Bazedoxifene and Conjugated Estrogen for the Prevention of Breast Cancer in Women with Menopausal Symptoms at Increased Risk for Breast Cancer

Inclusion Criteria

• Women ages 45-65
• Current vasomotor symptoms (hot-flashes, night sweats or both). These 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 in one of the four menopausal status categories, as defined below * Age 45-65 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 45-65 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 50-65 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: Menopausal 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
• Body mass index (BMI) < 35 kg/m^2 (women with severe or morbid obesity are excluded to reduce the possibility of hepatic impairment due to steatosis)
• Creatinine < 2.0 mg/dL within the past 12 months
• Bilirubin < 2.5 mg/dL within the past 12 months
• Albumin > 3.4 g/dL within the past 12 months
• Risk Factors/Level. Moderate risk of developing breast cancer based on either by having any one or more of the following: * First or 2nd degree relative with breast cancer age 60 or younger * Prior breast biopsy showing proliferative breast disease or multiple prior biopsies * 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) * 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); or 10 year risk based on the Breast Cancer Surveillance Consortium tool Version 2. Average risk for women in the same age-group is based on the Surveillance, Epidemiology, and End Results (SEER) Program provided by the NCI * High mammographic density (Volpara categories c or d or Breast Imaging Reporting and Data System [BIRADs] density assessment as heterogeneously or extremely dense [c or d])
• 3-dimensional (3D) mammogram performed within the prior 3 months with Volpara assessment showing fibroglandular volume (FGV). The entire breast must be incorporated in a single view for both the right and left breast (i.e., women whose breasts are so large that the images must be captured as a mosaic are not eligible). A minimum FGV is required, depending upon BMI: * For women with BMI < 25 kg/m^2, FDG must average at least 20 cm^3 per breast (i.e., 20 cm^3 if only one breast evaluable and 40 cm^3 total if both breasts evaluable). * For women with BMI of 25-35 kg/m^2, FDG must average at least 30 cm^3 per breast (i.e., 30 cm^3 if only one breast evaluable and 60 cm3 total if both breasts evaluable). This will constitute the baseline mammogram. If no mammogram meeting these criteria is available, but a prior mammogram showed BIRADs b, c, or d category density and/or investigator estimated visual dense area of at least 25%, a study-provided 3D mammogram with Volpara software may be performed to document the above eligibility criteria. It will then constitute the baseline mammogram. For women without a prior mammogram with high breast density appreciated on physical exam, a study-provided 3D mammogram with Volpara software may be performed to document the above eligibility criteria
• 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
• Willing to comply with study procedures: * Have blood drawn for screening tests - comprehensive metabolic panel * Have blood drawn to archive serum at baseline and 6-month visits (and 12 months for women originally randomized to wait list control and subsequently taking BZA+CE for the next 6 months) * Undergo a history, physical, and breast exam at baseline and 6-month visits (and 12 months for women originally randomized to wait list control and subsequently taking BZA+CE for the next 6 months). History, physical exam and breast exam performed by a study-associated clinician within 3 months prior to enrollment may be substituted for baseline evaluations * Have a mammogram at University of Kansas Medical Center (KUMC) with Volpara volumetric density at baseline and 6- month visits (and 12 months for women originally randomized to wait list control and subsequently taking BZA+CE for the next 6 months) * Have a study-provided abbreviated MRI at KUMC at baseline and 6-month visits. An abbreviated MRI performed within 3 months of randomization may be substituted as the baseline exam * Provide a stool sample at baseline and 6 months * Be contacted by the trial coordinator by phone, email, or text at months 1 and 3 (and months 7 and 9 for women originally randomized to wait list control and subsequently taking BZA+CE for the next 6 months) * Complete Mayo Clinic hot flash assessment at baseline and 6-month visits (and month 12 for women originally randomized to wait list control and subsequently taking BZA+CE for the next 6 months) * Women 45-55 with a functional uterus (e.g., no prior endometrial ablation), menstrual period in the past 12 months, and heterosexually active, must be agreeable to use some non-hormonal form of contraception while taking BZA+CE unless husband or partner has had a vasectomy
• Able to understand and sign an informed consent form for screening and for intervention
• INCLUSION CRITERIA FOR IMAGING (MRI) STUDIES:
• For women with intact uterus and ovary(ies) and less than age 55, a negative pregnancy test is required

Exclusion Criteria

• A prior biopsy showing pleomorphic lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), or invasive breast cancer
• Have a predisposition to or prior history of thromboembolism, deep venous thrombosis, pulmonary embolism, or stroke
• History of renal or liver disease or clinically significant abnormalities of liver and renal function tests
• Known hypoparathyroidism or recent history of triglycerides > 300 mg/dl
• Prior invasive ovarian or endometrial cancer
• Women who 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
• Any other condition or intercurrent illness that in the opinion of the investigator makes the woman a poor candidate for BZA+CE
• Current anticoagulant use other than low dose aspirin
• Taking systemic hormones within two months (eight weeks) prior to baseline MRI and mammogram
• Taking tamoxifen, raloxifene, Duavee, or any selective estrogen receptor modulator, or an aromatase inhibitor within 6 months prior to baseline MRI and mammogram
• EXCLUSION CRITERIA FOR DISPENSING OF BZA+CE:
• Mammogram and/or abbreviated MRI interpreted as concerning for cancer – unless recommended breast biopsy has been performed and confirmed as benign
• Dispensing of BZA+CE for those randomized to receive it immediately does not occur within 3 months of baseline MRI
• Unwilling to comply with future study procedures
• Started hormone replacement, selective estrogen receptor modulator, or aromatase inhibitor after baseline studies performed but prior to randomization