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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

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Abstract

Musculoskeletal adverse events (MSAEs) and vasomotor symptoms (VMSs) are known side-effects of aromatase inhibitors, and may be related to genetic variations of the aromatase gene (CYP19A1). We investigated the relationship between these specific AEs and single nucleotide polymorphisms (SNPs) in the CYP19A1 gene in postmenopausal, hormone receptor-positive early breast cancer (BC) patients treated with adjuvant exemestane for 5 years. Dutch patients who were randomized to receive 5 years of exemestane in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. A tagging-SNP approach was performed, covering 80 % of variations of the CYP19A1 gene with 30 SNPs. Logistic regression analyses were used to assess the risk of reporting VMSs or MSAEs in relation to genotypes within selected SNPs. Of 737 included patients, 281 patients reported at least one MSAE (n = 210) or VMS (n = 163). Homozygous AA genotype of rs934635 was associated with a significantly higher odds of MSAEs (multivariate odds ratio (OR) 4.66, p = 0.008) and VMSs (multivariate OR 2.78, p = 0.044). Regarding both rs1694189 and rs7176005, the homozygous variant genotypes (TT) were associated with a higher odds of VMSs, but not MSAEs (OR 1.758, p = 0.025 and OR 6.361, p = 0.021, respectively). Our exploratory analysis demonstrated that some CYP19A1 gene variations may be associated with MSAEs and/or VMSs. Specifically, patients with the homozygous variant rs934635 genotype reported more MSAEs and VMSs. Although further confirmatory studies are warranted, genomic profiling can help identify patients at an increased risk of reporting these specific AEs, potentiating further personalized BC treatment.

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References

  1. Rugo HS (2008) The breast cancer continuum in hormone-receptor-positive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors. Ann Oncol 19(1):16–27

    Article  PubMed  CAS  Google Scholar 

  2. James VH, Reed MJ, Purohit A (1992) Inhibition of oestrogen synthesis in postmenopausal women with breast cancer. J Steroid Biochem Mol Biol 43(1–3):149–153

    Article  PubMed  CAS  Google Scholar 

  3. Morales L, Pans S, Paridaens R, Westhovens R, Timmerman D, Verhaeghe J et al (2007) Debilitating musculoskeletal pain and stiffness with letrozole and exemestane: associated tenosynovial changes on magnetic resonance imaging. Breast Cancer Res Treat 104(1):87–91

    Article  PubMed  CAS  Google Scholar 

  4. Mortimer JE (2010) Managing the toxicities of the aromatase inhibitors. Curr Opin Obstet Gynecol 22(1):56–60

    Article  PubMed  Google Scholar 

  5. Morales L, Pans S, Verschueren K, Van CB, Paridaens R, Westhovens R et al (2008) Prospective study to assess short-term intra-articular and tenosynovial changes in the aromatase inhibitor-associated arthralgia syndrome. J Clin Oncol 26(19):3147–3152

    Article  PubMed  Google Scholar 

  6. Kanematsu M, Morimoto M, Honda J, Nagao T, Nakagawa M, Takahashi M et al (2011) The time since last menstrual period is important as a clinical predictor for non-steroidal aromatase inhibitor-related arthralgia. BMC Cancer 11:436

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Stearns V, Ullmer L, Lopez JF, Smith Y, Isaacs C, Hayes D (2002) Hot flushes. Lancet 360(9348):1851–1861

    Article  PubMed  CAS  Google Scholar 

  8. Cuzick J, Sestak I, Cella D, Fallowfield L (2008) Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: a retrospective analysis of the ATAC trial. Lancet Oncol 9(12):1143–1148

    Article  PubMed  CAS  Google Scholar 

  9. Fontein DB, Seynaeve C, Hadji P, Hille ET, van de Water W, Putter H et al (2013) 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 31(18):2257–2264

    Article  PubMed  CAS  Google Scholar 

  10. Haiman CA, Dossus L, Setiawan VW, Stram DO, Dunning AM, Thomas G et al (2007) Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women. Cancer Res 67(5):1893–1897

    Article  PubMed  CAS  Google Scholar 

  11. Talbott KE, Gammon MD, Kibriya MG, Chen Y, Teitelbaum SL, Long CM et al (2008) A CYP19 (aromatase) polymorphism is associated with increased premenopausal breast cancer risk. Breast Cancer Res Treat 111(3):481–487

    Article  PubMed  CAS  Google Scholar 

  12. Kristensen VN, Harada N, Yoshimura N, Haraldsen E, Lonning PE, Erikstein B et al (2000) Genetic variants of CYP19 (aromatase) and breast cancer risk. Oncogene 19(10):1329–1333

    Article  PubMed  CAS  Google Scholar 

  13. Dunning AM, Dowsett M, Healey CS, Tee L, Luben RN, Folkerd E et al (2004) Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 96(12):936–945

    Article  PubMed  CAS  Google Scholar 

  14. Wang L, Ellsworth KA, Moon I, Pelleymounter LL, Eckloff BW, Martin YN et al (2010) Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors. Cancer Res 70(1):319–328

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM et al (2011) Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 377(9762):321–331

    Article  PubMed  CAS  Google Scholar 

  16. Baak-Pablo R, Dezentje V, Guchelaar HJ, van der Straaten T (2010) Genotyping of DNA samples isolated from formalin-fixed paraffin-embedded tissues using preamplification. J Mol Diagn 12(6):746–749

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Wilkins K, LaFramboise T (2011) Losing balance: Hardy–Weinberg disequilibrium as a marker for recurrent loss-of-heterozygosity in cancer. Hum Mol Genet 20(24):4831–4839

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  18. McWhinney SR, McLeod HL (2009) Using germline genotype in cancer pharmacogenetic studies. Pharmacogenomics 10(3):489–493

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. van Huis-Tanja L, Kweekel D, Gelderblom H, Koopman M, Punt K, Guchelaar HJ et al (2013) Concordance of genotype for polymorphisms in DNA isolated from peripheral blood and colorectal cancer tumor samples. Pharmacogenomics 14(16):2005–2012

    Article  PubMed  CAS  Google Scholar 

  20. Goeman J, Solari A (2011) Multiple Testing for exploratory Research. Stat Sci 26(4):584–597

    Article  Google Scholar 

  21. Burstein HJ (2007) Aromatase inhibitor-associated arthralgia syndrome. Breast 16(3):223–234

    Article  PubMed  Google Scholar 

  22. Key T, Appleby P, Barnes I, Reeves G (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94(8):606–616

    Article  PubMed  CAS  Google Scholar 

  23. Simpson ER (2003) Sources of estrogen and their importance. J Steroid Biochem Mol Biol 86(3–5):225–230

    Article  PubMed  CAS  Google Scholar 

  24. Straume AH, Knappskog S, Lonning PE (2012) Effect of CYP19 rs6493497 and rs7176005 haplotype status on in vivo aromatase transcription, plasma and tissue estrogen levels in postmenopausal women. J Steroid Biochem Mol Biol 128(1–2):69–75

    Article  PubMed  CAS  Google Scholar 

  25. Cai H, Shu XO, Egan KM, Cai Q, Long JR, Gao YT et al (2008) Association of genetic polymorphisms in CYP19A1 and blood levels of sex hormones among postmenopausal Chinese women. Pharmacogenet Genomics 18(8):657–664

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  26. Ingle JN, Schaid DJ, Goss PE, Liu M, Mushiroda T, Chapman JA et al (2010) Genome-wide associations and functional genomic studies of musculoskeletal adverse events in women receiving aromatase inhibitors. J Clin Oncol 28(31):4674–4682

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Napoli N, Rastelli A, Ma C, Yarramaneni J, Vattikutti S, Moskowitz G et al (2013) Genetic polymorphism at Val(80) (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER(+) breast cancer. Bone 55(2):309–314

    Article  PubMed  CAS  Google Scholar 

  28. Riancho JA, Valero C, Naranjo A, Morales DJ, Sanudo C, Zarrabeitia MT (2007) Identification of an aromatase haplotype that is associated with gene expression and postmenopausal osteoporosis. J Clin Endocrinol Metab 92(2):660–665

    Article  PubMed  CAS  Google Scholar 

  29. Miron L, Negura L, Peptanariu D, Marinca M (2012) Research on aromatase gene (CYP19A1) polymorphisms as a predictor of endocrine therapy effectiveness in breast cancer. Rev Med Chir Soc Med Nat Iasi 116(4):997–1004

    PubMed  CAS  Google Scholar 

  30. Mao JJ, Su HI, Feng R, Donelson ML, Aplenc R, Rebbeck TR et al (2011) Association of functional polymorphisms in CYP19A1 with aromatase inhibitor associated arthralgia in breast cancer survivors. Breast Cancer Res 13(1):R8

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  31. Park IH, Lee YS, Lee KS, Kim SY, Hong SH, Jeong J et al (2011) Single nucleotide polymorphisms of CYP19A1 predict clinical outcomes and adverse events associated with letrozole in patients with metastatic breast cancer. Cancer Chemother Pharmacol 68(5):1263–1271

    Google Scholar 

  32. Colomer R, Monzo M, Tusquets I, Rifa J, Baena JM, Barnadas A et al (2008) A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma. Clin Cancer Res 14(3):811–816

    Article  PubMed  CAS  Google Scholar 

  33. Ghimenti C, Mello-Grand M, Grosso E, Scatolini M, Regolo L, Zambelli A et al (2013) Regulation of aromatase expression in breast cancer treated with anastrozole neoadjuvant therapy. Exp Ther Med 5(3):902–906

    PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors thank Professor J. J. Houwing for her help with the statistical evaluation and interpretation of our results. We are grateful for the support of all local study personnel for their contribution to the recruitment and follow-up of patients for this study and for collecting all data. This work was supported by an unrestricted research Grant from Pfizer (WS294136).

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

    Duveken B. Y. Fontein, Elma Meershoek-Klein Kranenbarg & Cornelis J. H. van de Velde

  2. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands

    Daniel Houtsma, Johan W. R. Nortier & Hans Gelderblom

  3. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, P.O. Box 9600, 2300, Leiden, The Netherlands

    Renee F. Baak-Pablo, Tahar R. J. H. M. van der Straaten & Henk-Jan Guchelaar

  4. Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands

    Hein Putter

  5. Department of Medical Oncology, Erasmus MC Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

    Caroline Seynaeve

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  1. Duveken B. Y. Fontein
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Correspondence to Henk-Jan Guchelaar.

Additional information

Duveken B. Y. Fontein and Daniel Houtsma have contributed equally.

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Fontein, D.B.Y., Houtsma, D., Nortier, J.W.R. 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 144, 599–606 (2014). https://doi.org/10.1007/s10549-014-2873-2

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  • DOI: https://doi.org/10.1007/s10549-014-2873-2

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