Breast Cancer Research and Treatment

, Volume 120, Issue 1, pp 175–183 | Cite as

Oral contraceptives and postmenopausal hormones and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers and noncarriers: the WECARE Study

  • Jane C. FigueiredoEmail author
  • Robert W. Haile
  • Leslie Bernstein
  • Kathleen E. Malone
  • Joan Largent
  • Bryan Langholz
  • Charles F. Lynch
  • Lisbeth Bertelsen
  • Marinela Capanu
  • Patrick Concannon
  • Ake Borg
  • Anne-Lise Børresen-Dale
  • Anh Diep
  • Sharon Teraoka
  • Therese Torngren
  • Shanyan Xue
  • Jonine L. Bernstein


The potential effects of oral contraceptive (OC) and postmenopausal hormone (PMH) use are not well understood among BRCA1 or BRCA2 (BRCA1/2) deleterious mutation carriers with a history of breast cancer. We investigated the association between OC and PMH use and risk of contralateral breast cancer (CBC) in the WECARE (Women’s Environment, Cancer, and Radiation Epidemiology) Study. The WECARE Study is a population-based case-control study of 705 women with asynchronous CBC and 1,398 women with unilateral breast cancer, including 181 BRCA1/2 mutation carriers. Risk-factor information was assessed by telephone interview. Mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing in all participants. Outcomes, treatment, and tumor characteristics were abstracted from medical records. Ever use of OCs was not associated with risk among noncarriers (RR = 0.87; 95% CI = 0.66–1.15) or BRCA2 carriers (RR = 0.82; 95% CI = 0.21–3.13). BRCA1 carriers who used OCs had a nonsignificant greater risk than nonusers (RR = 2.38; 95% CI = 0.72–7.83). Total duration of OC use and at least 5 years of use before age 30 were associated with a nonsignificant increased risk among mutation carriers but not among noncarriers. Few women had ever used PMH and we found no significant associations between lifetime use and CBC risk among carriers and noncarriers. In conclusion, the association between OC/PMH use and risk of CBC does not differ significantly between carriers and noncarriers; however, because carriers have a higher baseline risk of second primaries, even a potential small increase in risk as a result of OC use may be clinically relevant.


Breast cancer Asynchronous bilateral Contralateral Oral contraceptives Postmenopausal hormones BRCA1 BRCA2 



Oral contraceptives


Postmenopausal hormones


Estrogen receptor


High-performance liquid chromatography



This work was supported by the National Institutes of Health (U01-CA83178, R01-CA97397 and R01-CA42949). J.C.F. is supported in part by a post-PhD Research Fellowship from the National Cancer Institute of Canada (#017602). We thank all the individuals who participated in this study.

Conflict of interest statement

The authors declare that they have no competing interests.


  1. 1.
    Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E, Olopade OI, Eisen A, Weber B, McLennan J et al (2004) Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22(12):2328–2335CrossRefPubMedGoogle Scholar
  2. 2.
    Malone KE, Begg CB, Haile RW, Borg A, Concannon P, Tellhed L, Xue S, Teraoka S, Bernstein L, Capanu M, Reiner A, Riedel ER, Thomas DC, Mellemkjaer L, Lynch CF, Boice JD, Anton-Culver H, Bernstein JL. A population-based study of the relative and absolute risks of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2 (under review)Google Scholar
  3. 3.
    Narod SA, Dube MP, Klijn J, Lubinski J, Lynch HT, Ghadirian P, Provencher D, Heimdal K, Moller P, Robson M et al (2002) Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 94(23):1773–1779PubMedGoogle Scholar
  4. 4.
    Brohet RM, Goldgar DE, Easton DF, Antoniou AC, Andrieu N, Chang-Claude J, Peock S, Eeles RA, Cook M, Chu C et al (2007) Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol 25(25):3831–3836CrossRefPubMedGoogle Scholar
  5. 5.
    Haile RW, Thomas DC, McGuire V, Felberg A, John EM, Milne RL, Hopper JL, Jenkins MA, Levine AJ, Daly MM et al (2006) BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev 15(10):1863–1870CrossRefPubMedGoogle Scholar
  6. 6.
    McLaughlin JR, Risch HA, Lubinski J, Moller P, Ghadirian P, Lynch H, Karlan B, Fishman D, Rosen B, Neuhausen SL et al (2007) Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet Oncol 8(1):26–34CrossRefPubMedGoogle Scholar
  7. 7.
    Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, Isaacs C, Olopade OI, Neuhausen SL, vanz‘t Veer L 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):7804–7810CrossRefPubMedGoogle Scholar
  8. 8.
    Figueiredo JC, Bernstein L, Capanu M, Malone KE, Lynch CF, Anton-Culver H, Stovall M, Bertelsen L, Haile RW, Bernstein JL (2008) Oral contraceptives, postmenopausal hormones, and risk of asynchronous bilateral breast cancer: the WECARE study group. J Clin Oncol 26:1411–1418CrossRefPubMedGoogle Scholar
  9. 9.
    Bernstein JL, Langholz B, Haile RW, Bernstein L, Thomas DC, Stovall M, Malone KE, Lynch CF, Olsen JH, Anton-Culver H et al (2004) Study design: evaluating gene-environment interactions in the etiology of breast cancer–the WECARE study. Breast Cancer Res 6(3):R199–R214CrossRefPubMedGoogle Scholar
  10. 10.
    Begg CB, Haile RW, Borg A, Malone KE, Concannon P, Thomas DC, Langholz B, Bernstein L, Olsen JH, Lynch CF, Anton-Culver H, Capanu M, Liang X, Hummer AJ, Sima C, Bernstein JL (2008) Variation of breast cancer risk among BRCA1/2 carriers. JAMA 299(2):194–201CrossRefPubMedGoogle Scholar
  11. 11.
    Bernstein JL, Teraoka S, Haile RW, Borresen-Dale AL, Rosenstein BS, Gatti RA, Diep AT, Jansen L, Atencio DP, Olsen JH et al (2003) Designing and implementing quality control for multi-center screening of mutations in the ATM gene among women with breast cancer. Hum Mutat 21(5):542–550CrossRefPubMedGoogle Scholar
  12. 12.
    Langholz B, Borgan O (1995) Counter matching: a stratified nested case-control sampling method. Biometrika 82:69–79CrossRefGoogle Scholar
  13. 13.
    Huberman M, Langholz B (1999) Application of the missing-indicator method in matched case-control studies with incomplete data. Am J Epidemiol 150(12):1340–1345PubMedGoogle Scholar
  14. 14.
    Horn PL, Thompson WD (1988) Risk of contralateral breast cancer. Associations with histologic, clinical, and therapeutic factors. Cancer 62(2):412–424CrossRefPubMedGoogle Scholar
  15. 15.
    Bernstein JL, Thompson WD, Risch N, Holford TR (1992) Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer. Am J Epidemiol 136(8):925–936PubMedGoogle Scholar
  16. 16.
    Trentham-Dietz A, Newcomb PA, Nichols HB, Hampton JM (2006) Breast cancer risk factors and second primary malignancies among women with breast cancer. Breast Cancer Res Treat 105:195–207CrossRefPubMedGoogle Scholar
  17. 17.
    Li CI, Malone KE, Porter PL, Daling JR (2003) Epidemiologic and molecular risk factors for contralateral breast cancer among young women. Br J Cancer 89(3):513–518CrossRefPubMedGoogle Scholar
  18. 18.
    Ursin G, Henderson BE, Haile RW, Pike MC, Zhou N, Diep A, Bernstein L (1997) Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57(17):3678–3681PubMedGoogle Scholar
  19. 19.
    Milne RL, Knight JA, John EM, Dite GS, Balbuena R, Ziogas A, Andrulis IL, West DW, Li FP, Southey MC et al (2005) Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 14(2):350–356CrossRefPubMedGoogle Scholar
  20. 20.
    Lee E, Ma H, McKean-Cowdin R, Van Den Berg D, Bernstein L, Henderson BE, Ursin G (2008) Effect of reproductive factors and oral contraceptives on breast cancer risk in BRCA1/2 mutation carriers and noncarriers: results from a population-based study. Cancer Epidemiol Biomarkers Prev 17(11):3170–3178CrossRefPubMedGoogle Scholar
  21. 21.
    Armstrong K, Schwartz JS, Randall T, Rubin SC, Weber B (2004) Hormone replacement therapy and life expectancy after prophylactic oophorectomy in women with BRCA1/2 mutations: a decision analysis. J Clin Oncol 22(6):1045–1054CrossRefPubMedGoogle Scholar
  22. 22.
    Collaborative Group on Hormonal Factors in Breast Cancer (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58, 209 women with breast cancer and 101, 986 women without the disease. Lancet 358(9291):1389–1399CrossRefGoogle Scholar
  23. 23.
    Bane AL, Beck JC, Bleiweiss I, Buys SS, Catalano E, Daly MB, Giles G, Godwin AK, Hibshoosh H, Hopper JL et al (2007) BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. Am J Surg Pathol 31(1):121–128CrossRefPubMedGoogle Scholar
  24. 24.
    Foulkes WD, Stefansson IM, Chappuis PO, Begin LR, Goffin JR, Wong N, Trudel M, Akslen LA (2003) Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95(19):1482–1485PubMedGoogle Scholar
  25. 25.
    Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van’t Veer L, Garber JE, Evans G, Isaacs C, Daly MB, Matloff E et al (2002) Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346(21):1616–1622CrossRefPubMedGoogle Scholar
  26. 26.
    Eisen A, Lubinski J, Klijn J, Moller P, Lynch HT, Offit K, Weber B, Rebbeck T, Neuhausen SL, Ghadirian P 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):7491–7496CrossRefPubMedGoogle Scholar
  27. 27.
    Gronwald J, Tung N, Foulkes WD, Offit K, Gershoni R, Daly M, Kim-Sing C, Olsson H, Ainsworth P, Eisen A et al (2006) Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer 118(9):2281–2284CrossRefPubMedGoogle Scholar
  28. 28.
    Fan S, Wang J, Yuan R, Ma Y, Meng Q, Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID et al (1999) BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science 284(5418):1354–1356CrossRefPubMedGoogle Scholar
  29. 29.
    Fan S, Ma YX, Wang C, Yuan RQ, Meng Q, Wang JA, Erdos M, Goldberg ID, Webb P, Kushner PJ et al (2001) Role of direct interaction in BRCA1 inhibition of estrogen receptor activity. Oncogene 20(1):77–87CrossRefPubMedGoogle Scholar
  30. 30.
    Malone JL, Nelson AC, Lieberman R, Anderson S, Holt JT (2009) Oestrogen-mediated phosphorylation and stabilization of BRCA2 protein in breast. J Pathol 217(3):380–388CrossRefPubMedGoogle Scholar
  31. 31.
    Poole AJ, Li Y, Kim Y, Lin SC, Lee WH, Lee EY (2006) Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 314(5804):1467–1470CrossRefPubMedGoogle Scholar
  32. 32.
    Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S et al (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295(12):1379–1388CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Jane C. Figueiredo
    • 1
    Email author
  • Robert W. Haile
    • 1
  • Leslie Bernstein
    • 2
  • Kathleen E. Malone
    • 3
  • Joan Largent
    • 4
  • Bryan Langholz
    • 5
  • Charles F. Lynch
    • 6
  • Lisbeth Bertelsen
    • 7
  • Marinela Capanu
    • 8
  • Patrick Concannon
    • 9
  • Ake Borg
    • 10
  • Anne-Lise Børresen-Dale
    • 11
    • 12
  • Anh Diep
    • 1
  • Sharon Teraoka
    • 9
  • Therese Torngren
    • 10
  • Shanyan Xue
    • 1
  • Jonine L. Bernstein
    • 8
  1. 1.Department of Preventive Medicine, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Division of Cancer Etiology, Department of Population Sciences, City of Hope Comprehensive Cancer CenterNational Medical CenterDuarteUSA
  3. 3.Division of Public Health SciencesFred Hutchinson Cancer Research CenterSeattleUSA
  4. 4.Department of Epidemiology, College of Health SciencesUniversity of California, IrvineIrvineUSA
  5. 5.Division of Biostatistics, Department of Preventive Medicine, Keck School of MedicineUniversity of Southern CaliforniaLos AngelesUSA
  6. 6.Department of EpidemiologyUniversity of IowaIowa CityUSA
  7. 7.Institute of Cancer Epidemiology, Danish Cancer SocietyCopenhagenDenmark
  8. 8.Department of Epidemiology and BiostatisticsMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  9. 9.Department of Biochemistry & Molecular Genetics, Center for Public Health GenomicsUniversity of VirginiaCharlottesvilleUSA
  10. 10.Department of OncologyUniversity HospitalLundSweden
  11. 11.Faculty of MedicineUniversity of OsloMontebello, OsloNorway
  12. 12.Department of Genetics, Institute for Cancer Research, Norwegian Radium HospitalRikshospitalet University Hospital, MontebelloOsloNorway

Personalised recommendations