Comprehensive molecular
analysis of several prognostic signatures using molecular indices
related to hallmarks of breast cancer: proliferation index appears to
be the most significant component of all signatures
Sotiriou C, Haibe-Kains
B, Desmedt C, Wirapati P, Durbecq V, Harris
A, Larsimont D, Bontempi G, Buyse M, Delorenzi M,
and Piccart M.
Background. Although the
development of high-throughput gene expression technologies has led to
the identification of several “molecular signatures”
predicting clinical outcome, no attempt has yet been made to perform a
comprehensive analysis integrating well characterized biological
processes and gene expression data. Here we aim to elucidate the
relationship of gene expression patterns defined by several
biologically relevant indices with previously reported prognostic
signatures and their interaction with prognosis.
Patients and Methods. We first
selected prototype genes for several biological processes in breast
cancer such as basal/luminal phenotype, ERBB2, proliferation, fully
captured by the gene expression grade index, stroma/invasion,
angiogenesis, apoptosis and immune response (Sotiriou et al ASCO 2006).
We used a multivariate linear regression model to generate significant
gene lists associated with each prototype and applied them to several
previously reported prognostic signatures (70-gene, 76-gene, wound
healing, recurrence score, p53 and intrinsic gene-list). Multivariable
analyses were used to characterize the dependency patterns between
these indices for each prognostic signature and their impact on
survival using several microarray datasets.
Results. All signatures
comprised mainly proliferation and estrogen receptor (ER) index genes
(30%-78% of all genes). In both uni- and multivariate analysis,
proliferation index was the most significant component predicting
clinical outcome, achieving nearly similar performance when compared to
the original signatures in the original patient series (i.e.
70-gene-signature: HR 5.5, 95% CI [3.09-9.97]; proliferation index
(N=20 genes) HR 3.6, 95% CI [2.15-6.0]. Interestingly, its prognostic
value far more pronounced in ER-positive tumours, which was also
observed when we considered all original signatures. Proliferation
index genes performance was equivalent using an external independent
validation series.
Conclusion. This is the first
comprehensive gene expression analysis of many existing prognostic
signatures using molecular indices underlying several hallmarks of
breast cancer. Proliferation seems to be the common denominator of many
existing prognostic gene signatures, recapitulating their prognostic
power. Furthermore, its weight seems to be far more significant in
ER-positive disease.