Suppression of Ovarian Function With Either Tamoxifen or Exemestane Compared With Tamoxifen Alone in Treating Premenopausal Women With Hormone-Responsive Breast Cancer (SOFT)
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| ClinicalTrials.gov Identifier: NCT00066690 |
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Recruitment Status :
Active, not recruiting
First Posted : August 7, 2003
Results First Posted : September 22, 2016
Last Update Posted : March 11, 2021
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Sponsor:
International Breast Cancer Study Group
Collaborators:
Breast International Group
Cancer and Leukemia Group B
National Cancer Institute (NCI)
NSABP Foundation Inc
NCIC Clinical Trials Group
North Central Cancer Treatment Group
Southwest Oncology Group
Information provided by (Responsible Party):
International Breast Cancer Study Group
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Brief Summary:
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 studies 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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Estrogen Receptor Positive Breast Cancer Progesterone Receptor Positive Tumor Recurrent Breast Carcinoma Stage IA Breast Cancer Stage IB Breast Cancer Stage IIA Breast Cancer Stage IIB Breast Cancer Stage IIIA Breast Cancer | Drug: Exemestane Other: Laboratory Biomarker Analysis Procedure: Oophorectomy Other: Quality-of-Life Assessment Radiation: Radiation Therapy Drug: Tamoxifen Drug: Triptorelin | Phase 3 |
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 tamoxifen + ovarian function suppression (by triptorelin, oophorectomy, or ovarian irradiation) or exemestane + ovarian function suppression vs. tamoxifen alone. The primary comparison is ovarian function suppression with either tamoxifen or exemestane vs. tamoxifen alone.
- Compare the quality of life, including late side effects of early menopause, of 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) and intended initial method of ovarian function suppression (triptorelin vs oophorectomy vs ovarian irradiation). 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 then annually for 4 years.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 3066 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | December 17, 2003 |
| Actual Primary Completion Date : | May 2014 |
| Estimated Study Completion Date : | December 2025 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Breast cancer
MedlinePlus related topics:
Breast Cancer
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Tamoxifen
Tamoxifen 20mg orally daily for 5 years
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Other: Laboratory Biomarker Analysis
Correlative studies Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Drug: Tamoxifen Tamoxifen 20mg orally daily for 5 years
Other Names:
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Experimental: T+OFS
Tamoxifen 20mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)
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Other: Laboratory Biomarker Analysis
Correlative studies Procedure: Oophorectomy Undergo bilateral surgical oophorectomy
Other Names:
Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Radiation: Radiation Therapy Undergo ovarian irradiation
Other Names:
Drug: Tamoxifen Tamoxifen 20mg orally daily for 5 years
Other Names:
Drug: Triptorelin 3.75 mg by im injection q28 days for 5 years
Other Names:
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Experimental: E+OFS
Exemestane 25mg orally daily for 5 years plus ovarian function suppression (OFS; triptorelin (GnRH analogue) 3.75 mg by im injection q28 days for 5 years; or surgical oophorectomy; or ovarian irradiation)
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Drug: Exemestane
Exemestane 25mg orally daily for 5 years plus ovarian function suppression
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Procedure: Oophorectomy Undergo bilateral surgical oophorectomy
Other Names:
Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Radiation: Radiation Therapy Undergo ovarian irradiation
Other Names:
Drug: Triptorelin 3.75 mg by im injection q28 days for 5 years
Other Names:
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Primary Outcome Measures :
- Disease-free Survival [ Time Frame: 5-year estimates, reported at a median follow-up of 67 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 Outcome Measures :
- Breast Cancer-free Interval [ Time Frame: 5-year estimates, reported at a median follow-up of 67 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 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 [ Time Frame: 5-year estimates, reported at a median follow-up of 67 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 invasive breast cancer recurrence at distant site, or invasive contralateral breast cancer; or censored at date of last follow up.
- Overall Survival [ Time Frame: 8-year estimates, reported at a median follow-up of 8 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.
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| Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
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Premenopausal women (estradiol [E2] in the premenopausal range [according to institution parameters]) who meet the following criteria:
- Patients who did not receive chemotherapy should be randomized within 12 weeks after definitive surgery; such patients should have estradiol (E2) in the premenopausal range following surgery; the only patients who do not require testing of estradiol (E2) to confirm premenopausal status are those who have been menstruating regularly during the 6 months prior to randomization and have not used any form of hormonal contraception or any other hormonal treatments during the 6 months prior to randomization
- Patients who received prior adjuvant and/or neoadjuvant chemotherapy should be randomized after completing chemotherapy and within 8 months of the final dose of chemotherapy as soon as premenopausal status is confirmed; all such patients should have premenopausal status confirmed by an estradiol (E2) in the premenopausal range between 2 weeks and 8 months after completing chemotherapy
- Adjuvant trastuzumab (Herceptin ®) is allowable, and is not considered to be chemotherapy for eligibility timing determination
- Patients with temporary chemotherapy-induced amenorrhea who regain premenopausal status within eight months of the final dose of chemotherapy are eligible; (please note that some patients taking tamoxifen or aromatase inhibitors, even without evidence of menses, may have ovarian function recovery following chemotherapy and resume estradiol secretion); in patients wishing to participate in the study, with postmenopausal hormone levels shortly after chemotherapy, it is recommended to recheck their estradiol level at a later timepoint within 8 months of completing chemotherapy, even in the absence of return of menses
- Histologically proven, resected breast cancer; pathology material should be available for submission for central review as part of the quality control measures for this protocol
- Patients must have hormone receptor positive tumors; if there is more than one breast tumor, each tumor must be hormone receptor positive; hormone receptors must be determined using immunohistochemistry; estrogen receptor (ER) and/or progesterone receptor (PgR) must be greater than or equal to 10% of the tumor cells positive by immunohistochemical evaluation; biochemical determination alone is not acceptable
- The tumor must be confined to the breast and axillary nodes without detected metastases elsewhere, with the exception of tumor detected in internal mammary chain nodes by sentinel node procedure; patients who received neoadjuvant therapy must have had operable disease prior to neoadjuvant treatment to be eligible; patients who had a pathological evaluation with tru cut or core biopsy of invasive breast cancer prior to neoadjuvant therapy and were found to have no invasive tumor in the pathological specimen from definitive surgery are eligible; for these patients, pre-neoadjuvant tumor characteristics will be used for defining eligibility; in case of persistent disease, pathology findings from the definitive surgery should be used
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Patients must have had proper surgery for primary breast cancer with no known clinical residual loco-regional disease:
- A total mastectomy; radiotherapy is optional after mastectomy OR
- A breast-conserving procedure (lumpectomy, quadrantectomy or partial mastectomy with margins clear of invasive cancer and ductal breast carcinoma in situ [DCIS]); the local pathologist must document negative margins of resection in the pathology report; if all other margins are clear, a positive posterior (deep) margin is permitted, provided the surgeon documents that the excision was performed down to the pectoral fascia and all tumor has been removed; likewise, if all other margins are clear, a positive anterior (superficial; abutting skin) margin is permitted provided the surgeon documents that all tumor has been removed; radiation therapy to the conserved breast is required; patients may be randomized before, during or after completion of radiation therapy to the breast
- Either axillary lymph node dissection (pathological examination of at least 6 nodes recommended) or a negative axillary sentinel node biopsy (pN0[sn]) is required; patients with negative or microscopically axillary positive sentinel nodes (pN1mi: micrometastasis none > 2.0 mm) do not require further axillary therapy; those with positive sentinel nodes must have either an axillary dissection or radiation of axillary nodes
- For International Breast Cancer Study Groups (IBCSG) centers, patients must have completed baseline Quality of Life (QL) Forms prior to randomization; the only exceptions are cognitive or physical impairment that interferes with QL assessment or inability to read any of the languages available on IBCSG QL forms; for non-IBCSG centers, extent of participation in the QL study is to be determined at the activation of the trial for each cooperative group
- Written informed consent must be signed and dated by the patient and the investigator prior to randomization
- Patients must be accessible for follow-up
- Patients must be informed of and agree to data and tissue material transfer and handling, in accordance with national data protection guidelines
Exclusion Criteria:
- Patients who are postmenopausal (i.e., do not have an estradiol [E2] level in the premenopausal range) after surgery or after chemotherapy, whichever is later
- Patients with distant metastatic disease
- Patients with locally advanced inoperable breast cancer including inflammatory breast cancer or supraclavicular node involvement or with enlarged internal mammary nodes (unless pathologically negative) are not eligible; patients with involved internal mammary nodes detected by sentinel node biopsy that are not enlarged are eligible
- Patients with positive final margins (referring to only DCIS and invasive cancer, not lobular breast carcinoma in situ [LCIS]), except as noted; DCIS at a margin is permitted if a complete mastectomy has been performed
- Patients with clinically detectable residual axillary disease
- Patients with a history of prior ipsilateral or contralateral invasive breast cancer; patients with synchronous bilateral invasive breast cancer (diagnosed histologically within 2 months) are eligible if the bilateral disease meets all other eligibility criteria
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Patients with previous or concomitant invasive malignancy are not eligible; the exceptions are patients with the following (and only the following) malignancies (previous or concomitant) who are eligible if adequately treated:
- Basal or squamous cell carcinoma of the skin
- In situ non-breast carcinoma without invasion
- Contra- or ipsilateral in situ breast carcinoma
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Non-breast invasive malignancy diagnosed at least 5 years ago and without recurrence:
- Stage I papillary thyroid cancer
- Stage Ia carcinoma of the cervix
- Stage Ia or b endometrioid endometrial cancer
- Borderline or stage I ovarian cancer
- Patients with other non-malignant systemic diseases (cardiovascular, renal, hepatic, lung, etc.) that would prevent prolonged follow-up; patients with previous thrombosis (e.g., deep vein thrombosis [DVT]) and/or embolism can be included only if medically suitable
- Patients who have had a bilateral oophorectomy or ovarian irradiation; patients who will be recommended to undergo oophorectomy within 5 years (e.g., breast cancer susceptibility gene [BRCA]1/2 gene carriers) and therefore for whom randomization to a treatment arm without OFS is inappropriate
- Patients with a history of noncompliance to medical regimens and patients who are considered potentially unreliable
- Patients who are pregnant or lactating at the time of randomization or who desire a pregnancy within 5 years; patients planning to use additional hormonal therapy apart from the randomized treatment during the next five years including all types of hormonal contraception; a pregnancy test is recommended for women of child-bearing potential who are sexually active and not using reliable contraceptive methods
- Patients who received endocrine therapy (including neoadjuvant and adjuvant) for more than 8 months after their breast cancer diagnosis; patients who are receiving endocrine therapy at randomization (and have received it for less than 8 months) may continue such therapy until protocol-specified tamoxifen/exemestane is initiated
- Patients who were taking tamoxifen or other selective estrogen receptor modulator (SERM) (e.g. Raloxifene) or hormone replacement therapy (HRT) within one year prior to their breast cancer diagnosis; prior oral contraceptives are allowed
- Patients who have received GnRH analogues as part of their breast cancer treatment prior to randomization
- Patients with psychiatric, addictive, or any disorder that would prevent compliance with protocol requirements
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00066690
Locations
Show 500 study locations
Sponsors and Collaborators
International Breast Cancer Study Group
Breast International Group
Cancer and Leukemia Group B
National Cancer Institute (NCI)
NSABP Foundation Inc
NCIC Clinical Trials Group
North Central Cancer Treatment Group
Southwest Oncology Group
Investigators
| Principal Investigator: | Gini Fleming | International Breast Cancer Study Group |
Study Documents (Full-Text)
Documents provided by International Breast Cancer Study Group:
Documents provided by International Breast Cancer Study Group:
Statistical Analysis Plan [PDF] November 1, 2017
Study Protocol [PDF] July 14, 2011
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | International Breast Cancer Study Group |
| ClinicalTrials.gov Identifier: | NCT00066690 |
| Obsolete Identifiers: | NCT00917969, NCT02140190 |
| Other Study ID Numbers: |
IBCSG 24-02 / BIG 2-02 NCI-2009-01086 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) CDR0000316456 BIG 2-02 2004-000166-13 IBCSG-24-02 ( Other Identifier: CTEP ) U24CA075362 ( U.S. NIH Grant/Contract ) |
| First Posted: | August 7, 2003 Key Record Dates |
| Results First Posted: | September 22, 2016 |
| Last Update Posted: | March 11, 2021 |
| Last Verified: | February 2021 |
Keywords provided by International Breast Cancer Study Group:
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tamoxifen ovarian function suppression + tamoxifen ovarian function suppression + exemestane |
Additional relevant MeSH terms:
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Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Tamoxifen Triptorelin Pamoate Exemestane Tryptophan Molecular Mechanisms of Pharmacological Action Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Estrogen Antagonists Hormone Antagonists Antineoplastic Agents, Hormonal |
Antineoplastic Agents Selective Estrogen Receptor Modulators Estrogen Receptor Modulators Bone Density Conservation Agents Aromatase Inhibitors Steroid Synthesis Inhibitors Enzyme Inhibitors Luteolytic Agents Contraceptive Agents, Female Contraceptive Agents Reproductive Control Agents Contraceptive Agents, Hormonal Antidepressive Agents, Second-Generation Antidepressive Agents Psychotropic Drugs |