Bazedoxifene and Conjugated Estrogens for the Prevention of Breast Cancer in Peri- or Post-Menopausal Women at Increased Risk for Development of Breast Cancer

Inclusion Criteria

• Women ages 45 – 60 or ages 61-64 if their last mammogram was described as heterogeneously or extremely dense
• Current vasomotor symptoms (hot-flashes, night sweats or both). Hot flashes or night sweats do not need to be frequent or severe but should occur at least once a week. Women who feel that they would likely need a supplement or be at high risk of withdrawal if they were randomized to waitlist because of vasomotor symptoms are not good candidates for this trial
• Women must be postmenopausal or in menopause transition with no periods for at least two months. Menopausal description should conform to one of the four categories listed below. The specific classification category must be entered on the case report form. * Age 45-64 with an intact uterus and no periods in past 12 months. Amenorrhea is not thought to be due to endometrial ablation, Mirena intrauterine device (IUD) or other menses suppressing contraceptives. Category 1: Clinically Postmenopausal * Age 45-64 with an intact uterus and no periods in past 2 months immediately preceding eligibility testing; but has not been amenorrheic for 12 months. Amenorrhea not thought to be due to endometrial ablation, Mirena IUD or other menses suppressing contraceptives. Category 2: Late menopause transition * Age 50-64 and prior hysterectomy, prior endometrial ablation with subsequent lack of periods, or menses suppression due to Mirena IUD or other types of contraceptives. Category 3: Menopause transition by symptoms; uterus not intact or menses suppression; age >= 50 * Age 45-49 and prior hysterectomy, prior endometrial ablation with subsequent lack of periods, or menses suppression due to Mirena IUD or other types of contraceptives. Category 4: Menopause transition by symptoms uterus not intact or menses suppression; age 45-49
• In order to reduce cohort heterogeneity, all women must have at least one ovary
• BMI: =< 38 kg/m^2
• At least one breast without prior therapeutic radiation for invasive breast cancer or DCIS that can be assessed by Volpara (trademark) software * Note: this does not pertain to women who may have had prior chest irradiation for treatment of Hodgkin’s disease with some scatter to breast tissue
• Creatinine <2.0 mg/dL within the past 12 months (determination is made at local site)
• Bilirubin < 2.5 mg/dL within the past 12 months (determination is made at local site)
• Albumin > 3.4 g/dL within the past 12 months (determination is made at local site)
• Risk Factors/Level. Moderate risk of developing breast cancer based on having at least one or more of following: * First or second degree relative with breast cancer age 60 or younger * A prior breast biopsy showing proliferative breast disease, including hyperplasia or atypical hyperplasia, or lobular carcinoma in situ (LCIS) * 2 or more prior biopsies regardless of benign histology * Prior ER-PR- or low-risk ER+ DCIS that was treated with surgical removal of lesion with or without radiation therapy ** Surgical removal of DCIS is defined as no DCIS cells within 2 mm of the margin or if DCIS cells were present at the margin, a subsequent resection shows no DCIS cells and there were no residual calcifications on the mammogram, ** Low risk ER+ and/or PR+ DCIS is defined as that which is ≤ 2 cm in diameter, non-high grade and occurring in women who are 50 or older * 10-year relative risk of >= 2 X that for the average population for age group as calculated by IBIS Breast Cancer Risk Evaluation Tool version 8 (Tyrer-Cuzick) (http://www.ems-trials.org/riskevaluator/); or 10 year risk based on the Breast Cancer Surveillance Consortium tool version 2 (https://tools.bcsc-scc.org/BC5yearRisk/calculator.htm) * Women with known gene mutations associated with an increased risk for breast cancer such as ATM, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, STK11, P53, PTEN (Note: BRCA1/2 are excluded as women 45 and over should have undergone risk-reducing bilateral salpingo-oophorectomy) * Prior history of Hodgkin’s disease treated with mantle field irradiation
• Vaginal hormones: Low dose vaginal hormones, such as Estring, Vagifem, Imvexy, or 0.5 gram or less of conjugated estrogen vaginal cream twice weekly or less often, for vaginal dryness and dyspareunia may be continued at the same dose
• Systemic hormones: If previously on oral contraceptives or systemic hormone replacement such as pills, transdermal patches, oral troches, or injections, must be off for 8 weeks or more prior to baseline mammogram and random oeriareolar fine needle aspiration (RPFNA)
• INTERVENTION PHASE: BIRADs Class I-III mammogram suitable for assessment by Volpara software. This must be performed within 3 months prior to RPFNA. Mammograms read out as Class 0 or IV must be resolved with additional procedures prior to RPFNA or entry on intervention phase. Note that this process will be facilitated if the study consent form for purposes of screening is signed prior to obtaining the baseline screening mammogram. Also, women with a visual area of density of 25% or higher on a prior mammogram will have a greater chance of meeting both the minimum fibroglandular requirements and RPFNA cellular evaluability. For women with very large breasts: the entire breast must be able to be captured in one view. Women whose breast size require mosaic views will not be eligible. Volpara determined breast fibroglandular volume as read at site or KUMC must be evaluable for at least one breast and average at least 30 cm^3 per breast (i.e., 30 cm^3 if only one breast evaluable; 60 cm^3 if both breasts evaluable)
• INTERVENTION PHASE: RPFNA specimen must be received at KUMC in good condition with cellular integrity and evidence of ductal/lobular epithelial cells on Thinprep slides; but there is no requirement for a specific cell number, value for Ki-67, or cytomorphology
• INTERVENTION PHASE: Willing to comply with study procedures * Willing to have fasting blood drawn at baseline and 6 months * Willing to have dual energy x-ray absorptiometry (iDXA) at baseline and 6 months at KUMC. DXA is optional at other sites * Willing to have a repeat mammogram and RPFNA at 6 months following initiation of study drug. (12-month mammogram for waitlist control only is optional) * Willing to provide personal health history, family history of breast and ovarian cancer * Willing to undergo a limited physical exam including evaluation of heart, lungs, abdomen and liver, and breast exam (if not performed and documented within prior 3 months), plus weight, height, and waist measurement at baseline and 6-month visit * Willing to complete Menopause Quality of Life (MEN-QOL) questionnaire and a hot flash assessment at baseline and 6-month visits * Able to understand and willing to sign consent for study participation * If less than age 55, and uterus is functionally intact, and menstrual period in past 12 months and husband/partner has not had vasectomy, must be willing to use non-hormonal contraceptive precautions

Exclusion Criteria

• SCREENING: Have a predisposition to or prior history of thromboembolism, deep venous thrombosis, pulmonary embolism, stroke, or myocardial infarction * Note that individuals with a prior septic embolus only with no evidence of a clotting disorder are not excluded if cleared by their cardiologist or internist
• SCREENING: Prior bilateral oophorectomy (removal of only one ovary is acceptable)
• SCREENING: BRCA1/2 deleterious mutation
• SCREENING: LCIS specifically designated as pleomorphic in the pathology report
• SCREENING: Prior high-risk ER+ and/or PR+ DCIS, defined as high grade, > 2 cm in diameter or diagnosed at age < 50
• SCREENING: Prior DCIS with cancer cells at inked margin where there was not an additional resection
• SCREENING: Prior invasive breast cancer
• SCREENING: Prior invasive uterine or ovarian cancer
• SCREENING: Current renal or liver disease or clinically significant abnormalities of liver and renal function tests
• SCREENING: Known hypoparathyroidism or recent history of triglycerides > 300 mg/dl
• SCREENING: Women are sufficiently distressed by their vasomotor symptoms, such that they do not believe they would be able to remain on study for 6 months without additional medications if their hot flashes were not relieved
• SCREENING: Any other condition or intercurrent illness that in the opinion of the investigator makes the woman a poor candidate for RPFNA or treatment with BZA+CE
• SCREENING: Current anticoagulant use (must have discontinued for 3 weeks prior to fine-needle aspiration [FNA])
• SCREENING: Taking oral or transdermal systemic hormones within two months (eight weeks) prior to baseline blood, imaging studies or RPFNA. (Note that continued use of vaginal low dose hormonal preparations for dyspareunia is allowed if the woman had been on for at least 2 weeks prior to baseline testing)
• SCREENING: Taken tamoxifen, raloxifene, or an aromatase inhibitor within 6 months of baseline blood imaging or RPFNA
• STUDY INTERVENTION (RANDOMIZATION): Intercurrent illness which makes potential participant unsuitable for study
• STUDY INTERVENTION (RANDOMIZATION): Starting hormone replacement therapy (prescription pills, injections, patches) between mammogram/RPFNA and enrollment on study.