Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial

• Published in: JNCI : Journal of the National Cancer Institute Vol. 110; no. 6; pp. 616 - 627
• Main Authors: Roseweir, Antonia K, Bennett, Lindsay, Dickson, Ashley, Cheng, Kelvin, Quintayo, Mary-Anne, Bayani, Jane, McMillan, Donald C, Horgan, Paul G, van de Velde, Cornelis J H, Seynaeve, Caroline, Hasenburg, Annette, Kieback, Dirk G, Markopoulos, Christos, Dirix, Luc Y, Rea, Daniel W, Mallon, Elizabeth A, Bartlett, John M S, Edwards, Joanne
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.06.2018
• DOI: 10.1093/jnci/djx255
• ISSN: 0027-8874

Abstract 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 = 4631) from the TEAM trial (n = 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] = 0.71, 95% confidence interval [CI] = 0.59 to 0.85, P < .001), IKKα (HR = 0.74, 95% CI = 0.60 to 0.92, P = .005), Raf-1338 (HR = 0.64, 95% CI = 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR = 0.77, 95% CI = 0.64 to 0.92, P = .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKα, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR = 0.64, 95% CI = 0.52 to 0.77, P < .001). Patients with an all negative IKKα, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio = 0.56, 95% CI = 0.35 to 0.90). In multivariable analysis, the IKKα, Raf-1338, and ER167 score (P = .001) was an independent prognostic factor for RFS at 10 years in patients receiving sequential therapy. Conclusions The IKKα, 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.