Better
characterization of estrogen receptor (ER) positive luminal subtypes
using genomic grade.
Sotiriou C,
Wirapati P, Loi S, Desmedt C, Durbecq V, Harris A, Bergh J, Smeds J,
Haibe-Kains B, Larsimont D, Cardoso F, Buyse M, Delorenzi M, Piccart
M
Background: Several
microarray studies have shown that breast tumours can be grouped in at
least 4 to 5 individual subtypes namely basal-like, erbB2-like and
luminal-like A, B, C or 1, 2, 3.However, although the basal and the
erbB2 subtypes are repeatedly recognized as distinct entities, the
definition of luminal subtypes has been far from consistent between
published series. Refinement of their molecular definition is therefore
needed. In this study we sought to better characterize luminal subtypes
by applying gene expression grade index (GGI) as previously defined by
our group (Sotiriou et al. Proc Am Soc Clin Oncol, 2005), and to
correlate them with clinical outcome.
Material and Methods:
GGI was defined based on the 128 most significant genes identified by
gene expression profiling (GEP) in our training set of 64 ER-positive
histological grade (HG) 1 or 3 breast tumours. ER-positive tumours were
then classified as genomic grade (GG) 1 (GG1, low grade) or GG3 (high
grade) based on their GGI values in our unpublished dataset including a
series of 154 untreated and 175 tamoxifen-treated breast cancer
patients. We also used as external validation sets several previously
published datasets from Sorlie et al. 2001, van de Vijver, M. J. et al.
2002, Sotiriou et al. 2003, and Wang et al. 2005.
Results:
Almost all ER-positive tumours previously defined as luminal-like A or
1 subtype, which had the best clinical outcome, showed low GGI values
(low grade). In contrast, luminal B/C or 2/3 ER-positive tumours showed
high GGI values (high grade) similar to those of basal-like and
erbB2-like subtypes which are predominantly ER-negative. In other
words, GGI divided ER-positive tumours into two distinct subgroups
namely GG1 and GG3 having statistically distinct clinical outcome in
either untreated (HR: 3.93, 95% CI 2.28-6.76, p<0.0001) or
tamoxifen-treated (HR: 3.1, 95% CI 1.64-5.52, p=0.0002) populations.
Consistent results were found in each external validation dataset that
we have analysed despite differences in clinical populations and
microarray platforms.
Conclusion:
GG better identifies luminal subtypes in a highly reproducible manner
and the GG-defined subtypes show a statistically distinct clinical
outcome. We believe that a better characterization of the ER-positive
luminal subtypes has the potential to improve tailoring of breast
cancer management.