Emerging principles for the development of resistance to antihormonal therapy: implications for the clinical utility of fulvestrant |
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Authors: | Ariazi Eric A Lewis-Wambi Joan S Gill Shaun D Pyle Jennifer R Ariazi Jennifer L Kim Helen R Sharma Catherine G N Cordera Fernando Shupp Heather A Li Tianyu Jordan V Craig |
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Institution: | aFox Chase Cancer Center, Philadelphia, PA 19111-2497, USA |
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Abstract: | We seek to evaluate the clinical consequences of resistance to antihormonal therapy by studying analogous animal xenograft models. Two approaches were taken: (1) MCF-7 tumors were serially transplanted into selective estrogen receptor modulator (SERM)-treated immunocompromised mice to mimic 5 years of SERM treatment. The studies in vivo were designed to replicate the development of acquired resistance to SERMs over years of clinical exposure. (2) MCF-7 cells were cultured long-term under SERM-treated or estrogen withdrawn conditions (to mimic aromatase inhibitors), and then injected into mice to generate endocrine-resistant xenografts. These tumor models have allowed us to define Phase I and Phase II antihormonal resistance according to their responses to E2 and fulvestrant. Phase I SERM-resistant tumors were growth stimulated in response to estradiol (E2), but paradoxically, Phase II SERM and estrogen withdrawn-resistant tumors were growth inhibited by E2. Fulvestrant did not support growth of Phases I and II SERM-resistant tumors, but did allow growth of Phase II estrogen withdrawn-resistant tumors. Importantly, fulvestrant plus E2 in Phase II antihormone-resistant tumors reversed the E2-induced inhibition and instead resulted in growth stimulation. These data have important clinical implications. Based on these and prior laboratory findings, we propose a clinical strategy for optimal third-line therapy: patients who have responded to and then failed at least two antihormonal treatments may respond favorably to short-term low-dose estrogen due to E2-induced apoptosis, followed by treatment with fulvestrant plus an aromatase inhibitor to maintain low tumor burden and avoid a negative interaction between physiologic E2 and fulvestrant. |
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Keywords: | Breast cancer Estradiol Tamoxifen Raloxifene Fulvestrant |
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