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Breast Cancer Research
Published in: Breast Cancer Research 1/2016

Open Access 01-12-2016 | Research article

Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial

Authors: Harriet Johansson, Kathryn P. Gray, Olivia Pagani, Meredith M. Regan, Giuseppe Viale, Valentina Aristarco, Debora Macis, Antonella Puccio, Susanne Roux, Rudolf Maibach, Marco Colleoni, Manuela Rabaglio, Karen N. Price, Alan S. Coates, Richard D. Gelber, Aron Goldhirsch, Roswitha Kammler, Bernardo Bonanni, Barbara A. Walley, the TEXT principal investigators

Published in: Breast Cancer Research | Issue 1/2016

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Abstract

Background

Single nucleotide polymorphisms (SNPs) in the estrogen receptor 1 (ESR1) and cytochrome P450 19A1 (CYP19A1) genes have been associated with breast cancer risk, endocrine therapy response and side effects, mainly in postmenopausal women with early breast cancer. This analysis aimed to assess the association of selected germline CYP19A1 and ESR1 SNPs with early-onset hot flashes, sweating and musculoskeletal symptoms in premenopausal patients enrolled in the Tamoxifen and Exemestane Trial (TEXT).

Methods

Blood was collected from consenting premenopausal women with hormone-responsive early breast cancer, randomly assigned to 5-years of tamoxifen plus ovarian suppression (OFS) or exemestane plus OFS. DNA was extracted with QIAamp kits and genotyped for two CYP19A1 (rs4646 and rs10046) and three ESR1 (rs2077647, rs2234693 and rs9340799) SNPs by a real-time pyrosequencing technique. Adverse events (AEs) were recorded at baseline and 3-monthly during the first year. Associations of the genotype variants with grade ≥2 early-onset targeted AEs of hot flashes/sweating or musculoskeletal events were assessed using logistic regression models.

Results

There were 2660 premenopausal patients with breast cancer in the intention-to-treat population of TEXT, and 1967 (74 %) are included in this translational study. The CYP19A1 rs10046 variant T/T, represented in 23 % of women, was associated with a reduced incidence of grade ≥2 hot flashes/sweating (univariate odds ratio (OR) = 0.78; 95 % CI 0.63–0.97; P = 0.03), more strongly in patients assigned exemestane + OFS (TT vs CT/CC: OR = 0.65, 95 % CI = 0.48–0.89) than assigned tamoxifen + OFS (OR = 0.94, 95 % CI = 0.69–1.27, interaction P = 0.03). No association with any of the CYP19A1/ESR1 genotypes and musculoskeletal AEs was found.

Conclusion

The CYP19A1 rs10046 variant T/T favors lower incidence of hot flashes/sweating under exemestane + OFS treatment, suggesting endocrine-mediated effects. Based on findings from others, this SNP may potentially enhance treatment adherence and treatment efficacy. We plan to evaluate the clinical impact of this polymorphism during time, pending sufficient median follow up.

Trial registration

ClinicalTrials.gov NCT00066703, registered August 6, 2003.
Literature
1.
Burstein HJ, Lacchetti C, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression. J Clin Oncol. 2016;34:1689–701.CrossRefPubMed
2.
Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol. 2014;32:2255–69.CrossRefPubMedPubMedCentral
3.
Dowsett M, Forbes JF, Bradley R, Ingle J, Aihara T, Bliss J, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386:1341–52.CrossRefPubMed
4.
Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Lang I, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371:107–18.CrossRefPubMedPubMedCentral
5.
Schover LR. Premature ovarian failure and its consequences: vasomotor symptoms, sexuality, and fertility. J Clin Oncol. 2008;26:753–8.CrossRefPubMed
6.
Gallicchio L, Miller SR, Kiefer J, Greene T, Zacur HA, Flaws JA. Risk factors for hot flashes among women undergoing the menopausal transition: baseline results from the Midlife Women's Health Study. Menopause. 2015;22:1098–107.CrossRefPubMedPubMedCentral
7.
Dennerstein L, Lehert P, Burger HG, Guthrie JR. New findings from non-linear longitudinal modelling of menopausal hormone changes. Hum Reprod Update. 2007;13:551–7.CrossRefPubMed
8.
Dugan SA, Powell LH, Kravitz HM, Everson Rose SA, Karavolos K, Luborsky J. Musculoskeletal pain and menopausal status. Clin J Pain. 2006;22:325–31.CrossRefPubMed
9.
Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med. 2005;23:117–25.CrossRefPubMed
10.
Freeman EW, Sammel MD, Sanders RJ. Risk of long-term hot flashes after natural menopause: evidence from the Penn Ovarian Aging Study cohort. Menopause. 2014;21:924–32.CrossRefPubMedPubMedCentral
11.
Stearns V, Ullmer L, Lopez JF, Smith Y, Isaacs C, Hayes D. Hot flushes. Lancet. 2002;360:1851–61.CrossRefPubMed
12.
13.
Villa P, Lassandro AP, Amar ID, Vacca L, Moruzzi MC, Ferrandina G, et al. Impact of aromatase inhibitor treatment on vertebral morphology and bone mineral density in postmenopausal women with breast cancer. Menopause. 2016;23:33–9.CrossRefPubMed
14.
Schimdt N, Jacob L, Coleman R, Kostev K, Hadji P. The impact of treatment compliance on fracture risk in women with breast cancer treated with aromatase inhibitors in the United Kingdom. Breast Cancer Res Treat. 2016;155:151–7.CrossRefPubMed
15.
Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E, et al. Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst. 2004;96:936–45.CrossRefPubMed
16.
Wang L, Ellsworth KA, Moon I, Pelleymounter LL, Eckloff BW, Martin YN, et al. Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors. Cancer Res. 2010;70:319–28.CrossRefPubMedPubMedCentral
17.
Haiman CA, Dossus L, Setiawan VW, Stram DO, Dunning AM, Thomas G, et al. Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women. Cancer Res. 2007;67:1893–7.CrossRefPubMed
18.
Artigalas O, Vanni T, Hutz MH, Shton-Prolla P, Schwartz IV. Influence of CYP19A1 polymorphisms on the treatment of breast cancer with aromatase inhibitors: a systematic review and meta-analysis. BMC Med. 2015;13:139.CrossRefPubMedPubMedCentral
19.
Ding SL, Yu JC, Chen ST, Hsu GC, Hsu HM, Ho JY, et al. Diverse associations between ESR1 polymorphism and breast cancer development and progression. Clin Cancer Res. 2010;16:3473–84.CrossRefPubMed
20.
Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB, et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet. 2009;41:324–8.CrossRefPubMedPubMedCentral
21.
Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, et al. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation. 2002;105:1879–82.CrossRefPubMed
22.
Onland-Moret NC, van Gils CH, Roest M, Grobbee DE, Peeters PH. The estrogen receptor alpha gene and breast cancer risk (The Netherlands). Cancer Causes Control. 2005;16:1195–202.CrossRefPubMed
23.
Li LW, Xu L. Menopausal status modifies breast cancer risk associated with ESR1 PvuII and XbaI polymorphisms in Asian women: a HuGE review and meta-analysis. Asian Pac J Cancer Prev. 2012;13:5105–11.CrossRefPubMed
24.
Zhang Y, Zhang M, Yuan X, Zhang Z, Zhang P, Chao H, et al. Association between ESR1 PvuII, XbaI, and P325P polymorphisms and breast cancer susceptibility: a meta-analysis. Med Sci Monit. 2015;21:2986–96.CrossRefPubMedPubMedCentral
25.
Ioannidis JP, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB, et al. Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA. 2004;292:2105–14.CrossRefPubMed
26.
de Mattos CS, Trevisan CM, Peluso C, Adami F, Cordts EB, Christofolini DM, et al. ESR1 and ESR2 gene polymorphisms are associated with human reproduction outcomes in Brazilian women. J Ovarian Res. 2014;7:114.CrossRefPubMedPubMedCentral
27.
L'Esperance S, Frenette S, Dionne A, Dionne JY. Pharmacological and non-hormonal treatment of hot flashes in breast cancer survivors: CEPO review and recommendations. Support Care Cancer. 2013;21:1461–74.CrossRefPubMed
28.
Hope ACBA. Simplified Monte Carlo significance test procedure. J Roy Stat Soc B. 1968;30:582–98.
29.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting recommendations for tumor marker prognostic studies. J Clin Oncol. 2005;23:9067–72.CrossRefPubMed
30.
Fontein DB, Houtsma D, Nortier JW, Baak-Pablo RF, Kranenbarg EM, van der Straaten TR, et al. Germline variants in the CYP19A1 gene are related to specific adverse events in aromatase inhibitor users: a substudy of Dutch patients in the TEAM trial. Breast Cancer Res Treat. 2014;144:599–606.CrossRefPubMed
31.
32.
Henry NL, Skaar TC, Dantzer J, Li L, Kidwell K, Gersch C, et al. Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer. Breast Cancer Res Treat. 2013;138:807–16.CrossRefPubMedPubMedCentral
33.
Lunardi G, Piccioli P, Bruzzi P, Notaro R, Lastraioli S, Serra M, et al. Plasma estrone sulfate concentrations and genetic variation at the CYP19A1 locus in postmenopausal women with early breast cancer treated with letrozole. Breast Cancer Res Treat. 2013;137:167–74.CrossRefPubMed
34.
Mao JJ, Su HI, Feng R, Donelson ML, Aplenc R, Rebbeck TR, et al. Association of functional polymorphisms in CYP19A1 with aromatase inhibitor associated arthralgia in breast cancer survivors. Breast Cancer Res. 2011;13:R8.CrossRefPubMedPubMedCentral
35.
Wang J, Lu K, Song Y, Xie L, Zhao S, Wang Y, et al. Indications of clinical and genetic predictors for aromatase inhibitors related musculoskeletal adverse events in Chinese Han women with breast cancer. PLoS ONE. 2013;8:e68798.CrossRefPubMedPubMedCentral
36.
van Duijnhoven FJ, Peeters PH, Warren RM, Bingham SA, Uitterlinden AG, Van Noord PA, et al. Influence of estrogen receptor alpha and progesterone receptor polymorphisms on the effects of hormone therapy on mammographic density. Cancer Epidemiol Biomarkers Prev. 2006;15:462–7.CrossRefPubMed
37.
Henry NL, Azzouz F, Desta Z, Li L, Nguyen AT, Lemler S, et al. Predictors of aromatase inhibitor discontinuation as a result of treatment-emergent symptoms in early-stage breast cancer. J Clin Oncol. 2012;30:936–42.CrossRefPubMedPubMedCentral
38.
Fontein DB, Seynaeve C, Hadji P, Hille ET, van de Water W, Putter H, et al. Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis. J Clin Oncol. 2013;31:2257–64.CrossRefPubMed
39.
Mortimer JE, Flatt SW, Parker BA, Gold EB, Wasserman L, Natarajan L, et al. Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat. 2008;108:421–6.CrossRefPubMed
40.
Cuzick J, Sestak I, Cella D, Fallowfield L. Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: a retrospective analysis of the ATAC trial. Lancet Oncol. 2008;9:1143–8.CrossRefPubMed
41.
Huober J, Cole BF, Rabaglio M, Giobbie-Hurder A, Wu J, Ejlertsen B, et al. Symptoms of endocrine treatment and outcome in the BIG 1–98 study. Breast Cancer Res Treat. 2014;143:159–69.CrossRefPubMed
42.
Stearns V, Chapman JA, Ma CX, Ellis MJ, Ingle JN, Pritchard KI, et al. Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial. J Clin Oncol. 2015;33:265–71.CrossRefPubMed
Metadata
Title
Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial
Authors
Harriet Johansson
Kathryn P. Gray
Olivia Pagani
Meredith M. Regan
Giuseppe Viale
Valentina Aristarco
Debora Macis
Antonella Puccio
Susanne Roux
Rudolf Maibach
Marco Colleoni
Manuela Rabaglio
Karen N. Price
Alan S. Coates
Richard D. Gelber
Aron Goldhirsch
Roswitha Kammler
Bernardo Bonanni
Barbara A. Walley
the TEXT principal investigators
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2016
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-016-0771-8

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