The BIG 1-98 study aimed to compare the effectiveness of letrozole with that of tamoxifen in treating postmenopausal women who have breast cancer that has been surgically removed.

Oestrogen can stimulate the growth of breast cancer cells. For postmenopausal women with hormone receptor-positive (HR+) breast cancer, giving tamoxifen as hormonal therapy after surgery (adjuvant) significantly prolongs disease-free and overall survival. Tamoxifen fights breast cancer by blocking the uptake of oestrogen by the tumour cells. Five years of treatment with tamoxifen reduces the risk of breast cancer recurrence by 47% and the risk of death by 26% among these patients. Despite these benefits, about half the women so treated still relapse. Also, tamoxifen treatment is associated with rare but serious side effects, including endometrial cancer and thromboembolism.

The aromatase inhibitor letrozole fights breast cancer by reducing the production of oestrogen. Previous studies have shown that letrozole is an effective treatment for metastatic breast cancer and is also more effective than tamoxifen when given before surgery (neoadjuvant therapy).

The objectives of BIG 1-98 were 1) to compare the efficacy of letrozole with that of tamoxifen administered as monotherapy during the first 5 years following breast cancer surgery (adjuvant therapy); and 2) to compare these treatment regimens given sequentially, with the final aim to determine the most effective approach to minimise the side effects and the risk of cancer recurrence.  

These different treatment regimens were compared in terms of overall survival, disease-free and systemic-free survival, safety, and tolerability.

Results of the study indicated that adjuvant treatment with letrozole, as compared with tamoxifen, significantly reduced the risk of recurrent disease, especially at distant sites; it proved to be an effective option for standard adjuvant therapy, with a relatively favorable safety profile in postmenopausal women with hormone receptor-positive breast cancer.

Together with the BIG 1-97/MA.17 and BIG 2-97/IES studies, BIG 1-98 contributed to the body of evidence that aromatase inhibitors could be used as a safe alternative to tamoxifen, a drug used to treat oestrogen receptor-positive (ER+) breast cancer that is associated with dangerous side effects for some women.

Patients were assigned to four different treatment groups, each receiving a different endocrine therapy after surgery: either 5 years of monotherapy with tamoxifen (group 1) or with letrozole (group 2), or sequences of 2 years of one followed by 3 years of the other (groups 3 and 4). The enhanced design of the trial enabled two complementary analyses of efficacy and safety.

Collection of tumour specimens further enabled treatment comparisons based on tumour biology.

Postmenopausal women with operable, hormone receptor-positive breast cancer.

A total of 8,010 women with data that could be assessed were enrolled in this study.

This study was coordinated and sponsored by the International Breast Cancer Study Group (IBCSG) and was conducted under the Breast International Group (BIG) umbrella. Eight BIG groups, several independent groups, and a total of 245 hospitals participated.

Between March 1998 and May 2003, 8,028 patients were recruited in this trial. 18 withdrew consent and did not start treatment, leaving 8,010 patients.

The main results were published in 2005 in the New England Journal of Medicine.

Many reports and analyses related to the BIG 1-98 study have been published. Listed below are the publications of the main results and study follow-up.

• 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 2005; 353:2747-2757. doi: 10.1056/NEJMoa052258
• 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. 2007 Feb 10;25(5):486-92. doi: 10.1200/JCO.2006.08.8617. Epub 2007 Jan 2
• BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A, Goldhirsch A et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med Volume 361:766-776 August 20, 2009 Number 8
• Giobbie-Hurder A, Price KN, Gelber RD et al. 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
• Regan MM, Neven P, Giobbie-Hurder A et al. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8•1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. doi: 10.1016/S1470-2045(11)70270-4. Epub 2011 Oct 20
• Ruhstaller T, Giobbie-Hurder A, Colleoni M et al. Adjuvant letrozole and tamoxifen alone or sequentially for postmenopausal women with hormone receptor–positive breast cancer: long-term follow-up of the BIG 1-98 trial. J Clin Oncol. doi: 10.1200/JCO.18.0044. 2018 Nov 26

Novartis provided drugs and funding for this study, which was run according to BIG’s Principles or Research Conduct.

NCT00004205