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 (2) MCF-7 cells were cultured long-term under SERM-treated or estrogen withdrawn conditions (to mimic aromatase inhibitors), and then injected into mice to generate endocrine-resistant xenografts.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tumors were growth stimulated in response to estradiol (E(2)), but paradoxically, Phase II SERM and estrogen withdrawn-resistant tumors were growth inhibited by E(2). Fulvestrant did not support growth of Phases I and II SERM-resistant tumors, but did allow growth of Phase II estrogen withdrawn-resistant tumors.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: Eric A Ariazi, Joan S Lewis-Wambi, Shaun D Gill, Jennifer R Pyle, Jennifer L Ariazi, Helen R Kim, Catherine G N Sharma, Fernando Cordera, Heather A Shupp, Tianyu Li, V Craig Jordan
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 102 Issue 1-5 Pg. 128-38 (Dec 2006) ISSN: 0960-0760 [Print] England
• PMID: 17085047 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents, Hormonal
• Selective Estrogen Receptor Modulators
• Fulvestrant
• Estradiol

Topics

• Animals
• Antineoplastic Agents, Hormonal (therapeutic use)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm
• Estradiol (analogs & derivatives, therapeutic use)
• Fulvestrant
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms, Hormone-Dependent (drug therapy)
• Selective Estrogen Receptor Modulators (therapeutic use)