Pilot Study of Bazedoxifene Plus Conjugated Estrogen on Imaging and Blood Biomarkers

Inclusion Criteria:

* Women who report vasomotor symptoms (hot flashes or night sweats or both).
* No menstrual periods for at least 60 days.
* Age 45-65. Women age 45-49 with prior hysterectomy or endometrial ablation with rare or no periods due to ablation must have a Follicle Stimulating Hormone (FSH) of 25 mIU/ml or higher to be eligible.
* BMI \<36 kg/m2
* 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
  * Known carrier of moderate to high penetrance germline mutation
  * Prior breast biopsy showing proliferative breast disease or multiple prior biopsies
  * High mammographic density (Volpara® categories c or d or BIRADS density assessment as heterogeneously or extremely dense (c or d).
  * IBIS Breast Cancer Risk Evaluation Version 8 (http://www.emstrials.org/riskevaluator/). 10-year relative risk of \>2X that for the population for age group.
* Prior mammogram must have at least a Volpara® fibroglandular volume of 80 cm3 or BIRADs b, c, or d category density and/or investigator estimated visual dense area of at least 25%. 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). If no prior mammogram, but breast density is readily appreciated and documented on physical exam, a study-provided 3D mammogram with Volpara® software must be performed to document above eligibility criterion. It will then constitute the baseline mammogram.
* Willing to comply with study procedures:

  * Have blood drawn for screening tests - comprehensive metabolic panel (plus FSH if age 45-49 and no uterus or endometrial ablation)
  * Have blood drawn to archive serum for assay of estradiol, testosterone, progesterone, sex hormone binding globulin (SHBG), FSH 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.
  * 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.
* Participants on the optional random periareolar fine needle aspiration (RPFNA) procedures must meet eligibility criteria for participation on HSC4601, Breast Random Fine Needle Aspiration and/or Nipple Aspirate Fluid Collection of Breast Tissue to Aid in Short-term Risk Assessment. Participants must sign a separate optional consent for this study as well as for HSC4601. However, any eligibility criteria dealing with hormone replacement therapy and SERMs are excluded to allow the 6-month aspiration.
* Comprehensive Metabolic Panel shows clinically acceptable renal and hepatic function lab values.
* For women with intact uterus and ovary(ies) and less than age 55, a negative pregnancy test is required.

Exclusion Criteria:

* Risk: A prior biopsy showing pleomorphic lobular or ductal carcinoma in situ or invasive breast cancer.
* Medical Conditions:

  * Have a predisposition to or prior history of thromboembolism, deep venous thrombosis, pulmonary embolism, or stroke
  * History of renal or liver disease
  * Prior invasive ovarian or endometrial cancer
  * Any other condition or intercurrent illness that in the opinion of the investigator makes the woman a poor candidate for BZA+CE.
* Medications

  * Taking systemic hormones within two months (eight weeks) prior to baseline MRI and mammogram.
  * 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 12 months prior to baseline MRI and mammogram.

Exclusion Criteria after baseline studies:

* Mammogram with Volpara® software 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.