In recent years, mpMRI has emerged as a reliable tool for monitoring patients on AS (13, 16). The implementation of novel MRI analytic techniques such as diffusion-weighted imaging (DWI) and volumetric estimation algorithms have allowed for improved tumor characterization (17–19). More specifically, the apparent diffusion coefficient, which is calculated from DWI sequences, inversely correlates with PCa aggressiveness (18). Furthermore, automated calculations of lesion volume on mpMRI reliably correspond with PCa presence (18, 20). Marin et al. demonstrated that the use of semi-automated sizing algorithms to measure maximal tumor dimensions of suspicious lesions reliably correlated with actual tumor histologic diameter, and this practice should be considered during routine workup (20).

Several studies suggest using mpMRI in the initial diagnostic setting may classify patients as AS-eligible more reliably than traditional protocol criteria alone (21–23). In a study by Ouzzane et al., 10% of patients initially classified as appropriate for AS were reclassified as inappropriate following the detection of clinically silent lesions on mpMRI followed by targeted biopsy (22). When reviewed by an experienced radiologist, Porpiglia et al. suggests use of mpMRI alone may reliably predict pathologically significant PCa without confirmatory tissue biopsy (21). However, in a retrospective study of 118 patients, Dianat et al. found significant pathology could exist in the absence of a visible index lesion on MRI (24).

Over the past 10 years, the PIRADS has become an increasingly useful tool in both the initial diagnostic setting and for monitoring patients on AS (25–27). The PIRADS system is a five-point Likert scale applied to a suspicious lesion on MRI. An overall score is assigned to predict the likelihood that a suspicious lesion harbors clinically significant PCa (28, 29). In a retrospective analysis of more than 1,000 patients on AS, Venderink et al. demonstrated that a PIRADS cutoff of ≥3 could more reliably select patients for repeat biopsy than PSA density (PSAD) (26). In a study of 201 patients undergoing transperineal sector prostate biopsy, Grey et al. demonstrated that a strict cutoff of PI-RADS ≥3 would have allowed 44% of men to avoid undergoing repeat biopsy (25). However, 2.3% of those men still harbored significant PCa, raising the question as to what degree of specificity is necessary for proper management of patients on AS with presumably slow-growing disease (25). We identified three original investigations that compared a widely accepted AS protocol with a predictive nomogram incorporating PIRADS, and all three studies demonstrated a significant improvement in risk stratification (30–32).

More recently, a proposed PIRADS version 2 (PIRADSv2) was developed to reflect increasingly complex MRI interpretation with the application of multiple sequences such as DWI and dynamic contrast enhancement for interpretation of a single lesion (27, 29, 33). Validation studies comparing its utility to the original PIRADS algorithm are currently underway. However, early results indicate significant PCa may be overlooked as often as 5% of the time when using PIRADSv2 ≥3 as a cutoff (27). Furthermore, there is concern that the PIRADS algorithm may inaccurately characterize benign central zone (CZ) lesions. In a retrospective review of 73 patients who underwent MRI-fusion biopsy by Tan et al., 26 CZ lesions were graded as PIRADS 3 or greater. Only two (7.7%) of these suspicious lesions harbored PCa (34). Since evidence suggests PCa arising from the CZ can be more aggressive than peripheral and transitional zone cancers, modification of the PIRADS algorithm may be needed to better characterize CZ lesions (35, 36).

With mpMRI becoming an increasingly reliable predictor of histologic tumor burden, MRI–US fusion technology has been developed to perform targeted biopsy of suspicious prostatic lesions (37, 38). Several recently published investigations demonstrate performing targeted biopsies on men undergoing AS is superior to standard TRUS biopsy for the detection of newly significant PCa (39–42). Furthermore, Siddiqui et al. suggest performing MRI–US fusion targeted biopsy may reduce the number of insignificant PCa diagnoses, thus sparing patients from unnecessary biopsies (43).

However, there is conflicting data whether it is appropriate to only use MRI–US fusion biopsy, thus abandoning initial random TRUS guided sampling, for the detection of Gleason score (GS) upgrades in AS patients (39–41, 44). For example, Da Rosa et al. reported a 100% negative predictive value for detecting GS 6 to 7 upgrade when using MRI–US fusion in their cohort of 72 men on AS (40). Furthermore, a retrospective study by Nassiri et al. of more than 250 patients showed that 32 of 33 upgraded cases were from MRI-guided cores (41). In contrast, a study by Marliere et al., albeit with a smaller cohort, demonstrated both standard TRUS and targeted MRI–US fusion biopsies in the initial AS setting may still be necessary for adequate detection of all new GS upgrades (44).

Compared to standard TRUS sampling and MRI–US fusion targeted biopsy, evidence demonstrates saturation biopsy (24 or 30 core templated sampling) provides the greatest sensitivity for detection of significant PCa in the initial AS period (45–47). While this approach may provide enhanced detection, it also subjects patients to the burden of increased tissue acquisition. Pepe et al. proposed using a hybrid approach they referred to as “cognitive zonal fusion biopsy” (46). In this approach, all patients undergo mpMRI prior to a MRI–US fusion biopsy. If during the biopsy there is a discrepancy between what was found on MRI and what is visualized on US, two to six cores are obtained from the MRI region of interest. In their prospective study of 58 individuals who were either biopsy naïve or on AS, this approach reliably detected significant PCa (46).

There is mounting evidence that men on AS who underwent proper initial evaluation may be monitored with serial mpMRIs, and the interval for repeat biopsies may be lengthened (8, 48–52). In two separate studies of men on AS who underwent serial mpMRIs and MRI–US fusion biopsy, both Walton Diaz et al. and Felker et al. observed that stable findings on mpMRI significantly correlated with GS stability (48, 50). In a 2-year retrospective review of 162 men on AS, Frye et al. demonstrated that progression on repeat mpMRI significantly predicted pathological progression (8).

For men with small index lesions (≤7 mm), a retrospective review of more than 150 patients on AS demonstrated no change in either lesion size or pathologic characteristics during a 2-year surveillance period (51). This suggests that men on AS, whose lesions meet this size criteria, could potentially forgo any surveillance whatsoever for intervals up to 2 years. Siddiqui et al. developed a predictive nomogram based on serial mpMRI results for men on AS who underwent repeat MRI–US fusion biopsies over the course of 5 years. Based on whether targeted biopsy prompted disqualification from AS, their nomogram incorporating mpMRI could have potentially avoided repeat tissue biopsy sessions in up to 68% of men (49).

Kallikrein-related enzymes are a family of serine proteases with high homology (54). While the kallikrein-3 gene (KLK-3, or PSA) is among the most extensively investigated in relation to PCa, expression of all 15 kallikreins can be detected in prostate tissue (55). Recently a predictive tool comprising plasma total PSA, free PSA, intact PSA, and kallikrein-2 along with patient age, DRE and biopsy history known as the 4Kscore Test has gained attention as a novel risk stratification tool for patients with elevated PSA, and possibly newly diagnosed PCa (55–57). In a prospective study by the Canary Prostate Active Surveillance Study Investigators, which evaluated more than 700 men with newly diagnosed Gleason 6 PCa on AS, the 4Kscore reliably predicted GS upgrades on the first surveillance biopsy (57). However, there was a decreased utility in the 4Kscore Test for predicting GS upgrades on subsequent biopsies, suggesting it may only be beneficial in the initial AS period (57).

A novel urinary assay-based risk score called SelectMDx by MDxHealth combines serum PSA, PSAD and clinical factors such as age and prior negative biopsy with two mRNA signatures: urinary homeobox C6 and distal-less homeobox 1 (58). This relatively low-cost assay was recently implicated as a useful diagnostic aid for appropriately selecting men for undergoing prostate biopsy (58). In the setting of a prior negative biopsy, MDxHealth developed an additional assay called ConfirmMDx (59, 60). The ConfirmMDx assay utilizes methylation analyses of various oncogenes such as Ras and Adenomatous Polyposis Coli from a patient’s prior negative biopsy tissue to estimate the likelihood of obtaining a negative repeat biopsy (59). In a multicenter study of 350 subjects, Partin et al. reported an 88% negative predictive value of detecting significant PCa at 13-month follow-up. Furthermore, their multivariate model suggested ConfirmMDx may independently predict repeat negative biopsy in this setting (60).

The Prolaris test evaluates the RNA expression of 46 genes to evaluate tumor cell growth characteristics and may help risk stratify patients with PCa (61–63). The assay measures the cell cycle progression score, and has proven prognostic value in other malignancies such as breast cancer (64). Several recent investigations revealed performing the Prolaris test in the initial diagnostic setting may reliably risk stratify patients for AS, and potentially avoid unnecessary repeat biopsies for those with low risk Prolaris scores (61, 65).

The Oncotype Dx panel is a 17-gene reverse transcription polymerase chain reaction-based diagnostic assay that has been validated as a predictor of adverse pathology following prostatectomy in men with low-risk PCa (66–69). Eure et al. prospectively studied 297 patients on AS, and those who underwent Oncotype Dx screening were more likely to remain on AS (66). The authors suggest the predictive value of Oncotype Dx may provide both patients and clinicians with better peace of mind when opting to remain on AS given additional reassurance that AS is safe given a indolent genetic profile of disease.

The Decipher gene expression assay uses 22 genes to predict the risk of developing metastases following radical prostatectomy (70, 71). While there is evidence supporting its utility in the postoperative setting, we could not identify any studies evaluating the potential benefit of using the Decipher assay for AS patients undergoing conservative management.

Metamark Genetics Inc. developed a quantitative protein-based multiplex imaging platform designated ProMark as prognostic test for PCa. ProMark’s quantitative immunofluorescence method utilizes imaging platform and measure eight biomarkers directly on sections of biopsy tissue (72). Multiple studies have tested the utility of the ProMark assay in predicting biochemical recurrence after radical prostatectomy (73, 74).

The phosphatase and tensin homolog (PTEN) is a tumor suppressor gene whose function may be lost in patients with PCa (75). As such, measuring PTEN to predict PCa severity has gained attention as a possible way to stratify patients on AS (76, 77). In a retrospective study using tissue microarray specimens of over 600 patients who underwent radical prostatectomy, loss of PTEN was significantly correlated with PCa severity (76). Lokman et al. recently demonstrated that loss of PTEN on pathological analysis of surveillance targeted biopsies may predict future GS upgrading and AS discontinuation (76).

Majority of PCa show recurrent chromosomal rearrangement which leads predominantly to the fusion of the androgen-responsive promoter elements of the TMPRSS2 gene with ETS transcription factor ERG. This gene fusion leads to overexpression of ERG in PCa (78). In a study of 265 patients on AS, Berg et al. demonstrated ERG positivity was significantly associated with progression of disease (79). Furthermore, a separate study by Berg et al. showed ERG expression remains consistent from initial biopsy through surgical removal of the prostate (80). This temporal stability suggests clinicians could obtain ERG expression just one time at any point in a patient’s disease course, thus limiting the costs of re-sampling.

The PHI is a formula that incorporates the following PSA isoforms: total PSA, free PSA, and pro-PSA (81). PCA3 is a gene that expresses noncoding RNA which is extracted from the prostate following DRE (81, 82). Both assays have gained attention as potential tools for AS patient selection and monitoring (81–84). Recently, Cantiello et al. demonstrated both PHI and PCA3 may aid in the prediction pathologically insignificant PCa (84). However, this was a retrospective observational study, and few if any studies have investigated the predictive value of these biomarkers in a prospective clinical setting (81, 84).

The α-chemokine receptor, C–X–C chemokine receptor type 4 (CXCR4) and its ligand, stromal-derived-factor 1 (also known as CXCL12) are therapeutic targets in various epithelial, mesenchymal, and hematopoietic tumors (85, 86). Recent evidence suggests the CXCR4/CXCL12 interaction may be involved in PCa tumorigenesis (87, 88). In a retrospective review of patients who underwent radical prostatectomy, Goltz et al. demonstrated that aberrant CXCL12 methylation was correlated with GS and biochemical recurrence (89). They postulated that evaluating CXCL12 in the AS setting may be beneficial, but we failed to identify any studies to date that have evaluated this theory.

The detection of malignant circulating prostate cells (mCPCs) has gained attention as a novel, minimally invasive way to detect PCa status (90–92). By using immunocytochemistry and anti-PSA monoclonal antibodies, detection of plasma mCPCs may reliably identify low vs high risk PCa (92). In a retrospective study of 161 men on AS, Murray et al. demonstrated mCPC detection was superior to both the Chun nomogram and serum-free PSA for predicting the detection of clinically significant PCa (91). Using mCPC presence alone resulted in only two (<1%) missed PCa diagnoses, and both were low-grade disease.

Genome-wide association studies have implicated numerous SNPs in PCa development (93, 94). There is considerable interest in identifying SNPs associated with high risk PCa to aid in identifying patients eligible for AS (95). Recently, Kearns et al. identified a SNP associated with GS upgrading in a cohort of more than 200 patients on AS (96). Their findings warrant further investigation of the predictive insight SNPs may provide.