• Overall survival [ Designated as safety issue: No ]
• Systemic disease-free survival [ Designated as safety issue: No ]
• Quality of life [ Designated as safety issue: No ]
• Sites of first recurrence [ Designated as safety issue: No ]
• Late side effects of early menopause [ Designated as safety issue: Yes ]
• Causes of death without recurrence [ Designated as safety issue: No ]
• Incidence of second (nonbreast) malignancies [ Designated as safety issue: No ]

• Overall survival
• Systemic disease-free survival
• Quality of life
• Sites of first recurrence
• Late side effects of early menopause
• Causes of death without recurrence
• Incidence of second (nonbreast) malignancies

RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using triptorelin, exemestane, and tamoxifen may fight breast cancer by blocking the use of estrogen. It is not yet known whether giving triptorelin together with exemestane is more effective than triptorelin and tamoxifen in treating hormone-responsive breast cancer.

PURPOSE: This randomized phase III trial is studying triptorelin and exemestane to see how well they work compared to triptorelin and tamoxifen in treating premenopausal women with hormone-responsive breast cancer.

OBJECTIVES:

• Compare the disease-free and overall survival of premenopausal women with endocrine-responsive breast cancer when treated with triptorelin and exemestane vs triptorelin and tamoxifen.
• Compare the quality of life, including late side effects of early menopause, of patients treated with these regimens.
• Compare the sites of first treatment failure in patients treated with these regimens.
• Compare the incidence of second (non-breast) malignancies in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, concurrent adjuvant chemotherapy (yes vs no), and number of positive axillary and/or internal mammary lymph nodes (0 vs 1 or more). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive triptorelin intramuscularly on day 1 every 28 days. Patients in the adjuvant chemotherapy stratum receive chemotherapy concurrently with triptorelin for at least 2 months (if anthracycline is included) or at least 4 months (if no anthracycline is included). Beginning after the completion of chemotherapy or approximately 6-8 weeks after the initiation of triptorelin, patients receive oral tamoxifen daily.
• Arm II: Patients receive triptorelin as in arm I. Beginning after the completion of adjuvant chemotherapy or approximately 6-8 weeks after the initiation of triptorelin, patients also receive oral exemestane daily.

In both arms, treatment continues for 5 years in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, every 6 months for 2 years, and annually for 3 years.

Patients are followed every 3 months for 1 year, every 6 months for 5 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 2,639 patients will be accrued for this study.

• Drug: exemestane
• Drug: tamoxifen citrate

• Active Comparator: Beginning after the completion of adjuvant chemotherapy or approximately 6-8 weeks after the initiation of triptorelin, patients receive oral tamoxifen daily.
• Experimental: Beginning after the completion of adjuvant chemotherapy or approximately 6-8 weeks after the initiation of triptorelin, patients also receive oral exemestane daily.

DISEASE CHARACTERISTICS:

• Histologically confirmed breast cancer

• Completely resected disease

  • No clinically detectable residual loco-regional axillary disease

  • Prior surgery for primary breast cancer of 1 of the following types:

    • Total mastectomy with or without adjuvant radiotherapy
    • Breast-conserving procedure (e.g., lumpectomy, quadrantectomy, or partial mastectomy with margins negative* for invasive disease and ductal carcinoma in situ) with planned radiotherapy NOTE: *If all other margins are clear a positive posterior (deep) margin is permitted, provided the excision was performed down to the pectoral fascia and all tumor has been removed OR a positive anterior (superficial; abutting skin) margin is allowed provided all tumor was removed

• Tumor confined to the breast and axillary nodes

  • Tumor detected in internal mammary chain nodes by sentinel node procedure and is not enlarged is allowed

• Axillary lymph node dissection or a negative axillary sentinel node biopsy required

  • Patients with negative or microscopically positive axillary sentinel nodes are eligible
  • Positive sentinel nodes must have either axillary dissection or radiation of axillary nodes
• No distant metastases

• No locally advanced inoperable breast cancer, including any of the following:

  • Inflammatory breast cancer
  • Supraclavicular node involvement
  • Enlarged internal mammary nodes (unless pathologically negative)
• Bilateral synchronous invasive breast cancer allowed if disease meets all other eligibility criteria
• No prior ipsilateral or contralateral invasive breast cancer

• Hormone receptor status:

  • Estrogen and/or progesterone receptor positive

    • At least 10% of the tumor cells positive by immunohistochemistry
    • If > 1 breast tumor, each tumor must be hormone receptor positive

PATIENT CHARACTERISTICS:

Age

• Premenopausal

Sex

• Female

Menopausal status

• Premenopausal

  • Estradiol in the premenopausal range after prior surgery OR meets the following criteria:

    • Menstruating regularly for the past 6 months
    • Has not used any form of hormonal treatment (including hormonal contraception) within the past 6 months

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• No systemic hepatic disease that would preclude prolonged follow-up

Renal

• No systemic renal disease that would preclude prolonged follow-up

Cardiovascular

• No systemic cardiovascular disease that would preclude prolonged follow-up
• No prior thrombosis (e.g., deep vein thrombosis) and/or embolism unless patient is medically suitable

Pulmonary

• No systemic pulmonary disease that would preclude prolonged follow-up

Other

• Not pregnant or nursing
• Fertile patients must use effective nonhormonal contraception
• No history of noncompliance to medical regimens
• No other nonmalignant systemic disease that would preclude prolonged follow-up

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, nonbreast carcinoma in situ, contralateral or ipsilateral carcinoma in situ of the breast, or other nonrecurrent invasive nonbreast malignancy, including any of the following:

  • Stage I papillary thyroid cancer
  • Stage IA carcinoma of the cervix
  • Stage IA or B endometrioid endometrial cancer
  • Borderline or stage I ovarian cancer
• No psychiatric, addictive, or other disorder that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior or concurrent neoadjuvant or adjuvant trastuzumab allowed

Chemotherapy

• No prior neoadjuvant or adjuvant chemotherapy

Endocrine therapy

• No prior tamoxifen, other selective estrogen-receptor modulators (SERMs) (e.g., raloxifene), or hormone replacement therapy for more than 1 year before breast cancer diagnosis
• No prior neoadjuvant or adjuvant endocrine therapy since diagnosis of breast cancer
• No concurrent oral or transdermal hormonal therapy
• No other concurrent estrogen, progesterone, or androgens
• No other concurrent aromatase inhibitors
• No concurrent oral or other hormonal contraceptives (i.e., implants or depot injections)

Radiotherapy

• See Disease Characteristics
• No prior ovarian radiotherapy

Surgery

• See Disease Characteristics
• No prior bilateral oophorectomy

Other

• No concurrent bisphosphonates, except in the following cases:

  • Bone density is at least 1.5 standard deviations below the young adult normal mean
  • Participation in a randomized clinical study testing bisphosphonates in the adjuvant breast cancer setting
• No other concurrent investigational agents

• National Cancer Institute (NCI)
• Breast International Group