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