A new gene expression signature, the ClinicoMolecular Triad Classification, may improve prediction and prognostication of breast cancer at the time of diagnosis
Menée sur 149 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein et à l'aide de données portant sur 248 cas de cancer du sein, cette étude évalue l'intérêt d'une nouvelle signature génétique pour la classification clinique du cancer au moment du diagnostic
INTRODUCTION:When making treatment decisions, oncologists often stratify breast cancers (BCs) into a low-risk group (ER+, low grade); an intermediate-risk group (ER+, high grade); and a high-risk group that includes Her2+ and triple-negative (TN, ER-/PR-/Her2-) tumors. None of the currently available gene signatures correlates to this clinical classification. We aimed to develop a test that is practical for the oncologists, that offers both molecular characterization of BCs, and improved prediction of prognosis and treatment response.METHODS:We investigated the molecular basis of such clinical practice by grouping Her2+ and TN BCs together during clustering analyses on the genome-wide gene expression profiles of our training cohort, mostly derived from fine needle aspiration biopsies (FNABs) of 149 consecutive evaluable BCs. The analyses consistently divided these tumors into a three-cluster pattern, similar to clinical risk-stratification groups, that was reproducible in published microarray databases (n = 2487) annotated with clinical outcomes. The clinicopathologic parameters of each of these three molecular groups were also similar to clinical classification.RESULTS:The low-risk group had good outcomes and benefited from endocrine therapy. Both intermediate- and high-risk groups had poor outcomes and were resistant to endocrine therapy. The latter demonstrated the highest rate of complete pathological response to neoadjuvant chemotherapy; the highest activities in MYC, E2F1, Ras, beta-Catenin and IFN-gamma pathways; and poor prognosis predicted by 14 independent prognostic signatures. Based on a multivariate analysis, this new gene signature, termed ClinicoMolecular Triad Classification (CMTC), predicted recurrence and treatment response better than all pathologic parameters and other prognostic signatures.CONCLUSIONS:CMTC correlates well with current clinical classification of BCs and has the potential to be easily integrated into routine clinical practice readily. Using FNABs, CMTC can be determined at the time of diagnostic needle biopsies for tumors of all sizes. Using the public databases as the validation cohort in our analyses, CMTC appeared to be able to provide treatment guidance more accurately, could be available in preoperative settings and applicable to all BC types independent of size, receptor and nodal status. The unique oncogenic signaling pathway pattern of each CMTC group may provide guidance to new treatment strategies. Further validation of CMTC will required prospective randomized controlled trials.
Breast Cancer Research , article en libre accès, 2010