SABCS: Agent Aims at Restoring Hormone-Sensitive Status of Breast Cancer Tumor Cells

Charles Bankhead
SAN ANTONIO, Dec. 15 -- Breast cancer clinicians faced with tumor cells that have transformed during therapy, from hormone sensitive to insensitive, are trying to reverse the process with a lymphoma drug.When the histone deacetylase inhibitor vorinostat (Zolinza), approved for T-cell cutaneous lymphoma, was added to tamoxifen in a small study, there were major responses for four of 17 high-treated patients with metastatic disease whose tumor cells had become nonresponsive.
Action Points --->
Explain to interested patients that this study suggested that a histone deacetylase inhibitor may offer a new hormonal approach to treating breast cancer.
This study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication.
There was even one complete response, Pamela Munster, M.D., of the H. Lee Moffitt Cancer Center in Tampa, said at the San Antonio Breast Cancer Symposium here. Another five patients in the trial had prolonged disease stabilization lasting three to 12 months. Enrollment is planned for 43 patients.
"The results are encouraging," said Dr. Munster. "They suggest that adding vorinostat to tamoxifen may restore hormone sensitivity in patients who have not responded to prior treatment with aromatase inhibitors or adjuvant tamoxifen."
In lab experiments, investigators are also looking at histone deacetylase inhibition as a way to induce responsiveness in tumor cells that were hormone-receptor negative from the start.
A preclinical study reported here showed that combining the aromatase inhibitor letrozole (Femara) with a histone deacetylase inhibitor prevented the growth of an ER-negative cell line.
Many estrogen-receptor positive tumors exhibit primary or acquired resistance to anti-estrogen therapy, Dr. Munster noted. HDACs have a central role in transcription regulation and have been reported to restore sensitivity to hormone-based therapy by modulating estrogen and progesterone receptors.
In the ongoing clinical trial in Tampa, investigators are evaluating vorinostat's ability to restore ER-positive tumors' responsiveness to tamoxifen in patients with metastatic breast cancer. Dr. Munster reported findings from the first 18 patients enrolled in the study. The patients' ER-positive breast cancer had not responded to treatment with aromatase inhibitors and as many as three chemotherapy regimens.
The patients received vorinostat at 400 mg/day for three of four weeks plus tamoxifen at 20 mg every day. The most common nonhematologic toxicities were fatigue, nausea-vomiting, diarrhea, elevated liver enzymes, anorexia, and hyperglycemia. Most events were grade 2, but two patients developed venous thromboemboli.
"It's not clear whether the venous thromboembolism we observed was related to treatment," said Dr. Munster. "We intend to evaluate the issue further to determine the cause of these events."
Nonhematologic toxicity consisted of grade 2-3 thrombocytopenia in 17% of patients, grade 2 leukopenia in 17%, grade 2-3 lymphopenia in 22%, and grade 2-3 neutropenia in 12%.
The investigators observed H3 and H4 acetylation in peripheral blood mononuclear cells, indicating clinically relevant concentrations of vorinostat.
The preclinical study reported here examined the effects of vorinostate and two other histone deacetylase inhibitors (MS-275 and β-actin) on the MDA-MB-231 breast cancer cell line. The cells are both hormone refractory and estrogen receptor-negative but have detectable levels of aromatase, reported Gauri J. Sabnis, Pharm.D., of the University of Maryland in Baltimore.
In a series of lab experiments involving the cell line, investigators showed that:
Histone deacetylase inhibitors upregulate estrogen receptor
Histone deacetylase inhibitors upregulate aromatase in a dose-dependent manner
Combining a histone deacetylase inhibitor with the aromatase inhibitor letrozole inhibits growth of MDA-MB-231 in a dose-dependent manner
Dr. Sabnis and colleagues concluded that histone deacetylase inhibition upregulates estrogen receptor and aromatase expression, stimulates aromatase activity, and sensitizes ER-negative cancer cells to endocrine therapy. Combining an aromatase inhibitor or an anti-estrogen with a histone deacetylase inhibitor may represent a new strategy for treating estrogen receptor-negative breast cancers and possibly an alternative to chemotherapy, they added.
Dr. Munster's study was supported by the Department of Defense and Merck, and Dr. Sabnis' study was funded by the National Cancer Institute. Novartis provided the letrozole for Dr. Sabnis' study.
Drs. Munster and Sabnis had no disclosures.
Primary source: Breast Cancer Research and TreatmentSource reference:Lacevic M, et al "Phase II trial of the HDAC inhibitor, vorinostat, in combination with tamoxifen for patients with advanced breast cancer who have failed prior anti-hormonal therapy" Breast Cancer Res Treat 2007; 106 (Supp1): Abstract 2097.