Exemestane or Anastrozole in Treating Postmenopausal Women Who Have Undergone Surgery for Primary Breast Cancer
Exemestane or Anastrozole in Treating Postmenopausal Women Who Have Undergone Surgery for Primary Breast Cancer
RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy, using
 exemestane or anastrozole, may fight breast cancer by reducing the production of estrogen. It
 is not yet known whether exemestane is more effective than anastrozole in preventing the
 recurrence of breast cancer.

 PURPOSE: This randomized phase III trial is studying exemestane to see how well it works
 compared to anastrozole in preventing cancer recurrence in postmenopausal women who have
 undergone surgery for primary breast cancer.
OBJECTIVES:

 Primary

 -  Compare the event-free survival of postmenopausal women with receptor-positive primary
 breast cancer when treated with exemestane vs anastrozole.

 Secondary

 -  Compare the overall survival of patients treated with these regimens.

 -  Compare the time to distant recurrence in patients treated with these regimens.

 -  Compare the incidence of new primary contralateral breast cancer in patients treated
 with these regimens.

 -  Compare the incidence of all clinical fractures, specifically hip and vertebral
 fractures, in patients treated with these regimens.

 -  Compare cardiovascular morbidity and mortality (i.e., significant coronary heart
 disease, which includes myocardial infarctions and angina requiring percutaneous
 transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal
 strokes, and all vascular deaths) in patients treated with these regimens.

 -  Correlate therapy induced changes in breast density with plasma hormones and growth
 factors, drug levels of exemestane and anastrozole, genetic variation and breast cancer
 recurrence or contralateral events in patients treated with these regimens.

 -  Compare the toxic effects of these regimens in these patients.

 OUTLINE: This is a randomized, multicenter study. Patients are stratified according to lymph
 node status at diagnosis (negative vs positive vs unknown), prior adjuvant chemotherapy (yes
 vs no), and herceptin use (yes vs no). Patients are randomized to 1 of 2 treatment arms.

 -  Arm I: Patients receive oral exemestane (25 mg) once daily for 5 years.

 -  Arm II: Patients receive oral anastrozole (1 mg) once daily for 5 years. In both arms,
 treatment continues in the absence of disease progression or unacceptable toxicity.

 Patients are followed every 6 months during the first year of study participation and
 annually thereafter.

 PROJECTED ACCRUAL: A total of 6,840 patients will be accrued for this study.
DISEASE CHARACTERISTICS:

 -  Histologically confirmed invasive breast cancer

 -  pT1-3; pNX, pN0-2 or pN3*; M0

 -  Neoadjuvant patients are eligible no earlier than 3 weeks or later than 3 months
 after excisional surgery, provided both the clinical-diagnostic staging of cancer
 and postsurgical resection-pathologic staging of cancer meet the requirements for
 primary tumor, regional lymph nodes, and distant metastasis classification NOTE:
 *Only when the sole basis for this classification is the presence of 10 or more
 involved axillary lymph nodes

 -  Completely resected disease

 -  Primary surgery performed at least 3 weeks but no more than 3 months before study
 entry (if no chemotherapy was given)

 -  Primary surgery is defined as the last surgery at which histologic evidence
 of invasive or in situ disease was present in the pathology specimen

 -  Patients with positive sentinel lymph node biopsy are eligible provided they have
 had a subsequent axillary lymph node dissection

 -  No metachronous breast cancer

 -  Bilateral mammogram within the past 12 months unless initial surgery was a total
 mastectomy, in which case only a mammogram of the remaining breast is required

 -  No metastases confirmed by 1 of the following methods:

 -  Bone scan* (required only if alkaline phosphatase is at least 2 times normal
 and/or there are symptoms of metastatic disease)

 -  Abdominal ultrasound or CT scan (required only if AST/ALT or alkaline phosphatase
 is at least 2 times normal, unless the elevation is in the bone fraction)

 -  Chest x-ray NOTE: *Confirmatory x-ray, CT scan, or MRI required if the bone scan
 results are questionable

 -  No locally recurrent disease

 -  No prior or concurrent carcinoma in situ of the contralateral breast treated with
 partial mastectomy and/or hormonal therapy

 -  Patients with prior or concurrent carcinoma in situ of the ipsilateral breast are
 eligible provided the tumor was completely excised AND they have not received
 prior hormonal therapy

 -  Hormone receptor status:

 -  Estrogen receptor- and/or progesterone receptor-positive by immunohistochemistry
 or tumor receptor content ≥ 10 fmol/mg protein

 PATIENT CHARACTERISTICS:

 Age

 -  Postmenopausal

 Sex

 -  Female

 Menopausal status

 -  Postmenopausal prior to chemotherapy, defined as 1 of the following:

 -  Over 60 years of age

 -  Age 45-59 with spontaneous cessation of menses for more than 1 year prior to
 study entry

 -  Age 45-59 with menses ceasing (secondary to hysterectomy or spontaneously) within
 the past year AND a follicle-stimulating hormone (FSH) level prior to study entry
 in the postmenopausal range*

 -  Age 45-59, previously on hormone replacement therapy (HRT) and have discontinued
 HRT upon diagnosis of this malignancy AND has an FSH level prior to study entry
 in the postmenopausal range*

 -  Has undergone bilateral oophorectomy NOTE: *By institutional standards OR > 34.4
 IU/L if institutional range is not available)

 Performance status

 -  ECOG 0-2

 Life expectancy

 -  At least 5 years

 Hematopoietic

 -  WBC at least 3,000/mm^3 OR

 -  Granulocyte count at least 1,500/mm^3 AND

 -  Platelet count at least 100,000/mm^3

 Hepatic

 -  See Disease Characteristics

 -  AST and/or ALT less than 2 times upper limit of normal (ULN)*

 -  Alkaline phosphatase less than 2 times ULN* NOTE: *Unless imaging examinations have
 ruled out metastatic disease

 Renal

 -  Not specified

 Other

 -  Able to swallow study medication and have adequate unassisted oral intake in order to
 maintain reasonable nutrition status

 -  No other non-breast malignancy within the past 5 years except adequately treated
 nonmelanoma skin cancer, curatively treated carcinoma in situ of the cervix, or other
 curatively treated solid tumors with no evidence of disease for at least 5 years

 -  No other concurrent medical or psychiatric condition that would preclude study
 participation and/or interfere with results

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  Prior and concurrent trastuzumab (Herceptin®) allowed

 Chemotherapy

 -  See Disease Characteristics

 -  At least 3 weeks but no more than 3 months since prior chemotherapy

 -  Prior adjuvant chemotherapy allowed

 Endocrine therapy

 -  See Disease Characteristics

 -  No prior aromatase inhibitor

 -  No prior tamoxifen or other selective estrogen receptor modulators (SERMs) except
 raloxifene

 -  At least 3 weeks since prior raloxifene

 -  At least 3 weeks since prior and no concurrent over-the-counter products or
 supplements considered to have an estrogenic effect, including any of the following:

 -  Ginseng

 -  Ginkgo biloba

 -  Black cohosh

 -  Dong quai

 -  Fortified soy supplements (e.g., phytoestrogen preparations)

 -  At least 3 weeks since other prior hormonal therapy or steroids considered to have an
 estrogenic effect

 -  No concurrent estrogens, progesterones, androgens, or SERMs

 -  Concurrent intermittent vaginal estrogens (e.g., vagifem, estrogen vaginal cream,
 testosterone, estradiol vaginal gel, or Estring) allowed if other local measures
 for intractable vaginal atrophy are insufficient

 -  No other concurrent therapy that would have an estrogenic effect, including endocrine
 therapy, hormonal therapy, or steroid therapy

 Radiotherapy

 -  See Disease Characteristics

 -  Prior adjuvant radiotherapy allowed

 -  Concurrent radiotherapy allowed

 Surgery

 -  See Disease Characteristics