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 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.