Abstract
Triple Negative Breast Cancers (TNBC) is a heterogeneous disease at the molecular and clinical level with poor outcome. Molecular subclassification of TNBCs is essential for optimal use of current therapies and for development of new drugs. microRNAs (miRNA) are widely recognized as key players in cancer progression and drug resistance; investigation of their involvement in a TNBC cohort may reveal biomarkers for diagnosis and prognosis of TNBC. Here we stratified a large TNBC cohort into Core Basal (CB, EGFR and/or CK5, 6 positive) and five negative (5NP) if all markers are negative. We determined the complete miRNA expression profile and found a subset of miRNAs specifically deregulated in the two subclasses.We identified a 4-miRNA signature given by miR-155, miR-493, miR-30e and miR-27a expression levels, that allowed subdivision of TNBCs not only into CB and 5NP subgroups (sensitivity 0.75 and specificity 0.56; AUC=0.74) but also into high risk and low risk groups. We tested the diagnostic and prognostic performances of both the 5 IHC marker panel and the 4-miRNA expression signatures, which clearly identify worse outcome patients in the treated and untreated subcohorts. Both signatures have diagnostic and prognostic value, predicting outcomes of patient treatment with the two most commonly used chemotherapy regimens in TNBC: anthracycline or anthracycline plus taxanes. Further investigations of the patients’ overall survival treated with these regimens show that regardless of IHC group subdivision, taxanes addition did not benefit patients, possibly due to miRNA driven taxanes resistance. TNBC subclassification based on the 5 IHC markers and on the miR-155, miR-493, miR-30e, miR-27a expression levels are powerful diagnostic tools. Treatment choice and new drug development should consider this new subtyping and miRNA expression signature in planning low toxicity, maximum efficacy therapies.
Highlights
Triple-negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and HER-2 expression, account for 12% to 24% of all breast cancers
Basal-like breast cancer has become commonly known as triple-negative breast cancer (TNBC), lacking estrogen receptor (ER) and progesterone receptor (PR) expression as well as human epidermal growth factor receptor 2 (HER2) amplification; not all TNBCs are identified as basal-like by gene expression, and not all basal-like tumors are Triple Negative (TN) [7]
FISH analysis for the HER2 gene was performed, with no gene amplification observed in all the tested cases.Cases were categorized based on their IHC profiles into two subclasses: (I) triple-negative cancers (i.e. ER-PR-HER2 negative) expressing epidermal growth factor receptor (EGFR) and/or cytokeratin 5/6 (CK5/6), here referred to as CB, the so called “basal-like” as defined by mRNA expression analysis; and (II) cancers negative for the five markers, referred to as the 5NP subclass, triple negative cancers that express neither EGFR nor CK5/6, or “non basal” if considering the definition by mRNA expression
Summary
Triple-negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and HER-2 expression, account for 12% to 24% of all breast cancers. Six different TNBC subtypes, defined by abrogation of signaling pathways, have been identified: basal-like 1 and 2 (BL1 and BL2), immunomodulatory, mesenchymal, mesenchymal stem-like, and luminal androgen receptorexpressing [1]. These molecular entities have shown significant differences in terms of incidence, risk factors, prognosis and response to treatment [1,2,3]. Cost and complexity issues can render gene expression profiling impractical as a routine hospital diagnostic tool, while immunohistochemical (IHC) marker detection is feasible for the majority of institutions
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