Clinical Phase II Study of Vorinostat, a Hydroxamic Type Histone Deacetylase Inhibitor, in Combination with Tamoxifen To Reverse Acquired Hormone Resistance in Breast Cancer Patients Who Progressed on Hormone Therapy.
Authors: Munster P. , Lacevic M. , Thomas S. , Ismail-Khan R. , Rugo H. , Melisko M. , Minton S. 
Published: December 2010

Background: Primary or acquired resistance to hormonal therapy remains a major clinical challenge in patients with breast cancer. The most commonly used approach to modulate estrogen receptor signaling includes the use of a selective estrogen receptor modulator or down-regulator, or an aromatase inhibitor. Recently, inhibition of histone deacetylases (HDAC) has emerged as a novel strategy to modulate the estrogen and progesterone receptors by a different mechanism. This study seeks to test whether the addition of an HDAC inhibitor to tamoxifen may reverse acquired hormone resistance.Methods: Patients with estrogen receptor (ER) positive metastatic breast cancer who progressed on prior hormonal therapy with one or two aromatase inhibitors, and up to three chemotherapy regimens for metastatic cancer were treated with 400 mg vorinostat daily for 21 of 28 days and 20 mg tamoxifen daily, continuously. Patients previously treated with tamoxifen in the adjuvant, but not in the metastatic setting, were eligible. Bone only disease was permissible if at least one lesion measured 1 cm by MRI.Results: The study enrolled 43 female patients with a median age of 56 years (range 34-71). To date 42 patients with ER-positive breast cancer completed at least 1 cycle of therapy with a median number of 4 (1-24) cycles and a median duration of response of 8 months. Prior hormonal therapy included at least one aromatase inhibitor in 41 (98%) patients and two aromatase inhibitors in 22 (52%) of the patients; 21 (50%) of the patients received at least one chemotherapy regimen for metastatic disease, and 22 (52%) patients had received adjuvant tamoxifen. Of the 34 patients evaluable for response to date, 7 (21%) had a confirmed partial response and one additional patient with bone only disease had a response by PET/CT, another 4 (12%) patients had stable disease for ≥ 6 months. Dose reductions from 400 mg to 300 mg vorinostat were required in 30% of patients and to 200 mg in 18%. Major grade 3/4 toxicities included fatigue (5 pts, 12%), anorexia/weight loss (2 pts, 5%), nausea/vomiting (2 pts, 5%), hypokalemia (1 pt, 2%), liver enzyme elevations (1 pt, 2%), lymphopenia (7 pts, 16%), thrombocytopenia (3 pts, 7%) and neutropenia (6 pts, 14%). Pulmonary emboli were observed in 2 (5%) patients. Common grade 2 toxicities were fatigue (14%), nausea/vomiting/diarrhea (21%), hyperglycemia (19%), anorexia (12%), and myelosuppression (19%). Histone H3 and H4 acetylation was seen at day 8 suggesting adequate vorinostat plasma levels in the majority of patients.Conclusions: These findings suggest that the addition of the HDAC inhibitor, vorinostat to tamoxifen in patients who have progressed on prior hormonal therapy and including prior adjuvant tamoxifen is tolerable and demonstrates efficacy.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6100.