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1.  Reduced Rate of Repeated Prostate Biopsies Observed in ConfirmMDx Clinical Utility Field Study 
American Health & Drug Benefits  2014;7(3):129-134.
Background
The diagnosis of prostate cancer is dependent on histologic confirmation in biopsy core tissues. The biopsy procedure is invasive, puts the patient at risk for complications, and is subject to significant sampling errors. An epigenetic test that uses methylation-specific polymerase chain reaction to determine the epigenetic status of the prostate cancer–associated genes GSTP1, APC, and RASSF1 has been clinically validated and is used in clinical practice to increase the negative predictive value in men with no history of prostate cancer compared with standard histopathology. Such information can help to avoid unnecessary repeat biopsies. The repeat biopsy rate may provide preliminary clinical utility evidence in relation to this assay's potential impact on the number of unnecessary repeat prostate biopsies performed in US urology practices.
Objective
The purpose of this preliminary study was to quantify the number of repeat prostate biopsy procedures to demonstrate a low repeat biopsy rate for men with a history of negative histopathology who received a negative epigenetic assay result on testing of the residual prostate tissue.
Methods
In this recently completed field observation study, practicing urologists used the epigenetic test called ConfirmMDx for Prostate Cancer (MDxHealth, Inc, Irvine, CA) to evaluate cancer-negative men considered at risk for prostate cancer. This test has been previously validated in 2 blinded multicenter studies that showed the superior negative predictive value of the epigenetic test over standard histopathology for cancer detection in prostate biopsies. A total of 5 clinical urology practices that had ordered a minimum of 40 commercial epigenetic test requisitions for patients with previous, cancer-negative biopsies over the course of the previous 18 months were contacted to assess their interest to participate in the study. Select demographic and prostate-screening parameter information, as well as the incidence of repeat biopsy, specifically for patients with a negative test result, was collected and merged into 1 collective database. All men from each of the 5 sites who had negative assay results were included in the analysis.
Results
A total of 138 patients were identified in these urology practices and were included in the analysis. The median age of the men was 63 years, and the current median serum prostate-specific antigen level was 4.7 ng/mL. Repeat biopsies had been performed in 6 of the 138 (4.3%) men with a negative epigenetic assay result, in whom no evidence of cancer was found on histopathology.
Conclusion
In this study, a low rate of repeat prostatic biopsies was observed in the group of men with previous histopathologically negative biopsies who were considered to be at risk for harboring cancer. The data suggest that patients managed using the ConfirmMDx for Prostate Cancer negative results had a low rate of repeat prostate biopsies. These results warrant a large, controlled, prospective study to further evaluate the clinical utility of the epigenetic test to lower the unnecessary repeat biopsy rate.
PMCID: PMC4070628  PMID: 24991397
2.  Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies 
Bju International  2011;110(1):56-62.
OBJECTIVE
To evaluate the performance of DNA methylation biomarkers in the setting of repeat biopsy in men with an initially negative prostate biopsy but a high index of suspicion for missed prostate cancer.
PATIENTS AND METHODS
We prospectively evaluated 86 men with an initial histologically negative prostate biopsy and high-risk features.
All men underwent repeat 12-core ultrasonography-guided biopsy.
DNA methylation of glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) was determined using tissue from the initially negative biopsy and compared with histology of the repeat biopsy.
The primary outcome was the relative negative predictive value (NPV) of APC compared with GSTP1, and its 95% confidence interval (CI).
RESULTS
On repeat biopsy, 21/86 (24%) men had prostate cancer.
APC and GSTP1 methylation ratios below the threshold (predicting no cancer) produced a NPV of 0.96 and 0.80, respectively. The relative NPV was 1.2 (95% CI: 1.06–1.36), indicating APC has significantly higher NPV.
Methylation ratios above the threshold yielded a sensitivity of 0.95 for APC and 0.43 for GSTP1.
Combining both methylation markers produced a performance similar to that of APC alone.
APC methylation patterns were consistent with a possible field effect or occurrence early in carcinogenesis.
CONCLUSION
APC methylation provided a very high NPV with a low percentage of false-negatives, in the first prospective study to evaluate performance of DNA methylation markers in a clinical cohort of men undergoing repeat biopsy.
The potential of APC methylation to reduce unnecessary repeat biopsies warrants validation in a larger prospective cohort.
doi:10.1111/j.1464-410X.2011.10718.x
PMCID: PMC3397791  PMID: 22077694
prostate cancer; biopsy; methylation; APC; GSTP1
3.  A tissue biopsy-based epigenetic multiplex PCR assay for prostate cancer detection 
BMC Urology  2012;12:16.
Background
PSA-directed prostate cancer screening leads to a high rate of false positive identifications and an unnecessary biopsy burden. Epigenetic biomarkers have proven useful, exhibiting frequent and abundant inactivation of tumor suppressor genes through such mechanisms. An epigenetic, multiplex PCR test for prostate cancer diagnosis could provide physicians with better tools to help their patients. Biomarkers like GSTP1, APC and RASSF1 have demonstrated involvement with prostate cancer, with the latter two genes playing prominent roles in the field effect. The epigenetic states of these genes can be used to assess the likelihood of cancer presence or absence.
Results
An initial test cohort of 30 prostate cancer-positive samples and 12 cancer-negative samples was used as basis for the development and optimization of an epigenetic multiplex assay based on the GSTP1, APC and RASSF1 genes, using methylation specific PCR (MSP). The effect of prostate needle core biopsy sample volume and age of formalin-fixed paraffin-embedded (FFPE) samples was evaluated on an independent follow-up cohort of 51 cancer-positive patients. Multiplexing affects copy number calculations in a consistent way per assay. Methylation ratios are therefore altered compared to the respective singleplex assays, but the correlation with patient outcome remains equivalent. In addition, tissue-biopsy samples as small as 20 μm can be used to detect methylation in a reliable manner. The age of FFPE-samples does have a negative impact on DNA quality and quantity.
Conclusions
The developed multiplex assay appears functionally similar to individual singleplex assays, with the benefit of lower tissue requirements, lower cost and decreased signal variation. This assay can be applied to small biopsy specimens, down to 20 microns, widening clinical applicability. Increasing the sample volume can compensate the loss of DNA quality and quantity in older samples.
doi:10.1186/1471-2490-12-16
PMCID: PMC3431995  PMID: 22672250
GSTP1; APC; RASSF1; Methylation; Epigenetics; Prostate cancer; Diagnosis; Multiplex; Singleplex; MSP

Results 1-3 (3)