RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by reducing the production of estrogen. Hormone therapy using tamoxifen may fight breast cancer by blocking the uptake of estrogen by the tumor cells. If is not yet known which treatment regimen is most effective for breast cancer.

PURPOSE: Randomized double-blind phase III trial to compare the effectiveness of letrozole with that of tamoxifen in treating postmenopausal women who have breast cancer that has been surgically removed.

OBJECTIVES:

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

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.

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

• Drug: letrozole
• Drug: tamoxifen citrate

• BIG 1-98 Collaborative Group; Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, Mauriac L, Forbes JF, Price KN, Regan MM, Gelber RD, Coates AS. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009 Aug 20;361(8):766-76.
• Giobbie-Hurder A, Price KN, Gelber RD. Design, conduct, and analyses of Breast International Group (BIG) 1-98: A randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer. Clin Trials. 2009 Jun;6(3):272-87.
• Rabaglio M, Sun Z, Price KN, Castiglione-Gertsch M, Hawle H, Thürlimann B, Mouridsen H, Campone M, Forbes JF, Paridaens RJ, Colleoni M, Pienkowski T, Nogaret JM, Láng I, Smith I, Gelber RD, Goldhirsch A, Coates AS; for the BIG 1-98 Collaborative and International Breast Cancer Study Groups. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol. 2009 May 27; [Epub ahead of print]
• Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole Compared With Tamoxifen for Elderly Patients With Endocrine-Responsive Early Breast Cancer: The BIG 1-98 Trial. J Clin Oncol. 2008 Mar 10; [Epub ahead of print]
• Doughty JC. A review of the BIG results: the Breast International Group 1-98 trial analyses. Breast. 2008 Jan;17 Suppl 1:S9-S14.
• Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG 1-98 Collaborative and International Breast Cancer Study Groups. 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. 2008 Jan;9(1):23-8. Epub 2007 Dec 20.
• Viale G, Giobbie-Hurder A, Regan MM, Coates AS, Mastropasqua MG, Dell'orto P, Maiorano E, Macgrogan G, Braye SG, Ohlschlegel C, Neven P, Orosz Z, Olszewski WP, Knox F, Thürlimann B, Price KN, Castiglione-Gertsch M, Gelber RD, Gusterson BA, Goldhirsch A. 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. 2008 Nov 3; [Epub ahead of print]
• Wardley AM. Understanding the BIG results: Insights from the BIG 1-98 trial analyses. Adv Ther. 2008 Dec;25(12):1257-75.
• Coates AS, Keshaviah A, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Lang I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. 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. 2007 Jan 2; [Epub ahead of print]
• Koeberle D, Thuerlimann B. Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98. Breast Cancer Res Treat. 2007;105 Suppl 1:55-66. Epub 2007 Oct 3.
• Mauriac L, Keshaviah A, Debled M, Mouridsen H, Forbes J, Thurlimann B, Paridaens R, Monnier A, Lang I, Wardley A, Nogaret JM, Gelber R, Castiglione-Gertsch M, Price K, Coates A, Smith I, Viale G, Rabaglio M, Zabaznyi N, Goldhirsch A. Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial. Ann Oncol. 2007 Feb 14; [Epub ahead of print]
• Monnier AM. The Breast International Group 1-98 trial: big results for women with hormone-sensitive early breast cancer. Expert Rev Anticancer Ther. 2007 May;7(5):627-34. Review.
• Mouridsen H, Keshaviah A, Coates AS, Rabaglio M, Castiglione-Gertsch M, Sun Z, Thürlimann B, Mauriac L, Forbes JF, Paridaens R, Gelber RD, Colleoni M, Smith I, Price KN, Goldhirsch A. 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. 2007 Nov 12; [Epub ahead of print]
• Viale G, Regan MM, Maiorano E, Mastropasqua MG, Dell'orto P, Bruun Rasmussen B, Raffoul J, Neven P, Orosz Z, Braye S, Ohlschlegel C, Thurlimann B, Gelber RD, Castiglione-Gertsch M, Price KN, Goldhirsch A, Gusterson BA, Coates AS. 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 Women With Early Breast Cancer: Results From the BIG 1-98 Collaborative Groups. J Clin Oncol. 2007 Aug 6; [Epub ahead of print]
• Forbes JF. The use of early adjuvant aromatase inhibitor therapy: contributions from the BIG 1-98 letrozole trial. Semin Oncol. 2006 Apr;33(2 Suppl 7):S2-7.
• Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardly A, Price KN, Goldhirsch A; Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57.
• Delea TE, El-Ouagari K, Karnon J, Sofrygin O. 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. 2007 Jul 26; [Epub ahead of print]
• Delea TE, Karnon J, Sofrygin O, Thomas SK, Papo NL, Barghout V. Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in hormone receptor-positive postmenopausal women with early-stage breast cancer. Clin Breast Cancer. 2007 Jun;7(8):608-18.
• Buzdar A, Chlebowski R, Cuzick J, Duffy S, Forbes J, Jonat W, Ravdin P. Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer. Curr Med Res Opin. 2006 Aug;22(8):1575-85. Review.
• Scott LJ, Keam SJ. Letrozole : in postmenopausal hormone-responsive early-stage breast cancer. Drugs. 2006;66(3):353-62. Review.
• Wardley AM. Emerging data on optimal adjuvant endocrine therapy: Breast International Group trial 1-98/MA.17. Clin Breast Cancer. 2006 Feb;6 Suppl 2:S45-50. Review.

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

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/mm^3
• Platelet count at least 100,000/mm^3
• 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

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

• Federation Nationale des Centres de Lutte Contre le Cancer
• Danish Breast Cancer Cooperative Group