Περίληψη:
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.
Συγγραφείς:
Roseweir, Antonia K.
Bennett, Lindsay
Dickson, Ashley
Cheng,
Kelvin
Quintayo, Mary-Anne
Bayani, Jane
McMillan, Donald C.
and 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.
and Bartlett, John M. S.
Edwards, Joanne
