Preoperative Testing of the Anti-Progesterone 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
estrogen alone.

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
immunohistochemistry).

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.

Inclusion Criteria:

- Female identified as a candidate for primary resection of breast cancer (invasive or
ductal carcinoma in situ) by a UCSD Breast Care Unit surgical oncologist

- Subjects must agree to contact the study coordinator prior to starting any new
medications, vitamins or herbals during, or for 2 weeks following, mifepristone use

- Subjects must agree to abstain from alcohol use while on mifepristone

- Age ≥18

- ECOG performance status 0-1

- Prior to starting mifepristone subjects must have a negative urine (βHCG combo with
on-board control) or blood pregnancy test and must be using one of the following
acceptable means of birth control prior to starting study drug; Barrier methods or
surgically sterile (tubal ligation, hysterectomy or partner with confirmed
vasectomy). Alternatively the subject must be one year post-menopausal defined as
greater than 12 months without a menstrual cycle

- Prior to starting mifepristone subjects must meet the following laboratory criteria;
Granulocytes > 1.5E9/l (grade ≤ 1); Platelets ≥ 100E9/l; Hemoglobin > 10 g/dl (grade
≤ 1); Creatinine < 1.5x normal reference range (grade ≤ 1); SGOT, SGPT, alk phos ≤ 1x
normal reference range; Total bilirubin < 1x normal reference range; Calcium < 11.5
mg/dl (grade ≤ 1); HBsAg = Negative; HCV Ab = Negative; INR < 1.5;

- Subjects must provide written informed consent

Exclusion Criteria:

- Not scheduled for surgery within 5 days of enrollment

- Subjects must not be on any therapy to treat breast cancer prior to surgical
resection, specifically medications or recent (within 1 month of diagnostic biopsy)
withdrawal of estrogen containing medication (eg. hormone replacement therapy)

- Subjects must not be on any medications, vitamins or herbals that are; potent
inhibitors of cytochrome P450 CYP3A4, or sensitive substrates for cytochrome P450
CYP3A4

- Subjects may not have any history of significant cardiovascular, renal or hepatic
disease requiring ongoing medical therapy or clinical intervention

- Subjects may not have a history of thrombophlebitis, thromboembolic disorder, or
cerebral vascular disease.

- Subjects may not have any known hypersensitivity to mifepristone

- Subjects may not have a BMI > 39

- Subjects may not have an IUD (Intrauterine contraceptive device), chronic adrenal
failure, concurrent long term steroid therapy, history of allergy to mifepristone,
hemorrhagic disorders or concurrent anticoagulant therapy, or inherited porphyrias