Skip to main content

Advertisement

SpringerLink
Log in

Optimizing the Use of Neoadjuvant Endocrine Therapy

  • Breast Cancer (B Overmoyer, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Nowadays, neoadjuvant endocrine therapy is a clinically acceptable (and sometimes preferred) strategy in patients with operable estrogen receptor-positive (ER+) breast cancer. Despite the overall effectiveness of endocrine therapy in breast cancer in all settings, de novo (primary) and acquired (secondary) endocrine therapy resistance remains a major clinical problem. Neoadjuvant endocrine therapy trials for breast cancer are not only a great opportunity to determine which ER+ breast cancers can be treated without chemotherapy, but also a great strategy to develop insights into the biologic basis for the efficacy of estrogen-receptor-targeting agents, alone or in combination, in an effort to counteract resistance to endocrine therapy and discover actionable molecular targets that can be the focus of future drug discovery efforts and/or translational/clinical investigation in ER+ breast cancers.

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

Access this article

Log in via an institution

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

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

  1. Horobin JM, Preece PE, Dewar JA, et al. Long-term follow-up of elderly patients with locoregional breast cancer treated with tamoxifen only. Br J Surg. 1991;78:213–7.

    Article  CAS  PubMed  Google Scholar 

  2. Bergman L, van Dongen JA, van Ooijen B, van Leeuwen FE. Should tamoxifen be a primary treatment choice for elderly breast cancer patients with locoregional disease? Breast Cancer Res Treat. 1995;34:77–83.

    Article  CAS  PubMed  Google Scholar 

  3. Eiermann W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol. 2001;12:1527–32.

    Article  CAS  PubMed  Google Scholar 

  4. Cataliotti L, Buzdar AU, Noguchi S, et al. Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the pre-operative “Arimidex” compared to tamoxifen (PROACT) trial. Cancer. 2006;106:2095–103.

    Article  CAS  PubMed  Google Scholar 

  5. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005;23:5108–16.

    Article  CAS  PubMed  Google Scholar 

  6. Ellis MJ, Suman VJ, Hoog J, et al. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype—ACOSOG Z1031. J Clin Oncol. 2011;29:2342–9. Neoadjuvant letrozole, anastrozole, and exemestane had surgical outcomes, PEPI socre, and Ki67 suppression and therefore are likely clinically equivalent. Post-treatment increase in Ki67 may identify treatment resistant cells.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Allevi G, Strina C, Andreis D, et al. Increased pathological complete response rate after a long-term neoadjuvant letrozole treatment in postmenopausal oestrogen and/or progesterone receptor-positive breast cancer. Br J Cancer. 2013;108:1587–92. Compared to a shorter duration of 4 or 8 months, a longer duration of neoadjuvant letrozole (12 months) resulted in higher clinical response rates and improved rates of pathologic complete response.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Semiglazov VF, Semiglazov VV, Dashyan GA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007;110:244–54.

    Article  CAS  PubMed  Google Scholar 

  9. Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002;2:101–12.

    Article  PubMed  Google Scholar 

  10. Clarke R, Skaar T, Leonessa F, et al. Acquisition of an antiestrogen-resistant phenotype in breast cancer: role of cellular and molecular mechanisms. Cancer Treat Res. 1996;87:263–83.

    CAS  PubMed  Google Scholar 

  11. Lu Q, Yue W, Wang J, et al. The effects of aromatase inhibitors and antiestrogens in the nude mouse model. Breast Cancer Res Treat. 1998;50:63–71.

    Article  CAS  PubMed  Google Scholar 

  12. Wiebe VJ, Osborne CK, Fuqua SA, DeGregorio MW. Tamoxifen resistance in breast cancer. Crit Rev Oncol Hematol. 1993;14:173–88.

    Article  CAS  PubMed  Google Scholar 

  13. Ellis MJ, Coop A, Singh B, et al. Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol. 2001;19:3808–16.

    CAS  PubMed  Google Scholar 

  14. Ellis MJ, Coop A, Singh B, et al. Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res. 2003;63:6523–31.

    CAS  PubMed  Google Scholar 

  15. Ellis MJ. Neoadjuvant endocrine therapy for breast cancer: more questions than answers. J Clin Oncol. 2005;23:4842–4.

    Article  CAS  PubMed  Google Scholar 

  16. Ellis MJ, Tao Y, Young O, et al. Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole. J Clin Oncol. 2006;24:3019–25.

    Article  CAS  PubMed  Google Scholar 

  17. Dowsett M et al. Greater Ki67 response after 2 weeks neoadjuvant treatment with anastrozole (A) than with tamoxifen (T) or anastrozole plus tamoxifen (C) in the IMPACT trial: a potential predictor of relapse-free survival. Breast Cancer Res Treat. 2003;82 Suppl 1:S6.

    Google Scholar 

  18. Dowsett M, Ebbs SR, Dixon JM, et al. Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer—a study from the IMPACT trialists. J Clin Oncol. 2005;23:2477–92.

    Article  CAS  PubMed  Google Scholar 

  19. Seo JH, Kim YH, Kim JS. Meta-analysis of pre-operative aromatase inhibitor versus tamoxifen in postmenopausal woman with hormone receptor-positive breast cancer. Cancer Chemother Pharmacol. 2009;63:261–6.

    Article  CAS  PubMed  Google Scholar 

  20. Dowsett M, Smith IE, Ebbs SR, et al. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007;99:167–70.

    Article  CAS  PubMed  Google Scholar 

  21. Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365:60–2.

    Article  CAS  PubMed  Google Scholar 

  22. Ellis MJ, Tao Y, Luo J, et al. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst. 2008;100:1380–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Chia YH, Ellis MJ, Ma CX. Neoadjuvant endocrine therapy in primary breast cancer: indications and use as a research tool. Br J Cancer. 2010;103:759–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. van de Vijver MJ, He YD, van’t Veer LJ, 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 

  25. Paik S, Shak S, Tang G, 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 

  26. Zhao M, Ramaswamy B. Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer. World J Clin Oncol. 2014;5:248–62.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Johnston SR. Integration of endocrine therapy with targeted agents. Breast Cancer Res. 2008;10 Suppl 4:S20.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009;9:631–43.

    Article  CAS  PubMed  Google Scholar 

  29. Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008;29:217–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29:4452–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Fedele P, Calvani N, Marino A, et al. Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: where are we now and where are we going? Crit Rev Oncol Hematol. 2012;84:243–51.

    Article  PubMed  Google Scholar 

  32. McClelland RA, Barrow D, Madden TA, et al. Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex). Endocrinology. 2001;142:2776–88.

    CAS  PubMed  Google Scholar 

  33. Robertson JFR, Gutteridge E, Cheung KL, et al. Gefitinib (ZD1839) is active in acquired tamoxifen-resistant oestrogen receptor positive and ER-negative breast cancer: results from a phase II study. Proc Am Soc Clin Oncol. 2003;22:A23.

    Article  Google Scholar 

  34. Nicholson RI, Hutcheson IR, Harper ME, et al. Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer. Endocr Relat Cancer. 2001;8:175–82.

    Article  CAS  PubMed  Google Scholar 

  35. Yue W, Wang JP, Conaway MR, et al. Adaptive hypersensitivity following long-term estrogen deprivation: involvement of multiple signal pathways. J Steroid Biochem Mol Biol. 2003;86:265–74.

    Article  CAS  PubMed  Google Scholar 

  36. Lavinsky RM, Jepsen K, Heinzel T, et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci U S A. 1998;95:2920–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Shou J, Massarweh S, Osborne CK, et al. Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 2004;96:926–35.

    Article  CAS  PubMed  Google Scholar 

  38. Shin I, Miller T, Arteaga CL. ErbB receptor signaling and therapeutic resistance to aromatase inhibitors. Clin Cancer Res. 2006;12:1008s–12.

    Article  CAS  PubMed  Google Scholar 

  39. Kunisue H, Kurebayashi J, Otsuki T, et al. Anti-HER2 antibody enhances the growth inhibitory effect of anti-oestrogen on breast cancer cells expressing both oestrogen receptors and HER2. Br J Cancer. 2000;82:46–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Kurokawa H, Lenferink AE, Simpson JF, et al. Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res. 2000;60:5887–94.

    CAS  PubMed  Google Scholar 

  41. Jelovac D, Sabnis G, Long BJ, et al. Activation of mitogen-activated protein kinase in xenografts and cells during prolonged treatment with aromatase inhibitor letrozole. Cancer Res. 2005;65:5380–9.

    Article  CAS  PubMed  Google Scholar 

  42. Sabnis GJ, Jelovac D, Long B, Brodie A. The role of growth factor receptor pathways in human breast cancer cells adapted to long-term estrogen deprivation. Cancer Res. 2005;65:3903–10.

    Article  CAS  PubMed  Google Scholar 

  43. Ropero S, Menendez JA, Vazquez-Martin A, et al. Trastuzumab plus tamoxifen: anti-proliferative and molecular interactions in breast carcinoma. Breast Cancer Res Treat. 2004;86:125–37.

    Article  CAS  PubMed  Google Scholar 

  44. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–12.

    Article  CAS  PubMed  Google Scholar 

  45. Kurokawa H, Arteaga CL. Inhibition of erbB receptor (HER) tyrosine kinases as a strategy to abrogate antiestrogen resistance in human breast cancer. Clin Cancer Res. 2001;7:4436s–42. discussion 4411s-4412s.

    CAS  PubMed  Google Scholar 

  46. Polychronis A, Sinnett HD, Hadjiminas D, et al. Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomised trial. Lancet Oncol. 2005;6:383–91.

    Article  CAS  PubMed  Google Scholar 

  47. Smith IE, Walsh G, Skene A, et al. A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer. J Clin Oncol. 2007;25:3816–22.

    Article  CAS  PubMed  Google Scholar 

  48. Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554–9.

    Article  CAS  PubMed  Google Scholar 

  49. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68:6084–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Campbell RA, Bhat-Nakshatri P, Patel NM, et al. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem. 2001;276:9817–24.

    Article  CAS  PubMed  Google Scholar 

  51. Yamnik RL, Digilova A, Davis DC, et al. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem. 2009;284:6361–9.

    Article  CAS  PubMed  Google Scholar 

  52. Crowder RJ, Phommaly C, Tao Y, et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009;69:3955–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Creighton CJ, Fu X, Hennessy BT, et al. Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen receptor (ER) levels and activity in ER+ breast cancer. Breast Cancer Res. 2010;12:R40.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Miller TW, Hennessy BT, Gonzalez-Angulo AM, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120:2406–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann Oncol. 2014;25:2357–62. The addition of everolimus to exemestate in hormone receptor positive, HER2-negative advanced breast cancer improved progression free survival by 4.6 months, but did not result in a statistically significant improvement in overal survival.

    Article  CAS  PubMed  Google Scholar 

  56. Mayer IA, Abramson VG, Isakoff SJ, et al. Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2014;32:1202–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Baselga J, Semiglazov V, van Dam P, 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. 2009;27:2630–7.

    Article  CAS  PubMed  Google Scholar 

  58. Sabnis G, Goloubeva O, Jelovac D, et al. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway improves response of long-term estrogen-deprived breast cancer xenografts to antiestrogens. Clin Cancer Res. 2007;13:2751–7.

    Article  CAS  PubMed  Google Scholar 

  59. Miller TW, Hennessy BT, Gonzalez-Angulo AM, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120:2406–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Fox EM, Arteaga CL, Miller TW. Abrogating endocrine resistance by targeting ERalpha and PI3K in breast cancer. Front Oncol. 2012;2:145.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Laila S. Agrawal declares that she has no conflict of interest.

Ingrid A. Mayer has received research support as well as compensation for service on an advisory board from Novartis.

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.

Funding Support

This study has received a funding support from the Breast Cancer Specialized Program of Research Excellence (SPORE) P50 CA098131.

Author information

Authors and Affiliations

  1. Department of Medicine, Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    Laila S. Agrawal & Ingrid A. Mayer

  2. Division of Hematology/Oncology, Department of Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 777 PRB, Nashville, TN, 37232-6307, USA

    Ingrid A. Mayer

Authors
  1. Laila S. Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ingrid A. Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ingrid A. Mayer.

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

Agrawal, L.S., Mayer, I.A. Optimizing the Use of Neoadjuvant Endocrine Therapy. Curr Oncol Rep 17, 33 (2015). https://doi.org/10.1007/s11912-015-0455-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-015-0455-z

Keywords

Search

Navigation