Phase II trial of vorinostat, a histone deacetylase inhibitor to restore the hormone sensitivity to the anti-estrogen tamoxifen in patients with advanced breast cancer having failed prior aromatase inhibitor therapy

Abstract

3501 Background: Modulation of estrogen receptor signaling is one of the most successful modalities in the treatment of estrogen receptor (ER) positive breast cancers. Many estrogen receptor-positive tumors show primary or acquired resistance to anti-estrogen therapy. Histone deacetylases (HDAC) play a central role in transcriptional regulation and HDAC inhibitors have been reported to restore sensitivity to anti-hormonal therapy by modulation of estrogen as well as progesterone receptors. Here, we report preliminary 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 failed prior therapy with aromatase inhibitors and up to three chemotherapy regimes were administered vorinostat (SAHA) 400 mg daily for three of four weeks and tamoxifen 20 mg daily, continuously. Histone acetylation was evaluated in peripheral blood mononuclear cells and baseline HDAC enzyme expression was evaluated in tumor blocks. Results: To date, 19 patients [median age 56 years (36–71)] have been enrolled and 17 patients were evaluated for response. Two patients (2/18, 11%) had a pulmonary embolus./DVT. Three patients (3/18, 17%) had Grade 3 fatigue, and one patient each (1/18, 6%) had diarrhea, nausea/vomiting, weight loss, AST/ALT elevations, neutropenia or thrombocytopenia. Predominant Grade 2 toxicities included fatigue, nausea/vomiting, anorexia, bleeding and myelosuppression. Four patients had an objective response (1 complete, 3 partial responses: 4/17, 24%), of those 50% had prior chemotherapy and 75% had failed two aromatase inhibitors for metastatic disease, 50% had failed prior tamoxifen. One additional patient had stable disease for 12 months. H3 and H4 histone acetylation was seen at day 8 suggesting adequate PK levels. Histone acetylation, baseline HDAC expression and PK data will be presented. Conclusions: These findings suggest that the addition of an HDAC inhibitor to tamoxifen in patients who have failed prior aromatase inhibitors or adjuvant tamoxifen may restore hormone sensitivity. No significant financial relationships to disclose.