Abstract
BackgroundProstate cancer diagnosis using the PSA test remains controversial because of overdiagnosis and overtreatment of potentially indolent cancers. There remains a need to increase the diagnostic lead time and to target treatment to patients with significant disease. One possible approach to overcome the limitations of PSA is to screen men for the molecular signature of early PCA, monitor the rate of disease progression and target treatment to patients who are likely to benefit from it. Such an approach requires a large panel of markers that define a molecular clock for PCA. We recently developed a panel of 19 markers for the non-invasive detection of PCA from urine DNA. It raised the possibility that additional methylation markers could be successfully analyzed from urine DNA, a prerequisite for increasing the diagnostic lead time and enabling disease monitoring.MethodsWe developed semi-quantitative polymerase chain reaction assays for 13 additional markers and determined their methylation status in 150 urine DNAs from 94 patients with elevated PSA. Eighty five samples were obtained following DRE and 65 samples were from first void. We combined the data of the 13 new markers with the previously reported 19 markers and calculated the sensitivity, specificity, negative and positive predictive values at every threshold from one to 32 positive markers.ResultsUsing 10of32 positive markers as the threshold to recommend a biopsy yields a sensitivity of 81% (95% CI 0.68–0.93) and 93% (95% CI 0.84–1.02) and a specificity of 76% (95% CI 0.63–0.88) and 77% (95% CI 0.63–0.91) from DRE and FV DNA, respectively. The PPV was 71% and 77% and the NPV was 85% and 93% from DRE and FV, respectively.ConclusionsThis study shows that large marker panels can be analyzed from urine DNA without loss of sensitivity or specificity. Using 32 markers improved the stratification of patients undergoing screening for PCA particularly for patients below the 10of32 threshold. The results show the utility of larger biomarker panels for PCA diagnosis and suggest that the development of the panels needed to monitor disease progression could be successfully accomplished.
Highlights
Prostate cancer diagnosis using the prostate specific antigen (PSA) test remains controversial because of overdiagnosis and overtreatment of potentially indolent cancers
Over the last 2 decades, prostate cancer (PCA) screening using the prostate specific antigen (PSA) test exposed the complexities and challenges associated with early screening for a common cancer [1]
The improved lead time resulted in only a modest reduction in PCAspecific mortality and was not sufficient to diagnose all prostate cancers while curable [4]
Summary
Prostate cancer diagnosis using the PSA test remains controversial because of overdiagnosis and overtreatment of potentially indolent cancers. One possible approach to overcome the limitations of PSA is to screen men for the molecular signature of early PCA, monitor the rate of disease progression and target treatment to patients who are likely to benefit from it. A number of non-invasive diagnostic and prognostic tests have been developed to improve on PSA screening but none have achieved the accuracy needed to safely reduce overtreatment [14,15,16,17,18] Their primary objective is to predict the likelihood of a significant cancer in patients with elevated PSA. Measuring the rate of disease progression will enable the targeting of treatment to patients with high risk tumors before the cancer becomes disseminated These tests will likely require large panels of markers that can be detected in circulating DNA and correlated with disease grade and stage
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