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

: 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.