Exemestane or Anastrozole in Treating Postmenopausal Women Who Have Undergone Surgery for Primary Breast Cancer

A Randomized Phase III Trial Of Exemestane Versus Anastrozole In Postmenopausal Women With Receptor Positive 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