Phase I Trial of Endoxifen Gel Versus Placebo in Women Undergoing Breast Surgery

Inclusion Criteria:

* Women scheduled for unilateral or bilateral mastectomy for breast cancer therapy, pathology confirmed stage 0-III (including ductal carcinoma in situ), or prophylaxis (BRCA1/2 mutation carriers, women with strong family history or lobular carcinoma in situ or other conditions where prophylactic mastectomy has been elected)
* Age \>= 18 years (since breast cancer is not a pediatric disease and no safety data are available for ENX use in children)
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%)
* Total bilirubin \< 1.5 x upper limit of normal (ULN) (in women with prior documented bilirubin elevations consistent with Gilbert's syndrome, total bilirubin up to 3 x ULN will be allowed)
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) \< 2.5 x ULN
* Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) \< 2.5 x ULN
* Creatinine \< 2 x ULN
* Alkaline phosphatase \< 2.5 x ULN
* Blood urea nitrogen \< 2 x ULN
* Ability to understand and the willingness to sign a written informed consent document which includes a requirement to apply study agent to sensitive body parts daily
* Willingness and ability to schedule mastectomy 21-28 days following start of study agent; women with breast implants may participate
* Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e. tanning beds) for the duration of study agent dosing
* Negative urine or serum pregnancy test result, for participants of child bearing potential; female of child-bearing potential is any woman (regardless of sexual orientation, whether she has undergone a tubal ligation, or remains celibate by choice) who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; AND has had a menstrual period at any time in the preceding 12 consecutive months)
* The effects of topical ENX gel on the developing human fetus are unknown; for this reason, women of child-bearing potential and their male partners must agree to use effective forms of birth control (abstinence is not an allowed method) 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

Exclusion Criteria:

* The presence of gross skin invasion/ulceration by the breast cancer, or inflammatory changes with skin edema AND erythema; Note: Paget's disease is permitted
* Women receiving a "nipple delay" procedure prior to mastectomy
* Women with skin diseases (psoriasis, eczema)
* A history of thromboembolic disorder
* Endometrial intraepithelial neoplasia (also known as atypical hyperplasia) or a high risk of uterine cancer, defined here as known carriers of Lynch syndrome mutations (MLH1, MSH2, MSH6, PMS2)
* Participants may not have received any other investigational agents in the previous 3 months
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to tamoxifen
* Taken tamoxifen or other selective estrogen/progesterone receptor modulators (SERMs/SPRMs) within two years prior to entering study or been required to discontinue SERM therapy due to thromboembolic or uterine toxicity
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* History of prior breast cancer-specific therapy within the previous 2 years (chemotherapy, radiation, anti-HER2 agents, endocrine agents, everolimus, CDK4-6 inhibitors); previous unilateral radiation of the contralateral side in women scheduled for mastectomy is allowed; study gel will be applied to both breasts
* History of prior mastectomy
* Pregnant or breastfeeding
* Patients receiving neoadjuvant chemotherapy with curative intent
* Men are excluded from this study since breast cancer is men is rare and there are no data regarding skin penetration of topical breast cancer prevention agents through male chest wall skin (which is thicker and harrier than female chest wall skin)
* Current users of other topical medications on the breast skin must be willing and able to discontinue use for the duration of participation; body lotion and other non-medicinal topical compounds may be applied \> 4 hours after study gel application