Oral Tamoxifen vs. TamGel vs. Control in Women With Atypical Hyperplasia, Lobular Carcinoma In Situ, or Increased Breast Cancer Risk

Inclusion Criteria:

• Willing to return to enrolling institution for follow-up

• Willing to complete required testing

• Ability to complete questionnaire by themselves or with assistance

• Female (sex that was assigned at birth)

• Ipsilateral intact breast with histology confirmation of atypical ductal or lobularhyperplasia, or lobular carcinoma in situ (LCIS), within the last 12 months, whethersurgically excised or not.; OR neither AH nor LCIS but increased breast cancer riskdefined as either:

• Gail model (Breast Cancer Risk Assessment Tool) 5 year breast cancer risk of >= 3%, or

• International Breast Intervention Study model 10 year breast cancer risk of >= 5%.

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

• The effects of topical afimoxifene (4-OHT) gel on the developing human fetus at therecommended therapeutic dose are unknown. However, oral tamoxifen is PregnancyCategory D-positive evidence of human fetal risk. For this reason, and becausetriphenylethylene antiestrogens, including tamoxifen, are known to be teratogenic,women of childbearing potential and their male partners must agree to use at leastone effective form of birth control (abstinence is not an allowed method) prior tostudy entry and for the duration of study participation, and for 2 months followingthe last dose of study medications (participant can resume oral birth control pillsfor effective birth control measures after post-treatment biopsy is done). Effectivebirth control methods during treatment are: copper and Mirena intrauterine device (IUD), diaphragm/cervical cap/shield, spermicide, contraceptive sponge, condoms.Tubal Ligation is an acceptable method of birth control. Women of childbearingpotential must have a negative pregnancy test within five days before starting studymedications. Should a woman become pregnant or suspect she is pregnant whileparticipating in this study, she should inform her study physician immediately.

• Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e.tanning beds) for the duration of the study.

• Participants must have acceptable organ and marrow function as judged by treatingphysician's evaluation of baseline laboratory data.

• Negative pregnancy (serum or urine) test if of childbearing potential and/orfollicle stimulating hormone (FSH) to verify menopausal status.

Exclusion Criteria:

• Clinically suspicious mass/lesions

• Breast cancer in the past 5 years.

• Patients with any history of venous thromboembolic disease, regardless of timeframe (history of varicose veins and superficial phlebitis is allowed).

• Current pregnancy or lactation.

• History of other prior breast cancer-specific therapy within the previous 2 years (chemotherapy, anti-HER2 agents, endocrine agents, everolimus, CDK4-6 inhibitors).

• Cytotoxic chemotherapy for any indication in last 2 years.

• Prior use of selective estrogen receptor modulator (SERMS) or AIs includingtamoxifen, raloxifene, anastrozole, letrozole, or exemestane for prevention ortherapy within the past 5 years unless:

• 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.

• Exogenous sex steroid, including oral contraceptive pill use within 1 month prior topretreatment breast biopsy. Use of vaginally administered estrogens and hormonecoated IUD such as Mirena is permitted.

• History of any prior ipsilateral breast radiotherapy. Previous unilateral radiationof the contralateral side is allowed.

• Skin lesions on the breast that disrupt the stratum corneum (e.g., eczema,ulceration).

• History of endometrial neoplasia

• Current smoker. Cessation for at least 6 weeks

• Current users of potent inhibitors of tamoxifen metabolism. The potent inhibitors oftamoxifen metabolism are: bupropion, cinacalcet, fluoxetine, paroxetine, quinidine.

• Participants may not be receiving any other investigational agents within 90 days ofenrollment or during this study.

• History of allergic reactions to tamoxifen.

• Uncontrolled intercurrent illness that in the judgement of the treating physicianwould make them unsuitable for study participation

• Current use of anticoagulation medications.

• Patients who are breastfeeding.

• Hemoglobin < 10 g/dL (within 30 days of randomization).

• Leukocytes < 3,000/microliter (within 30 days of randomization).

• Platelets < 100,000/microliter (within 30 days of randomization).

• Total bilirubin > 1.5 x institutional upper limit of normal (ULN) (within 30 days ofrandomization).

• Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) > 1.5 x ULN (within 30 days of randomization).

• Alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) > 1.5 xULN (within 30 days of randomization).

• Alkaline phosphatase, S > 1.5 x ULN (within 30 days of randomization).

• Albumin, S > 1.5 x ULN (within 30 days of randomization).

• Protein, total, S > 1.5 x ULN (within 30 days of randomization).

• Creatinine > 1.5 x ULN (within 30 days of randomization).

• Antithrombin III <80% of normal.

• Fibrinogen >1000 mg/dL.

• Patients who are taking any medications, herbal products, or over the counter (OTC)products that are moderate or strong CYP2D6 inhibitors or CYP3A inducers. Patientsshould also refrain from starting any drug or product with these properties duringthe study. This is to avoid any potential interactions with tamoxifen or 4-OHT.

• Clinically significant arrhythmia requiring ongoing medication for control /treatment, especially those with high risk of QT prolonging effects.

• Identification of a clinically suspicious mass on examination.