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Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer

Nature Reviews Clinical Oncology volume 16, pages 296–311 (2019)Cite this article

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Abstract

Women with early-stage oestrogen receptor (ER)-positive (ER+) breast cancer who receive standard endocrine therapy for 5 years remain at risk of distant recurrence for at least 15 years after treatment discontinuation. The extension of the duration of adjuvant endocrine therapy to 10 years has been shown to reduce the risk of recurrence only in a subset of women and, to date, predictive biomarkers of benefit from therapy do not exist. In this Review, we briefly explore the epidemiology of late recurrence (>5 years after diagnosis) in patients with ER+ breast cancer. The mechanisms underlying this phenomenon remain poorly understood; we discuss the evidence currently available on processes such as alterations of gene expression or specific genomic aberrations and examine several models used for risk prognostication and for estimating the presence of minimal residual disease, as well as the relevance of these prediction tools for clinicians and patients. Our aim is to enable clinicians to make well-informed decisions on whether to extend endocrine therapy for each individual patient.

Key points

  • Oestrogen receptor (ER)-positive (ER+) breast cancer is at least as likely to recur beyond 5 years as it is before 5 years from diagnosis.

  • Extended endocrine therapy is likely to improve survival in a subgroup of women with ER+ breast cancer; all women should be evaluated for their likely risk of recurrence at the completion of 5 years of endocrine therapy.

  • Clinical and genomic expression models can help stratify patients for their risk of late recurrence, but most are not predictive of benefit from extended endocrine therapy.

  • Dormancy of ER+ breast cancer occurs through a multitude of mechanisms; microscopic disease can emerge from dormancy in some women in response to unidentified triggers.

  • Monitoring of minimal residual disease through circulating tumour cells and circulating tumour DNA is likely to prove beneficial for anticipating late recurrence.

  • An individualized, patient-centred approach to long-term risk management is essential owing to the protracted length of survivorship and its ensuing complexity.

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Fig. 1: Outcomes of women with oestrogen receptor-positive breast cancer.
Fig. 2: Potential effects of a 5-year course of adjuvant endocrine therapy with or without chemotherapy on the natural history of subclinical micrometastatic disease.
Fig. 3: Coexistence of two modes of dormancy: cellular quiescence and balanced proliferation and cell death.
Fig. 4: Decision-making aid for clinical and genomic testing.

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References

  1. Esserman, L. J. et al. Biologic markers determine both the risk and the timing of recurrence in breast cancer. Breast Cancer Res. Treat. 129, 607–616 (2011).

    PubMed  PubMed Central  Google Scholar 

  2. Pan, H. et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N. Engl. J. Med. 377, 1836–1846 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. Cancer Research UK. Breast cancer statistics. CRUK http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer (2018).

  4. Dodson, A. et al. ER, PR and HER2 biomarkers in UK and Irish clinical breast cancer testing: analysis of results from>168,000 patients. Cancer Res. 78, (Suppl.), PR-08-16 (2017).

    Google Scholar 

  5. Cancer Research UK. Breast cancer incidence (invasive) statistics. CRUK https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/incidence-invasive (2018).

  6. Rosenberg, P. S., Barker, K. A. & Anderson, W. F. Estrogen receptor status and the future burden of invasive and in situ breast cancers in the United States. J. Natl Cancer Inst. 107, djv159 (2015).

    PubMed  PubMed Central  Google Scholar 

  7. Early Breast Cancer Trialists’ Collaborative Group. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 386, 1341–1352 (2015).

    Google Scholar 

  8. Fisher, B., Dignam, J., Bryant, J. & Wolmark, N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J. Natl Cancer Inst. 93, 684–690 (2001).

    CAS  PubMed  Google Scholar 

  9. Davies, C. et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381, 805–816 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Gray, R. G. et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J. Clin. Oncol. 31, S5 (2013).

    Google Scholar 

  11. Goss, P. E. et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J. Natl Cancer Inst. 97, 1262–1271 (2005).

    CAS  PubMed  Google Scholar 

  12. Mamounas, E. P. et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J. Clin. Oncol. 26, 1965–1971 (2008).

    CAS  PubMed  Google Scholar 

  13. Goss, P. E. et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N. Engl. J. Med. 375, 209–219 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Tjan-Heijnen, V. C. G. et al. Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial. Lancet Oncol. 18, 1502–1511 (2017).

    CAS  PubMed  Google Scholar 

  15. Blok, E. J. et al. Optimal duration of extended adjuvant endocrine therapy for early breast cancer; results of the IDEAL trial (BOOG 2006–2005). J. Natl Cancer Inst. 110, 40–48 (2018).

    Google Scholar 

  16. Baselga, J. et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J. Clin. Oncol. 27, 2630–2637 (2009).

    CAS  PubMed  Google Scholar 

  17. Gomis, R. R. & Gawrzak, S. Tumor cell dormancy. Mol. Oncol. 11, 62–78 (2017).

    PubMed  PubMed Central  Google Scholar 

  18. Zhang, X. H., Giuliano, M., Trivedi, M. V., Schiff, R. & Osborne, C. K. Metastasis dormancy in estrogen receptor-positive breast cancer. Clin. Cancer Res. 19, 6389–6397 (2013).

    CAS  PubMed  Google Scholar 

  19. Aguirre-Ghiso, J. A. Models, mechanisms and clinical evidence for cancer dormancy. Nat. Rev. Cancer 7, 834–846 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sosa, M. S., Avivar-Valderas, A., Bragado, P., Wen, H. C. & Aguirre-Ghiso, J. A. ERK1/2 and p38alpha/beta signaling in tumor cell quiescence: opportunities to control dormant residual disease. Clin. Cancer Res. 17, 5850–5857 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Yeh, A. C. & Ramaswamy, S. Mechanisms of cancer cell dormancy—another hallmark of cancer? Cancer Res. 75, 5014–5022 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ogba, N. et al. Luminal breast cancer metastases and tumor arousal from dormancy are promoted by direct actions of estradiol and progesterone on the malignant cells. Breast Cancer Res. 16, 489 (2014).

    PubMed  PubMed Central  Google Scholar 

  23. Fluegen, G. et al. Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments. Nat. Cell Biol. 19, 120–132 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Johnson, R. W. et al. Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat. Cell Biol. 18, 1078–1089 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gao, H. et al. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150, 764–779 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lawson, D. A. et al. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 526, 131–135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Naumov, G. N. et al. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J. Natl Cancer Inst. 98, 316–325 (2006).

    PubMed  Google Scholar 

  29. Dunbier, A. K. et al. Molecular profiling of aromatase inhibitor-treated postmenopausal breast tumors identifies immune-related correlates of resistance. Clin. Cancer Res. 19, 2775–2786 (2013).

    CAS  PubMed  Google Scholar 

  30. Denkert, C. et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J. Clin. Oncol. 28, 105–113 (2010).

    CAS  PubMed  Google Scholar 

  31. Heindl, A. et al. Relevance of spatial heterogeneity of immune infiltration for predicting risk of recurrence after endocrine therapy of ER+breast cancer. J. Natl Cancer Inst. 110, 166–175 (2018).

    Google Scholar 

  32. Kim, R. S. et al. Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. PLOS ONE 7, e35569 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lu, X. et al. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell 20, 701–714 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    CAS  PubMed  Google Scholar 

  35. Gawrzak, S. et al. MSK1 regulates luminal cell differentiation and metastatic dormancy in ER( + ) breast cancer. Nat. Cell Biol. 20, 211–221 (2018).

    CAS  PubMed  Google Scholar 

  36. Walter, D. et al. Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells. Nature 520, 549–552 (2015).

    PubMed  Google Scholar 

  37. Naumov, G. N. et al. Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res. Treat. 82, 199–206 (2003).

    CAS  PubMed  Google Scholar 

  38. Hurst, R. E., Bastian, A., Bailey-Downs, L. & Ihnat, M. A. Targeting dormant micrometastases: rationale, evidence to date and clinical implications. Ther. Adv. Med. Oncol. 8, 126–137 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Hurst, R. E. et al. Identification of novel drugs to target dormant micrometastases. BMC Cancer 15, 404 (2015).

    PubMed  PubMed Central  Google Scholar 

  40. Goss, P. E. & Chambers, A. F. Does tumour dormancy offer a therapeutic target? Nat. Rev. Cancer 10, 871–877 (2010).

    CAS  PubMed  Google Scholar 

  41. Bear, H. D. et al. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 16, 1037–1048 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee, E. S. et al. Factors associated with late recurrence after completion of 5-year adjuvant tamoxifen in estrogen receptor positive breast cancer. BMC Cancer 16, 430 (2016).

    PubMed  PubMed Central  Google Scholar 

  43. Sestak, I. et al. Factors predicting late recurrence for estrogen receptor-positive breast cancer. J. Natl Cancer Inst. 105, 1504–1511 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Dowsett, M. et al. Integration of clinical variables for the prediction of late distant recurrence in patients with estrogen receptor-positive breast cancer treated with 5 years of endocrine therapy: CTS5. J. Clin. Oncol. 36, 1941–1948 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Cuzick, J. et al. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J. Clin. Oncol. 29, 4273–4278 (2011).

    PubMed  Google Scholar 

  46. Bianchini, G. et al. Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers. Breast Cancer Res. 15, R86 (2013).

    PubMed  PubMed Central  Google Scholar 

  47. Dowsett, M. et al. Estrogen receptor expression in 21-gene recurrence score predicts increased late recurrence for estrogen-positive/HER2-negative breast cancer. Clin. Cancer Res. 21, 2763–2770 (2015).

    CAS  PubMed  Google Scholar 

  48. Lin, Y. C., Lee, Y. C., Li, L. H., Cheng, C. J. & Yang, R. B. Tumor suppressor SCUBE2 inhibits breast-cancer cell migration and invasion through the reversal of epithelial-mesenchymal transition. J. Cell Sci. 127, 85–100 (2014).

    PubMed  Google Scholar 

  49. Cheng, C. J. et al. SCUBE2 suppresses breast tumor cell proliferation and confers a favorable prognosis in invasive breast cancer. Cancer Res. 69, 3634–3641 (2009).

    CAS  PubMed  Google Scholar 

  50. Wilson, T. R. et al. The molecular landscape of high-risk early breast cancer: comprehensive biomarker analysis of a phase III adjuvant population. NPJ Breast Cancer 2, 16022 (2016).

    PubMed  PubMed Central  Google Scholar 

  51. Dubsky, P. et al. The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. Br. J. Cancer 109, 2959–2964 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Filipits, M. et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin. Cancer Res. 17, 6012–6020 (2011).

    CAS  PubMed  Google Scholar 

  53. Sgroi, D. C. et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol. 14, 1067–1076 (2013).

    PubMed  PubMed Central  Google Scholar 

  54. van de Vijver, M. J. et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002).

    PubMed  Google Scholar 

  55. Paik, S. et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N. Engl. J. Med. 351, 2817–2826 (2004).

    CAS  PubMed  Google Scholar 

  56. Paik, S. et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J. Clin. Oncol. 24, 3726–3734 (2006).

    CAS  PubMed  Google Scholar 

  57. Sparano, J. A. et al. Prospective validation of a 21-gene expression assay in breast cancer. N. Engl. J. Med. 373, 2005–2014 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Sestak, I. et al. Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol. 4, 545–553 (2018).

    PubMed  PubMed Central  Google Scholar 

  59. Wolmark, N. et al. Prognostic impact of the combination of recurrence score and quantitative estrogen receptor expression (ESR1) on predicting late distant recurrence risk in estrogen receptor-positive breast cancer after 5 years of tamoxifen: results from NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14. J. Clin. Oncol. 34, 2350–2358 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Parker, J. S. et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27, 1160–1167 (2009).

    PubMed  PubMed Central  Google Scholar 

  61. Dowsett, M. et al. Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J. Clin. Oncol. 31, 2783–2790 (2013).

    PubMed  Google Scholar 

  62. Sestak, I. et al. Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. J. Clin. Oncol. 33, 916–922 (2015).

    CAS  PubMed  Google Scholar 

  63. Buus, R. et al. Comparison of EndoPredict and EPclin with Oncotype DX recurrence score for prediction of risk of distant recurrence after endocrine therapy. J. Natl Cancer Inst. 108, djw149 (2016).

    PubMed Central  Google Scholar 

  64. Jerevall, P. L. et al. Prognostic utility of HOXB13:IL17BR and molecular grade index in early-stage breast cancer patients from the Stockholm trial. Br. J. Cancer 104, 1762–1769 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Rutqvist, L. E. & Johansson, H. Long-term follow-up of the randomized Stockholm trial on adjuvant tamoxifen among postmenopausal patients with early stage breast cancer. Acta Oncol. 46, 133–145 (2007).

    CAS  PubMed  Google Scholar 

  66. Zhang, Y. et al. Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early- and late-distant recurrence. Clin. Cancer Res. 19, 4196–4205 (2013).

    CAS  PubMed  Google Scholar 

  67. Schroeder, B. et al. Risk stratification with Breast Cancer Index for late distant recurrence in patients with clinically low-risk (T1N0) estrogen receptor-positive breast cancer. NPJ Breast Cancer 3, 28 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. Sgroi, D. C. et al. Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker. J. Natl Cancer Inst. 105, 1036–1042 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Filipits, M. et al. The PAM50 risk-of-recurrence score predicts risk for late distant recurrence after endocrine therapy in postmenopausal women with endocrine-responsive early breast cancer. Clin. Cancer Res. 20, 1298–1305 (2014).

    CAS  PubMed  Google Scholar 

  70. Cheng, Q. et al. A signature of epithelial-mesenchymal plasticity and stromal activation in primary tumor modulates late recurrence in breast cancer independent of disease subtype. Breast Cancer Res. 16, 407 (2014).

    PubMed  PubMed Central  Google Scholar 

  71. Buus, R. et al. Novel 18-gene signature predicts early and late relapse in ER+/HER2- breast cancer patients [abstract B14]. Presented at the 2015 NCRI Cancer Conference in Liverpool.

  72. Yates, L. R. et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 32, 169–184 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

    Google Scholar 

  74. Jeselsohn, R. et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin. Cancer Res. 20, 1757–1767 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Fribbens, C. et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J. Clin. Oncol. 34, 2961–2968 (2016).

    CAS  PubMed  Google Scholar 

  76. Schiavon, G. et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci. Transl Med. 7, 313ra182 (2015).

    PubMed  PubMed Central  Google Scholar 

  77. Allouchery, V. et al. Circulating ESR1 mutations at the end of aromatase inhibitor adjuvant treatment and after relapse in breast cancer patients. Breast Cancer Res. 20, 40 (2018).

    PubMed  PubMed Central  Google Scholar 

  78. Miller, C. A. et al. Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers. Nat. Commun. 7, 12498 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Lopez-Knowles, E. et al. Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer. Breast Cancer Res. 17, 35 (2015).

    PubMed  PubMed Central  Google Scholar 

  80. Zhang, Y. et al. Copy number alterations that predict metastatic capability of human breast cancer. Cancer Res. 69, 3795–3801 (2009).

    CAS  PubMed  Google Scholar 

  81. Braun, S. et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N. Engl. J. Med. 353, 793–802 (2005).

    CAS  PubMed  Google Scholar 

  82. O’Leary, B. et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat. Commun. 9, 896 (2018).

    PubMed  PubMed Central  Google Scholar 

  83. Cristofanilli, M. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 351, 781–791 (2004).

    CAS  PubMed  Google Scholar 

  84. Rack, B. et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J. Natl Cancer Inst. 106, dju066 (2014).

    PubMed  PubMed Central  Google Scholar 

  85. Janni, W. J. et al. Pooled analysis of the prognostic relevance of circulating tumor cells in primary breast cancer. Clin. Cancer Res. 22, 2583–2593 (2016).

    CAS  PubMed  Google Scholar 

  86. Bauer, E. C. A. et al. Prevalence of circulating tumor cells in early breast cancer patients 2 and 5 years after adjuvant treatment. Breast Cancer Res. Treat. 171, 571–580 (2018).

    CAS  PubMed  Google Scholar 

  87. Sparano, J. et al. Association of circulating tumor cells with late recurrence of estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2018.2574 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Garcia-Murillas, I. et al. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci. Transl Med. 7, 302ra133 (2015).

    PubMed  Google Scholar 

  89. Meng, S. et al. Circulating tumor cells in patients with breast cancer dormancy. Clin. Cancer Res. 10, 8152–8162 (2004).

    PubMed  Google Scholar 

  90. Schairer, C., Mink, P. J., Carroll, L. & Devesa, S. S. Probabilities of death from breast cancer and other causes among female breast cancer patients. J. Natl Cancer Inst. 96, 1311–1321 (2004).

    PubMed  Google Scholar 

  91. Fagerlin, A., Zikmund-Fisher, B. J. & Ubel, P. A. Helping patients decide: ten steps to better risk communication. J. Natl Cancer Inst. 103, 1436–1443 (2011).

    PubMed  PubMed Central  Google Scholar 

  92. Moschetti, I., Cinquini, M., Lambertini, M., Levaggi, A. & Liberati, A. Follow-up strategies for women treated for early breast cancer. Cochrane Database Syst. Rev. 5, CD001768 (2016).

    Google Scholar 

  93. Custers, J. A. et al. Towards an evidence-based model of fear of cancer recurrence for breast cancer survivors. J. Cancer Surviv. 11, 41–47 (2017).

    PubMed  Google Scholar 

  94. Hawley, S. T. et al. Recurrence risk perception and quality of life following treatment of breast cancer. Breast Cancer Res. Treat. 161, 557–565 (2017).

    PubMed  Google Scholar 

  95. Fisher, B. et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J. Natl Cancer Inst. 88, 1529–1542 (1996).

    CAS  PubMed  Google Scholar 

  96. Jakesz, R. et al. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J. Natl Cancer Inst. 99, 1845–1853 (2007).

    CAS  PubMed  Google Scholar 

  97. Mamounas, E. et al. Effect of extended adjuvant endocrine therapy with letrozole (L) in postmenopausal women with hormone receptor (+) breast cancer after prior adjuvant therapy with an aromatase inhibitor (AI): NRG Oncology/NSABP B-42. Breast J. 32, S25–S26 (2017).

    Google Scholar 

  98. Sestak, I. et al. in Highlights from the 40th Annual San Antonio Breast Cancer Symposium (ed. Lathrop, K.) 4–5 (UT Health San Antonio, AACR and Baylor College of Medicine, 2017).

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Acknowledgements

J.R. is a Cridlan Ross Smith Charitable Trust clinical research fellow. The authors acknowledge support from the UK National Institute for Health Research Royal Marsden–Institute of Cancer Research Biomedical Research Centre. The authors are thankful to C. Isacke and A. Ring for providing internal review and feedback on this manuscript.

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Nature Reviews Clinical Oncology thanks J. Cortes, G. Viale and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK

    Juliet Richman & Mitch Dowsett

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Richman, J., Dowsett, M. Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer. Nat Rev Clin Oncol 16, 296–311 (2019). https://doi.org/10.1038/s41571-018-0145-5

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