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Abstract
Early detection is crucial for achieving a reduction in breast cancer mortality. Analysis of circulating cell-free microRNAs present in the serum of cancer patients has emerged as a promising new noninvasive biomarker for early detection of tumors and for predicting their molecular classifications. The rationale for this study was to identify subtype-specific molecular profiles of cell-free microRNAs for early detection of breast cancer in serum. Fifty-four early-stage breast cancers with 27 age-matched controls were selected for circulating microRNAs evaluation in the serum. The 54 cases were molecularly classified (luminal A, luminal B, luminal B Her2 positive, Her-2, triple negative). NanoString platform was used for digital detection and quantitation of 800 tagged microRNA probes and comparing the overall differences in serum microRNA expression from breast cancer cases with controls. We identified the 42 most significant (P ≤ 0.05, 1.5-fold) differentially expressed circulating microRNAs in each molecular subtype for further study. Of these microRNAs, 19 were significantly differentially expressed in patients presenting with luminal A, eight in the luminal B, ten in luminal B HER 2 positive, and four in the HER2 enriched subtype. AUC is high with suitable sensitivity and specificity. For the triple negative subtype miR-25-3p had the best accuracy. Predictive analysis of the mRNA targets suggests they encode proteins involved in molecular pathways such as cell adhesion, migration, and proliferation. This study identified subtype-specific molecular profiles of cell-free microRNAs suitable for early detection of breast cancer selected by comparison to the microRNA profile in serum for female controls without apparent risk of breast cancer. This molecular profile should be validated using larger cohort studies to confirm the potential of these miRNA for future use as early detection biomarkers that could avoid unnecessary biopsy in patients with a suspicion of breast cancer.
Highlights
Breast cancer is the most common female cancer in the world with an estimated 1.67 million new cases diagnosed worldwide in 2012 [1]. Both clinically and biologically breast cancer is a highly heterogeneous and guidelines provided by AJCC 7th Edition Staging for Breast suggest using a classification based on five molecular subtypes: luminal A, luminal B, luminal B HER2 positive, HER2-enriched, and triple negative [2]
The early-stage (CS I and II) cases (n=54) were selected from a bigger series of breast cancer patients diagnosed at Barretos Cancer Hospital (BCH), having the following features: age range 40-69 years old; no breast cancer recurrence; absence of family history/MIRIAD >10%; confirmation of tumor stage and molecular subtype; and availability of serum prior to chemotherapy or hormone therapy
We considered an area under the Receiver Operating Characteristic (ROC) curve (AUC) ≥ 0.8 as a cutoff for further investigation and we identified 36 out of 42 differentially miRNAs as suitable biomarkers in the subtypes luminal A, luminal B, luminal B HER-2 positive and HER2enriched (Table 2)
Summary
Breast cancer is the most common female cancer in the world with an estimated 1.67 million new cases diagnosed worldwide in 2012 [1]. Both clinically and biologically breast cancer is a highly heterogeneous and guidelines provided by AJCC 7th Edition Staging for Breast suggest using a classification based on five molecular subtypes: luminal A, luminal B, luminal B HER2 positive, HER2-enriched, and triple negative [2]. There is a critical shortage of noninvasive methods based on diagnostically sensitive and specific breast cancer biomarkers suitable for both early detection and subtype classification of tumors [7]
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