TY - JOUR
TI - Predictive Biomarkers for Endocrine Therapy: Retrospective Study in
Tamoxifen and Exemestane Adjuvant Multinational (TEAM) Trial
AU - Roseweir, Antonia K.
AU - Bennett, Lindsay
AU - Dickson, Ashley
AU - Cheng,
AU - Kelvin
AU - Quintayo, Mary-Anne
AU - Bayani, Jane
AU - McMillan, Donald C.
AU - and Horgan, Paul G.
AU - van de Velde, Cornelis J. H.
AU - Seynaeve,
AU - Caroline
AU - Hasenburg, Annette
AU - Kieback, Dirk G.
AU - Markopoulos,
AU - Christos
AU - Dirix, Luc Y.
AU - Rea, Daniel W.
AU - Mallon, Elizabeth A.
AU - and Bartlett, John M. S.
AU - Edwards, Joanne
JO - JNCI Journal of the National Cancer Institute
PY - 2018
VL - 110
TODO - 6
SP - 616-627
PB - OXFORD UNIV PRESS INC
SN - 0027-8874, 1460-2105
TODO - 10.1093/jnci/djx255
TODO - null
TODO - 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 alpha (HR =
0.74, 95% CI = 0.60 to 0.92, P .005), Raf-1(338) (HR 0.64, 95% CI =
0.52 to 0.80, P < .001), and p44/42 MAPK(202/204) (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 alpha, Raf-1(338), 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 alpha,
Raf-1(338), and ER167 score favored exemestane monotherapy (odds ratio =
0.56, 95% CI = 0.35 to 0.90). In multivariable analysis, the IKK alpha,
Raf-1(338), and ER167 score (P = .001) was an independent prognostic
factor for RFS at 10 years in patients receiving sequential therapy.
Conclusions: The IKK alpha, Raf-1(338), and ER167 score is an
independent predictive biomarker for lower recurrence on sequential
therapy. Negative expression may further offer predictive value for
exemestane monotherapy.
ER -