Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	30 and over	Pharmaceutical / Industry	IBCSG-1-98 DAN-DBCG-IBCSG-1-98, FRE-FNCLCC-IBCSG-1-98, EU-99022, IBCSG-18-98, NOVARTIS-2026703019, NCT00004205, BIG-I-98

Objectives

1. Compare adjuvant letrozole vs tamoxifen administered for 5 years in postmenopausal women with operable, hormone receptor-positive breast cancer.
2. Compare these treatment regimens given sequentially vs continuously in this patient population.
3. Compare these treatment regimens in terms of overall survival, disease-free and systemic-free survival, safety, and tolerability in this patient population.

Entry Criteria

Disease Characteristics:

• Histologically confirmed resectable adenocarcinoma of the breast
  • pT1, pT2, pT3, or minimal dermal involvement on pathology only
  • pN0, pN1, pN2, or M0
    • Negative nodal status
      • At least 8 nodes are negative
    • Unknown nodal status
      • Less than 8 nodes examined and no pathological finding
    • Positive nodal status
      • Any positive finding independent of the number of nodes examined
  • Negative sentinel node or no prior nodal dissection allowed if all other criteria met



• Must have had total mastectomy, lumpectomy, or quadrantectomy
  • Should have prior chest wall radiotherapy after segmental mastectomy or histopathologic T4 dermal involvement



• Stage I, II, or IIIa allowed if the tumor is completely removed macroscopically and margins of the resected tumor are microscopically free of tumor



• Must undergo chest wall radiotherapy or second resection if microscopic disease at the mastectomy margins



• No bilateral disease except in situ disease, either ductal or lobular of the contralateral breast



• Postmenopausal
  • Regardless of prior hormonal replacement therapy (HRT) or hysterectomy:
    • Bilateral oophorectomy and any age
    • Radiologic castration and amenorrheic for at least 3 months and any age
    • Nonpostmenopausal prior to adjuvant chemotherapy and completed at least 6 courses of prior cyclophosphamide, methotrexate, and fluorouracil (CMF) or at least 4 courses of prior anthracycline-cyclophosphamide continuation therapy and at least age 40 with follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) postmenopausal levels
  • No prior HRT:
    • Prior hysterectomy and less than age 55 with FSH/LH/E2 postmenopausal levels
    • Prior hysterectomy and at least age 55
  • No prior HRT or hysterectomy:
    • Amenorrhea more than 1 year and less than age 50
    • Amenorrhea more than 6 months and at least age 50
  • Prior HRT regardless of hysterectomy:
    • At least 1 month since prior HRT and less than age 55 with FSH/LH/E2 postmenopausal levels
    • At least 1 month since prior HRT and at least age 55
  • FSH/LH/E2 postmenopausal levels and uncategorized



• No distant metastases, including bone scans showing hot spots unconfirmed as benign disease or skeletal pain of unknown cause



• At least 10% hormone receptor-positive tumor cells



• Hormone receptor status:
  • Estrogen receptor positive

    AND/OR

  • Progesterone receptor positive

Prior/Concurrent Therapy:

Biologic therapy:

• Prior immunotherapy or biological response modifiers (e.g., interferon) allowed

Chemotherapy:

• See Disease Characteristics
• Prior adjuvant or neoadjuvant chemotherapy allowed
• Concurrent adjuvant chemotherapy allowed

Endocrine therapy:

• See Disease Characteristics
• Prior neoadjuvant hormonal therapy allowed (e.g., antiestrogens, progestins, or aromatase inhibitors) if no more than 4 months duration and no disease progression
• Prior corticosteroids allowed
• At least 4 weeks since prior HRT
• Prior adjuvant antiestrogen therapy allowed if less than 1 month duration and immediately after surgery, radiotherapy, and/or chemotherapy
• Prior antiestrogens for chemoprevention allowed if at least 18 months between completion of chemoprevention and diagnosis
• No other concurrent antiestrogens or aromatase inhibitors
• No concurrent raloxifene
• No concurrent systemic HRT with or without progestins of more than 3 months duration

Radiotherapy:

• See Disease Characteristics
• Concurrent radiotherapy allowed

Surgery:

• See Disease Characteristics

Other:

• At least 30 days since prior systemic investigational drugs
• At least 7 days since prior topical investigational drugs
• Concurrent bisphosphonates allowed

Patient Characteristics:

Age:

• 30 and over

Sex:

• Female

Menopausal status:

• Postmenopausal

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• WBC greater than 3,000/mm³
• Platelet count at least 100,000/mm³
• Hemoglobin greater than 10 g/dL

Hepatic:

• Bilirubin less than 3.0 mg/dL
• SGOT or SGPT less than 1.5 times upper limit of normal
• No hepatic disease that would preclude study

Renal:

• Creatinine less than 1.8 mg/dL
• No renal disease that would preclude study

Cardiovascular:

• No cardiovascular disease that would preclude study
• Prior deep vein thrombosis allowed if medically stable

Pulmonary:

• No lung embolism

Other:

• No other prior or concurrent malignancy within the past 5 years except adequately treated basal or squamous cell skin cancer or carcinoma in situ of the cervix
• No prior noncompliance to medical regimens
• No other nonmalignant systemic diseases that would preclude follow-up
• HIV negative

Expected Enrollment

A total of 5,180 patients (1,295 per treatment arm) will be accrued for this study within 6 years.

Outline

This is a randomized, double-blind, multicenter study. Patients are stratified according to adjuvant chemotherapy (prior therapy vs no prior or concurrent therapy vs concurrent therapy), prior surgery (modified radical mastectomy vs a lesser surgical procedure), and participating center. Patients are randomized to one of four treatment arms.

• Arm I: Patients receive adjuvant oral tamoxifen daily for 5 years.



• Arm II: Patients receive adjuvant oral letrozole daily for 5 years.



• Arm III: Patients receive adjuvant oral tamoxifen daily for 2 years followed by adjuvant oral letrozole daily for 3 years.



• Arm IV: Patients receive adjuvant oral letrozole daily for 2 years followed by adjuvant oral tamoxifen daily for 3 years.

Patients may receive concurrent radiotherapy. Some patients receive concurrent adjuvant chemotherapy beginning within 8 weeks after surgery and continuing for no more than 6 months.

Patients are followed annually.

Crivellari D, Sun Z, Coates AS, et al.: Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol 26 (12): 1972-9, 2008.[PUBMED Abstract]

Doughty JC: A review of the BIG results: the Breast International Group 1-98 trial analyses. Breast 17 (Suppl 1): S9-S14, 2008.[PUBMED Abstract]

Mouridsen HT, Giobbie-Hurder A, Mauriac L, et al.: BIG 1-98: a randomized double-blind phase III study evaluating letrozole and tamoxifen given in sequence as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. [Abstract] 31st Annual San Antonio Breast Cancer Symposium, December 10-14, 2008, San Antonio, Texas. A-13, 2008.

Rasmussen BB, Regan MM, Lykkesfeldt AE, et al.: Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol 9 (1): 23-8, 2008.[PUBMED Abstract]

Viale G, Giobbie-Hurder A, Regan MM, et al.: Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 26 (34): 5569-75, 2008.[PUBMED Abstract]

Wardley AM: Understanding the BIG results: Insights from the BIG 1-98 trial analyses. Adv Ther 25 (12): 1257-75, 2008.[PUBMED Abstract]

Coates AS, Keshaviah A, Thürlimann B, et al.: Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 25 (5): 486-92, 2007.[PUBMED Abstract]

Coates AS, Mouridsen H, Sun Z, et al.: Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: updated safety analysis of trial BIG 1-98. [Abstract] J Clin Oncol 25 (Suppl 18): A-521, 2007.

Crivellari D, Sun Z, Coates AS, et al.: Aromatase inhibitors (AI) for elderly patients: efficacy, compliance and safety according to patient age in the BIG 1-98 trial. [Abstract] J Clin Oncol 25 (Suppl 18): A-9033, 501s, 2007.

Koeberle D, Thuerlimann B: Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98. Breast Cancer Res Treat 105 (Suppl 1): 55-66, 2007.[PUBMED Abstract]

Mauriac L, Keshaviah A, Debled M, et al.: Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial. Ann Oncol 18 (5): 859-67, 2007.[PUBMED Abstract]

Monnier AM: The Breast International Group 1-98 trial: big results for women with hormone-sensitive early breast cancer. Expert Rev Anticancer Ther 7 (5): 627-34, 2007.[PUBMED Abstract]

Mouridsen H, Keshaviah A, Coates AS, et al.: Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: safety analysis of BIG 1-98 trial. J Clin Oncol 25 (36): 5715-22, 2007.[PUBMED Abstract]

Rasmussen BB, Regan MM, Lykkesfeldt AE, et al.: Central assessment of ER, PgR and HER2 in BIG 1-98 evaluating letrozole (L) compared to tamoxifen (T) as initial adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. [Abstract] J Clin Oncol 25 (18 Suppl 20): A-538, 2007.

Viale G, Regan MM, Maiorano E, et al.: Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG 1-98. J Clin Oncol 25 (25): 3846-52, 2007.[PUBMED Abstract]

Forbes JF: The use of early adjuvant aromatase inhibitor therapy: contributions from the BIG 1-98 letrozole trial. Semin Oncol 33 (2 Suppl 7): S2-7, 2006.[PUBMED Abstract]

Thürlimann B, Keshaviah A, Coates AS, et al.: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353 (26): 2747-57, 2005.[PUBMED Abstract]

Delea TE, El-Ouagari K, Karnon J, et al.: Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in postmenopausal women with hormone-receptor positive early breast cancer from a Canadian perspective. Breast Cancer Res Treat 108 (3): 375-87, 2008.[PUBMED Abstract]

Delea TE, Karnon J, Sofrygin O, et al.: Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in hormone receptor-positive postmenopausal women with early-stage breast cancer. Clin Breast Cancer 7 (8): 608-18, 2007.[PUBMED Abstract]

Buzdar A, Chlebowski R, Cuzick J, et al.: Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer. Curr Med Res Opin 22 (8): 1575-85, 2006.[PUBMED Abstract]

Scott LJ, Keam SJ: Letrozole : in postmenopausal hormone-responsive early-stage breast cancer. Drugs 66 (3): 353-62, 2006.[PUBMED Abstract]

Wardley AM: Emerging data on optimal adjuvant endocrine therapy: Breast International Group trial 1-98/MA.17. Clin Breast Cancer 6 (Suppl 2): S45-50, 2006.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

International Breast Cancer Study Group

Beat Thurlimann, MD, Protocol chair		Ph: 41-71-494-1888 Email: beat.thuerlimann@kssg.ch

Federation Nationale des Centres de Lutte Contre le Cancer

Louis Mauriac, MD, Protocol chair		Ph: 33-56-333-258 Email: mauriac@bergonie.org

Danish Breast Cancer Cooperative Group

Henning Mouridsen, MD, PhD, Protocol chair		Ph: 45-3545-8500 Email: hmouridsen@rh.dk

Registry Information
Official Title		A Phase III Study to Evaluate Letrozole as Adjuvant Endocrine Therapy for Postmenopausal Women with Receptor (ER and/or PgR) Positive Tumors
Trial Start Date		1998-03-18
Registered in ClinicalTrials.gov		NCT00004205
Date Submitted to PDQ		1999-12-02
Information Last Verified		2001-03-14