Definition of clinically
distinct molecular subtypes in estrogen receptor positive breast
carcinomas through use of genomic grade.
Loi S, Haibe-Kains B, Desmedt C,
Lallemand F, Tutt AM, Gillet C, Harris A, Bergh J, Foekens JA, Klijn J,
Larsimont D, Buyse M Bontempi G, Delorenszi M, Piccart MJ, Sotiriou C
Background
: A number of microarray studies
have reported distinct molecular profiles of breast cancers (BC):
“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. Refinement of their molecular definition is therefore
needed.
Materials and methods: We have
previously reported a “gene-expression grade index” (GGI) which defines
histological 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 to 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 biological 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 datasets. This study emphasizes the important role of
proliferation-related genes in predicting prognosis in ER-positive
BC.