Abstract
To reduce treatment of indolent prostate cancer (PCa), biomarkers are needed to improve identification of patients with a low-risk of having aggressive disease. Over-treatment of these patients occurs because of uncertainty in the aggressiveness of the entire tumor based on the biopsies, which do not accurately sample multifocal tumors. Circulating microRNAs (miRNAs) are stable serum markers and differential miRNA levels occur in men with PCa. The goal of this study was to identify circulating miRNAs that were associated with aggressive or indolent PCa. We measured circulating miRNAs in 150 patients prior to surgery and compared the miRNA levels to the pathology of the entire radical prostatectomy specimen. For this study we used an exceptionally well-characterized cohort of patients who had benign prostatic hyperplasia (BPH), low-grade or high-grade PCa. Low-grade was defined as patients with 100% Gleason grade 3 tumor as determined by step-wise sectioning. High-grade PCa patients had 30-90% Gleason grade 4+5 in the tumor. BPH patients had at least two biopsies negative for PCa. Twenty one miRNAs were selected for analysis. The miRNAs were quantified by RT-qPCR and analyzed by logistic regression. High levels of 14 miRNAs were exclusively present in the serum from patients with low-grade PCa or BPH, compared to men with high-grade PCa who had consistently low levels. The expression levels of the 14 miRNAs were combined into a “miR Score” which had a negative predictive value (NPV) of 0.939 to predict absence of high-grade PCa among PCa and BPH patients. Biochemical recurrence (BCR) was known for the PCa patients and a combined “miR Risk Score” accurately classified a subset of patients with low risk of BCR (NPV 0.941). In summary, measurement of serum miRNAs may have pre-surgical utility in combination with clinical risk calculators to identify patients with low risk of harboring aggressive PCa.
Highlights
Prostate cancer (PCa) remains the second leading cause of cancer death, only ~10% of the 233,000 expected men who will be diagnosed with prostate cancer (PCa) in 2014 will have potentially lethal disease [1]
Considering the significant morbidities associated with PCa treatment improved risk stratification is needed to identify these low-risk patients and reduce treatment of indolent PCa
Sera from 50 men with benign prostatic hyperplasia (BPH) were obtained during office visits for clinical evaluation during this same time period and absence of PCa was confirmed by at least two sets of ultrasound-guided needle biopsies
Summary
Prostate cancer (PCa) remains the second leading cause of cancer death, only ~10% of the 233,000 expected men who will be diagnosed with PCa in 2014 will have potentially lethal disease [1]. Patients with indolent PCa and a low-risk of having aggressive disease may be monitored safely by active surveillance [4, 5], but there can be uncertainty with this determination. Considering the significant morbidities associated with PCa treatment (impotence, incontinence, pain, infertility) improved risk stratification is needed to identify these low-risk patients and reduce treatment of indolent PCa. The uncertainty in PCa prognosis is due the fact the prostate biopsies do not adequately sample the prostate tumor, the trend is to treat most men with PCa to avoid not treating a man who had aggressive disease that was missed by the biopsy.
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