Epigenetic Signature: A New Player as Predictor of Clinically Significant Prostate Cancer (PCa) in Patients on Active Surveillance (AS)

Abstract

Widespread prostate-specific antigen (PSA) testing notably increased the number of prostate cancer (PCa) diagnoses. However, about 30% of these patients have low-risk tumors that are not lethal and remain asymptomatic during their lifetime. Overtreatment of such patients may reduce quality of life and increase healthcare costs. Active surveillance (AS) has become an accepted alternative to immediate treatment in selected men with low-risk PCa. Despite much progress in recent years toward identifying the best candidates for AS in recent years, the greatest risk remains the possibility of misclassification of the cancer or missing a high-risk cancer. This is particularly worrisome in men with a life expectancy of greater than 10–15 years. The Prostate Cancer Research International Active Surveillance (PRIAS) study showed that, in addition to age and PSA at diagnosis, both PSA density (PSA-D) and the number of positive cores at diagnosis (two compared with one) are the strongest predictors for reclassification biopsy or switching to deferred treatment. However, there is still no consensus upon guidelines for placing patients on AS. Each institution has its own protocol for AS that is based on PRIAS criteria. Many different variables have been proposed as tools to enrol patients in AS: PSA-D, the percentage of freePSA, and the extent of cancer on biopsy (number of positive cores or percentage of core involvement). More recently, the Prostate Health Index (PHI), the 4 Kallikrein (4K) score, and other patient factors, such as age, race, and family history, have been investigated as tools able to predict clinically significant PCa. Recently, some reports suggested that epigenetic mapping differs significantly between cancer patients and healthy subjects. These findings indicated as future prospect the use of epigenetic markers to identify PCa patients with low-grade disease, who are likely candidates for AS. This review explores literature data about the potential of epigenetic markers as predictors of clinically significant disease.

Neutrophil, Platelets, and Eosinophil to Lymphocyte Ratios Predict Gleason Score Upgrading in Low-Risk Prostate Cancer Patients

“…Despite several clinical and biochemical parameters being proposed as a means to select the best candidates for AS in recent times [14,[26][27][28], the possibility of misclassification of cancer or missing a high-risk cancer remains a relevant clinical issue. Several authors reported that inflammatory response in tumor microenvironment plays a key role in cancer malignant phenotype [29,30].…”

“…Recently, preoperative neural network software, based on mpMRI variables, PSA level, and GS has been reported to predict insignificant prostate cancer, particularly in the context of clinically non-palpable tumors, suggesting a prognostic and pathologic predictive role in very low-risk PCa [13]. Some authors suggested that risk scores based on the mRNA liquid biopsy assay combined with traditional clinical risk factors identified men at risk of harboring high-grade PCa on prostate biopsy, suggesting the use of epigenetic testing for prostate cancer detection using methylation-specific PCR and cancer-associated epigenetic biomarkers in predicting pathological features at RP [14,15].…”

Advances in Biomarkers for PCa Diagnostics and Prognostics—A Way towards Personalized Medicine

“…Serum markers are the subject in the vast majority of publications ( n = 8) with focus on PCa diagnostic and prognostic [ 19 , 20 , 21 , 22 , 23 ] or evaluation of advanced/metastatic disease stages [ 24 , 25 , 26 ]. Two of the four reviews further summarize biomarkers for PCa diagnostic [ 27 ] or active surveillance [ 28 ] while the other two reviews have special topics like nanoparticles as theranostic vehicles [ 29 ] or PCa stem cells [ 30 ]. Four working groups published results by using immunohistochemistry in prostate, lymph node or bone tissue [ 31 , 32 , 33 , 34 ].…”

“…Ferro and colleagues [ 28 ] provided a comprehensive overview of biomarkers as predictors of clinical significant PCa and for PCa patients under active surveillance. The main topics were further epigenetic signatures with DNA methylation, histone modifications, and noncoding RNA, which all could potentially provide new tools for PCa prognosis [ 28 ].…”

The management of active surveillance in prostate cancer: validation of the Canary Prostate Active Surveillance Study risk calculator with the Spanish Urological Association Registry

“…Although new biomarkers and data from multiparametric Magnetic Resonance Imaging (mpMRI) could improve its predictive accuracy [ 16 – 19 ], the real strength of this new tool relies on its variables: age, PSA, months from last biopsy, percentage of positive cores for PCa on the last Bx and number of prior negative Bx; all of them available and reproducible elsewhere. Both criteria, new biomarkers such as PCA3 and PHI [ 20 ] and mpMRI [ 21 ], have shown their ability for a better selection of patients for AS when referred to pathological results of radical prostatectomy specimens, but they will need to demonstrate clear advantages in gaining accuracy, but also their cost-effectiveness, if they are to be regularly introduced in AS protocols.…”