Abstract
PurposeFulvestrant is a selective estrogen receptor downregulator (SERD) that is approved for first- or second-line use as a single agent or in combination with cyclin dependent kinase or phosphatidylinositol 3-kinase inhibitors for the treatment of metastatic breast cancer. Fulvestrant exhibits exceptionally effective antitumor activity in preclinical models of breast cancer, a success that has been attributed to its robust SERD activity despite modest receptor downregulation in patient tumors. By modeling human exposures in animal models we probe the absolute need for SERD activity.MethodsThree xenograft models of endocrine therapy-resistant breast cancer were used to evaluate the efficacy of fulvestrant administered in doses historically used in preclinical studies in the field or by using a dose regimen intended to model clinical exposure levels. Pharmacokinetic and pharmacodynamic analyses were conducted to evaluate plasma exposure and intratumoral ER downregulation.ResultsA clinically relevant 25 mg/kg dose of fulvestrant exhibited antitumor efficacy comparable to the historically used 200 mg/kg dose, but at this lower dose it did not result in robust ER downregulation. Further, the antitumor efficacy of the lower dose of fulvestrant was comparable to that observed for other oral SERDs currently in development.ConclusionThe use of clinically unachievable exposure levels of fulvestrant as a benchmark in preclinical development of SERDs may negatively impact the selection of those molecules that are advanced for clinical development. Further, these studies suggest that antagonist efficacy, as opposed to SERD activity, is likely to be the primary driver of clinical response.
Highlights
Estrogens play a critical role in the development of female reproductive tissues and contributes to the development and progression of breast cancer
As a first step to evaluate in vivo exposure of fulvestrant in mice, we initially conducted a simple PK analysis in which Nu:J mice received a single injection of 25 or 200 mg/kg fulvestrant, and plasma was collected for analysis from mice euthanized 1, 3, 5, or 7 days after administration
In order to assess the relationship between dose and efficacy of fulvestrant on the growth of a clinically relevant xenograft model of endocrine therapy-resistant breast cancer, tamoxifen-resistant (TamR) xenograft tumors were established orthotopically in ovariectomized tamoxifen-treated (5 mg/60 days administered by continuous release pellet) female Nu:J mice
Summary
Estrogens play a critical role in the development of female reproductive tissues and contributes to the development and progression of breast cancer. With an antiendocrine therapy in the adjuvant setting, consisting of either the selective estrogen receptor modulator (SERM) tamoxifen or an aromatase inhibitor (AI, e.g., anastrozole, letrozole, exemestane) [1] These adjuvant therapies have proven effective to reduce the incidence of progression to metastatic disease. Patients that present with or progress to advanced metastatic breast cancer are typically treated with an antiendocrine therapy as part of a more aggressive treatment regimen [2]. In this setting, these treatments are not curative, with a significant number of cancers exhibiting de novo or rapidly acquired resistance to existing antiestrogens and aromatase inhibitors. After progression during SERM and AI therapy, other endocrine therapies can be effective, including the steroidal selective estrogen receptor degrader (SERD) fulvestrant, megestrol acetate (a progesterone receptor agonist), or high-dose estrogens [3,4,5]
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