Breast Cancer Research and Treatment

, Volume 127, Issue 1, pp 233–241 | Cite as

Risk of second breast cancer according to estrogen receptor status and family history

  • Christine BouchardyEmail author
  • Simone Benhamou
  • Gérald Fioretta
  • Helena M. Verkooijen
  • Pierre O. Chappuis
  • Isabelle Neyroud-Caspar
  • Monica Castiglione
  • Vincent Vinh-Hung
  • Georges Vlastos
  • Elisabetta Rapiti


A recent study reported an increased risk of contralateral estrogen-negative breast cancer after a first primary estrogen-negative breast cancer. Our study aims to confirm this result and to evaluate how the risk of second breast cancer occurrence is affected by family history of breast cancer and anti-estrogen treatment. We included all 4,152 women diagnosed with breast cancer between 1995 and 2007, using data from the population-based Geneva Cancer Registry. We compared the incidence of second breast cancer among patients according to estrogen receptor (ER) status with that expected in the general population by age-period Standardized Incidence Ratios (SIRs). Among the cohort, 63 women developed second breast cancer. Patients with ER-positive first tumors had a decreased risk of second breast cancer occurrence (SIR: 0.67, 95% CI: 0.48–0.90), whereas patients with ER-negative primary tumors had an increased risk (SIR: 1.98, 95% CI: 1.19–3.09) limited to ER-negative second tumors (SIR: 7.94, 95% CI: 3.81–14.60). Patients with positive family history had a tenfold (SIR: 9.74, 95% CI: 3.57–21.12) higher risk of ER-negative second tumor which increased to nearly 50-fold (SIR: 46.18, 95% CI: 12.58–118.22) when the first tumor was ER-negative. Treatment with anti-estrogen decreased the risk of second ER-positive tumors but not ER-negative tumors. The risk of second ER-negative breast cancer is very high after a first ER-negative tumor, in particular among women with strong family history. Surveillance and prevention of second cancer occurrence should consider both ER status of the first tumor and family history.


Breast cancer Estrogen receptor status Second cancer Family history 



We thank Stina Blagojevic for technical and editorial assistance, the Cancer registry team for providing data and support, and Robin Schaffar for assistance in statistical analyses.


The set-up of the Family breast cancer registry was financially supported by the Swiss Cancer League (OCS 01380-08-2003, OCS 02070-04-2007); HM Verkooijen was financially supported by the Swiss Science Foundation, PROSPER Grant (3233-069350).


  1. 1.
    Chen Y, Thompson W, Semenciw R, Mao Y (1999) Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev 8(10):855–861PubMedGoogle Scholar
  2. 2.
    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Tamoxifen for early breast cancer: an overview of the randomised trials (1998) Lancet 351 (9114): 1451–1467Google Scholar
  3. 3.
    Li CI, Malone KE, Weiss NS, Daling JR (2001) Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer. J Natl Cancer Inst 93(13):1008–1013PubMedCrossRefGoogle Scholar
  4. 4.
    Kaas R, Peterse JL, Hart AA, Voogd AC, Rutgers EJ, Van Leeuwen FE (2003) The influence of tamoxifen treatment on the oestrogen receptor in metachronous contralateral breast cancer. Br J Cancer 88(5):707–710PubMedCrossRefGoogle Scholar
  5. 5.
    Swain SM, Wilson JW, Mamounas EP, Bryant J, Wickerham DL, Fisher B, Paik S, Wolmark N (2004) Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer. J Natl Cancer Inst 96(7):516–523PubMedCrossRefGoogle Scholar
  6. 6.
    Arpino G, Weiss HL, Clark GM, Hilsenbeck SG, Osborne CK (2005) Hormone receptor status of a contralateral breast cancer is independent of the receptor status of the first primary in patients not receiving adjuvant tamoxifen. J Clin Oncol 23(21):4687–4694PubMedCrossRefGoogle Scholar
  7. 7.
    Esserman LJ, Ozanne EM, Dowsett M, Slingerland JM (2005) Tamoxifen may prevent both ER+ and ER− breast cancers and select for ER− carcinogenesis: an alternative hypothesis. Breast Cancer Res 7(6):R1153–R1158PubMedCrossRefGoogle Scholar
  8. 8.
    Stark A, Lu M, Mackowiak P, Linden M (2005) Concordance of the hormone receptors and correlation of HER-2/neu overexpression of the metachronous cancers of contralateral breasts. Breast J 11(3):183–187PubMedCrossRefGoogle Scholar
  9. 9.
    Li CI, Daling JR, Porter PL, Tang MT, Malone KE (2009) Adjuvant hormonal therapy for breast cancer and risk of hormone receptor-specific subtypes of contralateral breast cancer. Cancer Res 69(17):6865–6870PubMedCrossRefGoogle Scholar
  10. 10.
    Bernstein JL, Lapinski RH, Thakore SS, Doucette JT, Thompson WD (2003) The descriptive epidemiology of second primary breast cancer. Epidemiology 14(5):552–558PubMedCrossRefGoogle Scholar
  11. 11.
    Weitzel JN, Robson M, Pasini B, Manoukian S, Stoppa-Lyonnet D, Lynch HT, McLennan J, Foulkes WD, Wagner T, Tung N, Ghadirian P, Olopade O, Isaacs C, Kim-Sing C, Moller P, Neuhausen SL, Metcalfe K, Sun P, Narod SA (2005) A comparison of bilateral breast cancers in BRCA carriers. Cancer Epidemiol Biomarkers Prev 14(6):1534–1538PubMedCrossRefGoogle Scholar
  12. 12.
    Chen Y, Semenciw R, Kliewer E, Shi Y, Mao Y (2001) Incidence of second primary breast cancer among women with a first primary in Manitoba, Canada. Breast Cancer Res Treat 67(1):35–40PubMedCrossRefGoogle Scholar
  13. 13.
    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):513–518PubMedCrossRefGoogle Scholar
  14. 14.
    Ji J, Hemminki K (2007) Risk for contralateral breast cancers in a population covered by mammography: effects of family history, age at diagnosis and histology. Breast Cancer Res Treat 105(2):229–236PubMedCrossRefGoogle Scholar
  15. 15.
    Hemminki K, Vaittinen P (1999) Familial risks in second primary breast cancer based on a family cancer database. Eur J Cancer 35(3):455–458PubMedCrossRefGoogle Scholar
  16. 16.
    Trentham-Dietz A, Newcomb PA, Nichols HB, Hampton JM (2007) Breast cancer risk factors and second primary malignancies among women with breast cancer. Breast Cancer Res Treat 105(2):195–207PubMedCrossRefGoogle Scholar
  17. 17.
    Louwman WJ, Vulto JC, Verhoeven RH, Nieuwenhuijzen GA, Coebergh JW, Voogd AC (2007) Clinical epidemiology of breast cancer in the elderly. Eur J Cancer 43(15):2242–2252PubMedCrossRefGoogle Scholar
  18. 18.
    Horn PL, Thompson WD (1988) Risk of contralateral breast cancer: associations with factors related to initial breast cancer. Am J Epidemiol 128(2):309–323PubMedGoogle Scholar
  19. 19.
    Dougherty SM, Mazhawidza W, Bohn AR, Robinson KA, Mattingly KA, Blankenship KA, Huff MO, McGregor WG, Klinge CM (2006) Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells. Endocr Relat Cancer 13(1):113–134PubMedCrossRefGoogle Scholar
  20. 20.
    Ivanova MM, Mazhawidza W, Dougherty SM, Minna JD, Klinge CM (2009) Activity and intracellular location of estrogen receptors alpha and beta in human bronchial epithelial cells. Mol Cell Endocrinol 305(1–2):12–21PubMedCrossRefGoogle Scholar
  21. 21.
    Dubey S, Siegfried JM, Traynor AM (2006) Non-small-cell lung cancer and breast carcinoma: chemotherapy and beyond. Lancet Oncol 7(5):416–424PubMedCrossRefGoogle Scholar
  22. 22.
    Niikawa H, Suzuki T, Miki Y, Suzuki S, Nagasaki S, Akahira J, Honma S, Evans DB, Hayashi S, Kondo T, Sasano H (2008) Intratumoral estrogens and estrogen receptors in human non-small cell lung carcinoma. Clin Cancer Res 14(14):4417–4426PubMedCrossRefGoogle Scholar
  23. 23.
    Stabile LP, Lyker JS, Gubish CT, Zhang W, Grandis JR, Siegfried JM (2005) Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects. Cancer Res 65(4):1459–1470PubMedCrossRefGoogle Scholar
  24. 24.
    Kurian AW, McClure LA, John EM, Horn-Ross PL, Ford JM, Clarke CA (2009) Second primary breast cancer occurrence according to hormone receptor status. J Natl Cancer Inst 101(15):1058–1065PubMedCrossRefGoogle Scholar
  25. 25.
    Bouchardy C (2007) Switzerland, Geneva. In: Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, Boyle P (eds) Cancer incidence in five continents vol. IX. International Agency for Research on Cancer, Lyon, pp 369–370Google Scholar
  26. 26.
    Fritz A, Percy C, A A, Shanmugaratnam K, Sobin L, Parkin DM, Whelan S (eds) (2000) ICD-O International classification of diseases for oncology. World Health Organization, GenevaGoogle Scholar
  27. 27.
    Coleman MP, Hermon C, Douglas A (1989) Person-Years (PYRS). A Fortran program for cohort study analysis. IARC Internal Report no. 89/006. International Agency for Research on Cancer, LyonGoogle Scholar
  28. 28.
    Verkooijen HM, Fioretta G, Chappuis PO, Vlastos G, Sappino AP, Benhamou S, Bouchardy C (2004) Set-up of a population-based familial breast cancer registry in Geneva, Switzerland: validation of first results. Ann Oncol 15(2):350–353PubMedCrossRefGoogle Scholar
  29. 29.
    Graeser MK, Engel C, Rhiem K, Gadzicki D, Bick U, Kast K, Froster UG, Schlehe B, Bechthold A, Arnold N, Preisler-Adams S, Nestle-Kraemling C, Zaino M, Loeffler M, Kiechle M, Meindl A, Varga D, Schmutzler RK (2009) Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27(35):5887–5892PubMedCrossRefGoogle Scholar
  30. 30.
    Brown M, Bauer K, Pare M (2010) Tumor marker phenotype concordance in second primary breast cancer, California, 1999–2004. Breast Cancer Res Treat 120(1):217–227PubMedCrossRefGoogle Scholar
  31. 31.
    Porter PL, El Bastawissi AY, Mandelson MT, Lin MG, Khalid N, Watney EA, Cousens L, White D, Taplin S, White E (1999) Breast tumor characteristics as predictors of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst 91(23):2020–2028PubMedCrossRefGoogle Scholar
  32. 32.
    Fisher ER, Redmond CK, Liu H, Rockette H, Fisher B (1980) Correlation of estrogen receptor and pathologic characteristics of invasive breast cancer. Cancer 45(2):349–353PubMedCrossRefGoogle Scholar
  33. 33.
    Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, Martino S, Perez EA, Muss HB, Norton L, Hudis C, Winer EP (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295(14):1658–1667PubMedCrossRefGoogle Scholar
  34. 34.
    Fisher B, Redmond C, Fisher ER, Caplan R (1988) Relative worth of estrogen or progesterone receptor and pathologic characteristics of differentiation as indicators of prognosis in node negative breast cancer patients: findings from National Surgical Adjuvant Breast and Bowel Project Protocol B-06. J Clin Oncol 6(7):1076–1087PubMedGoogle Scholar
  35. 35.
    Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ (2007) Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 18(7):1133–1144PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Christine Bouchardy
    • 1
    Email author
  • Simone Benhamou
    • 1
    • 2
    • 3
  • Gérald Fioretta
    • 1
  • Helena M. Verkooijen
    • 1
    • 4
  • Pierre O. Chappuis
    • 5
  • Isabelle Neyroud-Caspar
    • 1
  • Monica Castiglione
    • 1
  • Vincent Vinh-Hung
    • 6
  • Georges Vlastos
    • 7
  • Elisabetta Rapiti
    • 1
  1. 1.Geneva Cancer Registry, Institute for Social and Preventive Medicine, University of GenevaGenevaSwitzerland
  2. 2.INSERM, U946, Fondation Jean Dausset-CEPHParisFrance
  3. 3.CNRS UMR8200, Gustave-Roussy InstituteVillejuifFrance
  4. 4.Department of Epidemiology and Public HealthNational University of SingaporeSingaporeSingapore
  5. 5.Department of Internal Medicine, Department of Genetic Medicine and LaboratoryGeneva University HospitalsGenevaSwitzerland
  6. 6.Division of Radiation OncologyGeneva University HospitalsGenevaSwitzerland
  7. 7.Senology Unit, Department of Gynecology and ObstetricsGeneva University HospitalsGenevaSwitzerland

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