglisi F, Lambertini M, Osa EO, Manno M, Del Mastro L. Anti-Müllerian hormone: determination of ovarian reserve in early breast cancer patients. Endocr Relat Cancer. 2014;21:R51–65.CrossRefPubMed
11.
Perry JR, Day F, Elks CE, Sulem P, Thompson DJ, Ferreira T, et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014;514:92–7.CrossRefPubMedPubMedCentral
12.
De Bruin JP, Bovenhuis H, van Noord PAH, Pearson PL, van Arendonk JAM, te Velde ER, et al. The role of genetic factors in age at natural menopause. Hum Reprod. 2001;16:2014–8.CrossRefPubMed
13.
Stearns V, Schneider B, Henry L, Hayes DF, Flockhart DA. Breast cancer treatment and ovarian failure: risk factors and emerging genetic determinants. Nat Rev Cancer. 2006;6:886–93.CrossRefPubMed
14.
Colvin M, Padgett CA, Fenselau C. A biologically active metabolite of cyclophosphamide. Cancer Res. 1973;33:915–8.PubMed
15.
Ngamjanyaporn P, Thakkinstian A, Verasertniyom O, Chatchaipun P, Vanichapuntu M, Nantiruj K, et al. Pharmacogenetics of cyclophosphamide and CYP2C19 polymorphism in Thai systemic lupus erythematosus. Rheumatol Int. 2011;31:1215–8.CrossRefPubMed
16.
Singh G, Saxena N, Aggarwal A, Misra R. Cytochrome P450 polymorphism as a predictor of ovarian toxicity to pulse cyclophosphamide in systemic lupus erythematosus. J Rheumatol. 2007;34:731–3.PubMed
17.
Takada K, Arefayene M, Desta Z, Yarboro CH, Boumpas DT, Balow JE, et al. Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis. Arthritis Rheum. 2004;50:2202–10.CrossRefPubMed
18.
Su HI, Sammel MD, Velders L, Horn M, Stankiewicz C, Matro J, et al. Association of cyclophosphamide drug-metabolizing enzyme polymorphisms and chemotherapy-related ovarian failure in breast cancer survivors. Fertil Steril. 2010;94:645–54.CrossRefPubMed
19.
Wessels AM, Flockhart DA, Carpenter JS, Radovich M, Li L, Miller KD, et al. Cytochrome P450 polymorphisms and their relationship with premature ovarian failure in premenopausal women with breast cancer receiving doxorubicin and cyclophosphamide. Breast J. 2011;17:536–8.CrossRefPubMed
20.
Joyce H, McCann A, Clynes M, Larkin A. Influence of multidrug resistence and drug transport proteins on chemotherapy drug metabolism. Expert Opin Drug Metab Toxicol. 2015;11:795–809.CrossRefPubMed
21.
Liu T, Li Q. Organic anion-transporting polypeptides: a novel approach for cancer therapy. J Drug Target. 2014;22:14–22.CrossRefPubMed
22.
König J, Seithel A, Gradhand U, Fromm MF. Pharmacogenomics of human OATP transporters. Naunyn-Schmiedeberg’s Arch Pharmacol. 2006;372:432–43.CrossRef
23.
Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63:157–81.CrossRefPubMed
24.
Gerber B, von Minckwitz G, Stehle H, Reimer T, Felberbaum R, Maass N, et al. Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. J Clin Oncol. 2011;29:2334–41.CrossRefPubMed
25.
Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009;41:1149–60.CrossRefPubMed
26.
Evans WE, McLeod HL. Pharmacogenomics – drug disposition, drug targets, and side effects. N Engl J Med. 2003;348:538–49.CrossRefPubMed
27.
28.
SEARCH Collaborative Group, Link E, Parish S, Armitage J, Heath S, Matsuda F, Gut I, et al. SLCO1B1 variants and statin-induced myopathy – a genomewide study. N Engl J Med. 2008;359:789–99.CrossRef
29.
Abe T, Kakyo M, Tokui T, Nakagomi R, Nishio T, Nakai D, et al. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem. 1999;274:17159–63.CrossRefPubMed
30.
Treviño LR, Shimasaki N, Yang W, Panetta JC, Cheng C, Pei D, et al. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol. 2009;27:5972–8.CrossRefPubMedPubMedCentral
31.
van der Deure WM, Friesema EC, de Jong FJ, de Rijke YB, de Jong FH, Uitterlinden AG, et al. Organic anion transporter 1B1: an important factor in hepatic thyroid hormone and estrogen transport and metabolism. Endocrinology. 2008;149:4695–701.CrossRefPubMed
32.
Lee E, Schumacher F, Lewinger JP, Neuhausen SL, Anton-Culver H, Horn-Ross PL, et al. The association of polymorphisms in hormone metabolic pathway genes, menopausal hormone therapy, and breast cancer risk: a nested case–control study in the California teachers study cohort. Breast Cancer Res. 2011;13:R37.CrossRefPubMedPubMedCentral
33.
34.
Lee S, Kil WJ, Chun M, Kang SY, Kang SH, Oh YT. Chemotherapy-related amenorrhea in premenopausal women with breast cancer. Menopause. 2009;16:98–103.CrossRefPubMed
35.
Valentini A, Finch A, Lubinski J, Byrski T, Ghadirian P, Kim-Sing C, et al. Chemotherapy-induced amenorrhea in patients with breast cancer with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2013;31:3914–9.CrossRefPubMedPubMedCentral
36.
Wong M, O’Neill S, Walsh G, Smith IE. Goserelin with chemotherapy to preserve ovarian function in pre-menopausal women with early breast cancer: menstruation and pregnancy outcomes. Ann Oncol. 2013;24:133–8.CrossRefPubMed
37.
Munster P, Moore AP, Ismail-Khan R, Cox CE, Lacevic M, Gross-King M, et al. Randomized trial using gonadotropin-releasing hormone agonists triptorelin for the preservation of varian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol. 2012;30:533–8.CrossRefPubMedPubMedCentral
38.
Elgindy EA, El-Haieg DO, Khorshid OM, Ismail EI, Abdelgawad M, Sallam HN, et al. Gonadotrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial. Obstet Gynecol. 2013;121:78–86.CrossRefPubMed
39.
Turner NH, Partridge A, Sanna G, Di Leo A, Biganzoli L. Utility of gonadotropin-releasing hormone agonists for fertility preservation in young breast cancer patients: the benefit remains uncertain. Ann Oncol. 2013;24:2224–35.CrossRefPubMed
40.
Moore HCF, Unger JM, Philipps KA, Boyle F, Hitre E, Porter D, et al. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med. 2015;372:923–32.CrossRefPubMedPubMedCentral
41.
Najafi S, Djavid GE, Mehrdad N, Rajaii E, Alavi N, Olfatbakhsh A, et al. Taxane-based regimens as a risk factor for chemotherapy-induced amenorrhea. Menopause. 2011;18:208–12.PubMed
42.
Molina JR, Barton DL, Loprinzi CL. Chemotherapy-induced ovarian failure: manifestations and management. Drug Saf. 2005;28:401–16.CrossRefPubMed
Metadata
Title
SLCO1B1*5 polymorphism (rs4149056) is associated with chemotherapy-induced amenorrhea in premenopausal women with breast cancer: a prospective cohort study
Authors
Toralf Reimer
Sarah Kempert
Bernd Gerber
Hans-Jürgen Thiesen
Steffi Hartmann
Dirk Koczan
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2373-3

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