Refining Tamoxifen Dose for Premenopausal Breast Cancer Risk Reduction (RENAISSANCE): A Phase II Single Arm Trial
Summary
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.
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.
Arms & interventions
- ProcedureBiopsy Procedure
Undergo biopsy
- ProcedureBiospecimen Collection
Undergo collection of blood samples
- ProcedureMammography
Undergo mammography
- OtherQuestionnaire Administration
Ancillary studies
- DrugTamoxifen
Given PO
Outcome measures
Primary
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.
Time frame: At 6, 12, and 18 months
Secondary
Plasma levels of major tamoxifen (TAM) metabolites
Time frame: At 6, 12, and 18 months
Longitudinal change in serum biomarkers of tamoxifen response
Time frame: From baseline up to 18 months
Baseline dense area
Time frame: Up to 18 months
Patient-reported symptoms
Time frame: At baseline, 6, 12, and 18 months
Adherence to final tamoxifen dose
Time frame: Up to 18 months
Eligibility criteria
Study locations (11)
University of Arizona Cancer Center - Prevention Research Clinic
Tucson, Arizona, 85719
Northwestern University
Chicago, Illinois, 60611
University of Illinois College of Medicine - Chicago
Chicago, Illinois, 60612
University of Kansas Cancer Center
Kansas City, Kansas, 66160
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan, 48109
Washington University School of Medicine
St Louis, Missouri, 63110
Case Western Reserve University
Cleveland, Ohio, 44106
Medical University of South Carolina
Charleston, South Carolina, 29425
UT MD Anderson Cancer Center
Houston, Texas, 77030