Skip to main content
Springer Nature Link
Log in

Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: a case–control study

  • Epidemiology
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Many BRCA1 mutation carriers undergo elective surgical oophorectomy (often before menopause) to manage their elevated risk of developing ovarian cancer. It is important to clarify whether or not the use of hormone replacement therapy (HRT) to mitigate the symptoms associated with surgical or natural menopause is safe in women with an inherited BRCA1 mutation and no personal history of breast or ovarian cancer. We conducted a case–control analysis of 432 matched pairs of women with a BRCA1 mutation. Detailed information on HRT use after menopause (duration, type, age at first/last use, formulation) was obtained from a research questionnaire administered at the time of study enrollment. Conditional logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI) associated with HRT use. The mean duration of HRT use after menopause was 4.3 years among the cases and 4.4 years among the controls (P = 0.83). The adjusted OR for breast cancer comparing all women who ever used HRT to those who never used HRT was 0.80 (95 % CI 0.55–1.16; P = 0.24). Findings did not differ by type of menopause (natural vs. surgical), by recency of use, by duration of use, and by formulation type. These findings suggest that a short course of HRT should not be contra-indicated for BRCA1 mutation carriers who have undergone menopause and who have no personal history of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Collaborative Group on Hormonal Factors in Breast Cancer (1997) Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350(9084):1047–1059

    Article  Google Scholar 

  2. Rossouw JE et al (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288(3):321–333

    Article  CAS  PubMed  Google Scholar 

  3. Beral V (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362(9382):419–427

    Article  CAS  PubMed  Google Scholar 

  4. Chen WY et al (2004) Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma. Cancer 101(7):1490–1500

    Article  CAS  PubMed  Google Scholar 

  5. Beral V et al (2011) Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst 103(4):296–305

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Narod SA (2011) Hormone replacement therapy and the risk of breast cancer. Nat Rev Clin Oncol 8(11):669–676

    Article  CAS  PubMed  Google Scholar 

  7. Chlebowski RT et al (2013) Estrogen plus progestin and breast cancer incidence and mortality in the Women’s Health Initiative Observational Study. J Natl Cancer Inst 105(8):26–35

    Article  Google Scholar 

  8. Anderson GL et al (2012) Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 13(5):476–486

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Reeves GK et al (2006) Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol 7(11):910–918

    Article  CAS  PubMed  Google Scholar 

  10. Kotsopoulos J et al (2010) Risk factors for ductal and lobular breast cancer: results from the nurses’ health study. Breast Cancer Res 12(6):R106

    Article  PubMed Central  PubMed  Google Scholar 

  11. Clarke CA et al (2006) Recent declines in hormone therapy utilization and breast cancer incidence: clinical and population-based evidence. J Clin Oncol 24(33):e49–e50

    Article  PubMed  Google Scholar 

  12. Eheman CR et al (2009) The changing incidence of in situ and invasive ductal and lobular breast carcinomas: United States, 1999–2004. Cancer Epidemiol Biomarkers Prev 18(6):1763–1769

    Article  PubMed  Google Scholar 

  13. Kumle M (2008) Declining breast cancer incidence and decreased HRT use. Lancet 372(9639):608–610

    Article  PubMed  Google Scholar 

  14. Eisen A et al (2008) Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 100(19):1361–1367

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Rebbeck TR et al (2005) Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 23(31):7804–7810

    Article  CAS  PubMed  Google Scholar 

  16. Heemskerk-Gerritsen BA et al (2015) Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. J Natl Cancer Inst 107(5):djv033

    Article  PubMed  Google Scholar 

  17. Finch AP et al (2014) Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 32(15):1547–1553

    Article  PubMed Central  PubMed  Google Scholar 

  18. Metcalfe KA et al (2008) International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int J Cancer 122(9):2017–2022

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Finch A, Evans G, Narod SA (2012) BRCA carriers, prophylactic salpingo-oophorectomy and menopause: clinical management considerations and recommendations. Women’s Health 8(5):543–555

    Article  CAS  PubMed  Google Scholar 

  20. Kotsopoulos J et al (2014) Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers. Breast Cancer Res Treat 143(3):579–586

    Article  CAS  PubMed  Google Scholar 

  21. Widschwendter M et al (2013) The sex hormone system in carriers of BRCA1/2 mutations: a case-control study. Lancet Oncol 14(12):1226–1232

    Article  CAS  PubMed  Google Scholar 

  22. Finch AP et al (2014) Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 32(15):1547–1553

    Article  PubMed Central  PubMed  Google Scholar 

  23. Beral V, Million C (2003) Women Study, Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362(9382):419–427

    Article  CAS  PubMed  Google Scholar 

  24. Pike MC et al (1993) Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 15(1):17–35

    CAS  PubMed  Google Scholar 

  25. Horwitz KB et al (2008) Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts. Proc Natl Acad Sci USA 105(15):5774–5779

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Horwitz KB, Sartorius CA (2008) Progestins in hormone replacement therapies reactivate cancer stem cells in women with preexisting breast cancers: a hypothesis. J Clin Endocrinol Metab 93(9):3295–3298

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Gonzalez-Suarez E et al (2010) RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468(7320):103–107

    Article  CAS  PubMed  Google Scholar 

  28. Schramek D et al (2010) Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468(7320):98–102

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Joshi PA et al (2010) Progesterone induces adult mammary stem cell expansion. Nature 465(7299):803–807

    Article  CAS  PubMed  Google Scholar 

  30. Joshi PA et al (2015) RANK signaling amplifies WNT-responsive mammary progenitors through R-SPONDIN1. Stem Cell Rep 5(1):31–44

    Article  CAS  Google Scholar 

  31. Mavaddat N et al (2012) Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 21(1):134–147

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Kotsopoulos J et al (2005) Changes in body weight and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 7(5):R833–R843

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Kotsopoulos J et al (2005) Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer Causes Control 16(6):667–674

    Article  PubMed  Google Scholar 

  34. Kropp S et al (2007) Good agreement between physician and self-reported hormone therapy data in a case-control study. J Clin Epidemiol 60(12):1280–1287

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would also like to thank the study coordinators Marcia Llacuachaqui, Farah Shoukat, and Alejandra Ragone, as well as the students and staff Ellen MacDougall, Zoella Pasta, Nida Mian, Jennifer Ng, Sarah Chin, Hamida Begum, Harmeet Chaudhary, and Yaminee Charavanapavan who helped with the data collection and data entry. Joanne Kotsopoulos is the recipient of a Cancer Care Ontario Research Chair in Population Studies and a Canadian Cancer Society Career Development Award in Prevention. Charis Eng is the recipient of the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic and of the ACS Clinical Research Professorship. Susan L. Neuhausen was partially supported by the Morris and Horowitz Endowed Professorship, and her work was supported by a grant from the National Cancer Institute, National Institutes of Health (R01CA74415). Steven A. Narod is the recipient of a Tier I Canada Research Chair. This study was supported by a Canadian Cancer Society Research Institute grant (703058). Patients were recruited for study from the City of Hope Clinical Cancer Genomics Community Research Network, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. Siranoush Manoukian is affiliated with the Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.

Author information

Authors and Affiliations

  1. Women’s College Research Institute, Women’s College Hospital, 76 Grenville Street, 6th Floor, Toronto, ON, M5S 1B2, Canada

    Joanne Kotsopoulos, Ping Sun & Steven A. Narod

  2. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland

    Tomasz Huzarski, Jacek Gronwald & Jan Lubinski

  3. Inherited Cancer Research Group, Department for Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

    Pal Moller

  4. Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

    Pal Moller

  5. Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE, USA

    Henry T. Lynch

  6. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Susan L. Neuhausen

  7. Division of Human Genetics, The Ohio State University Medical Center, Comprehensive Cancer Center, Columbus, OH, USA

    Leigha Senter

  8. Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

    Rochelle Demsky

  9. Department of Molecular Genetics, University of Toronto, Toronto, Canada

    Rochelle Demsky

  10. Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montréal, QC, Canada

    William D. Foulkes

  11. Genomic Medicine Institute and Center for Personalized Genetic Healthcare, Cleveland Clinic, Cleveland, OH, USA

    Charis Eng

  12. Gynecology Oncology, Cedars Sinai Medical Center, Los Angeles, CA, USA

    Beth Karlan

  13. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Nadine Tung

  14. Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    Christian F. Singer

Authors
  1. Joanne Kotsopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomasz Huzarski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jacek Gronwald
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pal Moller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Henry T. Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Susan L. Neuhausen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Leigha Senter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rochelle Demsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William D. Foulkes
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Charis Eng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Beth Karlan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nadine Tung
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Christian F. Singer
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ping Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jan Lubinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Steven A. Narod
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven A. Narod.

Ethics declarations

Competing Interests

The authors declare that they have no conflict of interest.

Additional information

The members of the Hereditary Breast Cancer Clinical Study Group are given in Appendix.

Appendix

Appendix

Carrie Snyder, Aletta Poll, Sonia Nanda, Andrea Eisen, Ellen Warner, Wendy Meschino, Barry Rosen, Susan Armel, Peter Ainsworth, Karen Panabaker, Gillian Mitchell, Melanie Taylor, Jeffrey N. Weitzel, Fergus Couch, Siranoush Manoukian, Christine Rappaport, Barbara Pasini, Mary B. Daly, Olufunmilayo Olopade, Linda Steele, Howard Saal, Taya Fallen, Marie Wood, Wendy McKinnon, Dawna Gilchrist, Edmond Lemire, Albert E. Chudley, Kim Serfas, Kevin Sweet, Louise Bordeleau, Christine Elser, Seema Panchal, Dana Zakalik, Tuya Pal, Susan T. Vadaparamdil, Ophira Ginsburg, Stephanie Hurst, Carey A. Cullinane, Robert E. Reilly, Joanne L. Blum, Theodora Ross, Caitlin Mauer, Ava Kwong, Cezary Cybulski, Jeanna McCuaig, Judy Garber, Charmaine Kim-Sing, Sofia Merajver, Eitan Friedman, Daniel Rayson, David Euhus, Claudine Isaacs, Kelly Metcalfe, Timothy Rebbeck, Gareth Evans and Anna Jakubowska.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kotsopoulos, J., Huzarski, T., Gronwald, J. et al. Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: a case–control study. Breast Cancer Res Treat 155, 365–373 (2016). https://doi.org/10.1007/s10549-016-3685-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-016-3685-3

Keywords

Search

Navigation