Breast Cancer
Conditions
Keywords
stage II breast cancer, stage IIIA breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, stage IA breast cancer, stage IB breast cancer
Brief summary
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.
Detailed description
OBJECTIVES: * Compare the disease-free survival, breast cancer-free interval, distant recurrence-free interval 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. OUTLINE: This is a randomized, international, multicenter study. Patients are stratified according to planned use of concurrent adjuvant chemotherapy (yes vs no), and number of positive lymph nodes (0 vs 1 or more). Treatment duration is 5 years. Patients are followed every 3 months for 1 year, every 6 months for 5 years, and then annually thereafter. Quality of life is assessed at baseline, every 6 months for 2 years, and annually for 3 years.
Interventions
DRUGexemestane
DRUGtamoxifen
DRUGtriptorelin
Sponsors
ETOP IBCSG Partners Foundation
National Cancer Institute (NCI)
Breast International Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | 5-year estimate reported at a median follow-up of 72 months | Estimated percentage of patients alive and disease-free at 5 years from randomization, where disease-free survival is defined as the time from randomization to the first appearance of one of the following: invasive breast cancer recurrence at local, regional, or distant site, invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without cancer event; or censored at date of last follow up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Breast Cancer-free Interval | 5-year estimate reported at a median follow-up of 72 months | Estimated percentage of patients alive and disease-free at 5 years from randomization, where breast cancer-free interval is defined as the time from randomization to the invasive breast cancer recurrence at local, regional, or distant site, or invasive contralateral breast cancer; or censored at date of last follow up. |
| Distant Recurrence-free Interval | 5-year estimates reported at a median follow-up of 72 months | Estimated percentage of patients alive and disease-free at 5 years from randomization, where distant recurrence-free interval is defined as the time from randomization to breast cancer recurrence at a distant site; or censored at date of last follow-up |
| Overall Survival | 8-year estimates, reported at a median follow-up of 9 years | Estimated percentage of patients alive at 8 years from randomization, where overall survival is defined as the time from randomization to death from any cause; or censored at date last known alive. |
Countries
Australia, Belgium, Brazil, Canada, Egypt, Germany, Hungary, India, Italy, New Zealand, Peru, Slovenia, South Africa, Sweden, Switzerland, United Kingdom, United States
Contacts
STUDY_CHAIROlivia Pagani, MD
Oncology Institute of Southern Switzerland
STUDY_CHAIRBarbara Walley, MD, FRCPC
Tom Baker Cancer Centre
Participant flow
Recruitment details
2672 patients were randomized between 7Nov03 and 7Apr11 at 182 centers in 15 countries.
Participants by arm
| Arm | Count |
|---|---|
| T+OFS Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin. | 1,328 |
| E+OFS Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin. | 1,332 |
| Total | 2,660 |
Baseline characteristics
| Characteristic | Total | T+OFS | E+OFS |
|---|---|---|---|
| Age, Continuous Age | 43 years | 44 years | 43 years |
| HER2 status Negative | 174 percent of participants | 87 percent of participants | 87 percent of participants |
| HER2 status Positive | 24 percent of participants | 12 percent of participants | 12 percent of participants |
| HER2 status Unknown | 2 percent of participants | 1 percent of participants | 1 percent of participants |
| Lymph-node status Negative | 104 percent of participants | 52 percent of participants | 52 percent of participants |
| Lymph-node status Positive | 96 percent of participants | 48 percent of participants | 48 percent of participants |
| Sex: Female, Male Female | 2660 Participants | 1328 Participants | 1332 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Tumor grade 1 | 34 percent of participants | 17 percent of participants | 17 percent of participants |
| Tumor grade 2 | 111 percent of participants | 56 percent of participants | 55 percent of participants |
| Tumor grade 3 | 53 percent of participants | 26 percent of participants | 27 percent of participants |
| Tumor grade unknown | 2 percent of participants | 1 percent of participants | 1 percent of participants |
| Tumor size <=2 cm | 119 percent of participants | 60 percent of participants | 59 percent of participants |
| Tumor size >=2 cm | 79 percent of participants | 39 percent of participants | 40 percent of participants |
| Tumor size unknown | 2 percent of participants | 1 percent of participants | 1 percent of participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| other Total, other adverse events | 1,293 / 1,321 | 1,298 / 1,317 |
| serious Total, serious adverse events | 484 / 1,321 | 496 / 1,317 |
Outcome results
Primary
Disease-free Survival
Estimated percentage of patients alive and disease-free at 5 years from randomization, where disease-free survival is defined as the time from randomization to the first appearance of one of the following: invasive breast cancer recurrence at local, regional, or distant site, invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without cancer event; or censored at date of last follow up.
Time frame: 5-year estimate reported at a median follow-up of 72 months
Population: Intention-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T+OFS | Disease-free Survival | 87.3 percentage of participants |
| E+OFS | Disease-free Survival | 91.1 percentage of participants |
p-value: 0.000295% CI: [0.602, 0.855]Log Rank
Secondary
Breast Cancer-free Interval
Estimated percentage of patients alive and disease-free at 5 years from randomization, where breast cancer-free interval is defined as the time from randomization to the invasive breast cancer recurrence at local, regional, or distant site, or invasive contralateral breast cancer; or censored at date of last follow up.
Time frame: 5-year estimate reported at a median follow-up of 72 months
Population: Intention-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T+OFS | Breast Cancer-free Interval | 88.8 percentage of participants |
| E+OFS | Breast Cancer-free Interval | 92.8 percentage of participants |
p-value: <0.000195% CI: [0.548, 0.804]Log Rank
Secondary
Distant Recurrence-free Interval
Estimated percentage of patients alive and disease-free at 5 years from randomization, where distant recurrence-free interval is defined as the time from randomization to breast cancer recurrence at a distant site; or censored at date of last follow-up
Time frame: 5-year estimates reported at a median follow-up of 72 months
Population: Intention-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T+OFS | Distant Recurrence-free Interval | 92.0 percentage of participants |
| E+OFS | Distant Recurrence-free Interval | 93.8 percentage of participants |
p-value: 0.0295% CI: [0.624, 0.967]Log Rank
Secondary
Overall Survival
Estimated percentage of patients alive at 8 years from randomization, where overall survival is defined as the time from randomization to death from any cause; or censored at date last known alive.
Time frame: 8-year estimates, reported at a median follow-up of 9 years
Population: Intention-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T+OFS | Overall Survival | 93.3 percentage of participants |
| E+OFS | Overall Survival | 93.4 percentage of participants |
p-value: 0.8495% CI: [0.79, 1.22]Log Rank