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 intactamenorrhea for 12 months and not on any form of contraception, or amenorrheafor greater than 2 months with serum follicle-stimulating hormone (FSH) inpostmenopausal range (>= 25 IU/L). Women with ovaries and a prior hysterectomyor endometrial ablation < age 55 must have a FSH within the postmenopausalrange. Women may be on vaginal low dose estrogen preparations for vaginaldryness. Women over age 50 with a levonorgestrel intrauterine device in placefor 2 or more years are also eligible if FSH is in the postmenopausal range andthey 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 testprior 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 documentedin 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 frozenaliquots 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) foundon breast biopsy

• History of unilateral ductal carcinoma in situ treated with unilateralmastectomy, lumpectomy, or local excision with or without radiation andthis treatment was completed at least 3 months prior to the screeningRPFNA

• 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 evaluationtool (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) withonset 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 eitherthe maternal or paternal linage without regard to age

• Bilateral breast cancer or breast and ovarian cancer in the same first orsecond degree relative without regard to age

• Primary source documentation of risk is required and must be submitted to thelead academic organization (LAO) for review along with the eligibilitychecklist

• Risk factor: Atypical hyperplasia or LCIS; Primary source document: Copyof 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 notesconfirming the diagnosis, treatment plan and treatment end date(s)

• Risk factor: Mammographic density; Primary source document: Copy of clinicnote 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 knownbenign 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]) =< 3.0x institutional upper limit of normal

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients on chronic suppressive antiviral therapy for herpes simplex virus (HSV) areeligible

• 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 consentdocument

• Most recent screening mammogram must be performed ≤ 12 months prior to RPFNA andmust be reported as BIRAD 1 or 2. If BIRAD 0 then follow-up diagnostic imaging mustbe BIRAD 1 or 2 or cleared clinically with radiology recommendation of return toannual 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 orwith evidence of disease (other than non-melanoma skin cancer) within the past 2 years

• Currently breastfeeding (concern that tamoxifen may be in breast milk) ornursing 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 withinthe 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 ofaspirin (81mg or higher) and aspirin containing products (81 mg or higher) atleast 3 weeks prior to each RPFNA

• Note: Women may resume daily use of aspirin and aspirin containingproducts 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 estrogenreceptor degrader for more than 2 months

• Note: Women with < 2 months of these drugs must be off for at least 6months before they may begin biomarker screening tests

• Greater than 1 gram daily of omega-3 fatty acid supplement within the last 6months

• 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 orbiologic composition to tamoxifen or omega-3 fatty acid or generic Lovaza orcompounds of similar chemical composition

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