A new gene expression signature, the ClinicoMolecular Triad Classification, may improve prediction and prognostication of breast cancer at the time of diagnosis

Abstract

IntroductionWhen making treatment decisions, oncologists often stratify breast cancer (BC) into a low-risk group (low-grade estrogen receptor-positive (ER+)), an intermediate-risk group (high-grade ER+) and a high-risk group that includes Her2+ and triple-negative (TN) tumors (ER-/PR-/Her2-). None of the currently available gene signatures correlates to this clinical classification. In this study, we aimed to develop a test that is practical for oncologists and offers both molecular characterization of BC and improved prediction of prognosis and treatment response.MethodsWe investigated the molecular basis of such clinical practice by grouping Her2+ and TN BC together during clustering analyses of the genome-wide gene expression profiles of our training cohort, mostly derived from fine-needle aspiration biopsies (FNABs) of 149 consecutive evaluable BC. The analyses consistently divided these tumors into a three-cluster pattern, similarly to clinical risk stratification groups, that was reproducible in published microarray databases (n = 2,487) annotated with clinical outcomes. The clinicopathological parameters of each of these three molecular groups were also similar to clinical classification.ResultsThe low-risk group had good outcomes and benefited from endocrine therapy. Both the intermediate- and high-risk groups had poor outcomes, and their BC was resistant to endocrine therapy. The latter group demonstrated the highest rate of complete pathological response to neoadjuvant chemotherapy; the highest activities in Myc, E2F1, Ras, β-catenin and IFN-γ pathways; and poor prognosis predicted by 14 independent prognostic signatures. On the basis of multivariate analysis, we found that this new gene signature, termed the "ClinicoMolecular Triad Classification" (CMTC), predicted recurrence and treatment response better than all pathological parameters and other prognostic signatures.ConclusionsCMTC correlates well with current clinical classifications of BC and has the potential to be easily integrated into routine clinical practice. Using FNABs, CMTC can be determined at the time of diagnostic needle biopsies for tumors of all sizes. On the basis of using public databases as the validation cohort in our analyses, CMTC appeared to enable accurate treatment guidance, could be made available in preoperative settings and was applicable to all BC types independently of tumor size and receptor and nodal status. The unique oncogenic signaling pathway pattern of each CMTC group may provide guidance in the development of new treatment strategies. Further validation of CMTC requires prospective, randomized, controlled trials.

Validation of the prognostic gene portfolio, ClinicoMolecular Triad Classification, using an independent prospective breast cancer cohort and external patient populations

“…As in our previous study [4], this study showed that CMTC-1 was again correlated with low tumor grade, and CMTC-2 and CMTC-3 were associated with high grade in both the second internal cohort (Figure 2A) and the new external validation cohort (Table 1). Patient’s age, tumor size and lymph node status were not associated with CMTC in the internal validation cohort of the 284 breast cancers, but these variables became statistically significant in the new larger external validation cohort of 2,181 breast cancers: more younger patients were found in CMTC-3 than in CMTC1-1 and CMTC-2; more patients with a larger tumor size or lymph node positive disease were found in CMTC-2 and CMTC-3 than in CMTC-1 (Table 1).…”

“…The ability of CMTC to predict prognosis of breast cancers was strongly supported by the analyses on the first external validation cohort reported previously [4]. This cohort consisted of 2,239 breast cancers collected from 13 breast cancer datasets using Affymetrix and Agilent microarray platforms, and had a median follow-up of 6.33 years.…”

“…Finally, the gene expression profile of the resulting CMTC gene set still matched and outperformed these known independent gene signatures [4]. In this study, the CMTC prognostic framework with 12 microarray-based gene signatures [9-20] was reproduced in the internal validation cohort with 284 breast cancers (Figure 2B).…”

“…In the previous study, the Illumina platform was used in our training cohort, whereas Affymetrix and Agilent platforms were used in the external validation cohort [4]. In this study, the Illumina platform was used in our second internal cohort and the two newly published external breast cancer datasets.…”

Failure Patterns in Resected Pancreas Adenocarcinoma

“…Most patients are treated similarly using an empiric gemcitabine-based approach, despite the fact that pancreatic adenocarcinoma is a heterogeneous disease with significant molecular differences between tumors [3]. In the modern era of molecular profiling, there has been a push to identify molecular signatures that could be used to predict tumor biology, and perhaps tailor treatment [4-8]. …”