Breast Cancer Research and Treatment

, Volume 143, Issue 3, pp 579–586 | Cite as

Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers

  • Joanne Kotsopoulos
  • Jan Lubinski
  • Pal Moller
  • Henry T. Lynch
  • Christian F. Singer
  • Charis Eng
  • Susan L. Neuhausen
  • Beth Karlan
  • Charmaine Kim-Sing
  • Tomasz Huzarski
  • Jacek Gronwald
  • Jeanna McCuaig
  • Leigha Senter
  • Nadine Tung
  • Parviz Ghadirian
  • Andrea Eisen
  • Dawna Gilchrist
  • Joanne L. Blum
  • Dana Zakalik
  • Tuya Pal
  • Ping Sun
  • Steven A. NarodEmail author
  • Hereditary Breast Cancer Clinical Study Group


It is not clear if early oral contraceptive use increases the risk of breast cancer among young women with a breast cancer susceptibility gene 1 (BRCA1) mutation. Given the benefit of oral contraceptives for the prevention of ovarian cancer, estimating age-specific risk ratios for oral contraceptive use and breast cancer is important. We conducted a case–control study of 2,492 matched pairs of women with a deleterious BRCA1 mutation. Breast cancer cases and unaffected controls were matched on year of birth and country of residence. Detailed information about oral contraceptive use was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the odds ratios (OR) and 95 % confidence intervals (CI) for the association between oral contraceptive and breast cancer, by age at first use and by age at diagnosis. Among BRCA1 mutation carriers, oral contraceptive use was significantly associated with an increased risk of breast cancer for women who started the pill prior to age 20 (OR 1.45; 95 % CI 1.20–1.75; P = 0.0001) and possibly between ages 20 and 25 as well (OR 1.19; 95 % CI 0.99–1.42; P = 0.06). The effect was limited to breast cancers diagnosed before age 40 (OR 1.40; 95 % CI 1.14–1.70; P = 0.001); the risk of early-onset breast cancer increased by 11 % with each additional year of pill use when initiated prior to age 20 (OR 1.11; 95 % CI 1.03–1.20; P = 0.008). There was no observed increase for women diagnosed at or after the age of 40 (OR 0.97; 95 % CI 0.79–1.20; P = 0.81). Oral contraceptive use before age 25 increases the risk of early-onset breast cancer among women with a BRCA1 mutation and the risk increases with duration of use. Caution should be taken when advising women with a BRCA1 mutation to take an oral contraceptive prior to age 25.


BRCA1 Oral contraceptives Breast cancer 



Breast cancer susceptibility gene 1


Odds ratios


Confidence interval


Relative risk



We would also like to acknowledge the study coordinators Adriana Valentini, Marcia Llacuachaqui, and Alejandra Ragone, as well as the students and staff Jennifer Ng, Kristi De Buono, Kate Bisnaire, Dina Nikitina, Anneli Loo, Bita Khorram, Dina Gordon, Courtney May, Michelle Jones, Jose Miguel Lozano, 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 is partially supported by the Morris and Horowitz Endowed Professorship and her work was supported by a grant from the NIH, R01CA74415. Tuya Pal’s work is supported by a grant from the Florida Biomedical Research Program, IBG-09. Steven Narod is the recipient of a Canada Research Chair tier I.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    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):1117–1130PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Narod SA (2010) BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin Oncol 7(12):702–707PubMedCrossRefGoogle Scholar
  3. 3.
    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):667–674PubMedCrossRefGoogle Scholar
  4. 4.
    Gronwald J et al (2006) Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland. Breast Cancer Res Treat 95(2):105–109PubMedCrossRefGoogle Scholar
  5. 5.
    Chang-Claude J et al (1997) Modifying effect of reproductive risk factors on the age at onset of breast cancer for German BRCA1 mutation carriers. J Cancer Res Clin Oncol 123(5):272–279PubMedGoogle Scholar
  6. 6.
    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):1094–1098PubMedCrossRefGoogle Scholar
  7. 7.
    Kotsopoulos J et al (2012) Oophorectomy after menopause and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 21(7):1089–1096Google Scholar
  8. 8.
    Kotsopoulos J et al (2007) Age at first birth and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 105(2):221–228PubMedCrossRefGoogle Scholar
  9. 9.
    Cullinane CA et al (2005) Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers. Int J Cancer 117(6):988–991PubMedCrossRefGoogle Scholar
  10. 10.
    Moorman PG et al (2010) Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis. Breast Cancer Res Treat 124(2):441–451PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Eisen A et al (2008) Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 100(19):1361–1367PubMedCrossRefGoogle Scholar
  12. 12.
    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):7804–7810PubMedCrossRefGoogle Scholar
  13. 13.
    Russo J et al (1981) Influence of age and parity on the susceptibility of rat mammary gland epithelial cells in primary cultures to 7,12-dimethylbenz(a)anthracene. In Vitro 17(10):877–884PubMedCrossRefGoogle Scholar
  14. 14.
    Narod SA et al (2002) Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 94(23):1773–1779PubMedCrossRefGoogle Scholar
  15. 15.
    Iodice S et al (2010) Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer 46(12):2275–2284PubMedCrossRefGoogle Scholar
  16. 16.
    Moorman PG et al (2013) Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis. J Clin Oncol 31(33):4188–4198Google Scholar
  17. 17.
    Cibula D et al (2011) Tubal ligation and the risk of ovarian cancer: review and meta-analysis. Hum Reprod Update 17(1):55–67PubMedCrossRefGoogle Scholar
  18. 18.
    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. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 350(9084):1047–1059 Google Scholar
  19. 19.
    Gierisch JM et al (2013) Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev 22(11):1931–1943Google Scholar
  20. 20.
    Zhu H et al (2012) Oral contraceptive use and risk of breast cancer: a meta-analysis of prospective cohort studies. Eur J Contracept Reprod Health Care 17(6):402–414PubMedCrossRefGoogle Scholar
  21. 21.
    Nelson HD et al (2012) Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Ann Intern Med 156(9):635–648PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Hilakivi-Clarke L, de Assis S, Warri A (2013) Exposures to synthetic estrogens at different times during the life, and their effect on breast cancer risk. J Mammary Gland Biol Neoplasia 18(1):25–42PubMedCrossRefGoogle Scholar
  23. 23.
    Gaffield ME, Culwell KR, Ravi A (2009) Oral contraceptives and family history of breast cancer. Contraception 80(4):372–380PubMedCrossRefGoogle Scholar
  24. 24.
    Phipps AI et al (2011) Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. J Natl Cancer Inst 103(6):470–477PubMedCrossRefGoogle Scholar
  25. 25.
    Dolle JM et al (2009) Risk factors for triple-negative breast cancer in women under the age of 45 years. Cancer Epidemiol Biomarkers Prev 18(4):1157–1166PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Ma H et al (2010) Use of four biomarkers to evaluate the risk of breast cancer subtypes in the women’s contraceptive and reproductive experiences study. Cancer Res 70(2):575–587PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Bronson RA (1981) Oral contraception: mechanism of action. Clin Obstet Gynecol 24(3):869–877PubMedCrossRefGoogle Scholar
  28. 28.
    Gaspard UJ et al (1983) Plasma hormone levels in women receiving new oral contraceptives containing ethinyl estradiol plus levonorgestrel or desogestrel. Contraception 27(6):577–590PubMedCrossRefGoogle Scholar
  29. 29.
    Fortner RT et al (2012) Association between reproductive factors and urinary estrogens and estrogen metabolites in premenopausal women. Cancer Epidemiol Biomarkers Prev 21(6):959–968PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Isaksson E et al (2001) Effects of oral contraceptives on breast epithelial proliferation. Breast Cancer Res Treat 65(2):163–169PubMedCrossRefGoogle Scholar
  31. 31.
    Garcia y, Narvaiza D et al (2008) Effect of combined oral contraceptives on breast epithelial proliferation in young women. Breast J 14(5):450–455CrossRefGoogle Scholar
  32. 32.
    Hunter DJ et al (1997) Reproducibility of oral contraceptive histories and validity of hormone composition reported in a cohort of US women. Contraception 56(6):373–378PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Joanne Kotsopoulos
    • 1
  • Jan Lubinski
    • 2
  • Pal Moller
    • 3
  • Henry T. Lynch
    • 4
  • Christian F. Singer
    • 5
  • Charis Eng
    • 6
  • Susan L. Neuhausen
    • 7
  • Beth Karlan
    • 8
  • Charmaine Kim-Sing
    • 9
  • Tomasz Huzarski
    • 2
  • Jacek Gronwald
    • 2
  • Jeanna McCuaig
    • 10
  • Leigha Senter
    • 11
  • Nadine Tung
    • 12
  • Parviz Ghadirian
    • 13
  • Andrea Eisen
    • 14
  • Dawna Gilchrist
    • 15
  • Joanne L. Blum
    • 16
  • Dana Zakalik
    • 17
  • Tuya Pal
    • 18
  • Ping Sun
    • 1
  • Steven A. Narod
    • 1
    Email author
  • Hereditary Breast Cancer Clinical Study Group
  1. 1.Familial Breast Cancer UnitWomen’s College Research InstituteTorontoCanada
  2. 2.Hereditary Cancer CenterPomeranian Medical UniversitySzczecinPoland
  3. 3.Inherited Cancer Research Group, Department for Medical Genetics, The Norwegian Radium HospitalOslo University HospitalOsloNorway
  4. 4.Department of Preventive Medicine and Public HealthCreighton University School of MedicineOmahaUSA
  5. 5.Department of Obstetrics and Gynecology, Comprehensive Cancer CenterMedical University of ViennaViennaAustria
  6. 6.Center for Personalized Genetic Healthcare, Genomic Medicine InstituteCleveland ClinicClevelandUSA
  7. 7.Department of Population SciencesBeckman Research Institute of City of HopeDuarteUSA
  8. 8.Women’s Cancer Program, Samuel Oschin Comprehensive Cancer InstituteCedars-Sinai Medical CenterLos AngelesUSA
  9. 9.BC Cancer AgencyVancouverCanada
  10. 10.Division of Gynecologic Oncology, Department of Obstetrics and GynecologyUniversity of TorontoTorontoCanada
  11. 11.Division of Human Genetics, Comprehensive Cancer CenterThe Ohio State University Medical CenterColumbusUSA
  12. 12.Beth Israel Deaconess Medical CenterBostonUSA
  13. 13.Epidemiology Research UnitResearch Center of the University of Montreal Hospital Centre (CRCHUM)MontrealCanada
  14. 14.Toronto-Sunnybrook Regional Cancer CenterTorontoCanada
  15. 15.Department of Medicine GeneticsUniversity of AlbertaEdmontonCanada
  16. 16.Hereditary Cancer Risk ProgramBaylor University Medical CenterDallasUSA
  17. 17.Cancer Genetics ProgramBeaumont HospitalRoyal OakUSA
  18. 18.Department of Cancer EpidemiologyMoffitt Cancer CenterTampaUSA

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