Finding the Best Tamoxifen Dose for Breast Cancer Risk Reduction in Premenopausal Women, RENAISSANCE Trial

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

This phase II trial evaluates response-guided low-dose tamoxifen for reducing breast density in women who are at higher than average risk for breast cancer. Increasing breast density is a well established risk factor for breast cancer. Tamoxifen is a selective estrogen receptor modulator. It works by blocking the effects of the hormone estrogen in the breast. Tamoxifen has been shown to reduce breast density, even at reduced dosages, and is approved for the prevention of breast cancer.

Study Overview

• Status: Recruiting
• Conditions: Breast Carcinoma; Breast Atypical Ductal Hyperplasia; Breast Atypical Lobular Hyperplasia; Breast Ductal Carcinoma In Situ; Breast Lobular Carcinoma In Situ; Estrogen Receptor-Positive Breast Carcinoma
• Intervention / Treatment: Other: Questionnaire Administration; Procedure: Biospecimen Collection; Drug: Tamoxifen; Procedure: Mammography; Procedure: Biopsy Procedure

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate whether the overall proportion of premenopausal tamoxifen responders (defined by absolute dense area reduction on mammogram of > 10%) can be increased through a strategy of within-individual dose escalation among non-responders from 5 mg per day to 10 mg per day.

SECONDARY OBJECTIVES:

I. To assess the association of plasma levels of major tamoxifen metabolites with tamoxifen dose and breast density changes from baseline.

II. To evaluate longitudinal change from baseline in serum biomarkers of tamoxifen response at each dose level: sex hormone binding globulin (SHBG), insulin like growth factor 1 (IGF-1) and C-reactive protein (CRP).

III. To assess the association of baseline dense area (continuous variable) with tamoxifen response.

IV. To evaluate the impact of tamoxifen dose on participant-reported symptoms (Breast Eight Symptom Scale, BESS).

V. To evaluate the impact of tamoxifen dose on adherence to final tamoxifen dose.

EXPLORATORY OBJECTIVES:

I. To evaluate breast tissue-based biomarkers (in research biopsy samples) that associate with tamoxifen response at six months, comparing within-person change in responders and non-responder.

II. To assess the association between single nucleotide polymorphisms that overlap between risk of breast cancer and dense are of breasts; and others that relate to efficiency of tamoxifen metabolism.

III. To evaluate change in breast cancer risk estimates from baseline to 18 months, as assessed by an AI (artificial intelligence) tool and compare changes by dose group.

OUTLINE: This is a within-participant dose-escalation study of tamoxifen.

Participants receive tamoxifen 5mg orally (PO) once daily (QD) for 6 months. Participants with absolute dense area reduction (aDAR) >= 10% on mammogram at 6 months continue receiving tamoxifen 5mg PO QD for 12 months. Participants with aDAR < 10% at 6 months are escalated to receive tamoxifen 10mg PO QD for 6 months. Participants with aDAR >= 10% after 6 months of tamoxifen 10mg continue receiving tamoxifen 10 mg PO QD for 6 months. Participants with aDAR < 10% after 6 months of tamoxifen 10mg are given the option of continuing tamoxifen 10mg or escalating to receive tamoxifen 20mg PO QD for 6 months. Participants undergo mammography and collection of blood samples at screening and on study. Participants may optionally undergo biopsy at screening and on study.

After completion of study intervention, patients are followed up at 4 weeks.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • Recruiting
      • University of Arizona Cancer Center - Prevention Research Clinic
      • Principal Investigator: Sima Ehsani Chimeh
      • Contact: Sima Ehsani Chimeh; Phone Number: 520-626-2873; Email: simaehsani@arizona.edu
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University
      • Principal Investigator: Seema A. Khan
      • Contact: Seema A. Khan; Phone Number: 312-503-4236; Email: s-khan2@northwestern.edu
    • Chicago, Illinois, United States, 60612
      • Recruiting
      • University of Illinois College of Medicine - Chicago
      • Contact: Kent F. Hoskins; Phone Number: 312-996-1581; Email: khoski@uic.edu
      • Principal Investigator: Kent F. Hoskins
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Recruiting
      • University of Kansas Cancer Center
      • Contact: Carol J. Fabian; Phone Number: 913-588-7791; Email: cfabian@kumc.edu
      • Principal Investigator: Carol J. Fabian
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Elizabeth A. Mittendorf; Phone Number: 617-582-9980; Email: emittendorf@bwh.havard.edu
      • Principal Investigator: Elizabeth A. Mittendorf
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
      • Principal Investigator: Judy E. Garber
      • Contact: Judy E. Garber; Phone Number: 617-632-3891; Email: judy_garber@dfci.harvard.edu
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan Rogel Cancer Center
      • Principal Investigator: Melissa L. Pilewskie
      • Contact: Melissa L. Pilewskie; Phone Number: 734-647-8902; Email: mpilewsk@med.umich.edu
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Adetunji T. Toriola; Phone Number: 314-286-2668; Email: a.toriola@wustl.edu
      • Principal Investigator: Adetunji T. Toriola
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Case Western Reserve University
      • Contact: Amanda L. Amin; Phone Number: 216-896-1787; Email: amanda.amin@uhhospitals.org
      • Principal Investigator: Amanda L. Amin
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • Medical University of South Carolina
      • Contact: Kevin S. Hughes; Phone Number: 843-876-4420; Email: hughkevi@musc.edu
      • Principal Investigator: Kevin S. Hughes
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • M D Anderson Cancer Center
      • Contact: Parijatham (Priya) S. Thomas; Phone Number: 713-792-6161; Email: psthomas@mdanderson.org
      • Principal Investigator: Parijatham (Priya) S. Thomas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Prevention (tamoxifen); Participants receive tamoxifen 5mg PO QD for 6 months. Participants with aDAR >= 10% on mammogram at 6 months continue receiving tamoxifen 5mg PO QD for 12 months. Participants with aDAR < 10% at 6 months are escalated to receive tamoxifen 10mg PO QD for 6 months. Participants with aDAR >= 10% after 6 months of tamoxifen 10mg continue receiving tamoxifen 10 mg PO QD for 6 months. Participants with aDAR < 10% after 6 months of tamoxifen 10mg are given the option of continuing tamoxifen 10mg or escalating to receive tamoxifen 20mg PO QD for 6 months. Participants undergo mammography and collection of blood samples at screening and on study. Participants may optionally undergo biopsy at screening and on study.

Other: Questionnaire Administration; Ancillary studies; Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Drug: Tamoxifen; Given PO; Other Names: TMX; Procedure: Mammography; Undergo mammography; Other Names: MG; Procedure: Biopsy Procedure; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Biopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of women who have a response at any time point	Tamoxifen response is defined as absolute dense area reduction (aDAR) of >= 10% on mammogram compared to baseline mammogram. A one sample exact binomial test for one proportion will be used, and the exact two-sided p-value will be reported. Response rate for the entire study population, as well as for the group of women who were dose-escalated, will be estimated and reported with the corresponding 95% confidence interval. Absolute and relative changes in dense area will be estimated using descriptive statistics (e.g., mean and standard deviation, or median and interquartile range), and, as a sensitivity analysis, a paired t-test or the signed rank test will be used to determine whether there was a reduction in dense area. Similar descriptive statistics will be performed in each dose sequence group for both the response rate and dense area changes.	At 6, 12, and 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma levels of major tamoxifen (TAM) metabolites	Will assess the association of plasma levels of major tamoxifen metabolites with tamoxifen dose and breast density changes from baseline. Metabolite levels will be summarized using standard descriptive statistics at each time point, and change patterns examined using graphical tools for longitudinal data. Will also examine the association of TAM metabolite levels in plasma with aDAR over time using exploratory graphical analyses of aDAR versus (vs.) concurrent metabolite level by time point and dose level. The overall analytic approach to determine whether metabolite levels are associated with aDAR will use linear mixed models.	At 6, 12, and 18 months
Longitudinal change in serum biomarkers of tamoxifen response	Will evaluate longitudinal change from baseline in serum biomarkers of tamoxifen response at each dose level: sex hormone binding globulin, insulin like growth factor 1 and C-reactive protein. Biomarker values and changes from baseline will be summarized using standard descriptive statistics at each time point by response status. Differences in baseline levels of these biomarkers between different dose sequence groups will be analyzed using linear regression models with biomarker value as the outcome, and dose cohort as the predictor. Will also use linear mixed models to examine biomarker change patterns over time.	From baseline up to 18 months
Baseline dense area	Will assess the association of baseline dense area (continuous variable) with tamoxifen response. Will be compared using linear regression models between 5 mg responders and non-responders at 6 months, and between dose sequence groups.	Up to 18 months
Patient-reported symptoms	Will evaluate the impact of tamoxifen dose on participant-reported symptoms using the Breast Eight Symptom Scale. Will examine patient reported outcome (PRO) patterns over time using graphical tools for longitudinal data, and will use descriptive statistics to summarize PRO values at various time points for groups of patients based on their more recent TAM dose level. Changes in PRO from baseline will be summarized similarly. Linear mixed models will be used.	At baseline, 6, 12, and 18 months
Adherence to final tamoxifen dose	Will evaluate the impact of tamoxifen dose on adherence to final tamoxifen dose. Adherence will be monitored during monthly participant contacts and by pill count and paper diary at each study visit. Will be summarized using descriptive statistics (mean and standard deviation, or median and interquartile range) for each time point and dose level and will be compared between dose levels at each time point using linear regression models. Adverse events will be summarized during each treatment period (0-6, 6-12 and 12-18 months) and dose level, as well as overall for each dose sequence group.	Up to 18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breast tissue-based biomarkers	Will evaluate breast tissue-based biomarkers and their association with tamoxifen response in participants who consent to the optional research biopsies. Will be compared between 5mg responders vs. non-responders at 6 months using a two-sample t-test or Wilcoxon rank sum test. In addition, logistic regression models may be used to determine the joint association between multiple baseline characteristics and tamoxifen response to 5 mg at 6 months.	At 6 months
Single nucleotide polymorphisms (SNPs)	Will evaluate the association between SNPs that overlap between risk of breast cancer and dense area of breasts. Others that relate to efficiency of tamoxifen metabolism will be explored.	Up to 18 months
Change in breast cancer risk estimates	Will evaluate change in breast cancer risk estimates as assessed by an artificial intelligence tool and compare changes by dose group. Changes will be compared between dose sequence groups using a two-sample t-test. In addition, analysis of covariance models may be fitted with 12-month score as the outcome, and dose group and baseline score as predictors.	From baseline to 18 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Seema A Khan, Northwestern University

Study record dates

Study Major Dates

• Study Start (Actual): September 27, 2024
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): September 30, 2028

Study Registration Dates

• First Submitted: December 27, 2023
• First Submitted That Met QC Criteria: December 27, 2023
• First Posted (Actual): December 28, 2023

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Skin Diseases; Breast Diseases; Carcinoma; Neoplasms, Ductal, Lobular, and Medullary; Carcinoma in Situ; Skin and Connective Tissue Diseases; Breast Carcinoma In Situ; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Organic Chemicals; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Benzene Derivatives; Diagnostic Techniques, Surgical; Stilbenes; Benzylidene Compounds; Tamoxifen; Biopsy; Specimen Handling
• Other Study ID Numbers: NCI-2023-10628 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA060553 (U.S. NIH Grant/Contract); UG1CA242596 (U.S. NIH Grant/Contract); UG1CA242635 (U.S. NIH Grant/Contract); UG1CA242643 (U.S. NIH Grant/Contract); UG1CA242632 (U.S. NIH Grant/Contract); UG1CA242609 (U.S. NIH Grant/Contract); INT23-14-01 (Other Identifier: DCP); NCI23-14-01 (Other Identifier: Northwestern University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: "NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No