Study of Anastrozole, Letrozole, or Exemestane With or Without Tamoxifen in Treating Postmenopausal Women With Hormone-Responsive Breast Cancer That Has Been Completely Removed By Surgery

Sponsor

Gruppo Italiano Mammella (GIM) (Other)

Overall Status

Unknown status

CT.gov ID

NCT00541086

Collaborator

(none)

3,697

Enrollment

Locations

Arms

160

Anticipated Duration (Months)

739.4

Patients Per Site

4.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking use of estrogen by the tumor cells. Anastrozole, letrozole, and exemestane may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether giving tamoxifen followed by anastrozole, letrozole, or exemestane is more effective than giving anastrozole, letrozole, or exemestane alone in treating breast cancer.

PURPOSE: This randomized phase III trial is studying giving tamoxifen followed by either anastrozole, letrozole, or exemestane to see how well it works compared to anastrozole, letrozole, or exemestane alone in treating postmenopausal women with hormone-responsive invasive breast cancer that has been completely removed by surgery.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: anastrozole Drug: exemestane Drug: letrozole Drug: tamoxifen citrate	Phase 3

Detailed Description

OBJECTIVES:

To compare sequential tamoxifen for 2 years followed by anastrozole, letrozole, or exemestane for 3 years vs anastrozole, letrozole, or exemestane for 5 years in terms of disease-free survival in postmenopausal women with nonrecurrent, nonmetastatic invasive endocrine-responsive breast cancer.
To compare disease-free survival in patients treated with anastrozole vs letrozole vs exemestane.

OUTLINE: This is a multicenter study. Patients are stratified according to hormone receptor status (estrogen receptor [ER]-positive and progesterone [PgR] receptor-positive disease vs ER-positive and PgR-negative disease vs ER-negative and PgR-positive disease vs ER- or PgR-positive disease or ER or PgR status unknown), HER-2/neu status (positive [3+ by IHC or positive by fluorescence in situ hybridization ( FISH)] vs negative vs unknown), prior chemotherapy (none vs adjuvant vs neoadjuvant vs both adjuvant and neoadjuvant), and nodal status (pN0 vs pN1 vs pN2 vs pN3). Patients are randomized to 1 of 6 treatment arms.

Arm I: Patients receive oral anastrozole once daily for 5 years.
Arm II: Patients receive oral exemestane once daily for 5 years.
Arm III: Patients receive oral letrozole once daily for 5 years.
Arm IV: Patients receive oral tamoxifen citrate once daily for 2 years followed by oral anastrazole once daily for 3 years.
Arm V: Patients receive oral tamoxifen citrate once daily for 2 years followed by oral exemestane once daily for 3 years.
Arm VI: Patients receive oral tamoxifen citrate once daily for 2 years followed by oral letrozole once daily for 3 years.

Treatment in all arms continues in the absence of disease recurrence or unacceptable toxicity.

After completion of study therapy, patients are followed periodically.

Study Design

Study Type:

Interventional

Actual Enrollment :

3697 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase III Study Comparing Anastrozole, Letrozole and Exemestane, Upfront (for 5 Years) or Sequentially (for 3 Years After 2 Years of Tamoxifen), as Adjuvant Treatment of Postmenopausal Patients With Endocrine-responsive Breast Cancer

Actual Study Start Date :

Mar 1, 2007

Anticipated Primary Completion Date :

Jul 1, 2020

Anticipated Study Completion Date :

Jul 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A - anastrozole Up-front adjuvant anastrozole for 5 years	Drug: anastrozole 1 mg per day, orally
Experimental: B - exemestane Up-front adjuvant exemestane for 5 years	Drug: exemestane 25 mg per day, orally
Experimental: C - letrozole Up-front adjuvant letrozole for 5 years	Drug: letrozole 2.5 mg per day, orally
Active Comparator: D - tamoxifen followed by anastrozole Switch adjuvant treatment with tamoxifen for 2 years followed by anastrozole for 3 years	Drug: anastrozole 1 mg per day, orally Drug: tamoxifen citrate 20 mg per day, orally
Active Comparator: E - tamoxifen followed by exemestane Switch adjuvant treatment with tamoxifen for 2 years followed by exemestane for 3 years	Drug: exemestane 25 mg per day, orally Drug: tamoxifen citrate 20 mg per day, orally
Active Comparator: F - tamoxifen followed by letrozole Switch adjuvant treatment with tamoxifen for 2 years followed by letrozolefor 3 years	Drug: letrozole 2.5 mg per day, orally Drug: tamoxifen citrate 20 mg per day, orally

Outcome Measures

Primary Outcome Measures

Disease-free survival [5 years]

Secondary Outcome Measures

Overall Survival [5 years]
Distant metastasis-free survival [5 years]
Cumulative incidence of contralateral breast cancer as first event [5 years]
Breast cancer-free survival [5 years]
Cumulative incidence and type of second non-breast invasive cancer [5 years]
Effects on lipid profile [5 years]
Toxicity as assessed by NCI CTCAE v3.0 [5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed invasive breast cancer completely removed by surgery
Any T, any N
No recurrent or metastatic disease
Estrogen or progesterone receptor-positive disease in primary tumor, as defined by 1 of the following:
At least 10% of tumor cells positive by immunohistochemistry
At least 10 fmol/mg cytosol protein by ligand binding assay
Patients with HER-2/neu positive tumors are eligible provided they receive trastuzumab (Herceptin®) according to the registered schedule

PATIENT CHARACTERISTICS:

Female
Postmenopausal, defined by ≥ 1 of the following:
Age ≥ 60 years
Age 45-59 and satisfying 1 or more of the following criteria:
Amenorrhea for ≥ 12 months AND intact uterus
Amenorrhea (secondary to hysterectomy, hormone replacement therapy (HRT), or chemotherapy) for < 12 months AND follicle-stimulating hormone within the postmenopausal range
Underwent prior bilateral oophorectomy at any age >18 years
No concurrent illness that contraindicates adjuvant endocrine treatment
No other invasive breast cancer or invasive malignancy within the past 10 years, except adequately cone-biopsied squamous cell or basal cell skin cancer or carcinoma in situ of the cervix
No concurrent disease that would place the patient at unusual risk

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Adjuvant or neoadjuvant chemotherapy must be completed prior to study entry
At least 1 month since prior and no concurrent HRT
More than 30 days since prior systemic investigational drugs
No prior tamoxifen as part of any breast cancer prevention study
Prior or concurrent locoregional radiotherapy allowed
No other concurrent experimental drugs
No concurrent bisphosphonates, unless indicated as treatment for osteoporosis

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Federico II University Medical School	Naples	Italy	80131
2	Istituto Nazionale per lo Studio e la Cura dei Tumori	Naples	Italy	80131
3	Seconda Universita di Napoli	Naples	Italy	80138
4	Arcispedale S. Maria Nuova	Reggio Emilia	Italy	42100
5	Istituti Fisioterapici Ospitalieri - Roma	Rome	Italy	00128