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4-hydroxytamoxifen Topical Gel in Reducing the Risk of Breast Cancer in Women with Mammographically Dense Breast

Trial Status: Closed to Accrual and Intervention

This randomized phase II trial studies whether putting afimoxifene (4-hydroxytamoxifen topical gel) on the breast skin lowers mammographic density compared with putting placebo gel on the breast skin. Women with dense breast tissue have a higher risk for developing breast cancer. 4-hydroxytamoxifen topical gel applied to the breast skin may allow the drug to get into the breast and lower risk of breast cancer with fewer unwanted effects than oral tamoxifen.

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
  • Platelets >= 100,000/microliter
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal (ULN)
  • Participant must have a gynecology examination within the last 5 years (gynecology examination is not required if participant had a hysterectomy)
  • Premenopausal women using a hormonal or 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 who are using postmenopausal hormones, and are planning to continue the same regimen through the study intervention are eligible to participate
  • 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, unwilling to use adequate contraception during study treatment duration, had given birth, or nursed at any time during the last 12 months * The effects of 4-OHT gel on the developing human fetus at the recommended dose are unknown; for this reason and because tamoxifen is known to be teratogenic, all heterosexually active women who may become pregnant 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); hormonal IUDs are also allowable methods of birth control; 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
  • 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
  • Women with a uterus and abnormal uterine bleeding, or prior diagnosis of endometrial hyperplasia, endometrial polyps, or endometrial cancer
  • Prior use of selective estrogen receptor modulators (SERMS) and aromatase inhibitors (AIs), except for a maximum of 3 months and at least 12 months prior
  • 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


Banner University Medical Center - Tucson
Contact: Pavani Chalasani
Phone: 520-626-0191


Moffitt Cancer Center
Contact: Nagi B. Kumar
Phone: 813-745-6885


Northwestern University
Contact: Seema Ahsan Khan
Phone: 312-503-4236


Dana-Farber Cancer Institute
Contact: Judy Ellen Garber
Phone: 617-632-5770


University of Minnesota / Masonic Cancer Center
Contact: Heather Beckwith
Phone: 612-625-4918


M D Anderson Cancer Center
Contact: Banu Arun
Phone: 713-792-2817


University of Wisconsin Hospital and Clinics
Contact: Lee Gravatt Wilke
Phone: 608-263-1164


I. To estimate and compare the percent change in mammographic breast density (using Cumulus software) from baseline to month 12 (or month 13-18 under the COVID-19 contingency plan) in women applying 2 mg afimoxifene (4-hydroxytamoxifen [4-OHT]) gel per breast versus placebo.

SECONDARY OBJECTIVES: (Note: Data from month 13-18 visit instead of month 12 will be used if participants were seen under the COVID-19 contingency plan)

I. To compare the Cumulus versus (vs.) Volpara breast density measurement methods to estimate percent change in mammographic breast density from baseline to month 12 in women applying 2 mg of 4-OHT gel per breast vs. placebo.

II. To compare the percentage of women who underwent a change in Breast Imaging Reporting and Data System (BIRADS) category, comparing pre-and post- treatment measurements, for recipients of active agent versus placebo.

III. To estimate percentage of women with >= 10% absolute decrease in quantitative mammographic density percentage between baseline and 12 months, comparing between treated group 2 mg per breast 4-OHT gel to placebo.

IV. To compare the 2-dimensional (2D) vs. 3-dimensional (3D) breast density measurement methods to estimate percent change in mammographic breast density from baseline to month 12 in women applying 2 mg of 4-OHT gel per breast vs. placebo.

V. To describe symptoms assessed by breast cancer prevention trial (BCPT) eight symptom scale (BESS) questionnaire and laboratory toxicity assessment (factor VIII [F VIII], Von Willebrand [vWB] factor, sex hormone-binding globulin [SHBG], lipid profile).

VI. To evaluate serum measurements of 4-OHT and related metabolite levels and factors related to tamoxifen exposures, such as insulin-like growth factor (IGF) pathway members, C-reactive protein (CRP), estradiol.

VII. To evaluate tissue biomarkers (among women undergoing optional pre- and post-treatment biopsies): terminal duct lobular unit (TDLU) involution; collagen structural changes; SETER/PR index: estrogen related transcription, Ki-67, COX-2, p16, CD68.

VIII. To examine whether any reductions in mammographic density seen after 1 year of 4-OHT vs. placebo gel application persist at 24 months, one year after gel application has stopped.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients apply placebo gel topically to each breast once daily (QD) for up to 52 weeks.

ARM B: Patients apply afimoxifene gel topically to each breast QD for up to 52 weeks.

After completion of study treatment, patients are followed up at 24 months.

Trial Phase Phase II

Trial Type Prevention

Lead Organization
M D Anderson Cancer Center

Principal Investigator
Banu Arun

  • Primary ID MDACC: 2017-0328
  • Secondary IDs NCI-2017-00244, MDA2016-07-02, N01-CN-2012-00034
  • ID NCT03063619