Predictive biomarkers for endocrine therapy: Retrospective study in tamoxifen and exemestane adjuvant multinational (TEAM) trial

Background: Aromatase inhibitors improve disease-free survival compared with tamoxifen in postmenopausal women with hormone receptor-positive breast cancer. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial compared exemestane monotherapy with sequential therapy of tamoxifen followed by exemestane. The trial failed to show a statistically significant difference between treatment arms. A robust translational program was established to investigate predictive biomarkers. Methods: A tissue microarray was retrospectively constructed using a subset of patient tissues (n ¼ 4631) from the TEAM trial (n ¼ 9766). Immunohistochemistry was performed for biomarkers, classed into three groups: MAPK pathway, NF-kappa B pathway, and estrogen receptor (ER) phosphorylation. Expression was analyzed for association with relapse-free survival (RFS) at 2.5 and 10 years and treatment regimen using Kaplan-Meier curves and log-rank analysis. All statistical tests were two-sided. Results: In univariate analysis, ER167 (hazard ratio [HR] ¼ 0.71, 95% confidence interval [CI] ¼ 0.59 to 0.85, P < .001), IKKa (HR ¼ 0.74, 95% CI ¼ 0.60 to 0.92, P ¼ .005), Raf-1338 (HR ¼ 0.64, 95% CI ¼ 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR ¼ 0.77, 95% CI ¼ 0.64 to 0.92, P ¼ .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKa, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR ¼ 0.64, 95% CI ¼ 0.52 to 0.77, P < .001). Patients with an all negative IKKa, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio ¼ 0.56, 95% CI ¼ 0.35 to 0.90). In multivariable analysis, the IKKa, Raf-1338, and ER167 score (P ¼ .001) was an independent prognostic factor for RFS at 10 years in patients receiving sequential therapy. Conclusions: The IKKa, Raf-1338, and ER167 score is an independent predictive biomarker for lower recurrence on sequential therapy. Negative expression may further offer predictive value for exemestane monotherapy.