Abstract
IntroductionUsing genome-wide expression profiles of a prospective training cohort of breast cancer patients, ClinicoMolecular Triad Classification (CMTC) was recently developed to classify breast cancers into three clinically relevant groups to aid treatment decisions. CMTC was found to be both prognostic and predictive in a large external breast cancer cohort in that study. This study serves to validate the reproducibility of CMTC and its prognostic value using independent patient cohorts.MethodsAn independent internal cohort (n = 284) and a new external cohort (n = 2,181) were used to validate the association of CMTC between clinicopathological factors, 12 known gene signatures, two molecular subtype classifiers, and 19 oncogenic signalling pathway activities, and to reproduce the abilities of CMTC to predict clinical outcomes of breast cancer. In addition, we also updated the outcome data of the original training cohort (n = 147).ResultsThe original training cohort reached a statistically significant difference (p < 0.05) in disease-free survivals between the three CMTC groups after an additional two years of follow-up (median = 55 months). The prognostic value of the triad classification was reproduced in the second independent internal cohort and the new external validation cohort. CMTC achieved even higher prognostic significance when all available patients were analyzed (n = 4,851). Oncogenic pathways Myc, E2F1, Ras and β-catenin were again implicated in the high-risk groups.ConclusionsBoth prospective internal cohorts and the independent external cohorts reproduced the triad classification of CMTC and its prognostic significance. CMTC is an independent prognostic predictor, and it outperformed 12 other known prognostic gene signatures, molecular subtype classifications, and all other standard prognostic clinicopathological factors. Our results support further development of CMTC portfolio into a guide for personalized breast cancer treatments.
Highlights
Using genome-wide expression profiles of a prospective training cohort of breast cancer patients, ClinicoMolecular Triad Classification (CMTC) was recently developed to classify breast cancers into three clinically relevant groups to aid treatment decisions
We recently reported a clinical triad classification system using a genomic approach based on the common gene expression pattern of human epidermal growth factor receptor 2 (HER2) positive and triple negative (HER2+/TN) breast cancers
CMTC had the highest hazard ratio (HR) in the original external validation cohort among the 12 known gene signatures as prognostic indicators for breast cancer relapse [4]. These results demonstrated the reproducibility of CMTC as one of the best independent prognostic predictors when compared to these 12 other known prognostic gene signatures
Summary
Using genome-wide expression profiles of a prospective training cohort of breast cancer patients, ClinicoMolecular Triad Classification (CMTC) was recently developed to classify breast cancers into three clinically relevant groups to aid treatment decisions. Since the first gene expression profile describing the molecular subtypes of breast cancers [1], numerous gene signatures have been developed mainly by answering specific clinical or biological questions, often by dichotomizing the targeted sub-populations into a good and a bad risk group. Many of these gene signatures have claimed the association of many important clinicopathological variables. As part of the development of CMTC into a clinical tool to guide personalized prognostication and treatment decisions for breast cancer patients, we aimed to validate CMTC using an updated training cohort with a longer follow-up, a second larger and independent prospective cohort and a new external validation cohort to demonstrate that CMTC is reproducible, independent and clinically relevant
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