Predictive Biomarkers for Endocrine Therapy: Retrospective Study in Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial
Research output: Contribution to journal › Article
Colleges, School and Institutes
- University of Glasgow
- Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON, Canada.
- Leiden University Medical Centre, Dept. Neurosurgery, Leiden, The Netherlands.
- Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
- University Hospital Mainz, Mainz, Germany.
- Helios Medical Centre, Schleswig, Germany.
- Athens University Medical School, Athens, Greece.
- St. Augustinus Hospital, Antwerp, Belgium.
- Department of Pathology, Queen Elizabeth University Hospital, Glasgow, UK.
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.
|Number of pages||12|
|Journal||Journal of the National Cancer Institute|
|Publication status||Published - 1 Jun 2018|