A Biomarker Study of Mifepristone in Early Stage Breast Cancer
Secondary objectives of this study include; (1) Measuring objective response in tumor size
with treatment, (2) Establishing the safety and tolerability of short term mifepristone
exposure in early stage breast cancer patients, and (3) Performing exploratory studies of
expression of related targets following drug exposure.
Anti-estrogen therapy has been a mainstay of breast cancer treatment for over three decades.
It is highly effective and has modest toxicity, certainly in comparison to chemotherapy.
The selective estrogen receptor modulator tamoxifen has the longest history but a number of
aromatase inhibitors and the anti-estrogen fulvestrant are also in widespread use along with
ovarian ablation for pre-menopausal women. Given the success of this approach, and the
highly analogous parallel progesterone signal, it is unfortunate that anti-progesterone
therapy has not been similarly pursued. Additionally, data from the Woman's Health
Initiative trial reveal a potentially significant role for progesterone in breast cancer
development and growth. Healthy postmenopausal women treated with the combination of
estrogen and progesterone over a 5 year period were 24% more likely to develop invasive
breast cancer and had larger tumors at diagnosis. Notably this effect was not seen in
post-hysterectomy women treated with estrogen alone over nearly 7 years. In fact a
non-statistically significant reduction in breast cancer incidence was observed with
The anti-progesterone mifepristone has been found to reduce proliferation in normal breast
tissue. Even a low dose of mifepristone (50mg every other day for 3 months) demonstrated a
statistically significant reduction in breast cell proliferation (measured by Ki-67
Higher doses of mifepristone, 200mg daily, have been used in patients with metastatic breast
cancer for durations of almost 2 years without serious toxicity. Response rates were only
11% but no grade 4 or 5 toxicities occurred. Some grade 3 toxicities occurred, including
lethargy, nausea, vomiting, and skin rash. These rashes resolved with temporary
discontinuation of drug and did not recur when drug was resumed.
As a whole these data strongly support research into anti-progesterone therapy for early
stage breast cancer. To our knowledge this is the first such study.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Change in proliferation by Ki-67 immunohistochemistry.
Richard B Schwab, MD
University of California, San Diego
United States: Food and Drug Administration
|Moores UCSD Cancer Center||La Jolla, California 92093-0658|