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  • Review Article
  • Published:

Bilateral breast cancers

Key Points

  • On average, the annual risk of contralateral breast cancer following a diagnosis of breast cancer is 0.5%, but this risk varies between individuals

  • A young age at first diagnosis is associated with a very high relative risk of contralateral breast cancer

  • The risk of contralateral breast cancer is increased in women with mutations in BRCA1, BRCA2, CHEK2 or a strong family history of breast cancer

  • The reduction in mortality associated with contralateral mastectomy is a consequence of the prevention of deaths from contralateral cancer

  • Risk assessment for contralateral breast cancer is appropriate before recommending contralateral mastectomy

Abstract

An increasingly large proportion of women with unilateral breast cancer are treated with bilateral mastectomy. The rationale behind bilateral surgery is to prevent a second primary breast cancer and thereby to avoid the resultant therapy and eliminate the risk of death from contralateral breast cancer. Bilateral mastectomy has been proposed to benefit women at high risk of contralateral cancer, such as carriers of BRCA1 and BRCA2 mutations, but for women without such mutations, the decision to remove the contralateral breast is controversial. It is important to evaluate the risk of contralateral breast cancer on an individual basis, and to tailor surgical treatment accordingly. On average, the annual risk of contralateral breast cancer is approximately 0.5%, but increases to 3% in carriers of a BRCA1 or BRCA2 mutation. Risk factors for contralateral breast cancer include a young age at first diagnosis of breast cancer and a family history of breast cancer. Contralateral mastectomy has not been proven to reduce mortality from breast cancer, but the benefit of such surgery is not expected to become apparent until the second decade after treatment. An alternative to contralateral mastectomy is adjuvant hormonal therapy (such as tamoxifen), but the extent of risk reduction is smaller (approximately 50%) compared to 95% or more for contralateral mastectomy. This Review focuses on the risk factors for contralateral breast cancer, and discusses the evidence that bilateral mastectomy might reduce mortality in patients with unilateral breast cancer.

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Figure 1: Contralateral breast cancer.

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References

  1. Barry, M. & Sacchini, V. When is contralateral mastectomy warranted in unilateral breast cancer? Expert Rev. Anticancer Ther. 11, 1209–1214 (2011).

    Article  PubMed  Google Scholar 

  2. Murphy, J. A., Milner, T. D. & O'Donoghue, J. M. Contralateral risk-reducing mastectomy in sporadic breast cancer. Lancet Oncol. 14, e262–e269 (2013).

    Article  PubMed  Google Scholar 

  3. Gilbert, A. Why more women are choosing double mastectomies [online], (2013).

    Google Scholar 

  4. Tuttle, T. M., Habermann, E. B., Grund, E. H., Morris, T. J. & Virnig, B. A. Increasing use of contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical treatment. J. Clin. Oncol. 25, 5203–5209 (2007).

    Article  PubMed  Google Scholar 

  5. King, T. A. et al. Clinical management factors contribute to the decision for contralateral prophylactic mastectomy. J. Clin. Oncol. 29, 2158–2164 (2011).

    Article  PubMed  Google Scholar 

  6. Rosenberg, S. M. et al. Perceptions, knowledge, and satisfaction with contralateral prophylactic mastectomy among young women with breast cancer: a cross-sectional survey. Ann. Intern. Med. 159, 373–381 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Banelli, B. et al. Pathological and molecular characteristics distinguishing contralateral metastatic from new primary breast cancer. Ann. Oncol. 21, 1237–1242 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Kim, M. Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315–1326 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hartman, M. et al. Incidence and prognosis of synchronous and metachronous bilateral breast cancer. J. Clin. Oncol. 25, 4210–4216 (2007).

    Article  PubMed  Google Scholar 

  10. Schaapveld, M. et al. The impact of adjuvant therapy on contralateral breast cancer risk and the prognostic significance of contralateral breast cancer: a population based study in the Netherlands. Breast Cancer Res. Treat. 110, 189–197 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Intra, M. et al. Clinicopathologic characteristics of 143 patients with synchronous bilateral invasive breast carcinomas treated in a single institution. Cancer 101, 905–912 (2004).

    Article  PubMed  Google Scholar 

  12. Huo, D., Melkonian, S., Rathouz, P. J., Khramtsov, A. & Olopade, O. I. Concordance in histological and biological parameters between first and second primary breast cancers. Cancer 117, 907–915 (2011).

    Article  PubMed  Google Scholar 

  13. Brennan, M. E. et al. Magnetic resonance imaging screening of the contralateral breast in women with newly diagnosed breast cancer: systematic review and meta-analysis of incremental cancer detection and impact on surgical management. J. Clin. Oncol. 27, 5640–5649 (2009).

    Article  PubMed  Google Scholar 

  14. King, T. A. et al. Occult malignancy in patients undergoing contralateral prophylactic mastectomy. Ann. Surg. 254, 2–7 (2011).

    Article  PubMed  Google Scholar 

  15. Sorbero, M. E., Dick, A. W., Beckjord, E. B. & Ahrendt, G. Diagnostic breast magnetic resonance imaging and contralateral prophylactic mastectomy. Ann. Surg. Oncol. 16, 1597–1605 (2009).

    Article  PubMed  Google Scholar 

  16. Chen, Y., Thompson, W., Semenciw, R. & Mao, Y. Epidemiology of contralateral breast cancer. Cancer Epidemiol. Biomarkers Prev. 8, 855–861 (1999).

    CAS  PubMed  Google Scholar 

  17. National Comprehensive Cancer Network (NCCN) in Breast Cancer NCCN Practice Guidelines in Oncology (ver. 2.2011) binv-16 (NCCN, 2011).

  18. Houssami, N., Ciatto, S., Martinelli, F., Bonardi, R. & Duffy, S. W. Early detection of second breast cancers improves prognosis in breast cancer survivors. Ann. Oncol. 20, 1505–1510 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Solin, L. J., Orel, S. G., Hwang, W. T., Harris, E. E. & Schnall, M. D. Relationship of breast magnetic resonance imaging to outcome after breast-conservation treatment with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ. J. Clin. Oncol. 26, 386–391 (2008).

    Article  PubMed  Google Scholar 

  20. Cancer Incidence in Five Continents Volume VIII (eds Parkin, D. M. et al.) (International Agency for Research on Cancer, 2002).

  21. Rutqvist, L. E. et al. Contralateral primary tumors in breast cancer patients in a randomized trial of adjuvant tamoxifen therapy. J. Natl Cancer Inst. 83, 1299–1306 (1991).

    Article  CAS  PubMed  Google Scholar 

  22. Vaittinen, P. & Hemminki, K. Risk factors and age-incidence relationships for contralateral breast cancer. Int. J. Cancer 88, 998–1002 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Kurian, A. W. et al. Second primary breast cancer occurrence according to hormone receptor status. J. Natl Cancer Inst. 101, 1058–1065 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Walsh, T. & King, M. C. Ten genes for inherited breast cancer. Cancer Cell 11, 103–105 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Metcalfe, K. et al. Predictors of contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. Br. J. Cancer 104, 1384–1392 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mavaddat, N. et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J. Natl Cancer Inst. 105, 812–822 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Malone, K. E. 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. 28, 2404–2410 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Narod, S. A. et al. A prior diagnosis of breast cancer is a risk factor for breast cancer in BRCA1 and BRCA2 carriers Curr. Oncol. (in press).

  29. Graeser, M. K. et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J. Clin. Oncol. 27, 5887–5892 (2009).

    Article  PubMed  Google Scholar 

  30. Gronwald, J. et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int. J. Cancer 118, 2281–2284 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Phillips, K. A. et al. Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J. Clin. Oncol. 31, 3091–3099 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Domchek, S. M. et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 304, 967–975 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Reding, K. W. 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. 123, 491–498 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Metcalfe, K. A. et al. International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers. Int. J. Cancer 122, 2017–2022 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lodder, L. N. et al. One year follow-up of women opting for presymptomatic testing for BRCA1 and BRCA2: emotional impact of the test outcome and decisions on risk management (surveillance or prophylactic surgery). Breast Cancer Res. Treat. 73, 97–112 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Evans, D. G. et al. Contralateral mastectomy improves survival in women with BRCA1/2-associated breast cancer. Breast Cancer Res. Treat. 140, 135–142 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Laitman, Y. et al. Rates of risk-reducing surgery in Israeli BRCA1 and BRCA2 mutation carriers. Clin. Genet. 85, 68–71 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Singer, C. F. et al. Clinical implications of genetic testing for BRCA1 and BRCA2 mutations in Austria. Clin. Genet. 85, 72–75 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Zhang, S. et al. Frequency of the CHEK2 1100delC mutation among women with breast cancer: an international study. Cancer Res. 68, 2154–2157 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Mellemkjaer, L. et al. Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study. Br. J. Cancer 98, 728–733 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Broeks, A. et al. Excess risk for contralateral breast cancer in CHEK2*1100delC germline mutation carriers. Breast Cancer Res. Treat. 83, 91–93 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Narod, S. A. Testing for CHEK2 in the cancer genetics clinic: ready for prime time? Clin. Genet. 78, 1–7 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Ghoussaini, M. & Pharoah, P. D. Polygenic susceptibility to breast cancer: current state-of-the-art. Future Oncol. 5, 689–701 (2009).

    Article  PubMed  Google Scholar 

  44. Teraoka, S. N. et al. Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study. Breast Cancer Res. 13, R114 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Horn, P. L. & Thompson, W. D. Risk of contralateral breast cancer: associations with factors related to initial breast cancer. Am. J. Epidemiol. 128, 309–323 (1998).

    Article  Google Scholar 

  46. Reiner, A. S. et al. Risk of asynchronous contralateral breast cancer in noncarriers of BRCA1 and BRCA2 mutations with a family history of breast cancer: a report from the Women's Environmental Cancer and Radiation Epidemiology Study. J. Clin. Oncol. 31, 433–439 (2013).

    Article  PubMed  Google Scholar 

  47. Poynter, J. N. et al. Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study. Cancer Causes Control 21, 839–846 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Largent, J. A. et al. Reproductive history and risk of second primary breast cancer: the WECARE study. Cancer Epidemiol. Biomarkers Prev. 16, 906–911 (2007).

    Article  PubMed  Google Scholar 

  49. Knight, J. A. et al. Alcohol intake and cigarette smoking and risk of a contralateral breast cancer: The Women's Environmental Cancer and Radiation Epidemiology Study. Am. J. Epidemiol. 169, 962–968 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Figueiredo, J. C. et al. Oral contraceptives, postmenopausal hormones, and risk of asynchronous bilateral breast cancer: the WECARE Study Group. J. Clin. Oncol. 26, 1411–1418 (2008).

    Article  PubMed  Google Scholar 

  51. Brooks, J. D. et al. Body mass index and risk of second primary breast cancer: the WECARE Study. Breast Cancer Res. Treat. 131, 571–580 (2012).

    Article  PubMed  Google Scholar 

  52. Boyd, N. F., Martin, L. J., Yaffe, M. J. & Minkin, S. Mammographic density and breast cancer risk: current understanding and future prospects. Breast Cancer Res. 13, 223 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Cil, T. et al. Mammographic density and the risk of breast cancer recurrence after breast-conserving surgery. Cancer 115, 5780–5787 (2009).

    Article  PubMed  Google Scholar 

  54. Sandberg, M. E. et al. Change of mammographic density predicts the risk of contralateral breast cancer: a case–control study. Breast Cancer Res. 15, R57 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Vogel, V. G. et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 trial: preventing breast cancer. Cancer Prev. Res. (Phila.) 3, 696–706 (2010).

    Article  CAS  Google Scholar 

  56. Goss, P. E. Letrozole in the extended adjuvant setting: MA.17. Breast Cancer Res. Treat. 105, 45–53 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Alkner, S. et al. Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women: results from a controlled randomised trial. Eur. J. Cancer 45, 2496–2502 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Early Breast Cancer Trialists Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365, 1687–1717 (2005).

  59. Arpino, G., Bardou, V. J., Clark, G. M. & Elledge, R. M. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res. 6, R149–R156 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Saltzman, B. S., Malone, K. E., McDougall, J. A., Daling, J. R. & Li, C. I. Estrogen receptor, progesterone receptor, and HER2-neu expression in first primary breast cancers and risk of second primary contralateral breast cancer. Breast Cancer Res. Treat. 135, 849–855 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Swain, S. M. et al. Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer. J. Natl Cancer Inst. 96, 516–523 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Arpino, G., Weiss, H. L., Clark, G. M., Hilsenbeck, S. G. & Osborne, C. K. 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, 4687–4694 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Safal, M. et al. Bilateral synchronous breast cancer and HER-2/neu overexpression. Breast Cancer Res. Treat. 72, 195–201 (2002).

    Article  PubMed  Google Scholar 

  64. Bessonova, L., Taylor, T. H., Mehta, R. S., Zell, J. A. & Anton-Culver, H. Risk of a second breast cancer associated with hormone-receptor and HER2/neu status of the first breast cancer. Cancer Epidemiol. Biomarkers Prev. 20, 389–396 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Stark, A., Lu, M., Mackowiak, P. & Linden, M. Concordance of the hormone receptors and correlation of HER-2/neu overexpression of the metachronous cancers of contralateral breasts. Breast J. 11, 183–187 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Russnes, H. G. et al. Paired distribution of molecular subtypes in bilateral breast carcinomas. Cancer Genet. 204, 96–102 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Coradini, D. et al. Is steroid receptor profile in contralateral breast cancer a marker of independence of the corresponding primary tumour? J. Cancer 34, 825–830 (1998).

    CAS  Google Scholar 

  68. Kollias, J. et al. Phenotypic similarities in bilateral breast cancer. Breast Cancer Res. Treat. 85, 255–261 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Weitzel, J. N. et al. A comparison of bilateral breast cancers in BRCA carriers. Cancer Epidemiol. Biomarkers Prev. 14, 1534–1538 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Suspitsin, E. N. et al. TP53 mutations in synchronous and metachronous bilateral breast carcinomas. Cancer Genet. Cytogenet. 184, 119–121 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Suspitsin, E. N. et al. Nonrandom distribution of oncogene amplifications in bilateral breast carcinomas: possible role of host factors and survival bias. Int. J. Cancer 120, 297–302 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Narod, S. A. Breast cancer in young women. Nat. Rev. Clin. Oncol. 9, 460–470 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Narod, S. A. A model for breast cancer risk based on stem-cell theory. Curr. Oncol. 19, 9–11 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Dontu, G., El-Ashry, D. & Wicha, M. S. Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol. Metab. 15, 193–197 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Ruark, E. et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 493, 406–410 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Pal, B. et al. Global changes in the mammary epigenome are induced by hormonal cues and coordinated by Ezh2. Cell Rep. 3, 411–426 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Narod, S. A. The impact of contralateral mastectomy on mortality in BRCA1 and BRCA2 mutation carriers with breast cancer. Breast Cancer Res. Treat. 128, 581–583 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Brewster, A. M. et al. Association between contralateral prophylactic mastectomy and breast cancer outcomes by hormone receptor status. Cancer 118, 5637–5643 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Herrinton, L. J. et al. Efficacy of prophylactic mastectomy in women with unilateral breast cancer: a cancer research network project. J. Clin. Oncol. 23, 4275–4286 (2005).

    Article  PubMed  Google Scholar 

  80. Bedrosian, I., Hu, C. Y. & Chang, G. J. Population-based study of contralateral prophylactic mastectomy and survival outcomes of breast cancer patients. J. Natl Cancer Inst. 102, 401–409 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Tyrer, J., Duffy, S. W. & Cuzick, J. A breast cancer prediction model incorporating familial and personal risk factors. Stat. Med. 23, 1111–1130 (2004).

    Article  PubMed  Google Scholar 

  82. Campbell, H. E., Taylor, M. A., Harris, A. L. & Gray, A. M. An investigation into the performance of the Adjuvant! Online prognostic programme in early breast cancer for a cohort of patients in the United Kingdom. Br. J. Cancer 101, 1074–1084 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wishart, G. C. et al. PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer. Breast Cancer Res. 12, R1 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Steven A. Narod.

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Narod, S. Bilateral breast cancers. Nat Rev Clin Oncol 11, 157–166 (2014). https://doi.org/10.1038/nrclinonc.2014.3

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