integrating both clinicopathological and gene expression data in more
than 1500 samples: Proliferation captured by gene expression grade
index appears to be the strongest prognostic factor in breast cancer
Wirapati P, Loi S, Haibe-Kains B, Desmedt C, Tutt A., Ellis P., Buyse M, Delorenzi M, Piccart
Although, the development of high-throughput gene expression
technologies has allowed the identification of several molecular
signatures predicting clinical outcome, no attempt has been made yet to
perform a comprehensive analysis integrating both clinicopathological,
and gene expression data. Here, we aim to elucidate the relationship
between clinical parameters and tumor markers, with gene expression
patterns and their interaction with prognosis.
Methods: We analyzed gene
expression and clinical data from several published studies, including
more than 1500 BC patients. We developed several gene expression
indices associated with different biological stages of disease
characterized by the expression of hormone receptors, HER2
amplification, p53 mutation, angiogenesis, tumor invasion and
proliferation. Multivariable analyses were used to characterize the
dependency patterns between these indices and their impact on survival.
Results: Estrogen receptor (ER)
and HER2 indices were the most prominent discriminators dichotomizing
tumor samples into two main subsets in agreement with the previously
proposed BC subtypes. Tumor proliferation, assessed by our previously
reported gene expression index (GGI), was the most strongly associated
with prognosis (HR 2.29, CI 1.88-2.78, p<0.0001). Almost all ER- and
HER2+ tumors were associated with high GGI scores. In contrast, ER+ and
HER2- tumors showed a whole range of GGI values. Within the high
proliferation subset, ER- and HER2+ indices did not have any prognostic
value. Similar results were found with relation to p53 mutation index.
Nodal status and tumor size, which essentially measure the duration of
disease, retained prognostic value in addition to proliferation.
captured by the GGI appears to be a key biological factor, downstream
of ER, HER2 and p53. Although understanding the upstream factors is
important for advancing biological knowledge and therapeutic
interventions, GGI seems to be the most important factor predicting
clinical outcome in BC and deserves consideration as stratification
factor in clinical trials.