Finding the best dose of tamoxifen to reduce breast cancer risk in premenopausal women

Refining Tamoxifen Dose for Premenopausal Breast Cancer Risk Reduction (RENAISSANCE): A Phase II Single Arm Trial

This study is testing if a higher dose of tamoxifen can help premenopausal women at higher risk for breast cancer by reducing breast density on mammograms.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 200 (estimated)
• Ages: 18 Years to 55 Years
• Sex: Female
• Sponsor: National Cancer Institute (NCI) (NIH)
• Locations: 11 sites (Tucson, Arizona and 10 other locations)
• Trial ID: NCT06184750 on ClinicalTrials.gov

What this trial studies

This phase II trial evaluates the effectiveness of low-dose tamoxifen in reducing breast density among premenopausal women at higher risk for breast cancer. The study aims to determine if increasing the tamoxifen dose from 5 mg to 10 mg can improve the proportion of women who respond positively, as indicated by a significant reduction in breast density on mammograms. Secondary objectives include assessing the relationship between tamoxifen metabolites and breast density changes, as well as evaluating participant-reported symptoms and adherence to the treatment. The trial also explores biomarkers associated with tamoxifen response through research biopsies.

Who should consider this trial

Good fit: Ideal candidates are premenopausal women under 50 with a history of estrogen receptor-positive breast conditions or those at elevated risk for breast cancer.

Not a fit: Patients who are postmenopausal or do not meet the specific risk criteria for breast cancer will not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide a more effective preventive strategy against breast cancer for women at high risk.

How similar studies have performed: Other studies have shown promise in using tamoxifen for breast cancer prevention, making this approach both relevant and potentially impactful.

Eligibility criteria

Inclusion Criteria:

* Premenopausal women at the time of enrollment defined by any of the following:

  * Age under 50 years and regular menstruation (most recent period within the past 3 months)
  * Age under 50 years and continuous hormonal contraception use and at least one intact ovary
  * Women who are not postmenopausal based on serum hormone levels. Women with estradiol =\< 30 pg/mL, follicle-stimulating hormone (FSH) \>= 30 IU/mL are eligible
* Women with any of the following:

  * A history of unilateral estrogen receptor (ER) positive ductal carcinoma in situ (DCIS) with local therapy completed (as determined by treating physician recommendation and patient acceptance) at least 1 month prior to study entry. (The untreated breast will be the study breast, for both imaging and optional biopsy)
  * Recent or prior lobular carcinoma in situ (LCIS), or any form of epithelial atypia, flat epithelial (FEA), atypical ductal hyperplasia (ADH), or atypical lobular hyperplasia (ALH)
  * Are risk eligible for preventive medication based on a five-year risk of 1.7% or greater, estimated with a validated model: the National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool, Tyrer-Cusick, Breast Cancer Surveillance Consortium. If the Tyrer-Cuzick model is used a ten-year risk of 3.4% or greater is acceptable
  * Are tamoxifen-eligible by American Society of Clinical Oncology (ASCO) guidelines (\>= 2-fold increased risk compared to peer if age \>= 45 years, and \>= 4-fold increased risk if age \< 45 years)
  * A history of mantle radiotherapy
  * A moderate penetrance germline pathogenic variant
* Participants ≥ 18 and ≤ 55 years old will be enrolled. Our trial objectives are not relevant to females under 18 years of age since breast cancer is extraordinarily rare in this age group, and there are no guidelines regarding use of tamoxifen in children, even if know to be at very high risk for breast cancer when older. Because no dosing or adverse event (AE) data are currently available on the use of tamoxifen in participants \< 18 years of age
* Eastern Cooperative Oncology Group (ECOG) performance status must be =\< 2 (Karnofsky \>= 60%)
* Human immunodeficiency virus (HIV)-infected patients are eligible to participate if they are on effective anti-retroviral therapy with undetectable viral load within the prior 6 months
* Women with evidence of chronic hepatitis B virus (HBV) infection, are also eligible if the HBV viral load is undetectable; they may be on suppressive therapy, if indicated
* Women with a history of hepatitis C virus (HCV) infection are eligible if treated and cured. For those who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Women with herpes simplex virus (HSV) infection are eligible if on chronic or as needed (due to a flare) suppressive antiviral therapy
* Hormonal contraceptive users are eligible and should maintain the same oral contraceptive preparation throughout the duration of the trial. For women who have a levonorgestrel-coated intra-uterine device, removal for medical reasons will be allowed
* The effects of tamoxifen on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because tamoxifen is known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
* Ability to understand and the willingness to sign a written informed consent document
* Breast Imaging Reporting and Data System (BIRAD) 1 or 2. If BIRAD 0, follow-up diagnostic imaging must be BIRAD 1 or 2 or cleared clinically with radiology recommendation of return to annual screening
* Women who are factor V leiden carriers and have not had a blood clot are eligible, if approved by their treating physician

Exclusion Criteria:

* BIRADS breast density category A on most recent mammogram
* History of selective estrogen receptor modulator (SERM) use within the past 5 years unless:

  * Use was less than 6 months duration in the past 5 years and not used in the 1 year prior to enrollment OR
  * Use was no greater than 2 months duration in the past 1 year and not used in the 6 months prior to enrollment
* History of invasive breast cancer
* Prior bilateral mastectomy or breast augmentation surgery including breast implants. Prior bilateral excisional surgical biopsy, mastopexy (breast lift) or mammoplasty (breast reduction) is allowed, as long as \> 1 year has passed since the procedure
* Women with "mosaic mammographic screening views", i.e., whose larger breast size precludes being imaged within a single mammographic screening view
* Current use of a strong CYP3A4 inducer or a strong CYP2D6 inhibitor unless willing and able to discontinue use and switch to an alternative medication for the duration of participation, under the advice of their physician. If the physician believes the current medication cannot be replaced, the participant will not be eligible
* Current use of Warfarin
* Planning to become pregnant within the next two years. Potential study participants will be questioned about this and excluded if they are planning pregnancy over the next 20 months
* History of thromboembolism, pulmonary embolism, thrombotic stroke, arterial thrombosis of the extremity or deep vein thrombosis. A history of superficial thrombophlebitis is allowed
* History of uterine cancer or atypical uterine hyperplasia with uterus intact
* Participants may not be receiving any other investigational agents
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to tamoxifen
* Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements
* Pregnant women are excluded from this study because tamoxifen a category D agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with tamoxifen. Breastfeeding should be discontinued if the mother is treated with tamoxifen
* Women with known gene mutations associated with an increased risk for breast cancer such as BRCA1/2, CDH1, PALB2, PTEN, STK11, or P53
* Current use of sex hormones (estrogen, progesterone, or androgens), unless part of oral contraception pills
* Prior invasive cancer, unless curatively treated, and all treatment was completed \> 5 years prior to enrollment

Where this trial is running

Tucson, Arizona and 10 other locations

• University of Arizona Cancer Center - Prevention Research Clinic — Tucson, Arizona, United States (Recruiting)
• Northwestern University — Chicago, Illinois, United States (Recruiting)
• University of Illinois College of Medicine - Chicago — Chicago, Illinois, United States (Recruiting)
• University of Kansas Cancer Center — Kansas City, Kansas, United States (Recruiting)
• Brigham and Women's Hospital — Boston, Massachusetts, United States (Recruiting)
• Dana-Farber Cancer Institute — Boston, Massachusetts, United States (Recruiting)
• University of Michigan Rogel Cancer Center — Ann Arbor, Michigan, United States (Recruiting)
• Washington University School of Medicine — St Louis, Missouri, United States (Recruiting)
• Case Western Reserve University — Cleveland, Ohio, United States (Recruiting)
• Medical University of South Carolina — Charleston, South Carolina, United States (Recruiting)
• M D Anderson Cancer Center — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Seema A Khan — Northwestern University

Conditions Breast Atypical Ductal Hyperplasia; Breast Atypical Lobular Hyperplasia; Breast Carcinoma; Breast Ductal Carcinoma In Situ; Breast Lobular Carcinoma In Situ; Estrogen Receptor-Positive Breast Carcinoma