Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer

Breast Cancer Clinical Trial

— BIG 1-98  

Official title:

A Phase III Study to Evaluate Letrozole as Adjuvant Endocrine Therapy for Postmenopausal Women With Receptor (ER and/or PgR) Positive Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00004205
• Other study ID #: CDR0000067451
• Secondary ID: IBCSG-18-98DAN-D
• Status: Completed
• Phase: Phase 3
• First received: January 21, 2000
• Last updated: December 8, 2017
• Start date: March 1998
• Est. completion date: June 30, 2016

Study information

• Verified date: December 2017
• Source: International Breast Cancer Study Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8028
• Est. completion date: June 30, 2016
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 30 Years to 120 Years

Eligibility

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

• Not postmenopausal at the start of adjuvant chemotherapy AND 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 45 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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• letrozole
Letrozole 2.5 mg daily oral administration.
• tamoxifen citrate
Tamoxifen 20 mg daily oral administration.

Locations

Country	Name	City	State
Denmark	Rigshospitalet	Copenhagen
France	Institut Bergonie	Bordeaux
Switzerland	Kantonsspital - St. Gallen	St. Gallen

Sponsors (3)

Lead Sponsor	Collaborator
International Breast Cancer Study Group	Danish Breast Cancer Cooperative Group, UNICANCER

Countries where clinical trial is conducted

Denmark,  France,  Switzerland, 

References & Publications (44)

Antonov J, Popovici V, Delorenzi M, Wirapati P, Baltzer A, Oberli A, Thürlimann B, Giobbie-Hurder A, Viale G, Altermatt HJ, Aebi S, Jaggi R. Molecular risk assessment of BIG 1-98 participants by expression profiling using RNA from archival tissue. BMC Can — View Citation

BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, Mauriac L, Forbes J, Price KN, Regan MM, Gelber RD, Coates AS. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer — View Citation

Bouzyk M, Gray KP, Regan MM, et al.: ESR1 and ESR2 polymorphisms in BIG 1-98 comparing adjuvant letrozole (L) versus tamoxifen (T) or their sequence for early breast cancer. [Abstract] J Clin Oncol 29 (Suppl 15): A-1002, 2011.

Breast International Group (BIG) 1-98 Collaborative Group, Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A. A comparison of letr — View Citation

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. — View Citation

Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five y — View Citation

Colleoni M, Giobbie-Hurder A, Regan MM, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Láng I, Smith I, Chirgwin J, Pienkowski T, Wardley A, Price KN, Gelber RD, Coates AS, Goldhirsch A. Analyses adjusting for selective crossover show impro — View Citation

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.

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 wi — View Citation

De Censi A, Sun Z, Thurlimann BJK, et al.: Bone mineral density (BMD) in participants (pts) of trial BIG 1-98 comparing adjuvant letrozole (L) versus tamoxifen (T) or their sequence. [Abstract] J Clin Oncol 29 (Suppl 15): A-516, 2011.

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. 2008 Apr;108(3):375-87. Epub 2007 Jul 26. — View Citation

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. — View Citation

Doughty JC. A review of the BIG results: the Breast International Group 1-98 trial analyses. Breast. 2008 Jan;17 Suppl 1:S9-S14. doi: 10.1016/S0960-9776(08)70003-1. Review. — View Citation

Ejlertsen B, Aldridge J, Nielsen KV, Regan MM, Henriksen KL, Lykkesfeldt AE, Müller S, Gelber RD, Price KN, Rasmussen BB, Viale G, Mouridsen H; Danish Breast Cancer Cooperative Group; BIG 1-98 Collaborative Group; International Breast Cancer Study Group. — View Citation

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. — View Citation

Giobbie-Hurder A, Price KN, Gelber RD; International Breast Cancer Study Group; BIG 1-98 Collaborative Group. Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamox — View Citation

Huober JB, Cole BF, Wu J, et al.: Symptoms of endocrine treatment and outcome: A retrospective analysis of the monotherapy arms of the BIG 1-98 trial. [Abstract] J Clin Oncol 29 (Suppl 15): A-522, 2011.

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. Erratum in: Breast Cancer Res Treat. 2008 Nov;112( — View Citation

Lipsitz M, Delea TE, Guo A. Cost effectiveness of letrozole versus anastrozole in postmenopausal women with HR+ early-stage breast cancer. Curr Med Res Opin. 2010 Oct;26(10):2315-28. doi: 10.1185/03007995.2010.510784. — View Citation

Mauriac L, Keshaviah A, Debled M, Mouridsen H, Forbes JF, Thürlimann B, Paridaens R, Monnier A, Láng I, Wardley A, Nogaret JM, Gelber RD, Castiglione-Gertsch M, Price KN, Coates AS, Smith I, Viale G, Rabaglio M, Zabaznyi N, Goldhirsch A; BIG 1-98 Collabor — View Citation

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. — View Citation

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 ear — View Citation

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. [Abstr

Phillips KA, Aldridge J, Ribi K, Sun Z, Thompson A, Harvey V, Thürlimann B, Cardoso F, Pagani O, Coates AS, Goldhirsch A, Price KN, Gelber RD, Bernhard J. Cognitive function in postmenopausal breast cancer patients one year after completing adjuvant endoc — View Citation

Phillips KA, Ribi K, Sun Z, Stephens A, Thompson A, Harvey V, Thürlimann B, Cardoso F, Pagani O, Coates AS, Goldhirsch A, Price KN, Gelber RD, Bernhard J. Cognitive function in postmenopausal women receiving adjuvant letrozole or tamoxifen for breast canc — View Citation

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; BIG 1-98 Collaborative and International — View Citation

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 — View Citation

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 canc

Regan MM, Colleoni M M, Giobbie-Hurder A, et al.: Adjusting for selective crossover in analyses of letrozole (Let) versus tamoxifen (Tam) in the BIG 1-98 trial. [Abstract] 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio,

Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG 1-98 Collaborative Group; International Breast Cancer Study Group (IBCSG). Asse — View Citation

Regan MM, Price KN, Giobbie-Hurder A, Thürlimann B, Gelber RD; International Breast Cancer Study Group and BIG 1-98 Collaborative Group. Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole an — View Citation

Ribi K, Aldridge J, Phillips K, et al.: Changes in cognitive function in postmenopausal women 1 year after completing adjuvant letrozole or tamoxifen in the Breast International Group (BIG) 1-98 trial. [Abstract] J Clin Oncol 28 (Suppl 15): A-527, 2010.

Ribi KE, Phillips KA, Sun Z, et al.: Cognitive function in postmenopausal women receiving adjuvant letrozole or tamoxifen in the Breast International Group (BIG) 1-98 trial. [Abstract] J Clin Oncol 27 (Suppl 15): A-510, 2009.

Scott LJ, Keam SJ. Letrozole : in postmenopausal hormone-responsive early-stage breast cancer. Drugs. 2006;66(3):353-62. Review. — View Citation

Skedgel C, Rayson D, Younis T, et al.: Direct and indirect economic evaluation of upfront and sequential adjuvant treatment in postmenopausal women with breast cancer based on the BIG 1-98 trial. [Abstract] J Clin Oncol 27 (Suppl 15): A-6594, 2009.

Sun Z, Goldhirsch A, Price KN, Colleoni M, Ravaioli A, Simoncini E, Campbell I, Gelber RD, Towler M. Bone Quality Test (BQT) scores of fingernails in postmenopausal patients treated with adjuvant letrozole or tamoxifen for early breast cancer. Breast. 200 — View Citation

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; B — View Citation

Viale G, Regan MM, Dell'Orto P, et al.: Central review of ER, PgR and HER2 in BIG 1-98 evaluating letrozole vs. letrozole followed by tamoxifen vs. tamoxifen followed by letrozole as adjuvant endocrine therapy for postmenopausal women with hormone recepto

Viale G, Regan MM, Dell'Orto P, Mastropasqua MG, Maiorano E, Rasmussen BB, MacGrogan G, Forbes JF, Paridaens RJ, Colleoni M, Láng I, Thürlimann B, Mouridsen H, Mauriac L, Gelber RD, Price KN, Goldhirsch A, Gusterson BA, Coates AS; BIG 1-98 Collaborative a — View Citation

Viale G, Regan MM, Maiorano E, Mastropasqua MG, Dell'Orto P, Rasmussen BB, Raffoul J, Neven P, Orosz Z, Braye S, Ohlschlegel C, Thürlimann B, Gelber RD, Castiglione-Gertsch M, Price KN, Goldhirsch A, Gusterson BA, Coates AS. Prognostic and predictive valu — View Citation

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. — View Citation

Wardley AM. Understanding the BIG results: Insights from the BIG 1-98 trial analyses. Adv Ther. 2008 Dec;25(12):1257-75. doi: 10.1007/s12325-008-0128-5. Review. — View Citation

Zaman K, Thürlimann B, Huober J, et al.: Modelling bone mineral density in Swiss breast cancer patients treated with letrozole, tamoxifen and sequences of letrozole and tamoxifen in the BIG 1-98 study (SAKK 21/07). [Abstract] 32nd Annual San Antonio Breas

Zaman K, Thürlimann B, Huober J, Schönenberger A, Pagani O, Lüthi J, Simcock M, Giobbie-Hurder A, Berthod G, Genton C, Brauchli P, Aebi S; Swiss Group for Clinical Cancer Research (SAKK). Bone mineral density in breast cancer patients treated with adjuvan — View Citation

* Note: There are 44 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease free survival.	Time from randomization to recurrence (including recurrence restricted to the breast after breast conserving treatment), metastasis, appearance of a second primary tumor, or death from any cause, whichever occurs first, assessed up to end of year 2015, for a maximum of 17 years	Up to end of year 2015
Secondary	Overall survival	Time from randomization to death from any cause, assessed up to end of year 2015, for a maximum of 17 years	Up to end of year 2015
Secondary	Safety	Morbidity information will be recorded using the Adverse Event Form (AE).	5 years after randomization.
Secondary	Systemic relapse	Time from randomization to appearance of any recurrent or metastatic disease in sites other than the local mastectomy scar, the ipsilateral breast in case of breast conservation, or the contralateral breast, assessed up to end of year 2015, for a maximum of 17 years	Up to end of year 2015