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

Research output: Contribution to journalArticle


  • Antonia K Roseweir
  • Lindsay Bennett
  • Ashley Dickson
  • Kelvin Cheng
  • Mary-Anne Quintayo
  • Jane Bayani
  • Donald C McMillan
  • Paul G Horgan
  • Cornelis J H van de Velde
  • Caroline Seynaeve
  • Annette Hasenburg
  • Dirk G Kieback
  • Christos Markopoulos
  • Luc Y Dirix
  • Elizabeth A Mallon
  • John M S Bartlett
  • Joanne Edwards

Colleges, School and Institutes

External organisations

  • 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.


Original languageEnglish
Pages (from-to)616-627
Number of pages12
JournalJournal of the National Cancer Institute
Issue number6
Publication statusPublished - 1 Jun 2018