Abstract P2-09-05: 12 years' median follow up (MFU) of BIG 1-98: Adjuvant letrozole, tamoxifen and their sequence for postmenopausal women with endocrine responsive early breast cancer
Authors: Thürlimann B , Giobbie-Hurder A , Colleoni M , Jensen M-B , Ejlertsen B , de Azambuja E , Neven P , Láng I , Gladieff L , Bonnefoi H , Harvey VJ , Spazzapan S , Tondini C , Price K , Piccart-Gebhart M , Regan MM , Gelber RD , Coates AS , Goldhirsch A 
Published: March 2017

Abstract
Background
The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial that compared five yrs of adjuvant treatment with letrozole, tamoxifen, or their sequence in postmenopausal women with hormone-receptor–positive early breast cancer. The study is conducted by the International Breast Cancer Study Group (IBCSG) on behalf of BIG. 8010 patients (pts) were enrolled between March 1998 and May 2003, and first results demonstrating a significant DFS benefit favoring letrozole compared with tamoxifen were reported in 2005 at 25.8 months' MFU. Subsequent updates showed continuing DFS benefit and updated results published in 2011 at 8.1 yrs' MFU showed OS benefit. Industry-sponsorship of the original BIG 1-98 ended in 2010; IBCSG launched an observational, non-interventional long-term follow-up study (BIG 1-98 LTFU) to collect survival, disease status and adverse events for an additional 5 yrs. We report results from BIG 1-98 LTFU at 12 yrs' MFU.
Methods
The original trial includes the 8010 patients enrolled. The potential BIG 1-98 LTFU cohort consisted of 148 academic medical centers with a maximum of 6843 pts who were alive and continuing follow-up when the original study ended. Response bias was addressed using weighting class adjustments estimated using multivariable logistic regression. Unadjusted incidence rates are reported here per 1000 pt-yrs with 95% Poisson confidence intervals. An updated abstract will include adjusted incidence rates, as well as estimates of OS and DFS based on a weighted Kaplan-Meier approach. The database will close in July 2016.
Results
As of May 2016, 81 centers participated in the BIG 1-98 LTFU study, contributing data from approximately 3900 pts (57%) and extending MFU to 12 yrs. Compared with the potential cohort of 6843 pts, the ~3900 in the LTFU analytic cohort were more likely to be under age 65 yrs at enrollment, have node-positive disease, and have tumors that were &lt; 2 cm, PgR positive (≥1%), and with no evidence of peritumoral vascular invasion. Extended adjuvant endocrine therapy for primary BC was continued in 2% of pts. Unadjusted incidence estimates of myocardial infarction increased during LTFU, while incidence of thromboembolic events and osteoporosis decreased (Table). Variations in incidence rates were noted depending on recording mechanism (e.g. registry, clinic visit, telephone, information from family).
Unadjusted Incidence Rate/1000 pt-yrs (95% CI)Adverse EventDuring original studyDuring LTFUMyocardial Infarction1.7 (1.4-2.0)3.5 (2.7-4.5)Thromboembolic event6.0 (5.4-6.6)2.5 (1.8-3.3)Osteoporosis23.6 (22.5-24.9)18.2 (16.3-20.3)Bone fractures17.2 (16.2-18.3)15.0 (13.2-16.9)
Overall 1845 deaths were reported; the unadjusted incidence of death was lower in the original study compared with during LTFU (21.9 vs. 26.6/1000 pt-yrs); incidence remained relatively stable for pts assigned to tamoxifen (24.9 vs. 25.2/1000 pt-yrs), and increased for pts assigned to letrozole (22.0 vs. 27.1/1000 pt-yrs).
Conclusions
The BIG 1-98 LTFU study has been successfully conducted. The additional data from the BIG 1-98 LTFU study provides important long-term clinical information about OS, DFS and adverse events.
Citation Format: Thürlimann B, Giobbie-Hurder A, Colleoni M, Jensen M-B, Ejlertsen B, de Azambuja E, Neven P, Láng I, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Price K, Piccart-Gebhart M, Regan MM, Gelber RD, Coates AS, Goldhirsch A. 12 years' median follow up (MFU) of BIG 1-98: Adjuvant letrozole, tamoxifen and their sequence for postmenopausal women with endocrine responsive early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-05.