PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer

Purpose To determine if response to endocrine therapy of breast cancer can be predicted by either a metabolic “flare reaction” detected by positron emission tomography (PET) with 2-[¹⁸F]-fluoro-2-deoxyglucose (FDG), induced by an estradiol challenge, or by estrogen-receptor (ER) status, determined by PET with the estrogen analog 16α-[¹⁸F]fluoroestradiol-17β (FES). Methods Fifty-one post-menopausal women with advanced estrogen-receptor positive breast cancer were studied. Patients underwent FES-PET and FDG-PET at baseline and repeat FDG-PET after 30 mg estradiol. Tracer uptakes was measured as the standardized uptake value (SUV). Patients were subsequently treated with either an aromatase inhibitor or fulvestrant. A prospectively defined cut-off SUV ≥ 2 for FES was considered positive for ER expression. A cutoff of ≥12% increase in SUV for FDG, determined by ROC analysis, represented metabolic flare. PET results were correlated with responsiveness to endocrine therapy. Results Seventeen patients responded and 34 patients did not respond to endocrine therapy. Four responders and one non-responder had a clinical flare reaction, while only the responders demonstrated metabolic flare. After estradiol challenge, a significantly higher mean (±SD) percent change in SUV for FDG was noted in responders (20.9 ± 24.2) compared with non-responders (−4.3 ± 11.0, P < 0.0001). On FES-PET, a higher tumor SUV was noted in responders (3.5 ± 2.5) compared with non-responders (2.1 ± 1.8, P = 0.0049). There was significantly longer overall survival in patients with metabolic flare than in those without flare regardless of type of endocrine therapy (P = 0.0062). Conclusion Baseline tumor FES uptake and metabolic flare after an estradiol challenge are both predictive of responsiveness to endocrine therapy in ER+ breast cancer.