Biological mechanisms that trigger breast cancer (BC) tumor progression are molecular subtype dependent.
Sotiriou C,
Desmedt C, Haibe-Kains B, Harris A, Larsimont D, Buyse M, Wirapati P, Delorenzi M, Bontempi G, Piccart
MJ
Background:
We have recently developed several gene expression indices related to
hallmarks of breast cancer involving various biological processes such
as tumor invasion, impairment of immune response, sustained
angiogenesis, evasion of apoptosis and self-sufficiency in growth
signal, and investigated their impact on clinical outcome. Here, we aim
to refine our biological understanding and the prognostic impact of
these indices according to the previously described molecular subtypes based on the estrogen (ER) and ERBB2 receptors.
Methods: Each of these indices
were developed in a series of 581 BC samples and then computed on
several publicly available microarray studies totaling over 2100 BC
patients. Multivariate analyses were used to study the dependency
patterns between these indices, the molecular subtypes and their impact
on survival.
Results: ER- /ERBB2- and ERBB2+
subgroups were significantly associated with high expression levels of
the proliferation, tumor invasion, angiogenesis and immune response
indices. Multivariate analysis showed that in the ER+/ERBB2- subgroup,
only tumor size and the proliferation and tumor invasion indices were
significantly associated with clinical outcome, with the proliferation
index having the largest HR and most significant p-value (HR 3.25; CI
2.31-4.56; p=1.2 10-11). In contrast, in the ER-/ERBB2- subgroup, only
tumor size (HR 2.08; CI 1.14-3.81; p=0.01) and immune response index
(HR 0.66; CI 0.46-0.95; p=0.02) were associated with prognosis whereas
in the ERBB2+ tumors only nodal status (HR 3.40; CI 0.96-12.10; p=0.05)
and tumor invasion index (HR 3.03; CI 1.32-6.95; p=0.009) showed
significant association with survival. Of interest, proliferation index
lost its significance as almost all ER-/ERBB2- and ERBB2 + tumors
showed high proliferation levels.
Conclusions: Although
proliferation seems to be the strongest parameter predicting clinical
outcome in ER+/ERBB2- subtype, immune response and tumor invasion
appear to be the main molecular mechanisms associated with prognosis in
the ER-/ERBB2- and ERBB2+ subgroups respectively. Defining these
clinico-genomic models in the specific molecular subgroups will be the
key to success for personalized medicine.