Emerging strategies to overcome resistance to endocrine therapy for breast cancer

Cancer and Metastasis Reviews - Tập 33 - Trang 791-807 - 2014
M. Firdos Ziauddin1, Dong Hua2, Shou-Ching Tang3,4
1Georgia Regents University Department of Surgery, Division of Surgical Oncology, Georgia Regents University Cancer Center, Augusta, USA
2Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
3Division of Hematology/Oncology, Georgia Regents University Cancer Center, Augusta, USA
4Georgia Regents University Cancer Center, Augusta, USA

Tóm tắt

Endocrine therapy of breast cancer is perhaps the oldest form of effective and well-tolerated targeted cancer systemic treatment, in both the adjuvant and metastatic disease settings. The most commonly used endocrine therapy agents are selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor downregulators. De novo or acquired resistance to these agents is a significant clinical problem. Preclinical and clinical investigations to understand this resistance have yielded significant advances in understanding cell signaling and the possible mechanisms of resistance. These mechanisms of resistance are as diverse as the biology of breast cancer and can arise from alterations in any of the cell signaling pathway components. A growing understanding of these mechanisms has provided rationale for development of strategies to overcome the resistance. Many of these mechanisms of resistance involve adaptive upregulation of alternate signaling pathways, such as growth factor signaling, and cross talk between estrogen receptor and growth factor signaling. Clinical trials are focusing on cotargeting these alternate pathways along with estrogen receptor signaling. It is becoming evident that, as with all cancer therapy, strategies to overcome resistance need to be individualized, and it is important to identify biomarkers to guide the use of these strategies. This manuscript systemically reviews the recent preclinical and clinical trials on the novel and pathway-driven agents that have shown significant promise in enhancing the efficacy and overcoming the resistance in the hormonal treatment of breast cancer. Future directions including biomarker selection and the role of next generation sequencing will be discussed.

Tài liệu tham khảo

Beatson, G. T. (1896). On the treatment of inoperable cases of carcinoma of the mammary: suggestions for a new method of treatment with illustrative cases. Lancet, 2, 104–107. 162–165. Levenson, A. S., & Jordan, V. C. (1997). MCF-7: the first hormone-responsive breast cancer cell line. Cancer Research, 57(15), 3071–3078. Early Breast Cancer Trialists’ Collaborative G. (2005). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet, 365(9472), 1687–717. Anderson, W. F., Katki, H. A., & Rosenberg, P. S. (2011). Incidence of breast cancer in the United States: current and future trends. Journal of the National Cancer Institute, 103(18), 1397–1402. Li, C. I., Daling, J. R., & Malone, K. E. (2003). Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. Journal of Clinical Oncology, 21(1), 28–34. Mouridsen, H., Gershanovich, M., Sun, Y., Perez-Carrion, R., Boni, C., Monnier, A., et al. (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. Journal of Clinical Oncology, 21(11), 2101–2109. Kaufmann, M., Bajetta, E., Dirix, L. Y., Fein, L. E., Jones, S. E., Zilembo, N., et al. (2000). 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. Journal of Clinical Oncology, 18(7), 1399–1411. Nilsson, S., & Gustafsson, J. A. (2011). Estrogen receptors: therapies targeted to receptor subtypes. Clinical Pharmacology and Therapeutics, 89(1), 44–55. Thomas, C., & Gustafsson, J. A. (2011). The different roles of ER subtypes in cancer biology and therapy. Nature Reviews Cancer, 11(8), 597–608. Klinge, C. M. (2000). Estrogen receptor interaction with co-activators and co-repressors. Steroids, 65(5), 227–251. Frasor, J., Danes, J. M., Komm, B., Chang, K. C., Lyttle, C. R., & Katzenellenbogen, B. S. (2003). Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology, 144(10), 4562–4574. Heldring, N., Pike, A., Andersson, S., Matthews, J., Cheng, G., Hartman, J., et al. (2007). Estrogen receptors: how do they signal and what are their targets. Physiological Reviews, 87(3), 905. Driggers, P. H., & Segars, J. H. (2002). Estrogen action and cytoplasmic signaling pathways. Part II: the role of growth factors and phosphorylation in estrogen signaling. Trends in endocrinology and metabolism: TEM, 13(10), 422–427. Segars, J. H., & Driggers, P. H. (2002). Estrogen action and cytoplasmic signaling cascades. Part I: membrane-associated signaling complexes. Trends in Endocrinology and Metabolism: TEM, 13(8), 349–354. Levin, E. R., & Pietras, R. J. (2008). Estrogen receptors outside the nucleus in breast cancer. Breast Cancer Research and Treatment, 108(3), 351–361. Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B., & Prossnitz, E. R. (2005). A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science, 307(5715), 1625–1630. Lupien, M., Meyer, C. A., Bailey, S. T., Eeckhoute, J., Cook, J., Westerling, T., et al. (2010). Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance. Genes & Development, 24(19), 2219–2227. Rocca, A., Farolfi, A., Bravaccini, S., Schirone, A., & Amadori, D. (2014). Palbociclib (PD 0332991): targeting the cell cycle machinery in breast cancer. Expert Opinion on Pharmacotherapy, 15(3), 407–420. Lange, C. A., & Yee, D. (2011). Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer. Endocrine-Related Cancer, 18(4), C19–C24. Renoir, J. M. (2012). Estradiol receptors in breast cancer cells: associated co-factors as targets for new therapeutic approaches. Steroids, 77(12), 1249–1261. Osborne, C. K., & Schiff, R. (2003). Growth factor receptor cross-talk with estrogen receptor as a mechanism for tamoxifen resistance in breast cancer. Breast, 12(6), 362–367. Cuzick, J., Sestak, I., Baum, M., Buzdar, A., Howell, A., Dowsett, M., et al. (2010). Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. The Lancet Oncology, 11(12), 1135–1141. Pritchard, K. I. (2003). The best use of adjuvant endocrine treatments. Breast, 12(6), 497–508. Osborne, C. K., Wakeling, A., & Nicholson, R. I. (2004). Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. British Journal of Cancer, 90(Suppl 1), S2–S6. Bartsch, R., Wenzel, C., Altorjai, G., Pluschnig, U., Mader, R. M., Gnant, M., et al. (2007). Her2 and progesterone receptor status are not predictive of response to fulvestrant treatment. Clinical Cancer Research, 13(15 Pt 1), 4435–4439. Mehta, A., & Tripathy, D. (2014). Co-targeting estrogen receptor and HER2 pathways in breast cancer. Breast, 23(1), 2–9. Shin, I., Miller, T., & Arteaga, C. L. (2006). ErbB receptor signaling and therapeutic resistance to aromatase inhibitors. Clinical Cancer Research, 12(3 Pt 2), 1008s–12s. Massarweh, S., & Schiff, R. (2007). Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities. Clinical Cancer Research, 13(7), 1950–1954. Creighton, C. J., Fu, X., Hennessy, B. T., Casa, A. J., Zhang, Y., Gonzalez-Angulo, A. M., et al. (2010). 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 Research : BCR, 12(3), R40. Kaufman, B., Mackey, J. R., Clemens, M. R., Bapsy, P. P., Vaid, A., Wardley, A., et al. (2009). Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. Journal of Clinical Oncology, 27(33), 5529–5537. Huober, J., Fasching, P. A., Barsoum, M., Petruzelka, L., Wallwiener, D., Thomssen, C., et al. (2012). Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer - results of the eLEcTRA trial. Breast, 21(1), 27–33. Cristofanilli, M., Valero, V., Mangalik, A., Royce, M., Rabinowitz, I., Arena, F. P., et al. (2010). Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. Clinical Cancer Research, 16(6), 1904–1914. Osborne, C. K., Neven, P., Dirix, L. Y., Mackey, J. R., Robert, J., Underhill, C., et al. (2011). Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer: a randomized phase II study. Clinical Cancer Research, 17(5), 1147–1159. Johnston, S., Pippen, J., Jr., Pivot, X., Lichinitser, M., Sadeghi, S., Dieras, V., et al. (2009). Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. Journal of Clinical Oncology, 27(33), 5538–5546. Miller, T. W., Balko, J. M., & Arteaga, C. L. (2011). Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. Journal of Clinical Oncology, 29(33), 4452–4461. Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, 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. Journal of clinical oncology. 2014. Maira, S. M., Pecchi, S., Huang, A., Burger, M., Knapp, M., Sterker, D., et al. (2012). Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Molecular Cancer Therapeutics, 11(2), 317–328. Baselga, J., Campone, M., Piccart, M., Burris, H. A., 3rd, Rugo, H. S., Sahmoud, T., et al. (2012). Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. The New England Journal of Medicine, 366(6), 520–529. Bachelot, T., Bourgier, C., Cropet, C., Ray-Coquard, I., Ferrero, J. M., Freyer, G., et al. (2012). Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. Journal of Clinical Oncology, 30(22), 2718–2724. Wolff, A. C., Lazar, A. A., Bondarenko, I., Garin, A. M., Brincat, S., Chow, L., et al. (2013). Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. Journal of Clinical Oncology, 31(2), 195–202. Baselga, J., Semiglazov, V., van Dam, P., Manikhas, A., Bellet, M., Mayordomo, J., et al. (2009). Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. Journal of Clinical Oncology, 27(16), 2630–2637. Dees, E. C., & Carey, L. A. (2013). Improving endocrine therapy for breast cancer: it’s not that simple. Journal of Clinical Oncology, 31(2), 171–173. Robertson, J. F., Ferrero, J. M., Bourgeois, H., Kennecke, H., de Boer, R. H., Jacot, W., et al. (2013). Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. The Lancet Oncology, 14(3), 228–235. Yeatman, T. J. (2004). A renaissance for SRC. Nature Reviews Cancer, 4(6), 470–480. Shupnik, M. A. (2004). Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation. Oncogene, 23(48), 7979–7989. Hiscox, S., Jordan, N. J., Smith, C., James, M., Morgan, L., Taylor, K. M., et al. (2009). Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells. Breast Cancer Research and Treatment, 115(1), 57–67. Morgan, L., Gee, J., Pumford, S., Farrow, L., Finlay, P., Robertson, J., et al. (2009). Elevated Src kinase activity attenuates Tamoxifen response in vitro and is associated with poor prognosis clinically. Cancer Biology & Therapy, 8(16), 1550–1558. Chen, Y., Guggisberg, N., Jorda, M., Gonzalez-Angulo, A., Hennessy, B., Mills, G. B., et al. (2009). Combined Src and aromatase inhibition impairs human breast cancer growth in vivo and bypass pathways are activated in AZD0530-resistant tumors. Clinical Cancer Research, 15(10), 3396–3405. Chen, Y., Alvarez, E. A., Azzam, D., Wander, S. A., Guggisberg, N., Jorda, M., et al. (2011). Combined Src and ER blockade impairs human breast cancer proliferation in vitro and in vivo. Breast Cancer Research and Treatment, 128(1), 69–78. Dasatinib-letrozole gets split verdict. Cancer Discovery. 2014;4(2):138–9. Wright, G.L., Blum, J., Krekow, L.K., McIntyre, K.J., Wilks, S.T., Rabe, A.C., et al. SABCS PD01-01: randomized phase II trial of fulvestrant with or without dasatinib in postmenopausal patients with hormone receptor-positive metastatic breast cancer previously treated with an aromatase inhibitor. Cancer Research. 2011; 71(24 Supplement 3). Llombart, A., Ravaioli, A., Strauss, L., Sy1, O., Abrahao, F., Geese, W.J., et al. PD01-02: randomized phase II study of dasatinib vs placebo in addition to exemestane in advanced ER/PR-positive breast cancer (BMS CA180-261 Study). Cancer Research. 2011; 71(24 Supplement 3). Moy, B., Neven, P., Lebrun, F., Bellet, M., Xu, B., Sarosiek, T., et al. Bosutinib in combination with the aromatase inhibitor letrozole: a phase II trial in postmenopausal women evaluating first-line endocrine therapy in locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer. The Oncologist. 2014. Moy, B., Neven, P., Lebrun, F., Bellet, M., Xu, B., Sarosiek, T., et al. Bosutinib in combination with the aromatase inhibitor exemestane: a phase II trial in postmenopausal women with previously treated locally advanced or metastatic hormone receptor-positive/HER2-negative breast cancer. The Oncologist. 2014. Thangavel, C., Dean, J. L., Ertel, A., Knudsen, K. E., Aldaz, C. M., Witkiewicz, A. K., et al. (2011). Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocrine-Related Cancer, 18(3), 333–345. Dean, J. L., Thangavel, C., McClendon, A. K., Reed, C. A., & Knudsen, E. S. (2010). Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene, 29(28), 4018–4032. Finn, R. S., Dering, J., Conklin, D., Kalous, O., Cohen, D. J., Desai, A. J., et al. (2009). PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Research: BCR, 11(5), R77. Finn, R.S., Crown, J., Lang, I., Boer, K., Bondarenko, I.M., Kulyk, S.O., et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). Cancer Research. 2012;72(24 Suppl):Abstract nr S1-6. Finn, R.S., Crown, J.P., Lang, I., Boer, K., Bondarenko, I.M., Kulyk, S.O., et al. Abstract CT01 Final results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). AACR Annual Meeting. 2014. Finn. R.S., Gelmon, K.A., Harbeck, N., Jones, S.E., Koehler, M., Martin, M., et al. A randomized, multicenter, double-blind phase III study of palbociclib (PD-0332991), an oral CDK 4/6 inhibitor, plus letrozole versus placebo plus letrozole for the treatment of postmenopausal women with ER(+), HER2(−) breast cancer who have not received any prior systemic anticancer treatment for advanced disease. Journal of Clinical Oncology, 2013 ASCO Annual Meeting Abstracts. 2013;31(15 suppl (May 20 Supplement)):TPS652. Malorni, L., Sanna, G.,, Pestrin, M., Siclari, O., Biganzoli, L., Biagioni, C., et al. editor Poster OT2-6-01 Phase 2 study of palbociclib (CDK 4/6 inhibitor) for ER positive, HER2-negative post-menopausal advanced breast cancer patients recurring after hormonal therapy (To Reverse Endocrine resistance - TREnd trial). San Antonio Breast Cancer Symposium. 2013. von Minckwitz, G., Bear, H., Bonnefoi, H., Colleoni, M., Gelmon, K., Gnant, M., et al. editor Poster OT2-6-11 PENELOPE: phase III study evaluating palbociclib (PD-0332991), a cyclin-dependent kinase (CDK) 4/6 inhibitor in patients with hormone-receptor-positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy (GBG-78/BIG1-13/NSABP B54 I). San Antonio Breast Cancer Symposium. 2013. West, A. C., & Johnstone, R. W. (2014). New and emerging HDAC inhibitors for cancer treatment. The Journal of Clinical Investigation, 124(1), 30–39. Thomas, S., & Munster, P. N. (2009). Histone deacetylase inhibitor induced modulation of anti-estrogen therapy. Cancer Letters, 280(2), 184–191. Margueron, R., Duong, V., Castet, A., & Cavailles, V. (2004). Histone deacetylase inhibition and estrogen signalling in human breast cancer cells. Biochemical Pharmacology, 68(6), 1239–1246. Yang, X., Ferguson, A. T., Nass, S. J., Phillips, D. L., Butash, K. A., Wang, S. M., et al. (2000). Transcriptional activation of estrogen receptor alpha in human breast cancer cells by histone deacetylase inhibition. Cancer Research, 60(24), 6890–6894. Yang, X., Phillips, D. L., Ferguson, A. T., Nelson, W. G., Herman, J. G., & Davidson, N. E. (2001). Synergistic activation of functional estrogen receptor (ER)-alpha by DNA methyltransferase and histone deacetylase inhibition in human ER-alpha-negative breast cancer cells. Cancer Research, 61(19), 7025–7029. Luu, T. H., Morgan, R. J., Leong, L., Lim, D., McNamara, M., Portnow, J., et al. (2008). A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. Clinical Cancer Research, 14(21), 7138–7142. Munster, P. N., Troso-Sandoval, T., Rosen, N., Rifkind, R., Marks, P. A., & Richon, V. M. (2001). The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Research, 61(23), 8492–8497. Hodges-Gallagher, L., Valentine, C. D., Bader, S. E., & Kushner, P. J. (2007). Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells. Breast Cancer Research and Treatment, 105(3), 297–309. Munster, P. N., Thurn, K. T., Thomas, S., Raha, P., Lacevic, M., Miller, A., et al. (2011). A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. British Journal of Cancer, 104(12), 1828–1835. Munster, P., Marchion, D., Bicaku, E., Lacevic, M., Kim, J., Centeno, B., et al. (2009). Clinical and biological effects of valproic acid as a histone deacetylase inhibitor on tumor and surrogate tissues: phase I/II trial of valproic acid and epirubicin/FEC. Clinical Cancer Research, 15(7), 2488–2496. Munster, P., Marchion, D., Bicaku, E., Schmitt, M., Lee, J. H., DeConti, R., et al. (2007). Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study. Journal of Clinical Oncology, 25(15), 1979–1985. Yardley, D. A., Ismail-Khan, R. R., Melichar, B., Lichinitser, M., Munster, P. N., Klein, P. M., et al. (2013). Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. Journal of Clinical Oncology, 31(17), 2128–2135. Thomas, S., Thurn, K. T., Raha, P., Chen, S., & Munster, P. N. (2013). Efficacy of histone deacetylase and estrogen receptor inhibition in breast cancer cells due to concerted down regulation of Akt. PLoS ONE, 8(7), e68973. Collins, L. C., Cole, K. S., Marotti, J. D., Hu, R., Schnitt, S. J., & Tamimi, R. M. (2011). Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses’ Health Study. Modern Pathology, 24(7), 924–931. Moinfar, F., Okcu, M., Tsybrovskyy, O., Regitnig, P., Lax, S. F., Weybora, W., et al. (2003). Androgen receptors frequently are expressed in breast carcinomas: potential relevance to new therapeutic strategies. Cancer, 98(4), 703–711. Gucalp, A., Tolaney, S., Isakoff, S. J., Ingle, J. N., Liu, M. C., Carey, L. A., et al. (2013). Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Clinical Cancer Research, 19(19), 5505–5512. Garay, J. P., & Park, B. H. (2012). Androgen receptor as a targeted therapy for breast cancer. American Journal of Cancer Research, 2(4), 434–445. Cochrane, D. R., Bernales, S., Jacobsen, B. M., Cittelly, D. M., Howe, E. N., D’Amato, N. C., et al. (2014). Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Research : BCR, 16(1), R7. Traina, T., Yardley, D., Patel, M., Elias, A., Gucalp, A., Peterson, A., et al.. Poster PD3-6 A phase 1 open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of enzalutamide (previously MDV3100) alone or in combination with an aromatase inhibitor in women with advanced breast cancer. San Antonio Breast Cancer Symposium. 2013. Tran, C., Ouk, S., Clegg, N. J., Chen, Y., Watson, P. A., Arora, V., et al. (2009). Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science, 324(5928), 787–790. De Amicis, F., Thirugnansampanthan, J., Cui, Y., Selever, J., Beyer, A., Parra, I., et al. (2010). Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Research and Treatment, 121(1), 1–11. Scher, H. I., Fizazi, K., Saad, F., Taplin, M. E., Sternberg, C. N., Miller, K., et al. (2012). Increased survival with enzalutamide in prostate cancer after chemotherapy. The New England Journal of Medicine, 367(13), 1187–1197. Traina, T., O’Shaughnessy, J., Kelly, C., Schwartzberg, L., Gucalp, A., Peterson, A., et al. Poster OT3-2-08 A phase 2 single-arm study of the clinical activity and safety of enzalutamide in patients with advanced androgen receptor-positive triple-negative breast cancer. San Antonio Breast Cancer Symposium. 2013. Yardley, D.A., Cortes, J., Burris, H., Peterson, A., Tudor, I., Stopatschinskaja, S., et al. Poster OT3-2-01 A phase 2 randomized, double-blind, placebo-controlled multicenter trial evaluating the efficacy and safety of enzalutamide in combination with exemestane in estrogen or progesterone receptor-positive and HER2-normal advanced breast cancer. San Antonio Breast Cancer Symposium. 2013. Goetz, M. P., Rae, J. M., Suman, V. J., Safgren, S. L., Ames, M. M., Visscher, D. W., et al. (2005). Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. Journal of Clinical Oncology, 23(36), 9312–9318. Hawse, J. R., Subramaniam, M., Cicek, M., Wu, X., Gingery, A., Grygo, S. B., et al. (2013). Endoxifen’s molecular mechanisms of action are concentration dependent and different than that of other anti-estrogens. PLoS ONE, 8(1), e54613. Sideras, K., Ingle, J. N., Ames, M. M., Loprinzi, C. L., Mrazek, D. P., Black, J. L., et al. (2010). Coprescription of tamoxifen and medications that inhibit CYP2D6. Journal of Clinical Oncology, 28(16), 2768–2776. Wu, X., Hawse, J. R., Subramaniam, M., Goetz, M. P., Ingle, J. N., & Spelsberg, T. C. (2009). The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Research, 69(5), 1722–1727. Goetz, M.P., Kuffel, M., Reinicke, K.E., Huang, Z., Bode, A.M., Cheng, J., et al. Poster P5-09-08 A comparison of the nongenomic effects of endoxifen and tamoxifen in aromatase inhibitor resistant breast cancer: differential effects on the estrogen receptor coregulator SRC3 (AIB1) and identification of PKC and PI3K as endoxifen substrates. San Antonio Breast Cancer Symposium. 2013. Goetz, M.P., Suman, V.J., Reid, J., Northfelt, D., Kuffel, M., Reinicke, K., et al. A first-in-human phase I study of endoxifen hydrochloride in women with hormone refractory, ER positive breast cancer. San Antonio Breast Cancer Symposium. 2013. Tang, S. C. (2002). BAG-1, an anti-apoptotic tumour marker. IUBMB Life, 53(2), 99–105. Tang, S. C., Beck, J., Murphy, S., Chernenko, G., Robb, D., Watson, P., et al. (2004). BAG-1 expression correlates with Bcl-2, p53, differentiation, estrogen and progesterone receptors in invasive breast carcinoma. Breast Cancer Research and Treatment, 84(3), 203–213. Tang, S. C., Shehata, N., Chernenko, G., Khalifa, M., & Wang, X. (1999). Expression of BAG-1 in invasive breast carcinomas. Journal of Clinical Oncology, 17(6), 1710–1719. Cutress, R. I., Townsend, P. A., Sharp, A., Maison, A., Wood, L., Lee, R., et al. (2003). The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription. Oncogene, 22(32), 4973–4982. Liu, H., Lu, S., Gu, L., Gao, Y., Wang, T., Zhao, J., et al. (2014). Modulation of BAG-1 expression alters the sensitivity of breast cancer cells to tamoxifen. Cellular Physiology and Biochemistry, 33(2), 365–374. Li, S., Shen, D., Shao, J., Crowder, R., Liu, W., Prat, A., et al. (2013). Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Reports, 4(6), 1116–1130. Robinson, D. R., Wu, Y. M., Vats, P., Su, F., Lonigro, R. J., Cao, X., et al. (2013). Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nature Genetics, 45(12), 1446–1451. Whitesell, L., Santagata, S., & Lin, N. U. (2012). Inhibiting HSP90 to treat cancer: a strategy in evolution. Current Molecular Medicine, 12(9), 1108–1124. Hrstka, R., Brychtova, V., Fabian, P., Vojtesek, B., & Svoboda, M. (2013). AGR2 predicts tamoxifen resistance in postmenopausal breast cancer patients. Disease Markers, 35(4), 207–212. Vanderlaag, K. E., Hudak, S., Bald, L., Fayadat-Dilman, L., Sathe, M., Grein, J., et al. (2010). Anterior gradient-2 plays a critical role in breast cancer cell growth and survival by modulating cyclin D1, estrogen receptor-alpha and survivin. Breast Cancer Research : BCR, 12(3), R32. Loh, Y. N., Hedditch, E. L., Baker, L. A., Jary, E., Ward, R. L., & Ford, C. E. (2013). The Wnt signalling pathway is upregulated in an in vitro model of acquired tamoxifen resistant breast cancer. BMC Cancer, 13, 174. Dubrovska, A., Hartung, A., Bouchez, L. C., Walker, J. R., Reddy, V. A., Cho, C. Y., et al. (2012). CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling. British Journal of Cancer, 107(1), 43–52. O'Hara, J., Vareslija, D., McBryan, J., Bane, F., Tibbitts, P., Byrne, C., et al. (2012). AIB1:ERalpha transcriptional activity is selectively enhanced in aromatase inhibitor-resistant breast cancer cells. Clinical Cancer Research, 18(12), 3305–3315. Hong, S. E., Kim, E. K., Jin, H. O., Kim, H. A., Lee, J. K., Koh, J. S., et al. (2013). S6K1 inhibition enhances tamoxifen-induced cell death in MCF-7 cells through translational inhibition of Mcl-1 and survivin. Cell Biology and Toxicology, 29(4), 273–282.