Official Title: “A Phase III Trial Evaluating The Role Of Ovarian Function Suppression And The Role Of Exemestane As Adjuvant Therapies For Premenopausal Women With Endocrine Responsive Breast Cancer”

RATIONALE: Estrogen can stimulate the growth of breast tumor cells. Ovarian function suppression combined with hormone therapy using tamoxifen or exemestane may fight breast cancer by reducing the production of estrogen. It is not yet known whether suppression of ovarian function plus either tamoxifen or exemestane is more effective than tamoxifen alone in preventing the recurrence of hormone-responsive breast cancer.

PURPOSE: This randomized phase III trial is studying ovarian suppression with either tamoxifen or exemestane to see how well they work compared to tamoxifen alone in treating premenopausal women who have undergone surgery for hormone-responsive breast cancer.

Study Type: Interventional

Study Design: Treatment, Randomized, Active Control

Study Primary Completion Date: July 2008

OBJECTIVES: - Compare ovarian function suppression (by triptorelin, oophorectomy, or ovarian irradiation) in combination with tamoxifen vs ovarian function suppression in combination with exemestane vs tamoxifen alone in patients with endocrine-responsive breast cancer. - Compare the disease-free and overall survival of patients treated with these regimens. - Compare the quality of life, including late side effects of early menopause, of patients treated with these regimens. - Compare the incidence of second (nonbreast) malignancies in patients treated with these regimens. - Compare the sites of first treatment failure in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, prior adjuvant/neoadjuvant 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 3 treatment arms. - Arm I: Patients receive oral tamoxifen daily. - Arm II: Patients receive tamoxifen as in arm I and ovarian function suppression by 1 of the following treatments: - Triptorelin intramuscularly once every 28 days - Surgical oophorectomy - Ovarian irradiation once daily for 4 or 5 days - Arm III: Patients receive oral exemestane daily and ovarian function suppression as in arm II.

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 then annually for 4 years.

After completion of study therapy, patients are followed periodically.

PROJECTED ACCRUAL: A total of 3,000 patients (1,000 per treatment arm) will be accrued for this study within 5 years.

Intervention(s) in this Clinical Trial

• Drug: exemestane
• Drug: tamoxifen citrate
• Drug: triptorelin
• Procedure: adjuvant therapy
• Procedure: oophorectomy
• Procedure: radiation therapy

Primary Measures

• Disease-free survival at 5 years
  • Safety Issue?: No

Secondary Measures

• Overall survival at 5 years
  • Safety Issue?: No
• Systemic disease-free survival at 5 years
  • Safety Issue?: No
• Quality of life as measured by presence of menopausal symptoms (e.g., hot flushes) and/or loss of sexual interest at 0, 6, 12,18, 24, 36, 48, 60, and 72 months from randomization
  • Safety Issue?: No

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
• Ductal carcinoma in situ at a margin is permitted if a complete mastectomy has been performed
• Breast-conserving procedure (e.g., lumpectomy, quadrantectomy, or partial mastectomy with margins clear* of invasive disease and ductal carcinoma in situ) with radiotherapy
• No more than 12 weeks since prior surgery if no adjuvant chemotherapy
• No more than 8 months since prior adjuvant chemotherapy 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 that are not enlarged is allowed
• Prior neoadjuvant therapy allowed provided disease was operable prior to neoadjuvant therapy
• Axillary lymph node dissection or a negative axillary sentinel node biopsy required
• Patients with microscopically positive axillary sentinel nodes or negative sentinal nodes do not require further axillary therapy
• Patients with positive sentinel nodes must have 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)
• No prior ipsilateral or contralateral invasive breast cancer
• Histologically diagnosed synchronous bilateral invasive breast cancer within the past 2 months allowed if the bilateral disease meets all other eligibility criteria
• Hormone receptor status:
• Estrogen and/or progesterone receptor positive
• Each tumor must be hormone receptor positive

PATIENT CHARACTERISTICS:

• Age
• Premenopausal
• Sex
• Female
• Menopausal status
• Premenopausal
• Estradiol in the premenopausal range, unless the patient meets the following criteria within the past 6 months:
• No chemotherapy
• Menstruating regularly
• No use of hormonal contraception
• No other use of hormonal treatments
• Temporary chemotherapy-induced amenorrhea allowed provided premenopausal status is confirmed by estradiol level within 8 months of the final dose of chemotherapy
• 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 prior or concurrent invasive malignancy except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or bladder, contralateral or ipsilateral carcinoma in situ of the breast, or nonbreast invasive malignancy diagnosed at least 5 years ago without recurrence, including only 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 and/or concurrent adjuvant, trastuzumab (herceptin) allowed
• Chemotherapy
• See Disease Characteristics
• Endocrine therapy
• More than 1 year since prior selective estrogen-receptor modulators (SERMs) before the breast cancer diagnosis
• No hormone replacement therapy during the year before the breast cancer diagnosis
• No prior endocrine therapy, including adjuvant or neoadjuvant therapy, for more than 8 months after breast cancer diagnosis
• No prior gonadotropin-releasing hormone analogues for breast cancer
• No concurrent oral or transdermal hormonal therapy
• No other concurrent estrogen, progesterone, or androgens
• No other concurrent aromatase inhibitors
• No concurrent hormone replacement therapy
• No concurrent oral or other hormonal contraceptives (i.e., implants or depot injections)
• No other concurrent SERMs (e.g., raloxifene)
• Radiotherapy
• See Disease Characteristics
• No prior ovarian radiotherapy
• Surgery
• See Disease Characteristics
• No prior bilateral oophorectomy
• No concurrent oophorectomy unless performed as part of this study
• No patients who have been recommended to undergo oophorectomy within the next 5 years (e.g., BRCA1/2 gene carrier)
• 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 agent

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: International Breast Cancer Study Group

Overall Clinical Trial Officials and Contacts

Prudence Francis, MD Study Chair Peter MacCallum Cancer Centre, Australia  

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00066690

Study ID Number: CDR0000316456

ClinicalTrials.gov Identifier: NCT00066690

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database

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