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18 F-Fluoroestradiol ( 18 F-FES)-PET Imaging in a Phase II Trial of Vorinostat to Restore Endocrine Sensitivity in ER+/HER2- Metastatic Breast Cancer

Histone deacetylase inhibitors (HDACi) may overcome endocrine resistance in estrogen receptor positive (ER+) metastatic breast cancer. We tested whether 18F-Fluoroestradiol (18F-FES)-PET imaging would elucidate pharmacodynamics of combination HDACi and endocrine therapy. Methods: Patients with ER+/HER2- metastatic breast cancer with prior clinical benefit from endocrine therapy but later progression on aromatase inhibitor (AI) therapy were given vorinostat (400mg daily) sequentially or simultaneously with AI. 18F-FES PET and 18F-Fluorodeoxyglucose (18F-FDG) PET scans were performed at baseline, week 2, and week 8. Results: Eight patients were treated sequentially, then 15 simultaneously. Eight patients had stable disease at week 8 and six of these eight patients had >6 months of stable disease. Higher baseline 18F-FES uptake was associated with longer progression-free survival (PFS). 18F-FES uptake did not systematically increase with vorinostat exposure, indicating no change in regional ER estradiol binding, and 18F-FDG uptake did not show significant decrease, as would have been expected with tumor regression. Conclusion: Simultaneous HDACi and AI dosing in patients with cancers resistant to AI alone showed clinical benefit (6+ months without progression) in 4 of 10 evaluable patients. Higher 18F-FES-PET uptake identified patients likely to benefit from combination therapy, but vorinostat did not change ER expression at the level of detection of 18F-FES-PET.

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S1047 Vorinostat (SAHA) Vorinostat (SAHA) is an HDAC inhibitor with IC50 of ~10 nM in a cell-free assay. Vorinostat abrogates productive HPV-18 DNA amplification.

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