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 one intact ovary * Women who are not postmenopausal based on serum hormone levels. Women with estradiol \> 30 pg/mL and 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 * 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 hormonal contraceptive preparation throughout the duration of the trial. Changing hormonal contraception after enrollment for medical reasons is 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; partner vasectomy) 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 (BIRADS) 1 or 2. Women with BIRADS 3 findings that have been biopsied and shown to be benign or are stable at 6-months follow-up are allowed * 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 * 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 at least 30 days prior to screening 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 hormonal contraception pills * Prior invasive cancer ≥ T1 (other than non-melanoma skin cancer), unless curatively treated, and all treatment was completed \> 5 years prior to enrollment