Polyendocrine Treatment in Estrogen Receptor–Positive Breast Cancer: A “FACT” Yet to Be Proven

Abstract

The estrogen receptor (ER) was one of the first molecular targets identified for cancer treatment. Today, endocrine agents that target ER are well-established standards of care for patients with breast cancer. These drugs have different mechanisms of action and can either directly alter ER function or deprive ER of its ligand. The selective ER downregulator fulvestrant is a pure antiestrogen that, on binding ER, induces a conformational change that disrupts ER transcriptional activity and accelerates ER degradation. These features are unique to fulvestrant. Other antiestrogens, such as tamoxifen or raloxifene, retain some estrogenic activity and do not reduce ER levels. 1 The aromatase inhibitors anastrozole, letrozole, and exemestane reduce levels of circulating estrogen in postmenopausal women by inhibiting the peripheral conversion of androgens to estradiol. In the premenopausal setting, a reduction of circulating estrogen levels is achieved via luteinizing hormone-releasing hormone (LHRH) agonists or other means of ovarian ablation. Given the diverse mechanisms of action of endocrine agents, rational drug combinations might improve the effectiveness of endocrine therapy. Some preclinical data support polyendocrine treatment strategies. Before reviewing the results of the preclinical studies that tested this approach, we should consider the preclinical models that were used and some of their potential limitations. Early in vivo studies with fulvestrant were undertaken in a xenograft model of MCF7, the prototypic ER-positive breast cancer cell line. In this model, tumor cells are injected subcutaneously into the mouse, and tumors are initially allowed to develop in an estrogenic environment that is provided by a subcutaneous estrogen pellet. After tumor formation, the estrogen pellet is removed and endocrine treatment is initiated. In this low-estrogen environment, fulvestrant has a more potent antitumor effect compared with estrogen deprivation (that mimics aromatase inhibitor treatment in this model) or tamoxifen. However, fulvestrant-resistant tumors eventually develop that are generally insensitive to subsequent treatment with tamoxifen or combinations of tamoxifen and fulvestrant. 2 In the same model, fulvestrant does not have a significant antitumor effect when mice continue to receive estrogen 3 ; this finding is consistent with data showing that estradiol can displace and therefore reactivate fulvestrant-bound ER. 4 These data suggest that fulvestrant might be more active in lowestrogen conditions. Subsequent studies that investigated the combination of fulvestrant with either tamoxifen or aromatase inhibitors were performed using MCF7 cells that were genetically modified to express high levels of aromatase (MCF7 Ca). MCF7 Ca cells are grown in ovariectomized mice that are supplemented with a source of androgens to allow for autocrine estrogen synthesis. Using this model, the combination of anastrozole plus fulvestrant showed equivalence in terms of tumor growth inhibition compared with anastrozole or fulvestrant alone. Similarly, no differences were observed between the combinations of fulvestrant plus tamoxifen or letrozole versus tamoxifen or letrozole alone. 5 More recently, experiments using the same model system but longer periods of observation of tumor growth and higher drug doses (doses of fulvestrant were increased approximately 100-fold) have shown different results, with the combination of fulvestrant plus an aromatase inhibitor (either letrozole or anastrozole) demonstrating