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.
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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.
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.
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.
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.
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.
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.
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.
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.
Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002;2:101–12.
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.
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.
Wiebe VJ, Osborne CK, Fuqua SA, DeGregorio MW. Tamoxifen resistance in breast cancer. Crit Rev Oncol Hematol. 1993;14:173–88.
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.
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.
Ellis MJ. Neoadjuvant endocrine therapy for breast cancer: more questions than answers. J Clin Oncol. 2005;23:4842–4.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Zhao M, Ramaswamy B. Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer. World J Clin Oncol. 2014;5:248–62.
Johnston SR. Integration of endocrine therapy with targeted agents. Breast Cancer Res. 2008;10 Suppl 4:S20.
Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009;9:631–43.
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.
Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29:4452–61.
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.
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.
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.
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.
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.
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.
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.
Shin I, Miller T, Arteaga CL. ErbB receptor signaling and therapeutic resistance to aromatase inhibitors. Clin Cancer Res. 2006;12:1008s–12.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Fox EM, Arteaga CL, Miller TW. Abrogating endocrine resistance by targeting ERalpha and PI3K in breast cancer. Front Oncol. 2012;2:145.
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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.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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This study has received a funding support from the Breast Cancer Specialized Program of Research Excellence (SPORE) P50 CA098131.
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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
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DOI: https://doi.org/10.1007/s11912-015-0455-z