Intermittent treatment of hormone-dependent breast cancer using exemestane: translational research from lab bench to bedside.

Abstract

Abstract Abstract #3040 Background and Rationale: Endocrine therapy agents such as aromatase inhibitors (AIs) have shown good clinical efficacy in the treatment of post-menopausal breast cancer patients. Currently, the major clinical hindrance with endocrine therapy is disease progression or acquired resistance. Intermittent treatment of endocrine therapy agents has been proposed in several clinical trials to address whether this treatment strategy can delay the onset of acquired resistance in hormone-dependent breast cancers. To support these clinical trials, we have performed a pre-clinical study using the steroidal AI exemestane (EXE) to understand potential molecular features that differentiate continuous treatment of EXE from intermittent administration.
 Methods: The ER+ and aromatase-overexpressing cell culture model system (MCF-7aro) was used in this pre-clinical study. The cells were treated either continuously (T+EXE Cont) or intermittently (T+EXE Interm) for 2 weeks with EXE and 1 week without EXE, in the presence of testosterone (T). In addition, a non-steroidal AI letrozole, was used in an identical intermittent manner.
 Results: Based on cell culture studies, acquired resistance was reached at 14 weeks in the T+EXE Cont treated cells, while T+EXE Interm cells were still responsive to EXE. At 34 weeks, acquired resistance developed in the T+EXE Interm cell lines, which demonstrates a delay in time to progression. The non-steroidal AI letrozole did not demonstrate a delay in acquired resistance using this intermittent model. Based on microarray analysis, we observed that gene expression of certain estrogen-responsive genes was elevated in the T+EXE Cont cells, while select genes showed lower levels of up-regulation in T+EXE Interm lines.
 Discussion: Based on our previous studies, up-regulation of a key estrogen-responsive gene, amphiregulin (AREG), is responsible for activating EGFR and mediating resistance to EXE. Expression of genes such as AREG are decreased in the T+EXE Interm cell lines, suggesting the suppression of growth factor signaling implicated in driving resistance. In addition, we have reported that EXE acts as an aromatase destabilizer at the protein level. Unlike letrozole or anastrozole, EXE-mediated protein degradation of aromatase may play a key role in reducing estrogen levels that are responsible for driving breast cancer survival and proliferation. Since these pre-clinical studies provide an important mechanistic basis for intermittent endocrine therapy, a clinical trial to evaluate the intermittent use of exemestane has been discussed and is planned to initiate in the near future. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3040.