Understanding resistance to hormonal therapy in estrogen avid breast cancer

Abstract

566 Background: The estrogen receptor (ER) is an essential target for endocrine therapy in breast cancer. We, and others, have tested an in vivo assay of ER function, [F-18]-16α-fluoroestradiol (FES) PET, which allows assessment of all sites of tumor spread and predicts response to hormonal therapy. However, not all patients with tumors bearing functional ER respond to therapy, suggesting the presence of mechanisms of resistance other than ER loss. Methods: 65 postmenopausal female patients with known ER+ metastatic (mostly bone and soft tissue dominant) breast cancer treated with aromatase inhibitors underwent PET FDG and FES imaging on an institutional imaging protocol (majority in second-line therapy). Hormone levels were assayed at the time of imaging, and biopsy specimens from either the primary tumor or metastasis were analyzed for expression of ER, PR, AR, PSA, HER2neu, and TopoIIα. Results: 49 (75%) patients had at least modest levels of retained ER expression, indicated by an average FES SUV > 1.5 at the tumor sites. We found serum estradiol, or estrone, levels >30pg/ml in 30% of patients. We found the majority of patients had PR, or AR expression, but few had EGFR or TopoIIα expression. FES SUV > 1.5 predicted response to therapy (p=.0006); no patient with an FES SUV < 1.5 had an objective response. Only 18/49 patients with SUV >1.5 responded to AI therapy. In the subset with FES SUV > 1.5, factors predicting lack of response to AI included PR negativity (p=.038) and/or detectable serum estradiol levels (p=.05). Conclusions: Quantitative PET FES predicts response to hormonal therapy. Estrogen levels may not be completely suppressed in patients on long-term AI therapy. Estradiol levels > 30pg/ml and lack of PR expression predict resistance to endocrine therapy in patients with tumors bearing functional ER expression. Efforts to monitor and reduce estradiol levels may offer therapeutic benefit to patients. No significant financial relationships to disclose.