Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade.
OBJECTIVE
A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed.


METHODS
We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high-or low-genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome.


RESULTS
Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations.


CONCLUSIONS
The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC.
Loi
Sherene
S
Jules Bordet Institute; Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium.
Haibe-Kains
Benjamin
B
Desmedt
Christine
C
Lallemand
Françoise
F
Tutt
Andrew M
AM
Gillet
Cheryl
C
Ellis
Paul
P
Harris
Adrian
A
Bergh
Jonas
J
Foekens
John A
JA
Klijn
Jan G M
JG
Larsimont
Denis
D
Buyse
Marc
M
Bontempi
Gianluca
G
Delorenzi
Mauro
M
Piccart
Martine J
MJ
Sotiriou
Christos
C
D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015999:Multivariate Analysis; D011379:Prognosis; D011960:Receptors, Estrogen / Q000032:analysis*; D013629:Tamoxifen / Q000627:therapeutic use
D011960:Receptors, Estrogen; D013629:Tamoxifen