Phase IIB Trial of Bazedoxifene Plus Conjugated Estrogens

Inclusion Criteria for Baseline Mammogram and RPFNA

Women age 45 - 60.

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.

Category 1: Clinically Postmenopausal. Age 45-60 with an intact uterus and no periods in past 12 months. Amenorrhea is not thought to be due to endometrial ablation, Mirena IUD or other menses suppressing contraceptives. No pre-study FSH is required.

Category 2: Late menopause transition. Age 45-60 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. No pre-study FSH is required.

Category 3: Menopause status cannot be determined by menstrual history; age ≥50. Age 50-60 and prior hysterectomy, prior endometrial ablation with subsequent lack of periods, or menses suppression due to Mirena IUD or other types of contraceptives. No pre-study FSH is required.

Category 4: Menopausal status cannot be accurately determined by menstrual history; age 45-49. 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. A pre-study FSH is required and must be ≥25 mIU/ml or in postmenopausal range by institutional laboratory standard.

Must have at least one ovary.

BMI: ≤ 35 kg/m2

At least one breast without prior therapeutic radiation that can be assessed by Volpara® software.

Chemistry profile showing reasonably normal renal and hepatic function: creatinine <2.0 mg/dL, bilirubin < 2.5 mg/dL, and albumin > 3.4 g/dL within the past 12 months.

Risk Factors/Level. Moderate risk of developing breast cancer based on having at least one of following:

• First or second degree relative with breast cancer age 60 or younger;
• A prior breast biopsy showing proliferative breast disease, including hyperplasia, atypical hyperplasia, or changes designated as lobular carcinoma in situ without evidence of pleomorphism
• 2 or more prior biopsies regardless of benign histology
• 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 ≥2X 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 a 5-year Gail Model Risk of ≥2X the average risk woman for age group (as calculated by the NCI Breast Cancer Risk Assessment Tool, http://www.cancer.gov/bcrisktoolmobile). Average risk for women in the same age-group is based on the Surveillance, Epidemiology, and End Results (SEER) Program provided by the NCI (http://srab.cancer.gov/devcan/).

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 RPFNA.

Exclusion Criteria for Screening

Conditions:

• Have a predisposition to or prior history of thromboembolism, deep venous thrombosis, pulmonary embolism, stroke, or myocardial infarction
• Prior bilateral oophorectomy
• BRCA1/2 deleterious mutation
• Pleomorphic LCIS, DCIS, prior invasive breast, uterine or ovarian cancer (estrogen dependent neoplasia)
• Current renal or liver disease or clinically significant abnormalities of liver and renal function tests.
• Known hypoparathyroidism or recent history of triglycerides > 300 mg/dl.
• 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.
• 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.

Medications

• Current anticoagulant use (must have discontinued for 3 weeks prior to FNA)
• 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)
• Taken tamoxifen, raloxifene, or an aromatase inhibitor within 6 months of baseline blood imaging or RPFNA

Inclusion Criteria for 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.

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 cm3 per breast (i.e., 30 cm3 if only one breast evaluable; 60 cm3 if both breasts evaluable).

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.

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 only).
• 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, 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 for Study Intervention (Randomization) Medical: Intercurrent illness which makes potential participant unsuitable for study; development of clinically significant abnormalities of liver or renal functions; or started hormone replacement therapy between mammogram/RPFNA and enrollment on study.