Phase II trial of the histone deacetylase inhibitor, vorinostat, to restore hormone sensitivity to the antiestrogen tamoxifen in patients with advanced breast cancer who progressed on prior hormone therapy

Abstract

1075 Background: Modulation of estrogen receptor signaling is one of the most successful modalities in the treatment of estrogen receptor (ER) positive breast cancers. However, hormone therapy resistance remains a challenging problem. Histone deacetylases (HDAC) have emerged as a recent strategy to interfere with hormone receptor signaling by modulating the estrogen and progesterone receptor. Here we report the findings from a phase II trial evaluating the HDAC inhibitor, vorinostat and the anti-estrogen, tamoxifen, placed in context with correlative studies. Methods: Patients with ER-positive metastatic breast cancer who progressed on prior hormonal therapy and up to three chemotherapy regimens were treated with 400 mg vorinostat daily for three of four weeks and 20 mg tamoxifen daily, continuously. Histone acetylation was evaluated in peripheral blood mononuclear cells. Results: To date, 29 patients [median age 53 years (34–71)] have been treated with the combination. Pulmonary emboli were observed in 2/29 (7%) patients. Other grade 3/4 toxicities included fatigue (5/29, 17%), anorexia (2/29, 7%), diarrhea (1/29, 3%), nausea/vomiting (3/29, 10%), hypokalemia (1/29, 3%), liver enzyme elevation (1/29, 3%), lymphopenia (5/29, 17%) and leukopenia (4/29, 13%). Predominant grade 2 toxicities included fatigue, nausea/vomiting/diarrhea, hyperglycemia, anorexia, and myelosuppression. Six (21%) patients had an objective response, and 3/29 (10%) additional patients had disease stabilization for >6 months; 13/29 (45%) patients had at least one prior chemotherapy regimen for metastatic disease, 28/29 (92%) patients had progressed after exposure to at least one and 16/29 (55%) patients after two aromatase inhibitors, and 18/29 (62%) patients had received prior adjuvant tamoxifen. H3 and H4 histone acetylation was seen at day 8 suggesting adequate vorinostat plasma levels. Histone acetylation and baseline HDAC expression will be presented. Conclusions: These findings suggest that the addition of an HDAC inhibitor to tamoxifen in patients who have progressed on prior hormonal therapy and/or adjuvant tamoxifen may restore hormone sensitivity. No significant financial relationships to disclose.