A Randomized, Double-blind, Placebo-controlled Study of 4-hydroxytamoxifen Topical Gel in Women with Mammographically Dense Breast

This randomized phase II trial studies how well afimoxifene works in reducing the risk of
breast cancer in women with mammographically dense breast. Estrogen can cause the growth of
breast cancer cells. Hormone therapy using afimoxifene may fight breast cancer by blocking
the use of estrogen by the tumor cells.

Inclusion Criteria:

- Women age 40-69 years, or less than 40 years if 5-year breast cancer Gail risk is ≥
1.66%.

- Mammographically dense breast (heterogeneously dense [C] or extremely dense [D], based
on American College of Radiology [ACR] BIRADS fifth edition classification or
heterogeneously dense [3] or extremely dense [4], based on ACR BIRADS fourth edition
classification) in either breast

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- White blood cells >= 3,000/microliter

- Absolute neutrophil count >= 1,500/microliter

- Platelets >= 100,000/microliter

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 1.5 × institutional upper limit of normal (ULN)

- Creatinine within normal institutional limits

- Participant must have a gynecology examination within the last 3 years, with no
atypical hyperplasia and no cancer

- Premenopausal women taking non hormonal intra-uterine device (IUD) birth control
method will be eligible, if they have been on the same IUD for at least 3 months prior
to enrollment and plan to continue using the same method throughout the study

- Women of child-bearing potential must agree to use a reliable nonhormonal
contraceptive method during the study and for 2 months after completing study
medications; reliable nonhormonal methods of contraception include barrier
contraception and an intra-uterine device (IUD); Note: women who had tubal ligation or
had a partner who had undergone a vasectomy (and are monogamous) are eligible for the
study and are not required to use barrier contraception

- If the participant is of childbearing potential, she must have a documented negative
urine pregnancy test within 7 days prior to randomization

- Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e.
tanning beds) for the duration of the study

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to 4-OHT gel

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, thromboembolic disease, or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant, or had given birth, or nursed at any time during the last 12 months

- Women with a previous history of invasive breast cancer or bilateral ductal carcinoma
in situ (DCIS) or current untreated DCIS; women with a history of cancer within the
last 3 years, except for non-melanoma skin cancer; women with unilateral DCIS (with or
without radiation therapy) are eligible as long as they have an unaffected breast

- Prior bilateral breast surgery (mastectomy, segmental mastectomy, or breast
augmentation surgery including breast implants or breast reductions)

- Women with "mosaic mammographic screening views", i.e., whose larger breast size
precludes being imaged within a single mammographic screening view

- Women with active liver disease, abnormal uterine bleeding, or prior diagnosis of
endometrial hyperplasia

- Prior use of selective estrogen receptor modulators (SERMS) and aromatase inhibitors
(AIs) for prevention or therapy

- Skin lesions on the breast that disrupt the stratum corneum (e.g., eczema, ulceration)

- Treatment with any investigational drug or investigational biologic within 30 days of
initiating study treatment or during the study