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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

Phase 3
Open (Enrolling)
Breast Cancer

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Trial Information

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


- Compare ovarian function suppression (by triptorelin, oophorectomy, or ovarian
irradiation) in combination with tamoxifen vs tamoxifen alone; exemestane vs tamoxifen
alone; and exemestane vs ovarian function suppression 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

- Compare the sites of first treatment failure in patients treated with these regimens.

- Compare the causes of death without cancer event

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)
. 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

Quality of life is assessed at baseline, every 6 months for 2 years, and then annually for 4

After completion of study therapy, patients are followed periodically.

NOTE: Effective April 30, 2010, enrollment will cease...except for sites outside North
America that are also participating in IBCSG-24-02-SOFT-EST

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

NOTE: Effective April 30, 2010, enrollment will cease...except for sites outside North
America that are also participating in IBCSG-24-02-SOFT-EST

Inclusion Criteria


- 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

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

- Patients with microscopically positive axillary sentinel nodes or negative
sentinel 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

- Hormone receptor status:

- Estrogen and/or progesterone receptor positive

- Each tumor must be hormone receptor positive



- Premenopausal


- 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

Performance status

- Not specified

Life expectancy

- Not specified


- Not specified


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


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


- 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


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


- 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


Biologic therapy

- Prior and/or concurrent adjuvant, trastuzumab (herceptin) allowed


- 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

- No other concurrent SERMs (e.g., raloxifene)


- See Disease Characteristics

- No prior ovarian radiotherapy


- 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)


- No concurrent bisphosphonates, except in the following cases:

- Bone density is at least 1.5 standard deviations below the young adult normal

- Participation in a randomized clinical study testing bisphosphonates in the
adjuvant breast cancer setting

- No other concurrent investigational agent

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Disease-free survival

Outcome Time Frame:

For first time at a median follow up approximately 5 years

Safety Issue:


Principal Investigator

Prudence Francis, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Peter MacCallum Cancer Centre, Australia


United States: Federal Government

Study ID:




Start Date:

August 2003

Completion Date:

Related Keywords:

  • Breast Cancer
  • stage II breast cancer
  • stage IIIA breast cancer
  • stage IA breast cancer
  • stage IB breast cancer
  • estrogen receptor-positive breast cancer
  • progesterone receptor-positive breast cancer
  • Breast Neoplasms



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