Abstract
Breast cancer is a hormone-dependent cancer like prostate cancer and endometrial cancer. Estrogen plays important roles in the development and progression of breast cancer. Endocrine therapy is the treatment of choice for estrogen receptor-and/or progesterone receptor-positive breast cancer. Endocrine therapy has been used for several purposes, including chemoprevention, preoperative treatment, postoperative adjuvant treatment and treatment for recurrent diseases. A large number of clinical trials have provided evidence showing the clinical benefits of various endocrine therapies for the treatment of breast cancer. The current status and recent advances in endocrine therapy for breast cancer are reviewed based on the results of current clinical trials. Future perspectives of endocrine therapy are also discussed.
Similar content being viewed by others
References
Leake R: (100 years of the endocrine battle against breast cancer).Lancet 347:1780–1781, 1996.
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N: (Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-l Study).J Natl Cancer Inst 90:1371–1388, 1998.
Cuzick J, Forbes J, Edwards R, Baum M, Cawthorn S, Coates A, Hamed A, Howell A, Powles T; IBIS investigators: (First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial).Lancet 360:817–824, 2002.
Powles T, Eeles R, Ashley S, Easton D, Chang J, Dowsett M, Tidy A, Viggers J, Davey J: (Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial).Lancet 352:98–101, 1998.
Veronesi U, Maisonneuve P, Rotmensz N, Costa A, Sacchini V, Travaglini R, D’Aiuto G, Lovison F, Gucciardo G, Muraca MG, Pizzichetta MA, Conforti S, Decensi A, Robertson C, Boyle P; Italian Tamoxifen Study Group: (Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women).J Natl Cancer Inst 95:160–165, 2003.
Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC: (The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation).JAMA 28:2189–2197, 1999.
Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S, Boyle P: (Overview of the main outcomes in breast-cancer prevention trials).Lancet 361:296–300, 2003.
Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, Secrest RJ, Cummings SR; CORE Investigators: (Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene).J Natl Cancer Inst 96:1751–1761, 2004.
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER Jr, Wade JL 3rd, Robidoux A, Margolese RG, James J, Lippman SM, Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N; National Surgical Adjuvant Breast and Bowel Project (NSABP): (Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P- 2 trial).JAMA 295:2727–2741, 2006.
Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists’ Group: (Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer).Lancet 365:60–62, 2005.
Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardly A, Price KN, Goldhirsch A; Breast International Group (BIG) 1-98 Collaborative Group: (A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer).N Engl J Med 353:2747–2757, 2005.
Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM; Intergroup Exemestane Study: (A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer).N Engl J Med 350:1081–1092, 2004.
Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J; ABCSG and the GABG: (Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial).Lancet 366:455–462, 2005.
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL: (A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer).N Engl J Med 349:1793–1802, 2003.
Cuzick J: (Aromatase inhibitors for breast cancer prevention).J Clin Oncol 23:1636–1643, 2005.
Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cus-sac A, Eremin J, Vinholes J, Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M; LET Neo-Adjuvant Breast Cancer Study Group: (Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study).Ann Oncol 12:1527–1532, 2001.
Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, Ashley SE, Francis S, Boeddinghaus I, Walsh G; IMPACT Trialists Group: (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 23:5108–5116, 2005.
Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Janicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M: (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 19:3808–3816, 2001.
Subbaramaiah K, Howe LR, Port ER, Brogi E, Fishman J, Liu CH, Hla T, Hudis C, Dannenberg AJ: (HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism).Cancer Res 66:5504–5511, 2006.
Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P: (Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase).Science 270:1491–1494, 1995.
Glaros S, Atanaskova N, Zhao C, Skafar DF, Reddy KB: (Activation function-1 domain of estrogen receptor regulates the agonistic and antagonistic actions of tamoxifen).Mol Endocrinol 20:996–1008, 2006.
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 365:1687–1717, 2005.
Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial.Lancet 341:1293–1298, 1993.
Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Romeo D, Sismondi P, Giai M, Genta F, Pacini P, Distante V, Bolognesi A, Aldrighetti D, Farris A: (Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial).J Clin Oncol 18:2718–2727, 2000.
Jonat W, Kaufmann M, Sauerbrei W, Blarney R, Cuzick J, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, Eiermann W, Szakolczai I, Palmer M, Schumacher M, Geberth M, Lisboa B; Zoladex Early Breast Cancer Research Association Study: (Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study).J Clin Oncol 20:4628–4635, 2002.
Jakesz R, Hausmaninger H, Kubista E, Gnant M, Menzel C, Bauernhofer T, Seifert M, Haider K, Mlineritsch B, Steindorfer P, Kwasny W, Fridrik M, Steger G, Wette V, Samonigg H; Austrian Breast and Colorectal Cancer Study Group Trial 5: (Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer—Austrian Breast and Colorectal Cancer Study Group Trial 5).J Clin Oncol 20:4621–4627, 2002.
Schmid P, Untch M, Wallwiener D, Kosse V, Bondar G, Vassiljev L, Tarutinov V, Kienle E, Luftner D, Possinger K; TABLE-study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate): (Cyclophosphamide, methotrexate and fluorouracil (CMF) versus hormonal ablation with leuprorelin acetate as adjuvant treatment of node-positive, premenopausal breast cancer patients: preliminary results of the TABLE-study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate)).Anticancer Res 22:2325–2332, 2002.
Boccardo F, Rubagotti A, Puntoni M, Guglielmini P, Amoroso D, Fini A, Paladini G, Mesiti M, Romeo D, Rinaldini M, Scali S, Porpiglia M, Benedetto C, Restuccia N, Buzzi F, Franchi R, Massidda B, Distante V, Amadori D, Sismondi P: (Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen Anastrozole Trial).J Clin Oncol 23:5138–5147, 2005.
Coombes RC, Paridaens R, Jassem J, van de Velde CJ, Delozier T, Jones SE, Hall E, Kilburn LS, Snowdon CF, Bliss JM for the Intergroup Exemestane Study (IES): (First mature analysis of the Intergroup Exemestane Study).Proc ASCO 24:18S, 2006.
Jonat W, Gnant M, Boccardo F, Kaufmann M, Rubagotti A, Jakesz R: (Switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-responsive early breast cancer: a meta-analysis of the ARNO 95 Trila, ABCSG Trial 8, and the ITA Trial).Breast Cancer Res Treat 94 Suppl 1: S11, 2005.
Cuzick J, Sasieni P, Howell A: Should aromatase inhibitors be used as initial adjuvant treatment or sequenced after tamoxifen?Br J Cancer 94:460–464, 2006.
Dowsett M, Cuzick J, Wale C, Howell T, Houghton J, Baum M: (Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: an hypothesis-generating study).J Clin Oncol 23:7512–7527, 2005.
Kurebayashi J: (Postoperative adjuvant therapy for premenopausal patients with breast cancer).Nippon Rinsho 64:1963–1969, 2006.(in Japanese with English abstract).
Dellapasqua S, Colleoni M, Gelber RD, Goldhirsch A: (Adjuvant endocrine therapy for premenopausal women with early breast cancer).J Clin Oncol 23:1736–1750, 2005.
Pico C, Martin M, Jara C, Barnadas A, Pelegri A, Balil A, Camps C, Frau A, Rodriguez-Lescure A, Lopez-Vega JM, De La Haba J, Tres A, Alvarez I, Alba E, Arcusa A, Oltra A, Batista N, Checa T, Perez-Carrion R, Curto J; GEICAM Group: (Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients. A GEICAM 9401 study).Ann Oncol 15:79–87, 2004.
Albain KS, Green SJ, Ravdin PM, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Schneider DJ, Abeloff MD, Norton L, Henderson IC, Lew D, Livingston RB, Martino S, Osborne CK: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814).Proc ASCO 21:37a (Abstract 143), 2002.
Noguchi S, Koyama H, Uchino J, Abe R, Miura S, Sugimachi K, Akazawa K, Abe O: (Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both in women with node-negative breast cancer: a pooled analysis of six randomized controlled trials).J Clin Oncol 23:2172–2184, 2005.
Kurebayashi J, Nukatsuka M, Nagase H, Nomura T, Hirono M, Yamamoto Y, Sugimoto Y, Oka T, Sonoo H: (Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells).Cancer Chemother Pharmacol 59:515–525, 2007.
Hortobagyi GN: (Treatment of breast cancer).N Engl J Med 339:974–984, 1998.
Sawka CA, Pritchard KI, Shelley W, DeBoer G, Paterson AH, Meakin JW, Sutherland DJ: (A randomized crossover trial of tamoxifen versus ovarian ablation for metastatic breast cancer in premenopausal women: a report of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial MA.1).Breast Cancer Res Treat 44:211–215, 1997.
Kaufmann M, Jonat W, Kleeberg U, Eiermann W, Janicke F, Hilfrich J, Kreienberg R, Albrecht M, Weitzel HK, Schmid H: (Goserelin, a depot gonadotrophin-releasing hormone agonist in the treatment of premenopausal patients with metastatic breast cancer. German Zoladex Trial Group).J Clin Oncol 7:1113–1119, 1989.
Klijn JG, Beex LV, Mauriac L, van Zijl JA, Veyret C, Wildiers J, Jassem J, Piccart M, Burghouts J, Beequart D, Seynaeve C, Mignolet F, Duchateau L: (Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study).J Natl Cancer Inst 92:903–911, 2000.
Forward DP, Cheung KL, Jackson L, Robertson JF: (Clinical and endocrine data for goserelin plus anastrozole as second-line endocrine therapy for premenopausal advanced breast cancer).Br J Cancer 90:590–594, 2004.
Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter JM, Azab M, Webster A, Plourde PV: (Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group).J Clin Oncol 14:2000–2011, 1996.
Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T, Tjabbes T, Chaudri HA, Hornberger U, Trunet PF: (Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate).J Clin Oncol 16:453–461, 1998.
Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn JL, Nasurdi C, Mennel RG, Cervek J, Fowst C, Polli A, di Salle E, Arkhipov A, Piscitelli G, Miller LL, Massimini G: (Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group).J Clin Oncol 18:1399–1411, 2000.
Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler M: (Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study).J Clin Oncol 18:3748–3757, 2000.
Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M: (Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group).J Clin Oncol 18:3758–3767, 2000.
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A, Dank M, Beequart D, Bapsy PP, Salminen E, Snyder R, ChaudriRoss H, Lang R, Wyld P, Bhatnagar A: (Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group).J Clin Oncol 21:2101–2109, 2003.
Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D, Biganzoli L, Cufer T, Duchateau L, Hamilton A, Lobelle JP, Piccart M; European Organization for the Research and Treatment of Cancer (EORTC)-Investigational Drug Branch for Breast Cancer (IDBBC): (Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer).Ann Oncol 14:1391–1398, 2003.
Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, Kleeberg UR, Come SE, Vergote I, Gertler S, Buzdar A, Webster A, Morris C: (Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: a prospective combined analysis of two multicenter trials).Cancer 98:229–238, 2003.
Cocconi G, De Lisi V, Boni C, Mori P, Malacarne P, Amadori D, Giovanelli E: (Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer. A prospective randomized study).Cancer 51:581–588, 1983.
A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. The Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia.J Clin Oncol 4:186–193, 1986.
Pritchard KI, Paterson AH, Paul NA, Zee B, Fine S, Pater J: (Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group).J Clin Oncol 14:2731–2737, 1996.
Kunisue H, Kurebayashi J, Otsuki T, Tang CK, Kurosumi M, Yamamoto S, Tanaka K, Doihara H, Shimizu N, Sonoo H: (Anti-HER2 antibody enhances the growth inhibitory effect of anti-oestrogen on breast cancer cells expressing both oestrogen receptors and HER2).Br J Cancer 82:46–51, 2000.
Kurokawa H, Lenferink AE, Simpson JF, Pisacane PI, Sliwkowski MX, Forbes JT, Arteaga CL: (Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells).Cancer Res 60:5887–5894, 2000.
Okubo S, Kurebayashi J, Otsuki T, Yamamoto Y, Tanaka K, Sonoo H: (Additive antitumour effect of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) and the antioestrogen fulvestrant (Faslodex, ICI 182,780) in breast cancer cells).Br J Cancer 90:236–244, 2004.
Argiris A, Wang CX, Whalen SG, DiGiovanna MP: (Synergistic interactions between tamoxifen and trastuzumab (Herceptin)).Clin Cancer Res 10:1409–1420, 2004.
Chu I, Blackwell K, Chen S, Slingerland J: (The dual ErbBl/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation-and estrogen-dependent gene expression in antiestrogen-resistant breast cancer).Cancer Res 65:18–25, 2005.
Gee JM, Harper ME, Hutcheson IR, Madden TA, Barrow D, Knowlden JM, McClelland RA, Jordan N, Wakeling AE, Nicholson RI: (The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro).Endocrinology 144:5105–5117, 2003.
Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin SK, Osborne CK: (Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance).Clin Cancer Res 10:331S-336S, 2004.
Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R: (Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu crosstalk in ER/HER2-positive breast cancer).J Natl Cancer Inst 96:926–935, 2004.
Johnston SR: (Combinations of endocrine and biological agents: present status of therapeutic and presurgical investigations).Clin Cancer Res 11:889s-899s, 2005.
Kurebayashi J: (Resistance to endocrine therapy in breast cancer).Cancer Chemother Pharmacol 56 Suppl 1:39–46, 2005.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Kurebayashi, J. Current clinical trials of endocrine therapy for breast cancer. Breast Cancer 14, 200–214 (2007). https://doi.org/10.2325/jbcs.954
Published:
Issue Date:
DOI: https://doi.org/10.2325/jbcs.954