Life following aromatase inhibitors – where now for endocrine sequencing?
- 89 Downloads
The third-generation non-steroidal aromatase inhibitors (AIs) are challenging tamoxifen as treatments of choice for early and advanced breast cancer in postmenopausal women with estrogen receptor (ER)-positive disease. However, patients who initially respond to AIs eventually develop resistance to treatment and experience disease progression. To establish the optimal endocrine therapy following AI resistance, it is essential to understand the mechanisms that contribute to the loss of response. Data from in vitro models have suggested that acquired AI resistance is due to enhanced sensitization to low estrogen levels during long-term estrogen deprivation (LTED). Cross-talk between the ER and various growth-factor-receptor signaling pathways, including human epidermal growth factor receptor 2, and the insulin-like growth factor pathway, may also be implicated. Therefore, endocrine therapies that abolish estrogen signaling via removal of the ER could be effective in patients with AI-resistant disease. Fulvestrant (‘Faslodex’) is a new ER antagonist with no agonist effects that binds, blocks and degrades the ER. Due to its unique mode of action and lack of cross-resistance with existing treatments, fulvestrant is an effective therapeutic agent for use in sequential endocrine regimens. Fulvestrant has established efficacy in tamoxifen-resistant disease and there is a growing body of evidence demonstrating its efficacy in patients with AI-resistant disease. In preclinical models, MCF-7 cells undergoing LTED are refractory to tamoxifen but sensitive to fulvestrant, suggesting fulvestrant is a more appropriate choice following AI resistance. The steroidal AI, exemestane is also an option in non-steroidal AI-resistant disease. Clinical trials are underway to compare fulvestrant with exemestane as an appropriate therapy following the onset of AI resistance.
Keywordsbreast cancer cell signaling EFECT endocrine therapy estrogen receptor epidermal growth factor fulvestrant gefitinib SOFEA tamoxifen
Unable to display preview. Download preview PDF.
We thank Dr Sarah Goodger from Complete Medical Communications Ltd, who provided medical writing support on behalf of AstraZeneca.
- 1.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, Becquart D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P, Bhatnagar A, (2003). 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 21:2101–2109CrossRefPubMedGoogle Scholar
- 2.Nabholtz JM, Bonneterre J, Buzdar A, Robertson JFR, Thürlimann B, for the Arimidex Writing Committee on behalf of the Investigators: Anastrozole (Arimidex™) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer 39:1684–1689, 2003Google Scholar
- 3.Boccardo F, Rubagotti A, Guglielmini P, Amoroso D, Fini A, Paladini G, Mesiti M, Romeo D, Rinaldini M, Scali S, Porpiglia M, Benedetto C: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Preliminary results of the Italian Tamoxifen Anastrozole (ITA) trial. J Clin Oncol, in press: 2005Google Scholar
- 4.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, (2004). A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer N Engl J Med 350:1081–1092CrossRefPubMedGoogle Scholar
- 5.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 (2003). A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer N Engl J Med 349:1793–1802CrossRefPubMedGoogle Scholar
- 7.Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, Chlebowski RT, Gelber R, Edge SB, Gralow J, Cobleigh MA, Mamounas EP, Goldstein LJ, Whelan TJ, Powles TJ, Bryant J, Perkins C, Perotti J, Braun S, Langer AS, Browman GP, Somerfield MR, (2005). American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004 J Clin Oncol 23: 619–629CrossRefPubMedGoogle Scholar
- 14.McClelland RA, Gee JM, Francis AB, Robertson JF, Blamey RW, Wakeling AE, Nicholson RI, (1996). Short-term effects of pure anti-oestrogen ICI 182780 treatment on oestrogen receptor, epidermal growth factor receptor and transforming growth factor-alpha protein expression in human breast cancer Eur J Cancer 32A: 413–416CrossRefPubMedGoogle Scholar
- 15.Pietras RJ, Marquez DC, Chen HW, Ayala R, Ramos LB, Slamon DJ, (2003). Improved antitumor therapy with Herceptin and Faslodex for dual targeting of HER-2 and estrogen receptor signalling pathways in human breast cancers with overexpression of HER-2/neu gene Breast Cancer Res Treat 82 (Suppl 1): S12 (abstract 22)Google Scholar
- 16.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, (2003). Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women – a prospective combined analysis of two multicenter trials Cancer 98: 229–238CrossRefPubMedGoogle Scholar
- 17.Ingle JN, Rowland KM, Suman VJ, Mirchandani D, Bernath AM, Camoriano JK, Perez EA, (2004). Evaluation of fulvestrant in women with advanced breast cancer and progression on prior aromatase inhibitor therapy: a phase II trial of the North Central Cancer Treatment Group Breast Cancer Res Treat 88 (Suppl 1): S38 (abstract 409)Google Scholar
- 18.Perey L, Paridaens R, Nolé F, Bonnefoi H, Aebi S, Goldhirsch A, Dietrich D, Thürlimann B, for the Swiss Group for Clinical Cancer Research (SAKK): Fulvestrant (Faslodex™) as hormonal treatment in postmenopausal patients with advanced breast cancer (ABC) progressing after treatment with tamoxifen and aromatase inhibitors: update of a phase II SAKK trial. Breast Cancer Res Treat 88(Suppl 1): S236, 2004 (abstract 6048)Google Scholar
- 19.Bertelli G, Garrone O, Merlano M, (2002). Sequential use of aromatase inactivators and inhibitors in advanced breast cancer. Proc Am Soc Clin Oncol 21: 60a (abstract 238)Google Scholar
- 20.Carlini P, Michelotti A, Giannarelli D, Conte PF, Salavadori B, Landucci E, Di Cosimo S, Fabi A, Papaldo P, Cognetti F, (2002). Exemestane (EXE) is an effective 3rd line hormonal therapy for postmenopausal metastatic breast cancer (MBC) patients (pts) pretreated with 3rd generation non steroidal aromatase inhibitors (nSAI) Ann Oncol 13 (Suppl 5): 48Google Scholar
- 21.Fernie NL, Zekri JM, Leonard RCF, Coleman RE, Cameron DA, (2003). Exemestane in metastatic breast cancer: effective therapy after 3rd generation aromatase inhibitor failure. Breast Cancer Res Treat 82 (Suppl 1): S104 (abstract 435)Google Scholar
- 22.Lønning PE, Bajetta E, Murray R, Tubiana-Hulin M, Eisenberg PD, Mickiewicz E, Celio L, Pitt P, Mita M, Aaronson NK, Fowst C, Arkhipov A, di Salle E, Polli A, Massimini G, (2005). Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial J Clin Oncol 18: 2234–2244Google Scholar
- 36.McClelland RA, Barrow D, Madden TA, Dutkowski CM, Pamment J, Knowlden JM, Gee JM, Nicholson RI, (2001). 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 142: 2776–2788CrossRefPubMedGoogle Scholar
- 38.Massarweh SA, Jiang S, Mohsin SK, DiPietro M, Wakeling AE, Osborne CK, Schiff R: Resistance to endocrine therapy in a xenograft model of HER-2 overexpressing breast cancer is accompanied by increased HER-2 but loss of IGF-1 receptor expression. Breast Cancer Res Treat 87(Suppl 1): 2003 (abstract 1007)Google Scholar