title: Emerging principles for the development of resistance to antihormonal therapy: implications for the clinical utility of fulvestrant.
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 (2) MCF-7 cells were cultured long-term under SERM-treated or estrogen withdrawn conditions (to mimic aromatase inhibitors), and then injected into mice to generate endocrine-resistant xenografts.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 E(2) and fulvestrant. Phase I SERM-resistant tumors were growth stimulated in response to estradiol (E(2)), but paradoxically, Phase II SERM and estrogen withdrawn-resistant tumors were growth inhibited by E(2). Fulvestrant did not support growth of Phases I and II SERM-resistant tumors, but did allow growth of Phase II estrogen withdrawn-resistant tumors.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 E(2) in Phase II antihormone-resistant tumors reversed the E(2)-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 E(2)-induced apoptosis, followed by treatment with fulvestrant plus an aromatase inhibitor to maintain low tumor burden and avoid a negative interaction between physiologic E(2) and fulvestrant.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ariazi
authors.forename: Joan S
authors.initials: JS
authors.lastname: Lewis-Wambi
authors.forename: Shaun D
authors.initials: SD
authors.lastname: Gill
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Pyle
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ariazi
authors.forename: Helen R
authors.initials: HR
authors.lastname: Kim
authors.forename: Catherine G N
authors.initials: CG
authors.lastname: Sharma
authors.forename: Fernando
authors.initials: F
authors.lastname: Cordera
authors.forename: Heather A
authors.initials: HA
authors.lastname: Shupp
authors.forename: Tianyu
authors.initials: T
authors.lastname: Li
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000077267:Fulvestrant; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020845:Selective Estrogen Receptor Modulators; D000077267:Fulvestrant; D004958:Estradiol