Skip to main content

Advertisement

SpringerLink
Log in

Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case–control study

  • Original Paper
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Background

Women with a breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) mutation are at increased risk for developing breast and ovarian cancer. Various reproductive and hormonal factors have been shown to modify the risk of breast cancer. These studies suggest that estrogen exposure and deprivation are important in the etiology of hereditary cancer. Many patients are interested in the possibility of an adverse effect of fertility treatment on breast cancer risk. It is important to evaluate whether or not infertility per se or exposure to fertility medications increase the risk of breast cancer in genetically predisposed women.

Methods

We conducted a matched case–control study of 1,380 pairs of women with a BRCA1 or BRCA2 mutation to determine if a history of infertility, the use of fertility medications, or undergoing in vitro fertilization (IVF) were associated with and increased the risk of breast cancer.

Results

Sixteen percent of the study subjects reported having experienced a fertility problem and 4% had used a fertility medication. Women who had used a fertility medication were not at significantly increased risk of breast cancer (odds ratio [OR] = 1.21; 95% confidence interval [CI] = 0.81–1.82) compared to non-users. Furthermore, there was no risk associated with a history of use of a fertility medication when the subjects were stratified by parity: (OR = 1.29; 95% CI = 0.83–2.01 for nulliparous women and OR = 0.81; 95% CI = 0.30–2.22 for parous women).

Conclusions

The results of this study suggest that the use of fertility medications does not adversely affect the risk of breast cancer among BRCA mutation carriers. Given the small sizes of the exposed subgroups, these findings should be interpreted with caution and confirmatory studies are required.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

BRCA1 :

Breast cancer susceptibility gene 1

BRCA2 :

Breast cancer susceptibility gene 2

IVF:

In vitro fertilization

OR:

Odds ratio

CI:

Confidence interval

References

  1. Henderson BE et al (1985) Do regular ovulatory cycles increase breast cancer risk? Cancer 56(5):1206–1208. doi:10.1002/1097-0142(19850901)56:5≤1206::AID-CNCR2820560541≥3.0.CO;2-9

    Article  PubMed  CAS  Google Scholar 

  2. Kelsey JL, Gammon MD, John EM (1993) Reproductive factors and breast cancer. Epidemiol Rev 15(1):36–47

    PubMed  CAS  Google Scholar 

  3. Lipworth L (1995) Epidemiology of breast cancer. Eur J Cancer Prev 4(1):7–30. doi:10.1097/00008469-199502000-00002

    Article  PubMed  CAS  Google Scholar 

  4. Klip H et al (2000) Cancer risk associated with subfertility and ovulation induction: a review. Cancer Causes Control 11(4):319–344. doi:10.1023/A:1008921211309

    Article  PubMed  CAS  Google Scholar 

  5. Venn A, Healy D, McLachlan R (2003) Cancer risks associated with the diagnosis of infertility. Best Pract Res Clin Obstet Gynaecol 17(2):343–367

    Article  PubMed  Google Scholar 

  6. Salhab M, Al Sarakbi W, Mokbel K (2005) In vitro fertilization and breast cancer risk: a review. Int J Fertil Womens Med 50(6):259–266

    PubMed  CAS  Google Scholar 

  7. Ford D et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62(3):676–689. doi:10.1086/301749

    Article  PubMed  CAS  Google Scholar 

  8. Risch HA et al (2001) Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68(3):700–710. doi:10.1086/318787

    Article  PubMed  CAS  Google Scholar 

  9. Antoniou A et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130. doi:10.1086/375033

    Article  PubMed  CAS  Google Scholar 

  10. King MC, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302(5645):643–646. doi:10.1126/science.1088759

    Article  PubMed  CAS  Google Scholar 

  11. Narod SA (2006) Modifiers of risk of hereditary breast cancer. Oncogene 25(43):5832–5836. doi:10.1038/sj.onc.1209870

    Article  PubMed  CAS  Google Scholar 

  12. Ayhan A et al (2004) Association between fertility drugs and gynecologic cancers, breast cancer, and childhood cancers. Acta Obstet Gynecol Scand 83(12):1104–1111. doi:10.1111/j.0001-6349.2004.00669.x

    Article  PubMed  Google Scholar 

  13. Lambe M et al (1994) Transient increase in the risk of breast cancer after giving birth. N Engl J Med 331(1):5–9. doi:10.1056/NEJM199407073310102

    Article  PubMed  CAS  Google Scholar 

  14. Kroman N et al (1997) Time since childbirth and prognosis in primary breast cancer: population based study. BMJ 315(7112):851–855

    PubMed  CAS  Google Scholar 

  15. Braga C et al (1996) Fertility treatment and risk of breast cancer. Hum Reprod 11(2):300–303

    PubMed  CAS  Google Scholar 

  16. Grabrick DM et al (2002) Association of correlates of endogenous hormonal exposure with breast cancer risk in 426 families (United States). Cancer Causes Control 13(4):333–341. doi:10.1023/A:1015292724384

    Article  PubMed  Google Scholar 

  17. Gauthier E, Paoletti X, Clavel-Chapelon F (2004) Breast cancer risk associated with being treated for infertility: results from the French E3N cohort study. Hum Reprod 19(10):2216–2221. doi:10.1093/humrep/deh422

    Article  PubMed  CAS  Google Scholar 

  18. Eisen A et al (2005) Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case–control study. J Clin Oncol 23(30):7491–7496. doi:10.1200/JCO.2004.00.7138

    Article  PubMed  Google Scholar 

  19. Gronwald J et al (2006) Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer 118(9):2281–2284. doi:10.1002/ijc.21536

    Article  PubMed  CAS  Google Scholar 

  20. 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. doi:10.1007/s10552-005-1724-1

    Article  PubMed  Google Scholar 

  21. Jernstrom H et al (2004) Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 96(14):1094–1098

    Article  PubMed  CAS  Google Scholar 

  22. Cullinane CA et al (2005) Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers. Int J Cancer 117:988–991

    Google Scholar 

  23. Key TJ, Pike MC (1988) The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer. Eur J Cancer Clin Oncol 24(1):29–43. doi:10.1016/0277-5379(88)90173-3

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  25. Riggs BL, Hartmann LC (2003) Selective estrogen-receptor modulators—mechanisms of action and application to clinical practice. N Engl J Med 348(7):618–629. doi:10.1056/NEJMra022219

    Article  PubMed  CAS  Google Scholar 

  26. Mokbel K (2003) Risk-reducing strategies for breast cancer—a review of recent literature. Int J Fertil Womens Med 48(6):274–277

    PubMed  Google Scholar 

  27. Terry KL et al (2006) A prospective study of infertility due to ovulatory disorders, ovulation induction, and incidence of breast cancer. Arch Intern Med 66(22):2484–2489. doi:10.1001/archinte.166.22.2484

    Article  Google Scholar 

  28. Rossing MA et al (1996) Risk of breast cancer in a cohort in infertile women. Gynecol Oncol 60(1):3–7. doi:10.1006/gyno.1996.0002

    Article  PubMed  CAS  Google Scholar 

  29. Burkman RT et al (2003) Infertility drugs and the risk of breast cancer: findings from the National Institute of Child Health and Human Development Women’s Contraceptive and Reproductive Experiences Study. Fertil Steril 79(4):844–851. doi:10.1016/S0015-0282(02)04950-6

    Article  PubMed  Google Scholar 

  30. Haning RV Jr et al (1979) Plasma estradiol window and urinary estriol glucuronide determinations for monitoring menotropin induction of ovulation. Obstet Gynecol 54(4):442–447

    PubMed  CAS  Google Scholar 

  31. Sallam HN et al (1999) Reference values for the midluteal plasma progesterone concentration: evidence from human menopausal gonadotropin-stimulated pregnancy cycles. Fertil Steril 71(4):711–714. doi:10.1016/S0015-0282(98)00531-7

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Joanne Kotsopoulos is supported by a fellowship from the Canadian Breast Cancer Foundation, Ontario Chapter. Charis Eng is a recipient of the Doris Duke Distinguished Clinical Scientist Award. Susan. L. Neuhausen was supported by NIH CA74415.

Authors’ Contributions

JK: study co-ordinator, analyzed data, performed literature review, prepared manuscript; CL: consultant regarding infertility and its treatment, reviewed exposure data; JL, JG, CKS, PG, HTL, PM, WDF, SR, SM, BP, NT, PA, SC: organized data collection and quality control for their individual centers, reviewed manuscript; PS: performed statistical analysis; SAN: conceived of study, project leader, edited manuscript.

Author information

Authors and Affiliations

  1. Women’s College Research Institute, Women’s College Hospital, University of Toronto, 790 Bay Street, 7th Floor, Toronto, ON, Canada, M5G 1N8

    Joanne Kotsopoulos, Ping Sun & Steven A. Narod

  2. Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada

    Joanne Kotsopoulos & Steven A. Narod

  3. Department of Gynaecology and Obstetrics, Sunnybrook Health Sciences Center, Woman’s College Hospital, University of Toronto, Toronto, ON, Canada

    Clifford L. Librach

  4. Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland

    Jan Lubinski & Jacek Gronwald

  5. British Columbia Cancer Agency, Vancouver, BC, Canada

    Charmaine Kim-Sing

  6. Epidemiology Research Unit, Département de Nutrition, Faculte du Medicine, Research Centre, Centre Hospitalier de l’Universitaire Montréal, CHUM Hôtel Dieu, Montreal, QC, Canada

    Parviz Ghadirian

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

    Henry T. Lynch

  8. Section for Inherited Cancer, Department of Medical Genetics, Rikshospitalet-Radiumhospitalet Medical Centre, 0310, Oslo, Norway

    Pal Moller

  9. Departments of Medicine, Human Genetics and Oncology, McGill University, Montreal, QC, Canada

    William D. Foulkes

  10. Department of Gynecologic Oncology, Princess Margaret Hospital, Toronto, Canada

    Susan Randall

  11. Medical Genetics Service, Department of Experimental Oncology and Laboratories, Istituto Nazionale Tumori, Milan, Italy

    Siranoush Manoukian

  12. Section of Genetics, University of Turin, Turin, Italy

    Barbara Pasini

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

    Nadine Tung

  14. London Regional Program, London Health Sciences Centre, London, ON, Canada

    Peter J. Ainsworth

  15. Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL, USA

    Shelly Cummings

Authors
  1. Joanne Kotsopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clifford L. Librach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan Lubinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacek Gronwald
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Charmaine Kim-Sing
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Parviz Ghadirian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Henry T. Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pal Moller
    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. Susan Randall
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Siranoush Manoukian
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Barbara Pasini
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nadine Tung
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Peter J. Ainsworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shelly Cummings
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ping Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Steven A. Narod
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Hereditary Breast Cancer Clinical Study Group

Corresponding author

Correspondence to Steven A. Narod.

Additional information

Other Members of the Hereditary Breast Cancer Clinical Study Group: D. Horsman, British Columbia Cancer Agency, Vancouver, BC, Canada; B. Rosen, Familial Ovarian Cancer Clinic, Princess Margaret Hospital, Toronto, ON, Canada; C. Isaacs, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, USA; S. Domchek, Departments of Hematology and Oncology, University of Pennsylvania, USA; R. Gershoni-Baruch, Institute of Genetics, Rambam Medical Center, Haifa, Israel; A. Eisen, Cancer Risk Assessment Clinic, Juravinksi Cancer Centre (Hamilton Regional Cancer Centre), Hamilton, ON, Canada; O. I. Olopade, Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL, USA; E. Friedman, The Suzanne Levy Gertner Oncogenetics Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Israel, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; H. M. Saal, Hereditary Cancer Program, Division of Human Genetics, Children’s Hospital Medical Center, Cincinnati, OH, USA; S. L. Neuhausen, Epidemiology Division, Department of Medicine, University of California, Irvine, USA; M. Daly, Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA; B. Karlan and R. N. Kurz, Gynecology Oncology, Cedars Sinai Medical Center, Los Angeles, CA, USA; C. Bellati, Section of Genetics, University of Turin, Turin; Italy C. Eng, Chair of Genomic Medicine Institute at the Cleveland Clinic Foundation Cleveland, Cleveland, OH, USA; K. Sweet, Clinical Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus OH, USA; T. Wagner, Department of Gynecology, Division of Senology, Medical University of Vienna and Private Trust for Breast Health, Austria; G. Rennert, National Cancer Control Center, Carmel Medical Center, Haifa, Israel; D. Provencher and C. Maugard, University of Montreal, Quebec, Canada; J. Garber, Dana Farber Cancer Center, W. McKinnon and M. Wood, University of Vermont; D. Gilchrist, University of Alberta; M. Osborne, Strang Cancer Prevention Centre, New York, NY, USA; J. McLennan, University of San Francisco, California, USA; S. Merajver, University of Michigan Comprehensive Cancer Cente;, B. Pasche and T. Fallen, Northwestern University Cancer Genetics Program, Chicago, Illinois, USA; E. Lemire, Division of Medical Genetics, Royal University Hospital and the University of Saskatchewan, Saskatoon, Canada; A. Chudley, Children’s Hospital, Winnipeg, Manitoba, Canada; J. Weitzel, Department of Cancer Genetics, City of Hope National Medical Center, Duarte, California, USA; W. S. Meschino, North York General, North York, ON, Canada; D. Rayson, Queen Elizabeth Health Sciences Centre, Halifax, Nova Scotia, Canada; G. Evans, Regional Genetics Service, St. Mary’s Hospital, Manchester, UK; D. Agnese, Division of Human Genetics, The Ohio State University; and H. Olsson, Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, Sweden.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kotsopoulos, J., Librach, C.L., Lubinski, J. et al. Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case–control study. Cancer Causes Control 19, 1111–1119 (2008). https://doi.org/10.1007/s10552-008-9175-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-008-9175-0

Keywords

Search

Navigation