Skip to main content
SpringerLink
Log in

The UZ Leuven Policy for Extended Adjuvant Anti-estrogen Therapy in Women With Early Estrogen Receptor-Positive Breast Cancer

  • Breast Cancer (P Neven, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion Statement

Five years after adjuvant endocrine treatment for estrogen receptor (ER)-positive breast cancer, patients have a 2 to 20 % risk of metastatic relapse during the next 5 years. Extended adjuvant endocrine therapy seems to further lower this. In UZ Leuven, extended endocrine therapy is now discussed unless the tumor was a grade 1–2, pT1N0, ER-positive, progesterone receptor (PR)-positive, HER2-negative lesion. After 5 years of adjuvant tamoxifen treatment for ER-positive breast cancer, we encourage women to take another 5 years of tamoxifen. If the tumor was lymph node-positive at diagnosis and patients are menopausal after the first 5 years of tamoxifen, we advise to take prolonged treatment with an oral aromatase inhibitor (AI). For this particular group, available data for extending endocrine therapy with an AI after 5 years of tamoxifen are strongest and more convincing for letrozole than for anastrozole or exemestane. Under these conditions, letrozole is reimbursed for 3 years in Belgium. If women are postmenopausal at diagnosis and already used an oral AI at any time during the first 5 years, we discuss an extra 5 years of tamoxifen. Results from ongoing clinical trials will tell us whether in these cases prolonged AI use is better than tamoxifen so that therapy can be adapted. Benefit from extended adjuvant endocrine therapy is likely larger with better compliance and potential side effects of extended endocrine therapy need to be discussed. Therefore, when advising extended adjuvant endocrine treatment, a balance should always be made between relapse risk and treatment tolerance/compliance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Recently published papers of particular importance have been highlighted as: • Of importance•• Of major importance

  1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–717.

    Article  Google Scholar 

  2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771–84.

    Article  Google Scholar 

  3. Burstein HJ, Prestrud AA, Seidenfeld J, Davidson NE, 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;28:3784–96.

    Article  PubMed  Google Scholar 

  4. Forbes JF, Dowsett M, Bradley R, Ingle JN, Aihara T, Bliss JM, et al. Patient-level meta-analysis of randomized trials of aromatase inhibitors (AI) versus tamoxifen (Tam). ASCO Annual Meeting 2014.

  5. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, 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;381:805–16. Important trial on extending initial tamoxifen treatment with another 5 years.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Gray RG, Rea D, Handley K, Bowden SJ, Perry P, Earl HM, 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. 2013;31:abstr 5. Important trial on extending initial tamoxifen treatment with another 5 years.

  7. Tormey DC, Gray R, Falkson HC. Postchemotherapy adjuvant tamoxifen therapy beyond 5 years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. J Natl Cancer Inst. 1996;88:1828–33.

    Article  CAS  PubMed  Google Scholar 

  8. Stewart HJ, Prescott RJ, Forrest AP. Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst. 2001;93:456–62.

    Article  CAS  PubMed  Google Scholar 

  9. Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than 5 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. 2001;93:684–90.

    Article  CAS  PubMed  Google Scholar 

  10. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, 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;97:1262–71.

    Article  CAS  PubMed  Google Scholar 

  11. Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. 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;30:718–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Jakesz R, Greil R, Gnant M, 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;99:1845–53.

    Article  CAS  PubMed  Google Scholar 

  13. Mamounas EP, Jeong JH, Wickerham DL, 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;26:1965–71.

    Article  CAS  PubMed  Google Scholar 

  14. Markopoulos C, Dafni U, Misitzis J, Zobolas V, Tzoracoleftherakis E, Koukouras D, et al. Extended adjuvant hormonal therapy with exemestane has no detrimental effect on the lipid profile of postmenopausal breast cancer patients: final results of the ATENA lipid substudy. Breast Cancer Res. 2009;11:R35.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Sestak I, Dowsett M, Zabaglo L, Lopez-Knowles E, Ferree S, Cowens JW, et al. Factors predicting late recurrence for estrogen receptor-positive breast cancer. J Natl Cancer Inst. 2013;105:1504–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Sestak I, Cuzick J, Dowsett M, Lopez-Knowles E, Filipits M, Dubsky P, 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. 2015;33:916–22.

    Article  CAS  PubMed  Google Scholar 

  17. Dubsky P, Brase JC, Jakesz R, Rudas M, Singer CF, Greil R, et al. The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. Br J Cancer. 2013;109:2959–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Mittempergher L, Saghatchian M, Wolf DM, Michiels S, Canisius S, Dessen P, et al. A gene signature for late distant metastasis in breast cancer identifies a potential mechanism of late recurrences. Mol Oncol. 2013;7:987–99.

    Article  CAS  PubMed  Google Scholar 

  19. Sgroi DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Schroeder B. 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. 2013;14:1067–76.

    Article  PubMed Central  PubMed  Google Scholar 

  20. van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009.

    Article  PubMed  Google Scholar 

  21. Buyse M, Loi S, van’t Veer L, Viale G, Delorenzi M, Glas AM, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98:1183–92.

    Article  CAS  PubMed  Google Scholar 

  22. Metzger Filho O, Ignatiadis M, Sotiriou C. Genomic Grade Index: an important tool for assessing breast cancer tumor grade and prognosis. Crit Rev Oncol Hematol. 2011;77:20–9.

    Article  PubMed  Google Scholar 

  23. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817–26.

    Article  CAS  PubMed  Google Scholar 

  24. Dowsett M, Sestak I, Lopez-Knowles E, Sidhu K, Dunbier AK, Cowens JW, 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. 2013;31:2783–90.

    Article  PubMed  Google Scholar 

  25. Zhang Y, Schnabel CA, Schroeder BE, Jerevall PL, Jankowitz RC, Fornander T, 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. 2013;19:4196–205.

    Article  CAS  PubMed  Google Scholar 

  26. Sgroi D, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Erlander MG, et al. Comparative performance of Breast Cancer Index (BCI) vs. Oncotype Dx and IHC4 in the prediction of late recurrence in hormonal receptor-positive lymph node-negative breast cancer patients: a TransATAC study. Cancer Res. 2012;72:S1–9.

    Google Scholar 

  27. Dubsky P, Brase JC, Fisch K, Jakesz R, Singer C, Greil R, et al. The EndoPredict score identifies late distant metastases in ER+/HER2− breast cancer patients. Cancer Res. 2012;72:S4–3.

    Article  Google Scholar 

  28. Sestak I, Cuzick J. Markers for the identification of late breast cancer recurrence. Breast Cancer Res. 2015;27:10.

    Article  Google Scholar 

  29. Knauer M, Filipits M, Dubsky P. Late recurrences in early breast cancer: for whom and how long is endocrine therapy beneficial? Breast Care. 2014;9:97–100.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American society of clinical oncology clinical practice guideline focused update. J Clin Oncol. 2014;32:2255–69. This paper gives an overview of the optimal duration of endocrine treatment according to ASCO guidelines.

    Article  PubMed  Google Scholar 

  31. Al-Mubarak M, Tibau A, Templeton AJ, Cescon DW, Ocana A, Seruga B, et al. Extended adjuvant tamoxifen for early breast cancer: a meta-analysis. PLoS One. 2014;9:e88238. This paper gives an overview of all benefits and harms of extended tamoxifen treatment compared to only 5 years of adjuvant tamoxifen treatment based on the 5 main studies on this topic.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Neven P, Joensuu H, Osborne K, Cardoso F, Loibl S, Linn S, et al. Tamoxifen therapy for patients with breast cancer. Lancet. 2013;381:2078.

    Article  PubMed  Google Scholar 

  33. Davies C, Gray R, Pan H, Peto R, ATLAS collaborative group. Tamoxifen therapy for patients with breast cancer—authors’ reply. Lancet. 2013;381:2078–9.

    Article  PubMed  Google Scholar 

  34. Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos E, Bellet M, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372:436–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Lang I, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371:107–18.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360:679–91.

    Article  CAS  PubMed  Google Scholar 

  37. Pfeiler G, Königsberg R, Filipcic L, Greil R, Stoeger H, Singer CF, et al. Follicle stimulating hormone (FSH) as a surrogate parameter for the effectiveness of endocrine therapy with or without zoledronic acid in premenopausal patients with breast cancer: An analysis of the prospective ABCSG-12 trial. J Clin Oncol. 2014;32:5s.

    Article  Google Scholar 

  38. Pfeiler G, Königsberg R, Fesl C, Mlineritsch B, Stoeger H, Singer CF, et al. Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol. 2011;29:2653–9.

    Article  CAS  PubMed  Google Scholar 

  39. Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol. 2015;26:313–20.

    Article  PubMed  Google Scholar 

  40. Ruddy KJ, DeSantis SD, Barry W, Guo H, Block CC, Borges V, et al. Extended therapy with letrozole and ovarian suppression in premenopausal patients with breast cancer after tamoxifen. Clin Breast Cancer. 2014;14:413–6.

    Article  CAS  PubMed  Google Scholar 

  41. Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, 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;26:1948–55.

    Article  CAS  PubMed  Google Scholar 

  42. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Livingston RB. Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann Oncol. 2013;24:355–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Strasser-Weippl K, Badovinac-Crnjevic T, Fan L, Goss PE. Extended adjuvant endocrine therapy in hormone-receptor positive breast cancer. Breast. 2013;22:S171–5. This is a cross-trial comparing extended tamoxifen treatment with extended AI treatment based on the ATLAS trial and important AI studies.

    Article  PubMed  Google Scholar 

  44. Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, 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;11:1135–41.

    Article  CAS  PubMed  Google Scholar 

  45. Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, 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;12:1101–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Cardoso F, Van’t Veer L, Rutgers E, Loi S, Mook S, Piccart-Gebhart MJ. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008;26:729–35.

    Article  PubMed  Google Scholar 

  47. Mann BS, Johnson JR, Kelly R, Sridhara R, Williams G, Pazdur R. Letrozole in the extended adjuvant treatment of postmenopausal women with history of early-stage breast cancer who have completed 5 years of adjuvant tamoxifen. Clin Cancer Res. 2005;11:5671–7.

    Article  CAS  PubMed  Google Scholar 

  48. Koch L, Jansen L, Herrmann A, Stegmaier C, Holleczek B, Singer S. Quality of life in long-term breast cancer survivors—a 10-year longitudinal population-based study. Acta Oncol. 2013;52:1119–28.

    Article  PubMed  Google Scholar 

  49. Fontein DB, Nortier JW, Liefers GJ, Putter H, Meershoek-Klein Kranenbarg E, van den Bosch J. High non-compliance in the use of letrozole after 2.5 years of extended adjuvant endocrine therapy. Results from the IDEAL randomized trial. Eur J Surg Oncol. 2012;38:110–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Kathleen Van Asten, An Poppe, Kevin Punie, Lynn Jongen, Anneleen Lintermans, Hans Wildiers, and Patrick Neven declare that they have no conflict 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.

Author information

Authors and Affiliations

  1. Department of Oncology, KU Leuven, 3000, Leuven, Belgium

    Kathleen Van Asten MSc, Lynn Jongen MSc, Hans Wildiers MD, PhD & Patrick Neven MD, PhD

  2. Department of Gynecology and Obstetrics, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    An Poppe MD, Anneleen Lintermans PhD & Patrick Neven MD, PhD

  3. Department of General Medical Oncology, University Hospitals Leuven, 3000, Leuven, Belgium

    Kevin Punie MD & Hans Wildiers MD, PhD

Authors
  1. Kathleen Van Asten MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. An Poppe MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin Punie MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lynn Jongen MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anneleen Lintermans PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hans Wildiers MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patrick Neven MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Neven MD, PhD.

Additional information

This article is part of the Topical Collection on Breast Cancer

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Van Asten, K., Poppe, A., Punie, K. et al. The UZ Leuven Policy for Extended Adjuvant Anti-estrogen Therapy in Women With Early Estrogen Receptor-Positive Breast Cancer. Curr. Treat. Options in Oncol. 16, 31 (2015). https://doi.org/10.1007/s11864-015-0349-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-015-0349-1

Keywords

Search

Navigation