Current Oncology Reports

, 16:358 | Cite as

The Optimal Duration of Adjuvant Endocrine Therapy for Early Stage Breast Cancer—With What Drugs and for How Long?

  • Stephen R. D. Johnston
  • Belinda Yeo
Breast Cancer (B Overmoyer, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Breast Cancer


Adjuvant endocrine therapy has made a significant impact in improving overall survival for women with hormone receptor (HR)-positive breast cancer. The anti-estrogen tamoxifen is the most widely used therapy, although in post-menopausal women, aromatase inhibitors (AIs) have further improved outcomes either as an alternative to tamoxifen for 5 years, or given in sequential fashion following initial tamoxifen therapy. However, late recurrence remains perhaps the biggest risk in HR-positive breast cancer, with more than half all recurrences occurring beyond 5 years since primary diagnosis. As such, the current debate is whether extended AI or prolonged tamoxifen therapy should be given, and if so, to whom. We review some of the recent studies that have addressed this question and demonstrated further reduction in risk of recurrence, and discuss the clinical issues that face women and their health care providers in determining who should use which drug, and for how long.


Tamoxifen Aromatase inhibitor HR-positive breast cancer Extended adjuvant therapy Risk of recurrence 


Compliance with Ethics Guidelines

Conflict of Interest

Stephen R.D. Johnston has been a consultant for Roche, AstraZeneca, Novartis, and GSK.

Belinda Yeo declares that she has no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Jordan VC et al. The St. Gallen Prize Lecture 2011: evolution of long-term adjuvant anti-hormone therapy: consequences and opportunities. Breast. 2011;20 Suppl 3:S1–11.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Yang G et al. Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs. Pharmacol Ther. 2013;139(3):392–404.PubMedCrossRefGoogle Scholar
  3. 3.
    Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998;339(22):1609–18.PubMedCrossRefGoogle Scholar
  4. 4.
    Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer. 1971;25(2):270–5.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687–717.Google Scholar
  6. 6.•
    Dignam JJ et al. Hazard of recurrence and adjuvant treatment effects over time in lymph node-negative breast cancer. Breast Cancer Res Treat. 2009;116(3):595–602. An imporatnt analysis of the risk of late recurrence in HR+ breast cancer.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.•
    Davies C et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771–84. This is the definitive overview that quantifies the magnitude of adjuvant tamoxifen’s benefit on reducing recurrence and improving survival, together with the carry over effect.PubMedCrossRefGoogle Scholar
  8. 8.
    Day R. Quality of life and tamoxifen in a breast cancer prevention trial: a summary of findings from the NSABP P-1 study. National Surgical Adjuvant Breast and Bowel Project. Ann N Y Acad Sci. 2001;949:143–50.PubMedCrossRefGoogle Scholar
  9. 9.
    Palmieri C, Jones A. The 2011 EBCTCG polychemotherapy overview. Lancet. 2012;379(9814):390–2.PubMedCrossRefGoogle Scholar
  10. 10.
    Cuzick J et al. Long-term results of tamoxifen prophylaxis for breast cancer–96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst. 2007;99(4):272–82.PubMedCrossRefGoogle Scholar
  11. 11.
    Visvanathan K et al. American society of clinical oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol. 2009;27(19):3235–58.PubMedCrossRefGoogle Scholar
  12. 12.
    Hernandez RK et al. Tamoxifen treatment and risk of deep venous thrombosis and pulmonary embolism: a Danish population-based cohort study. Cancer. 2009;115(19):4442–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348(24):2431–42.PubMedCrossRefGoogle Scholar
  14. 14.•
    Dowsett M et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010;28(3):509–18. A good overview of the benefit for aromatse inhibitors in HR+ postmenopausal early breast cancer in the various schedules in which they have been used.PubMedCrossRefGoogle Scholar
  15. 15.
    Burstein HJ et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010;28(23):3784–96.PubMedCrossRefGoogle Scholar
  16. 16.
    Mouridsen H et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009;361(8):766–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Coombes RC et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081–92.PubMedCrossRefGoogle Scholar
  18. 18.
    Buzdar A et al. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol. 2006;7(8):633–43.PubMedCrossRefGoogle Scholar
  19. 19.
    Hillner BE et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003;21(21):4042–57.PubMedCrossRefGoogle Scholar
  20. 20.••
    Goss PE et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349(19):1793–802. This was a landmark study which was the first to show that extended adjuvant therapy beyond 5 years further reduced risk of recurrnce in HR+ breast cancer, and improved overall survival in node positive patients.PubMedCrossRefGoogle Scholar
  21. 21.
    Goss PE 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. 2005;97(17):1262–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Goss PE et al. Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Cancer Institute of Canada Clinical Trials Group MA.17. J Clin Oncol. 2007;25(15):2006–11.PubMedCrossRefGoogle Scholar
  23. 23.•
    Goss PE et al. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008;26(12):1948–55. An important further analysis-17 study which showed that delayed switch to an AI after an interval from completion of 5 years of tamoxfen still priovded benefit to those at risk.PubMedCrossRefGoogle Scholar
  24. 24.
    Jin H et al. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012;30(7):718–21.PubMedCrossRefGoogle Scholar
  25. 25.
    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. 2007;99(24):1845–53.PubMedCrossRefGoogle Scholar
  26. 26.
    Mamounas EP 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. 2008;26(12):1965–71.PubMedCrossRefGoogle Scholar
  27. 27.
    Chia S, Bryce C, Gelmon K. The 2000 EBCTCG overview: a widening gap. Lancet. 2005;365(9472):1665–6.PubMedCrossRefGoogle Scholar
  28. 28.
    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. 1996;88(21):1529–42.PubMedCrossRefGoogle Scholar
  29. 29.
    Tormey DC, Gray R, Falkson HC. Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst. 1996;88(24):1828–33.PubMedCrossRefGoogle Scholar
  30. 30.••
    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. 2013;381(9869):805–16. The first of the studies to confirm the benefit of 10 versus 5 years of adjuvant tamoxifen.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.••
    Gray RG RD, Handley K, et al. ATTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6953 women with early breast cancer. Clin Oncol. 2013;31((suppl). abstr 5). The first presentation at ASCO 2013 of the second large trial of 10 versus 5 years of tamoxifen, which included a combined analysis of both studies and demonstrated the magntidue of the benefit and impact on late recurrence.Google Scholar
  32. 32.
    Duric VM et al. Patients’ preferences for adjuvant endocrine therapy in early breast cancer: what makes it worthwhile? Br J Cancer. 2005;93(12):1319–23.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Bertelsen L et al. Effect of systemic adjuvant treatment on risk for contralateral breast cancer in the Women’s Environment, Cancer and Radiation Epidemiology Study. J Natl Cancer Inst. 2008;100(1):32–40.PubMedCrossRefGoogle Scholar
  34. 34.
    Khatcheressian JL et al. Breast cancer follow-up and management after primary treatment: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(7):961–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Cuzick J et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11(12):1135–41.PubMedCrossRefGoogle Scholar
  36. 36.
    Regan MM et al. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8.1 years median follow-up. Lancet Oncol. 2011;12(12):1101–8.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Bliss JM et al. Disease-related outcomes with long-term follow-up: an updated analysis of the intergroup exemestane study. J Clin Oncol. 2012;30(7):709–17.PubMedCrossRefGoogle Scholar
  38. 38.
    Kaufmann M et al. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007;25(19):2664–70.PubMedCrossRefGoogle Scholar
  39. 39.
    Boccardo F et al. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: long term results of the Italian Tamoxifen Anastrozole trial. Eur J Cancer. 2013;49(7):1546–54.PubMedCrossRefGoogle Scholar
  40. 40.
    Dubsky PC et al. Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012;30(7):722–8.PubMedCrossRefGoogle Scholar
  41. 41.
    van de Velde CJ et al. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011;377(9762):321–31.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of MedicineRoyal Marsden NHS Foundation TrustLondonUK

Personalised recommendations