Low Dose Tamoxifen with or without Omega-3 Fatty Acids for Breast Cancer Risk Reduction

Inclusion Criteria

• Age 45 – 65
• Postmenopausal female * Postmenopausal is defined as prior removal of the ovaries, or if ovaries intact amenorrhea for 12 months and not on any form of contraception, or amenorrhea for greater than 2 months with serum follicle-stimulating hormone (FSH) in postmenopausal range (>= 25 IU/L). Women with ovaries and a prior hysterectomy or endometrial ablation < age 55 must have a FSH within the postmenopausal range. Women may be on vaginal low dose estrogen preparations for vaginal dryness. Women over age 50 with a levonorgestrel intrauterine device in place for 2 or more years are also eligible if FSH is in the postmenopausal range and they are not planning removal for the next 6 months ** Note: FSH will be done at time of screening
• Women with intact ovaries and uterus < age 55 must have a negative pregnancy test prior to randomization
• Obese (body mass index [BMI] >= 30 kg/m^2) OR overweight (BMI 25 to < 30 kg/m^2) WITH at least two or more of the following elements of metabolic syndrome documented in the past 180 days prior to randomization: * Waist circumference of >= 89 cm * Blood pressure over 130/85 mmHg (or current treatment for hypertension) * Fasting triglyceride (TG) level over 150 mg/dl * Fasting high-density lipoprotein (HDL) < 50 mg/dl (or current statin treatment) * Fasting glucose > 100 mg/dl * Note: BMI must be calculated within 28 days of randomization
• Willing to undergo a fasting blood draw and non-fasting RPFNA with fixed and frozen aliquots sent to University of Kansas Medical Center (KUMC)
• At increased risk of breast cancer per at least one of the following: * Personal medical history ** History of atypical hyperplasia or lobular carcinoma in situ (LCIS) found on breast biopsy ** History of unilateral ductal carcinoma in situ treated with unilateral mastectomy, lumpectomy, or local excision with or without radiation and this treatment was completed at least 3 months prior to the screening RPFNA ** High mammographic density determined by one of the following: *** Visual estimate of area of density (VAS) > 50%, *** Volpara (trademark) >= 15% dense volume (Volpara d) *** Breast Imaging Reporting and Data System (BIRADS) assessment = extremely dense (BIRADs D) * Genetic test result ** Germline gene mutation in ATM, BARD1, CDH1, CHEK2, NF1, PTEN, RAD51C, RAD51D, or STK11 ** Polygenic lifetime risk score >= 2x average or 25% * Calculated risk based on standard models ** Five-year Breast Cancer Risk Assessment Tool (BCRAT) (version 2.0) >= 1.66% (https://dceg.cancer.gov/tools/risk-assessment/bcra) ** Ten-year International Breast Cancer Intervention Study risk evaluation tool (IBIS) (version 8) >= 3% (http://www.ems-trials.org/riskevaluator/) ** Ten-year relative risk IBIS (version 8) >= 2X that for age group ** Ten- year Breast Cancer Surveillance Consortium (version 2) >= 3% (https://tools.bcscscc.org/BC5yearRisk/calculator.htm) * Family History ** Breast cancer in a first or second degree relative (female or male) with onset under age 50. (First degree relative = parent, sibling, or child. Second degree relative = grandparent, uncle, aunt, nephew, niece, half-sibling, grandchild or first cousin) ** Breast cancer in two or more first or second-degree relatives from either the maternal or paternal linage without regard to age ** Bilateral breast cancer or breast and ovarian cancer in the same first or second degree relative without regard to age * Primary source documentation of risk is required and must be submitted to the lead academic organization (LAO) for review along with the eligibility checklist ** Risk factor: Atypical hyperplasia or LCIS; Primary source document: Copy of pathology report or clinical note confirming the diagnosis ** Risk factor: Ductal carcinoma in situ (DCIS) and treatment history; Primary source document: Copies of pathology report or clinic notes confirming the diagnosis, treatment plan and treatment end date(s) ** Risk factor: Mammographic density; Primary source document: Copy of clinic note or mammogram report ** Risk factor: Genetic; Primary source document: Copy of genetic test report ** Risk factor: Calculated based on standard models; Primary source document: Copy of the calculation result
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) * Note: Higher total bilirubin levels (=< 3 mg/dL) can be allowed if due to known benign liver condition, i.e., Gilbert’s syndrome
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 3.0 x institutional upper limit of normal
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Women must have at least 1 unaffected untreated breast for fine needle aspiration. Women may have had prior unilateral breast radiation or mastectomy for DCIS
• Ability to understand and the willingness to sign a written informed consent document
• Most recent screening mammogram must be performed ≤ 12 months prior to RPFNA and must be reported as BIRAD 1 or 2. If BIRAD 0 then follow-up diagnostic imaging must be BIRAD 1 or 2 or cleared clinically with radiology recommendation of return to annual screening

Exclusion Criteria

• Exclusions based on current or past conditions: * Bilateral breast implants (danger of implant puncture with RPFNA) * Prior invasive breast cancer * Prior invasive uterine cancer * Other prior invasive cancer and haven’t completed cancer related therapy or with evidence of disease (other than non-melanoma skin cancer) within the past 2 years * Currently breastfeeding (concern that tamoxifen may be in breast milk) or nursing within past 12 months (concern about milk fistula with RPFNA) * Type I or type II diabetes mellitus requiring current pharmacologic treatment (including metformin, glucagon-like peptide 1 agonists, insulin, sulfonylurea) * Prior deep vein thrombosis, pulmonary embolus, or stroke * Prior gastric bypass surgery * History of chronic liver disease including NASH (nonalcoholic steatohepatitis) or cirrhosis * Planned initiation of a structured weight loss intervention * Current use of or plans to initiate a glucagon-like peptide 1 agonist within the next 6 months
• Exclusions based on medications: * Current use of prescription anticoagulants such as Coumadin (warfarin), direct-acting oral anticoagulants such as Xarelto (rivaroxaban) or Eliquis (apixaban) or heparin * Women who would not be able to or do not wish to discontinue daily use of aspirin (81mg or higher) and aspirin containing products (81 mg or higher) at least 3 weeks prior to each RPFNA ** Note: Women may resume daily use of aspirin and aspirin containing products 3 days after each RPFNA procedure * Planned removal of hormone intrauterine device within the next 6 months * Current use of hormone therapy (oral, transdermal, or injectable) ** Note: Vaginal estrogen is allowed * Prior treatment with tamoxifen, aromatase inhibitor or selective estrogen receptor degrader for more than 2 months ** Note: Women with < 2 months of these drugs must be off for at least 6 months before they may begin biomarker screening tests * Greater than 1 gram daily of omega-3 fatty acid supplement within the last 6 months * Current use of prescription immunosuppressive drugs * Current usage of CYP3A4 strong inducers rifampin or aminoglutethimide
• Participants may not be receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to tamoxifen or omega-3 fatty acid or generic Lovaza or compounds of similar chemical composition
• Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements