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

Gruppo Italiano Mammella (GIM)

Status and phase: Unknown; Phase 3

Conditions: Breast Cancer

Treatments: Drug: letrozole; Drug: tamoxifen citrate; Drug: anastrozole; Drug: exemestane

Study type: Interventional

Funder types: Other

Identifiers

NCT00541086

CDR0000570041

GIM-3-FATA

EU-20764

EUDRACT-2006-004018-42

Details and patient eligibility

About

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.

Full 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.

Enrollment: 3,697 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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3,697 participants in 6 patient groups

A - anastrozole

Experimental group

Description:

Up-front adjuvant anastrozole for 5 years

Treatment:

Drug: anastrozole

B - exemestane

Experimental group

Description:

Up-front adjuvant exemestane for 5 years

Treatment:

Drug: exemestane

C - letrozole

Experimental group

Description:

Up-front adjuvant letrozole for 5 years

Treatment:

Drug: letrozole

D - tamoxifen followed by anastrozole

Active Comparator group

Description:

Switch adjuvant treatment with tamoxifen for 2 years followed by anastrozole for 3 years

Treatment:

Drug: tamoxifen citrate

Drug: anastrozole

E - tamoxifen followed by exemestane

Active Comparator group

Description:

Switch adjuvant treatment with tamoxifen for 2 years followed by exemestane for 3 years

Treatment:

Drug: tamoxifen citrate

Drug: exemestane

F - tamoxifen followed by letrozole

Active Comparator group

Description:

Switch adjuvant treatment with tamoxifen for 2 years followed by letrozolefor 3 years

Treatment:

Drug: tamoxifen citrate

Drug: letrozole