Clinical Validation of an Epigenetic Assay to Predict Negative Histopathological Results in Repeat Prostate Biopsies

Abstract

Purpose The DOCUMENT multicenter trial in the United States validated the performance of an epigenetic test as an independent predictor of prostate cancer risk to guide decision making for repeat biopsy. Confirming an increased negative predictive value could help avoid unnecessary repeat biopsies. Materials and Methods We evaluated the archived, cancer negative prostate biopsy core tissue samples of 350 subjects from a total of 5 urological centers in the United States. All subjects underwent repeat biopsy within 24 months with a negative (controls) or positive (cases) histopathological result. Centralized blinded pathology evaluation of the 2 biopsy series was performed in all available subjects from each site. Biopsies were epigenetically profiled for GSTP1, APC and RASSF1 relative to the ACTB reference gene using quantitative methylation specific polymerase chain reaction. Predetermined analytical marker cutoffs were used to determine assay performance. Multivariate logistic regression was used to evaluate all risk factors. Results The epigenetic assay resulted in a negative predictive value of 88% (95% CI 85–91). In multivariate models correcting for age, prostate specific antigen, digital rectal examination, first biopsy histopathological characteristics and race the test proved to be the most significant independent predictor of patient outcome (OR 2.69, 95% CI 1.60–4.51). Conclusions The DOCUMENT study validated that the epigenetic assay was a significant, independent predictor of prostate cancer detection in a repeat biopsy collected an average of 13 months after an initial negative result. Due to its 88% negative predictive value adding this epigenetic assay to other known risk factors may help decrease unnecessary repeat prostate biopsies.

Genomic Predictors of Outcome in Prostate Cancer

“…In addition to intra/interfocal heterogeneity, a field effect of genetic changes should also be considered because cancer-related genetic changes are also detected in benign areas of the same prostate [99]. This is the underlying premise of new tests designed to predict the risk of finding cancer on repeat biopsy for men with a negative biopsy [79], as well as biopsy-based tissue tests designed to predict whole-gland pathologic features. Genomic analysis of tumor tissue may aid in overcoming the challenges of sampling error and the variability of traditional pathologic grading.…”

“…The test achieved a 90% negative predictive value (NPV) within 30 mo of the initial biopsy. In a recent validation trial, 88% NPV was reported, and the test was the most significant predictor of biopsy results [79]. The impact of the epigenetic test on rebiopsy rates was recently surveyed in five centers, and among 138 patients with a negative ConfirmMDx assay, only six patients (4%) underwent repeat biopsies [80].…”

Clinical Utility of Biomarkers in Localized Prostate Cancer

“…The sensitivity and specificity of the assay for the detection of subsequent PCa were 68 and 64 % with negative predictive value (NPV) of 90 % (95 % CI 87-93 %) [28]. Similarly, in a multi-center US study consisting of 350 men receiving repeat biopsy following initial negative biopsy, the methylation assay was associated with a sensitivity of 62 and 64 % and NPV of 88 % (95 % CI 85-91) [29]. A clinical utility field study consisting of patients from five US sites in whom the epigenetic assay had been ordered in the setting of an initial negative prostate biopsy examined the rates of subsequent biopsy.…”

Clinical relevance of prostate cancer genetic characterization: literature review

“…Выдающиеся результаты были получены A. W. Partin и соавт. [74] при оценке метилирования ДНК генов GSTP1, APC и RASSF1. Это исследование показало, что эпигенетический анализ имеет отрица-тельную предсказательную ценность 88 % и может использоваться в клинической практике.…”

“…Авторы считают, что при ком-бинации EVX1 и FGF1 отрицательная предсказательная ценность составила около 91 %, что немногим мень-ше, чем в исследовании A. W. Partin и соавт. [74]. Оче-видно, эти данные будут иметь значимое место в кли-нической практике через несколько лет.…”