Exemestane Compared With Tamoxifen in Treating Women With Locally Recurrent or Metastatic Breast Cancer

RANDOMIZED PHASE II STUDY IN FIRST LINE HORMONAL TREATMENT FOR METASTATIC BREAST CANCER WITH EXEMESTANE OR TAMOXIFEN IN POSTMENOPAUSAL PATIENTS

RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using exemestane or tamoxifen may fight cancer by blocking the uptake of estrogen.

PURPOSE: Randomized phase II/III trial to compare the effectiveness of exemestane with that of tamoxifen in treating postmenopausal women who have locally recurrent or metastatic breast cancer.

OBJECTIVES:

• Compare the efficacy of exemestane vs tamoxifen, in terms of progression-free survival, in postmenopausal women with locally recurrent or metastatic breast cancer.
• Determine the safety profile of exemestane in these patients.
• Compare the overall survival of these patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. (Phase II of this study closed as of 6/14/00). Patients are stratified by participating center, prior adjuvant tamoxifen (yes vs no), prior chemotherapy for metastatic disease (yes vs no), and dominant site of metastasis (visceral with or without others vs bone only vs bone and soft tissue vs soft tissue only).

Patients are randomized to receive either oral exemestane or oral tamoxifen daily. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 18 months and then at least every 6 months thereafter.

PROJECTED ACCRUAL: A total of 342 patients will be accrued for this study within 4.7 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically proven adenocarcinoma of the breast that is metastatic and progressive or locally recurrent and inoperable

• At least one bidimensionally measurable or evaluable lesion

  • Lytic bone lesions on x-ray/CT scan, surrounded by calcified bone, and at least 1 cm

  • Bidimensionally measurable extraosseous disease required for patients on bisphosphonates

  • The following are not considered evaluable:

    • Previously irradiated lesions
    • Lymphangitic spread
    • Ascites
    • Blastic bone lesions
    • Pleural effusions

• No rapidly progressive disease for which hormonal therapy is not indicated

• No massive visceral disease (i.e., more than one third of any organ)

• No brain metastases

• Hormone receptor status:

  • Estrogen receptor positive or progesterone receptor positive, defined by 1 of the following:

    • At least 10 femtomoles H3-estrogen or at least 20 femtomoles
    • H3 progesterone binding per mg of cytosol protein by DCC or sucrose density method
    • At least 0.10 femtomoles H3-estrogen or at least 0.20 femtomoles
    • H3-progesterone binding per mg of DNA by IF/EIA technique
    • Positive immunohistochemistry noted on pathology report

  • Unknown receptor status eligible provided:

    • Disease-free interval of at least 2 years since adjuvant therapy or initial surgery (if no adjuvant therapy), including most recently treated tumor in bilateral breast cancer if status unknown in one primary tumor

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Sex:

• Female

Menopausal status:

• Postmenopausal by 1 of the following:

  • Natural menopause and more than 1 year since last menstrual period (LMP)

  • Radiation-induced oophorectomy and more than 1 year since LMP

  • Chemotherapy induced menopause if:

    • At least 1 year since LMP (+ 1 year post-tamoxifen)
    • Serum FSH and LH and plasma estradiol levels in postmenopausal range
    • LHRH-induced amenorrhea

  • Surgical castration

    • Patients under age 56 with prior hysterectomy and 1 or both ovaries intact or tamoxifen-induced amenorrhea with at least 12 months since prior tamoxifen must have postmenopausal serum FSH and LH and plasma estradiol concentrations

Performance status:

• ECOG (WHO) 0-2

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin less than 1.5 times upper limit of normal (ULN)
• SGOT/SGPT less than 2.5 times ULN (less than 5 times ULN with liver metastases)

Renal:

• Creatinine less than 1.5 times ULN

Cardiovascular:

• No deep venous thrombosis

Other:

• No mental incapacitation
• No severe concurrent disease
• No prior or concurrent malignancy except curatively treated carcinoma in situ of the cervix or basal cell or squamous cell skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent immunotherapy

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks since chemotherapy for metastatic disease and recovered
• No more than 1 prior chemotherapy regimen for metastatic disease
• Prior adjuvant chemotherapy allowed if disease free for at least 6 months
• No concurrent chemotherapy

Endocrine therapy:

• No prior hormonal therapy for advanced disease (e.g., tamoxifen or LHRH agonists)
• Prior adjuvant tamoxifen allowed if disease free for at least 6 months
• No other concurrent hormonal therapy, including steroids

Radiotherapy:

• Recovered from toxic effects of prior radiotherapy
• Concurrent palliative radiotherapy, including whole brain irradiation, allowed

Surgery:

• See Disease Characteristics
• No prior ovariectomy for advanced disease

Other:

• No other concurrent investigational drugs
• Concurrent bisphosphonates allowed if short term (7 days) for hypercalcemia due to suspect tumor flare or if on prior bisphosphonates with bidimensionally measurable extraosseous lesion