Predictive Biomarkers for Endocrine Therapy : Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial
Menée à partir de l'analyse immunohistochimique de tissus tumoraux prélevés sur 4 631 patientes ménopausées atteintes d'un cancer du sein HR+ et incluses dans un essai évaluant l'exémestane en monothérapie ou en combinaison avec le tamoxifène, cette étude évalue l'association entre l'expression de protéines impliquées dans la phosphorylation du récepteur aux estrogènes ou les voies de signalisation de MAPK ou NF-kappa B et la survie sans récidive
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), IKK
α (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 IKK
α, 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 IKK
α, Raf-1338, and ER167 score favored exemestane monotherapy (odds ratio = 0.56, 95% CI
= 0.35 to 0.90). In multivariable analysis, the IKK
α, 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.
Journal of the National Cancer Institute , résumé, 2016