Abstract P3-10-02: Circulating miRNA Signature: Potential Screening and Prognostic Tool for Breast Cancer

Abstract

Abstract Introduction: Genetic profiling of breast tumors revolutionized the classification of breast cancer and unravelled the complexity of this phenotypically diverse disease. However there appears to be discordance between the various mRNA-based single sample predictors which stratify tumors into subgroups. Clinical decision making based on a tumor's mRNA expression is therefore concerning. The potential of mi(cro) RNAs as novel tumor markers has been the focus of recent scrutiny due to their tissue specificity, stability and superiority to mRNA in tumor classification. Additionally, the ability to quantify tumor-associated miRNAs in the circulation and their correlations with clinicopathologic variables, highlights their potential to improve upon existing breast tumor classification methods. Systemic miR-195 and let-7a have been shown to hold properties as breast tumor markers. The aim of this study was to identify a larger panel of miRNAs which augment the sensitivity and specificity of circulating miRNAs as diagnostic and prognostic markers for breast cancer. Methods: The expression levels of 9 miRNAs were evaluated in 345 preoperative cancer patients including 265 breast cancers and 80 non-breast malignancies, and 63 age-matched disease-free controls using RQ-PCR. MiRNA quantification was also performed on tumor tissue from 83 age and stage matched breast cancer patients. Advanced QBase Plus software and SPSS were used for biostatistical analysis of the data and correlation with clinicopathologic variables. Results: This study confirmed significantly deranged expression levels of systemic miR-195 and let-7a in an independent validation cohort of breast cancer patients (p < 0.001 and p < 0.001 respectively). In addition miR-181c and miR-342 were identified as breast cancer specific biomarkers. Elevated levels of this 4-miRNA signature in breast cancer patients, including those with in-situ carcinoma, increased the discriminatory power of this test for breast cancer (all types) to 94% (P<0.001). Circulating levels of these 4 miRNAs correlated with tumor miRNA expression, and decreased to basal levels by 2 weeks following curative tumor resection. Additionally circulating miRNA levels correlated with clinicopathological variables such as tumor size and hormone receptor status. A subset of 2 systemic miRNAs was predictive of the Luminal A subtype of breast cancer (ER/PR positive, Her2/neu negative) with 91% accuracy. Conclusion: This study validates the recent novel finding of dysregulated tumor-specific miRNAs in the circulation of breast cancer patients. Considering that the sensitivity of mammography is 75-90%, this circulating miRNA signature could improve upon existing breast cancer screening methods, given that it was significantly altered even in patients with in-situ carcinoma. These results indicate that circulating miRNA analysis holds immense potential in the future individualized management of breast cancer patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-02.