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

Abstract

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-[(18)F]-fluoro-2-deoxyglucose (FDG), induced by an estradiol challenge, or by estrogen-receptor (ER) status, determined by PET with the estrogen analog 16alpha-[(18)F]fluoroestradiol-17beta (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 >or= 2 for FES was considered positive for ER expression. A cutoff of >or=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.

Figures

Figure 1

The ROC analysis for % SUV changes for FDG demonstrated that a cutoff of 12% (arrow) increase in SUV for FDG shows the optimal tradeoff between sensitivity and specificity.

Figure 2

The baseline tumor FES (left) and percent change in tumor FDG (right) uptake after estradiol challenge in patients who responded and who did not respond to endocrine therapy.

Figure 3

A Kaplan-Meier model of overall survival based on metabolic flare (increase in FDG uptake ≥ 12%) (A) and clinical response (B) and FES uptake (C) showed that a significantly longer survival was seen in patients with metabolic flare and clinical responders than in those without flare and clinically non-responders regardless of type of hormonal therapy (p = 0.0062 and p = 0.0045, respectively). However, baseline FES uptake was not predictive of survival (p = 0.23).