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Tamoxifen and risk of contralateral breast cancer among women with inherited mutations in BRCA1 and BRCA2: a meta-analysis

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Abstract

Given the greatly elevated risks of contralateral breast cancer (CBC) observed in breast cancer patients who carry mutation in BRCA1 or BRCA2, the present meta-analysis was addressed to determine whether adjuvant tamoxifen treatment for breast cancer is associated with reduced CBC risk for these patients. We searched the database of PubMed for eligible studies about the effectiveness of tamoxifen on CBC risk among BRCA1/2 mutation carriers, and we calculated the pooled relative risks (RRs) for CBC risk along with 95 % confidence intervals (CIs). Fixed- or random-effects model was conducted according to study heterogeneity. Four non-overlapping studies met the inclusion criteria for the meta-analysis. Tamoxifen was found to be significantly associated with reduced risk of CBC among BRCA1/2 mutation carriers (summary RR = 0.56, 95 % CI = 0.41–0.76). Similar findings were observed in BRCA1 mutation carriers (summary RR = 0.47, 95 % CI = 0.37–0.60) and BRCA2 mutation carriers (summary RR = 0.39, 95 % CI = 0.28–0.54), respectively. In conclusion, tamoxifen significantly reduces the incidence of CBC among BRCA1/2 mutation carriers with primary unilateral breast cancer. It can reasonably be offered to breast cancer patients with BRCA1 or BRCA2 mutation for the prevention of CBC. Further studies are required to get a more precise estimation of the benefits and harms of tamoxifen in these patients.

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References

  1. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, et al. 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. 2003;72:1117–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Begg CB, Haile RW, Borg A, Malone KE, Concannon P, et al. Variation of breast cancer risk among BRCA1/2 carriers. JAMA. 2008;299:194–201.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Malone KE, Daling JR, Doody DR, Hsu L, Bernstein L, et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35–64 years. Cancer Res. 2006;66:8297–308.

    Article  CAS  PubMed  Google Scholar 

  4. Malone KE, Begg CB, Haile RW, Borg A, Concannon P, et al. Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol. 2010;28:2404–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2004;22:2328–35.

    Article  CAS  PubMed  Google Scholar 

  6. Pierce LJ, Levin AM, Rebbeck TR, Ben-David MA, Friedman E, et al. Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol. 2006;24:2437–43.

    Article  PubMed  Google Scholar 

  7. Verhoog LC, Brekelmans CT, Seynaeve C, Meijers-Heijboer EJ, Klijn JG. Contralateral breast cancer risk is influenced by the age at onset in BRCA1-associated breast cancer. Br J Cancer. 2000;83:384–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Collins IM, Milne RL, Weideman PC, McLachlan SA, Friedlander ML, et al. Preventing breast and ovarian cancers in high-risk BRCA1 and BRCA2 mutation carriers. Med J Aust. 2013;199:680–3.

    Article  PubMed  Google Scholar 

  9. Rutqvist LE, Cedermark B, Glas U, Mattsson A, Skoog L, et al. Contralateral primary tumors in breast cancer patients in a randomized trial of adjuvant tamoxifen therapy. J Natl Cancer Inst. 1991;83:1299–306.

    Article  CAS  PubMed  Google Scholar 

  10. Reding KW, Bernstein JL, Langholz BM, Bernstein L, Haile RW, et al. Adjuvant systemic therapy for breast cancer in BRCA1/BRCA2 mutation carriers in a population-based study of risk of contralateral breast cancer. Breast Cancer Res Treat. 2010;123:491–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Gronwald J, Robidoux A, Kim-Sing C, Tung N, Lynch HT, et al. Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat. 2014;146:421–7.

    Article  CAS  PubMed  Google Scholar 

  12. Phillips KA, Milne RL, Rookus MA, Daly MB, Antoniou AC, et al. Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2013;31:3091–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet. 2000;356:1876–81.

    Article  CAS  PubMed  Google Scholar 

  14. Gronwald J, Tung N, Foulkes WD, Offit K, Gershoni R, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer. 2006;118:2281–4.

    Article  CAS  PubMed  Google Scholar 

  15. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med. 1997;127:820–6.

    Article  CAS  PubMed  Google Scholar 

  16. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.

    CAS  PubMed  Google Scholar 

  17. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  18. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.

    Article  CAS  PubMed  Google Scholar 

  19. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. LaCroix AZ, Powles T, Osborne CK, Wolter K, Thompson JR, et al. Breast cancer incidence in the randomized PEARL trial of lasofoxifene in postmenopausal osteoporotic women. J Natl Cancer Inst. 2010;102:1706–15.

    Article  CAS  PubMed  Google Scholar 

  21. Martino S, Costantino J, McNabb M, Mershon J, Bryant K, et al. The role of selective estrogen receptor modulators in the prevention of breast cancer: comparison of the clinical trials. Oncologist. 2004;9:116–25.

    Article  CAS  PubMed  Google Scholar 

  22. Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652–62.

    Article  CAS  PubMed  Google Scholar 

  23. Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–37.

    Article  CAS  PubMed  Google Scholar 

  24. Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, et al. The effects of tibolone in older postmenopausal women. N Engl J Med. 2008;359:697–708.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Goss PE, Ingle JN, Ales-Martinez JE, Cheung AM, Chlebowski RT, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364:2381–91.

    Article  CAS  PubMed  Google Scholar 

  26. Johannsson OT, Idvall I, Anderson C, Borg A, Barkardottir RB, et al. Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer. 1997;33:362–71.

    Article  CAS  PubMed  Google Scholar 

  27. Robson M, Gilewski T, Haas B, Levin D, Borgen P, et al. BRCA-associated breast cancer in young women. J Clin Oncol. 1998;16:1642–9.

    CAS  PubMed  Google Scholar 

  28. Ansquer Y, Gautier C, Fourquet A, Asselain B, Stoppa-Lyonnet D. Survival in early-onset BRCA1 breast-cancer patients. Institut Curie Breast Cancer Group. Lancet. 1998;352:541.

    CAS  Google Scholar 

  29. Brekelmans CT, Tilanus-Linthorst MM, Seynaeve C, vd Ouweland A, Menke-Pluymers MB, et al. Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer. 2007;43:867–76.

    Article  CAS  PubMed  Google Scholar 

  30. Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S, et al. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet. 2013;381:1827–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Li CI, Malone KE, Weiss NS, Daling JR. Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer. J Natl Cancer Inst. 2001;93:1008–13.

    Article  CAS  PubMed  Google Scholar 

  32. Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26:1331–7.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Eisen A, Lubinski J, Klijn J, Moller P, Lynch HT, et al. Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case-control study. J Clin Oncol. 2005;23:7491–6.

    Article  PubMed  Google Scholar 

  34. Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304:967–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Heemskerk-Gerritsen BA, Seynaeve C, van Asperen CJ, Ausems MG, Collee JM, et al. Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. J Natl Cancer Inst. 2015;107(5). doi:10.1093/jnci/djv033.

  36. Ciarloni L, Mallepell S, Brisken C. Amphiregulin is an essential mediator of estrogen receptor alpha function in mammary gland development. Proc Natl Acad Sci USA. 2007;104:5455–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Harrison H, Simoes BM, Rogerson L, Howell SJ, Landberg G, et al. Oestrogen increases the activity of oestrogen receptor negative breast cancer stem cells through paracrine EGFR and Notch signalling. Breast Cancer Res. 2013;15:R21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Eakin CM, Maccoss MJ, Finney GL, Klevit RE. Estrogen receptor alpha is a putative substrate for the BRCA1 ubiquitin ligase. Proc Natl Acad Sci USA. 2007;104:5794–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Fan S, Wang J, Yuan R, Ma Y, Meng Q, et al. BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science. 1999;284:1354–6.

    Article  CAS  PubMed  Google Scholar 

  40. Cuzick J, Sestak I, Forbes JF, Dowsett M, Knox J, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014;383:1041–8.

    Article  CAS  PubMed  Google Scholar 

  41. Metcalfe KA, Snyder C, Seidel J, Hanna D, Lynch HT, et al. The use of preventive measures among healthy women who carry a BRCA1 or BRCA2 mutation. Fam Cancer. 2005;4:97–103.

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (81071753 81172505, 81202077 and 81272916), the Jiangsu Province’s Key Provincial Talents Program (BE 2011802), the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU (IRT-008) and a project Funded by the Priority Academic Program Development of Jiangsu higher Education Institutions (PAPD).

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The authors indicated no potential conflicts of interest.

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Correspondence to Lin Chen or Shui Wang.

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L. Xu, Y. Zhao, Z. Chen contributed equally to this work.

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Xu, L., Zhao, Y., Chen, Z. et al. Tamoxifen and risk of contralateral breast cancer among women with inherited mutations in BRCA1 and BRCA2: a meta-analysis. Breast Cancer 22, 327–334 (2015). https://doi.org/10.1007/s12282-015-0619-6

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  • DOI: https://doi.org/10.1007/s12282-015-0619-6

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