This randomized trial studies transdermal or oral telapristone acetate in treating patients undergoing surgery to remove the breast (mastectomy). Telapristone acetate may help prevent breast cancer from forming in premenopausal women. Giving telapristone acetate transdermally may be safer and have fewer side effects than oral administration.

PRIMARY OBJECTIVES:

I. To demonstrate that mean levels of telapristone (telapristone acetate) in breast tissue following gel application will result in levels that are not more than 50% lower than those following oral administration.

SECONDARY OBJECTIVES:

I. To assess whether plasma concentrations of telapristone are significantly lower with transdermal than oral therapy.

II. To compare within-breast variation of breast tissue concentration in transdermal and oral groups.

III. To measure changes in cell proliferation (marker of proliferation (Ki-67 labeling index).

IV. Explore changes in gene expression in breast tissue related to telapristone therapy.

V. Assess change in serum progesterone associated with telapristone therapy. VI. Assess the safety and tolerability of oral and transdermal administration. VII. Assess symptom measurements using BESS Questionnaire

OUTLINE: Participants are randomized to 1 of 2 treatment arms.

ARM I (TRANSDERMAL TELAPRISTONE ACETATE): Patients receive telapristone acetate transdermally and placebo orally (PO) once daily (QD) for 4 weeks.

ARM II (ORAL TELAPRISTONE ACETATE): Patients receive placebo transdermally and telapristone acetate PO QD for 4 weeks.

After completion of study treatment, patients are followed up at day 60.

Inclusion Criteria:

• Women scheduled for unilateral or bilateral mastectomy for breast cancer therapy, pathology confirmed stage 0-II (including ductal carcinoma in situ), or prophylaxis (breast cancer, early onset [BRCA] mutation carriers, women with strong family history or lobular carcinoma in situ or other conditions where prophylactic mastectomy has been elected)
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
• Total bilirubin < 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) < 2.5 x ULN
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x ULN
• Creatinine < 2 x ULN
• Alkaline phosphatase < 2.5 x ULN
• Blood urea nitrogen < 2 x ULN
• Willing to use non-hormonal contraception (adequate barrier-type contraception or intrauterine device [IUD]) from the time the pregnancy test is performed for the duration of study participation, and 30 days after study drug cessation (for women of childbearing potential only)
• Ability to understand and the willingness to sign a written informed consent document
• Willing and able to schedule mastectomy 4 weeks (+/- 7days) following start of study agent
• Willing to avoid exposing breast skin to natural or artificial sunlight (i.e. tanning beds) for the duration of study agent dosing
• Negative urine pregnancy test result, for participants of child bearing potential, within 5 days prior to first dose of study medication; female of child-bearing potential is any woman (regardless of sexual orientation, whether she has undergone a tubal ligation, or remains celibate by choice) who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; OR has had a menstrual period at any time in the preceding 12 consecutive months)
• Willing to use alcohol in moderation while taking study agent

Exclusion Criteria:

• The presence of skin invasion by the breast cancer, or inflammatory changes with skin edema AND erythema. Note: Paget's disease is permitted.
• Women receiving a "nipple delay" procedure prior to mastectomy.
• Women with skin diseases (psoriasis, eczema) on breast.
• A history of thromboembolic disorder or cerebral vascular disease
• Use of oral contraceptives or other hormonal treatments within eight weeks prior to the randomization or during the period of the study; women should not have used Depo-Provera in the preceding 6 months; use of hormone coated IUD like Mirena is allowed
• Participants may not have received any other investigational agents in the previous 3 months
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to telapristone (i.e. other progesterone antagonists)
• Taken tamoxifen or other selective estrogen/progesterone receptor modulators (SERMs/SPRMs) within two years prior to entering study or been required to discontinue SERM therapy due to thromboembolic or uterine toxicity
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• History of prior breast cancer-specific therapy within the previous 2 years; previous unilateral radiation in women scheduled for mastectomy of the contralateral side is allowed
• Pregnant or breastfeeding
• Currently taking spironolactone
• Recent history (within 6 months) of alcoholism or drug abuse
• Known active infection with human immunodeficiency virus (HIV), hepatitis A, B, or C