Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes
Desmedt
C, Haibe-Kains B, Wirapati P, Buyse M, Larsimont
D, Bontempi G, Delorenzi M, Piccart M and Sotiriou C
Purpose: Recently
prognostic gene expression signatures have been identified; however,
their performance has never been evaluated according to the previously
described molecular subtypes based on the estrogen (ER) and HER2
receptors and their biological meaning has remained unclear. Here we
aimed to perform a comprehensive meta-analysis integrating both
clinico-pathological and gene expression data, focusing on the main
molecular subtypes.
Experimental Design: We developed gene expression modules
related to key biological processes in breast cancer such as tumor
invasion, immune response, angiogenesis, apoptosis, proliferation, ER
and HER2 signaling, and then analyzed these modules together with
clinical variables and several prognostic signatures on publicly
available microarray studies (> 2100 patients).
Results: Multivariate analysis showed that in the ER+/HER2-
subgroup, only the proliferation module and the histological grade were
significantly associated with clinical outcome. In the ER-/HER2-
subgroup, only the immune response module was associated with
prognosis, whereas in the HER2+ tumors, the tumor invasion and immune
response modules displayed significant association with survival.
Proliferation was identified as the most important component of several
prognostic signatures, and their performance was limited to the
ER+/HER2- subgroup.
Conclusions: Although proliferation is the strongest parameter
predicting clinical outcome in the ER+/HER2- subtype, and the common
denominator of most prognostic gene signatures, immune response and
tumor invasion appear to be the main molecular processes associated
with prognosis in the ER-/HER2- and HER2+ subgroups respectively. These
findings may help to define new clinico-genomic models and to identify
new therapeutic strategies in the specific molecular subgroups.