Combined Estrogen Blockade of the Breast With Exemestane and Raloxifene in Postmenopausal Women With a History of Breast Cancer Who Have No Clinical Evidence of Disease
Combined Estrogen Blockade of the Breast With Exemestane and Raloxifene in Postmenopausal Women With a History of Breast Cancer Who Have No Clinical Evidence of Disease
The purpose of this research study is to learn about the effects of two drugs when they are
 given together. The names of the drugs are raloxifene and exemestane.

 Raloxifene is a drug that is related to estrogen. In the liver and bone, it acts like
 estrogen. In the breast and uterus it acts like an anti-estrogen. It has been used in
 postmenopausal women to prevent a disease called osteoporosis. This is a disease that
 decreases bone strength over many years and may finally lead to bone fractures. In a group of
 women who were taking the drug, it also seemed to decrease the chances of breast cancer and
 possibly endometrial cancer (cancer of the uterus). Therefore, we want to study it further to
 see if it prevents breast cancer. We also want to find out if it may be even better in
 preventing breast cancer if it is given with another drug.

 The other drug in this trial is exemestane. Exemestane is a type of drug that works to
 decrease estrogen levels in postmenopausal women. This type of drug is used in women for the
 treatment of breast cancer. Before we can decide if the two drugs combined are better for
 preventing breast cancer, we must first test these drugs together to make sure that they are
 safe. This safety testing is the purpose of this trial.
The objectives of this project are to investigate the safety and toxicity of the combination
 of raloxifene, a selective estrogen receptor modulator (SERM), with exemestane, a new
 steroidal aromatase inhibitor, in postmenopausal women with a history of breast cancer who
 have no clinical evidence of disease. The study cohort will consist of postmenopausal women
 with a history of AJCC Stage 0, I, II, or III breast cancer after completion of all planned
 adjuvant therapy. The study cohort is limited to patients who have not already received
 anti-estrogen therapy as part of post-operative adjuvant treatment. Patients with a history
 of invasive ER- and/or PR-positive breast cancer are eligible only if they have not received
 an anti-estrogen as part of adjuvant therapy, and they are at least 2 years from the time of
 their primary surgery.

 Tamoxifen has been shown to reduce the incidence of contralateral breast cancer regardless of
 the estrogen expression of the primary tumor and may therefore be offered as a
 chemopreventive agent to patients who have not received an anti-estrogen in the adjuvant
 setting. This population of patients is also a reasonable cohort in which to test other
 chemoprevention regimens. Our hypothesis is that the combination of raloxifene and exemestane
 may offer an alternative treatment for chemoprevention that may prove to be more effective
 than an anti-estrogen alone.

 Endpoints of the study are to determine whether the combination of raloxifene and exemestane
 is safe and tolerable with respect to:

 1. markers of bone turnover and bone mineral density

 2. the serum lipoprotein profile

 3. quality of life (in particular, symptoms of estrogen deficiency)

 4. pharmacokinetics and pharmacodynamics of both drugs.

 We will also determine the feasibility of using mammography and breast MRI imaging to assess
 the effects of the combination on radiographic breast density.

 As part of a correlative laboratory study of breast biopsy material, women may undergo an
 optional biopsy of their unaffected breast. Breast biopsy material will be evaluated both
 pre- and 3 months post-treatment to determine whether the combination will have an impact on
 breast tissue aromatase activity and breast tissue estrogen levels, and potential surrogate
 endpoint biological markers.
Inclusion Criteria:

 -  Postmenopausal women with a history of AJCC Stage 0, I, II or III breast cancer, with
 no clinical evidence of disease, after completion of all planned adjuvant therapy.
 Patients must not have received anti-estrogen therapy as part of their adjuvant
 treatment. Patients with a history of invasive ER- and/or PR-positive breast cancer
 are eligible only if they have not received an anti-estrogen as part of adjuvant
 therapy, and they are at least 2 years from the time of their primary surgery.

 -  Patients must have completed all planned adjuvant therapy, including surgery,
 chemotherapy, and radiation therapy, at least 4 weeks prior to treatment. There is no
 limit as to the amount of time that may have passed since completion of adjuvant
 therapy and initiation of treatment.

 -  Patients must be postmenopausal, as defined by either:

 1. No spontaneous menses for at least 5 years; women who have had a hysterectomy in
 this group, but have intact ovaries must have luteinizing hormone (LH) and
 follicle-stimulating hormone (FSH) levels within the postmenopausal range

 2. Spontaneous menses within the past 5 years, but amenorrheic (e.g. spontaneous or
 secondary to chemotherapy, radiation therapy or hysterectomy) for at least 12
 months, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
 levels within the postmenopausal range

 3. Bilateral oophorectomy

 -  Patients must have a history of breast cancer confirmed by the Department of Pathology
 at Memorial Sloan-Kettering Cancer Center.

 -  Patients must be at least 18 years old, and must be able to give written informed
 consent.

 -  Karnofsky performance status > 80%.

 -  Laboratory parameters:

 WBC =>3.0 x 106 cells/ml serum bilirubin <= 1.5 mg/dl serum creatinine <= 1.5 mg/dl serum
 AST (SGOT) <= 2x upper institutional normal CEA and CA15-3 within institutional normal
 limits

 Exclusion Criteria:

 -  Prior history of bilateral mastectomy.

 -  Prior history of ovarian or endometrial cancer.

 -  Prior or current history of osteoporosis, as defined by a lumbar-spine bone mineral
 density < 2.5 SD below the mean value for normal premenopausal women.

 -  Use of bisphosphonates or calcitonin within the past 3 months.

 -  Prior history of venous thrombosis or pulmonary embolism.

 -  Patients with unstable angina or New York Heart Association Class III or IV heart
 disease.

 -  Prior hormonal therapy within the past 3 months.