Background : The BIG 1-98 trial, a large international Phase III study, evaluated letrozole (Let) for 5 years (n=1546) vs. Let for 2 years followed by tamoxifen (Tam) for 3 years (L→T; n=1540) and vs. Tam for 2 years followed by Let for 3 years (T→L; n=1548) as initial adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. Patients with HER2-positive disease did not receive trastuzumab. Efficacy results were presented in SABCS 2008 and showed that neither of the sequential therapy arms significantly improved disease-free survival (DFS) compared with letrozole alone. Centrally-assessed ER, PgR and HER2 have now been evaluated as potential predictive factors for treatment selection. Methods : Tumor blocks for 3975 of the 4634 (86%) patients on these three treatment arms were centrally collected and assessed by the IBCSG Central Pathology Laboratory. The tumors were evaluated for ER and PgR content by immunohistochemistry (IHC), and for HER2 immunoreactivity by IHC and by FISH for IHC 1+ or 2+ tumors. DFS according to centrally-assessed ER, PgR and HER2 status was analyzed using multivariable Cox modeling. STEPP methodology was used to explore patterns of DFS differences according to quantitative values of receptor levels (% staining cells). Results: Upon central review, 3885 tumors were confirmed to express ER and are the focus of this analysis. PgR expression did not predict differential treatment effects among the 3 treatment arms. With only 240 (6.2%) HER2-positive tumors, there was a suggestion of differential treatment benefit relative to HER2 status, in particular of a benefit of Let for 5 yrs over Tam→Let in HER2-positive tumors. Discussion : Given the caveat of a low prevalence of HER2-positive tumors and absence of HER2-directed therapy in the BIG 1-98 trial population, there is a suggestion that Let for 5 years may be a better option than a sequence of Tam and Let among women with HER2-positive tumors. Thus it may be better to initiate and continue treatment of endocrine-responsive, HER2+ tumors with Let rather than a sequence of Tam and Let. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 76.