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

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 oneintact ovary

• Women who are not postmenopausal based on serum hormone levels. Women withestradiol =< 30 pg/mL, follicle-stimulating hormone (FSH) >= 30 IU/mL areeligible

• Women with any of the following:

• A history of unilateral estrogen receptor (ER) positive ductal carcinoma insitu (DCIS) with local therapy completed (as determined by treating physicianrecommendation and patient acceptance) at least 1 month prior to study entry. (The untreated breast will be the study breast, for both imaging and optionalbiopsy)

• Recent or prior lobular carcinoma in situ (LCIS), or any form of epithelialatypia, flat epithelial (FEA), atypical ductal hyperplasia (ADH), or atypicallobular 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 CancerSurveillance 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 notrelevant to females under 18 years of age since breast cancer is extraordinarilyrare in this age group, and there are no guidelines regarding use of tamoxifen inchildren, even if know to be at very high risk for breast cancer when older. Becauseno dosing or adverse event (AE) data are currently available on the use of tamoxifenin 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 ifthey are on effective anti-retroviral therapy with undetectable viral load withinthe prior 6 months

• Women with evidence of chronic hepatitis B virus (HBV) infection, are also eligibleif the HBV viral load is undetectable; they may be on suppressive therapy, ifindicated

• Women with a history of hepatitis C virus (HCV) infection are eligible if treatedand cured. For those who are currently on treatment, they are eligible if they havean undetectable HCV viral load

• Women with herpes simplex virus (HSV) infection are eligible if on chronic or asneeded (due to a flare) suppressive antiviral therapy

• Hormonal contraceptive users are eligible and should maintain the same oralcontraceptive preparation throughout the duration of the trial. For women who have alevonorgestrel-coated intra-uterine device, removal for medical reasons will beallowed

• The effects of tamoxifen on the developing human fetus at the recommendedtherapeutic dose are unknown. For this reason and because tamoxifen is known to beteratogenic, women of child-bearing potential must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation. Should a woman becomepregnant or suspect she is pregnant while participating in this study, she shouldinform her study physician immediately

• Ability to understand and the willingness to sign a written informed consentdocument

• Breast Imaging Reporting and Data System (BIRAD) 1 or 2. If BIRAD 0, follow-updiagnostic imaging must be BIRAD 1 or 2 or cleared clinically with radiologyrecommendation 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 yearsunless:

• Use was less than 6 months duration in the past 5 years and not used in the 1year prior to enrollment OR

• Use was no greater than 2 months duration in the past 1 year and not used inthe 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 sizeprecludes being imaged within a single mammographic screening view

• Current use of a strong CYP3A4 inducer or a strong CYP2D6 inhibitor unless willingand able to discontinue use and switch to an alternative medication for the durationof participation, under the advice of their physician. If the physician believes thecurrent 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 participantswill be questioned about this and excluded if they are planning pregnancy over thenext 20 months

• History of thromboembolism, pulmonary embolism, thrombotic stroke, arterialthrombosis of the extremity or deep vein thrombosis. A history of superficialthrombophlebitis 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 orbiologic composition to tamoxifen

• Uncontrolled intercurrent illness or psychiatric illness/social situations thatwould limit compliance with study requirements

• Pregnant women are excluded from this study because tamoxifen a category D agentwith the potential for teratogenic or abortifacient effects. Because there is anunknown but potential risk for AEs in nursing infants secondary to treatment of themother with tamoxifen. Breastfeeding should be discontinued if the mother is treatedwith tamoxifen

• Women with known gene mutations associated with an increased risk for breast cancersuch as BRCA1/2, CDH1, PALB2, PTEN, STK11, or P53

• Current use of sex hormones (estrogen, progesterone, or androgens), unless part oforal contraception pills

• Prior invasive cancer, unless curatively treated, and all treatment was completed > 5 years prior to enrollment