Prostate cancer is the second leading cause of cancer deaths in American men. Estimates for 2020 have shown that over 191,000 men will be diagnosed in the United States.1,2 Prostate cancer can be an indolent, non-aggressive disease or a fast-growing, aggressive disease with significant morbidity and mortality. Prostate cancer guidelines, therefore, aim to limit unnecessary detection and invasive procedures for indolent disease while maximizing the detection and treatment of aggressive cancer.
Prostate cancer screening with the prostate specific antigen (PSA) level has been an accepted approach to screening men for prostate cancer, and it is a statutorily covered Medicare benefit. The PSA level correlates with the risk of prostate cancer and the higher above the median PSA (for a given age group), the higher the risk for prostate cancer and aggressive prostate cancer. Approximately 30% of men with serum PSA levels between 4 and 10 ng/mL will be found to have prostate cancer, and total PSA levels >10 ng/mL confer a >67% likelihood of prostate cancer.3,4 As such, NCCN guidelines recommend that patients with a PSA >10 ng/mL should be encouraged to undergo biopsy.4 However, PSA is not a cancer-specific marker, and it is widely known that PSA values can be elevated and fluctuate for a variety of reasons other than cancer including inflammation, infection, and benign prostate hyperplasia.5,6 While the test is sensitive, its negative predictive value (NPV) is relatively low and there are numerous false positives.7,8 A cohort study of 1268 patients found that repeating the PSA resulted in normal (<4 ng/mL) values for nearly 25% of patients with initial PSA levels between 4 and 10 ng/mL.6 Moreover, compared with men who had an abnormal repeat PSA result, men with normal repeat PSA results were less likely to undergo biopsy and were approximately 80% less likely to have a diagnosis of prostate cancer and Gleason score of 7 or higher.6 False negative PSA results also occur. In the Prostate Cancer Prevention Trial, 15% of men with PSA levels ≤4.0 ng/mL (and normal DREs) were diagnosed with prostate cancer; of these, 14.9% had a Gleason score of 7 or higher.9 Therefore, there is not one particular value or cut-off with sufficiently high sensitivity and specificity for assessing prostate cancer risk.
Given the suboptimal ability of the PSA to accurately assess prostate cancer risk, there is ambiguity regarding its clinical value at various levels when reviewing associated outcomes subsequent to screening.8 A large multi-center randomized controlled study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, was conducted involving over 76,000 men from 55 to 74 years of age who received either annual PSA measurements and digital rectal examinations or their usual care.10 After 7 to 13 years of follow-up, the mortality rates were low in both groups and not significantly different.10,11 However, the study’s control arm included opportunistic screening for prostate cancer and therefore greatly confounded the results. Another large trial involving 8 European countries, the European Randomized study of Screening for Prostate Cancer (ERSPC), randomized 182,160 men between the ages of 50 and 74 to receive either screening for prostate cancer including PSA measurements or a ‘truer’ control arm (in which only a relatively small number of men had previously taken a PSA test).12 Patients received a prostate biopsy if there was a concern for cancer based on the screening data. This study subsequently followed patients for 16 years and found that the screening group had a significant relative reduction in prostate-cancer related mortality of 21% (reported at 13 years of follow-up) and an even larger absolute benefit and reduction in excess incidence with the longer follow-up time of 16 years.13,14
Although PSA screening has been associated with a significant reduction in prostate-cancer related mortality, it has also led to the increased incidence of prostate cancer, resulting in the overdiagnosis and overtreatment of indolent tumors, considered to be clinically insignificant.12,15-18 Autopsy studies have shown that among 70–79 year old men, more than one-third to one-half have indolent prostate cancer that would not have caused harm if undiagnosed and untreated.18 The performance of prostate biopsies, an invasive intervention, is currently the next step in diagnosis and management, and can involve significant complications, including hospitalization in approximately 1% of patients.19 Moreover, prostate biopsy is also prone to challenges such as sampling error, which may further lead to both over- and under-treatment,20 with the false-positive and complication rates from biopsy being higher in older men.7
The management of patients with prostate cancer may include active surveillance versus definitive therapy. From 1994 through 2002, a large study of men with localized prostate cancer diagnosed shortly after PSA screening randomized 731 subjects to radical prostatectomy vs observation. There was no significant difference in either prostate-cancer specific mortality or all-cause mortality through at least 12 years of follow-up.21 Although with longer follow-up, the mortality rate was lower in men who underwent prostatectomy, though this finding was not statistically significant.22 Additionally, urinary incontinence, ED, and bowel incontinence were significantly more common among those men who underwent a prostatectomy.22 In spite of these challenges, prostate cancer deaths have decreased by 50% since 1988, in large part due to enhanced screening measures.2,23,24
As a result of the ambiguous risk-benefit profile associated with prostate cancer screening and management, guidelines on screening have differed among national organizations over the years. In 2012, the United States Preventative Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer, in large part as a result of the initial PLCO and ERSPC reports.25 However, their most recent update recommended that screening for prostate cancer with a PSA test should be an individualized decision for men (aged 55 to 69 years) to discuss with their physicians, but cautioned that there is a significant risk of false positives and overtreatment with the possibility of significant complications such as erectile dysfunction (ED) and incontinence.26 Such guidance was similarly endorsed by the Choosing Wisely initiative, which also highlighted the American Urological Association’s (AUA) recommendation to consider a PSA test only after talking with one’s doctor about risk factors.27,28 Guidelines from the NCCN recommend PSA testing to screen for prostate cancer in men 45-75 years of age in average-risk patients (and 40-75 years of age in higher-risk patients) as a level 2A recommendation; testing men >75 years of age is only recommended in healthy men with few to no comorbidities and is a level 2B recommendation, as widespread testing in this age group would significantly increase rates of overdetection.4 Moreover, NCCN guidelines recommend repeat testing if an abnormally high PSA is observed, particularly if the value is close to the threshold value that prompts evaluation.4 In the case of a prior negative biopsy, the guidelines recommend repeat PSA and DRE at 6- to 24-month intervals with consideration of repeat biopsy based on results.4
It is evident that not all prostate cancers are the same, and detection and treatment should focus specifically on prostate cancers that are more likely to contribute to morbidity and mortality. It is also evident that there are challenges with PSA testing, and a PSA-based screening strategy has not been proven to help differentiate low risk from aggressive prostate cancer. First-generation PSA derivative assays (e.g., free PSA, complexed PSA) were designed to increase PSA specificity for prostate cancer, but not necessarily specificity for clinically significant cancer. Additionally, multiparametric MRI (mpMRI) significantly increases the detection of clinically significant, higher-risk disease and is recommended for many patients with elevated PSA levels being considered for initial and repeat biopsy. However, a negative MRI does not exclude the possibility of cancer.4,30 As such, there is clinical utility for diagnostic tests that can better refine the implications of an elevated PSA test to help distinguish men with potentially life-threatening cancer from men who have indolent prostate cancer or no prostate cancer.
The most current NCCN recommendations reflect the growing body of evidence supporting the use of prostate biomarkers to further identify, and risk stratify those patients at risk of high-grade prostate cancer requiring further management from those with low grade or indolent cancer who might not benefit from further intervention and who may be spared unnecessary biopsies and interventions. Such biomarkers are non-invasive (typically blood-or urine-based) and may contribute to improved sensitivity and specificity of screening, surpassing the limitations of PSA testing.4,31-33
There are numerous biomarker tests available for biopsy-naïve patients that may improve the detection of prostate cancer or higher-grade prostate cancer. Some of these are non-molecular (i.e., they do not detect DNA and/or RNA),and include the percent free PSA (%fPSA), 4Kscore, and Prostate Health Index (PHI). Free PSA (fPSA) is an unbound form of PSA that is FDA approved for use in men with normal DRE and PSA levels of 4-10 ng/mL. At a cutoff of 25% in men with PSA values between 4–10ng/mL, fPSA has been shown to detect the majority of prostate cancers while avoiding approximately 20% of unnecessary biopsies.34 The 4Kscore® measures kallikrein markers (including PSA and fPSA) in the blood and considers other clinical parameters such as age and DRE, which together have been reported to better detect clinically significant cancer.35-39 Finally, the Prostate Health Index (PHI) is a blood-based immunoassay that uses PSA, fPSA, and p2PSA (an isoform of fPSA) to calculate a score that categorizes a patient’s risk as low, moderate, or high. Studies have shown that the PHI improves the sensitivity of prostate cancer detection,43,44 discriminates high-grade cancer43,45 and can reduce the rate of prostate biopsies.46
Other pre-biopsy biomarker tests are molecular and measure the expression of genes or epigenetic changes associated with prostate cancer. Some of these couple gene expression with other clinical and laboratory parameters in multimodal models, to optimize their clinical performance.47-51 For example, SelectMDx® evaluates messenger ribonucleic acid (mRNA) levels of HOXC6 and DLX1 relative to Kallikrein-related Peptidase 3 (KLK3). When combined with additional clinical risk factors in a multimodal approach, prospective multicenter studies found that the area under the curve (AUC) of the receiver operating characteristic (ROC) reached 0.90 in predicting detection of high-grade prostate cancer; importantly, the risk score remained a strong predictor (AUC 0.78) in men with PSA levels <10 ng/mL.52 A urine exosome gene expression assay, the ExoDx™ Prostate IntelliScore (EPI), has also been reported to be statistically more predictive than standard of care (SOC) alone for predicting Gleason score of 7 (GS 7) prostate cancer from GS 6 and benign disease.50 A clinical utility study in men scheduled for initial biopsy found that, at a cutoff of 15.6, the test had a NPV of 89% and would reduce total biopsies by 20%; however, the test would miss 7% of high grade cancers.49 In men with a prior negative biopsy, a prospective clinical validation study found that the EPI test had a NPV of 92% and would have avoided 26% of unnecessary biopsies while missing 2% of high-grade cancers.53 Importantly, these results were independent of SOC and other clinical features.
In the post-biopsy setting, there are biomarkers that improve specificity in patients who have had at least 1 prior negative biopsy. Some of these are liquid biomarkers that overlap with those already discussed for use in biopsy-naïve patients, while others are tissue-based and should only be performed on a biopsy specimen. Some utilize gene expression data while others evaluate epigenetic markers such as hypermethylation in select genes thought to be associated with aggressive disease.54-57 Progensa® PCA3 is an mRNA expression assay that can be tested from post-DRE urine. In the post-biopsy setting, it has been shown to improve the specificity of prostate cancer detection and determine which patients should undergo a repeat biopsy. One multi-center study evaluating men with at least 1 prior negative prostate biopsy reported that those with a score of <25 were more than 4 times as likely to have a negative repeat biopsy as men with a score of ≥25.58 ConfirmMDx® is a multi-gene test that uses prostate biopsy tissue to assess the methylation status of 3 biomarkers (GSTP1, RASSF1, APC) associated with prostate cancer.54,57 The performance of this assay in large, blinded clinical validation studies demonstrated a NPV of 90% for all prostate cancer and 96% for high-grade disease, considerably higher than that afforded by standard histopathology review.54,56 A field observation study conducted in 138 patients with negative biopsies found a repeat biopsy rate of 4.3%,59 significantly lower than the 40% repeat biopsy rate reported in the PLCO trial, for patients with an initial negative biopsy.60
In summary, use of biomarker tests may help overcome the limitations of screening by PSA as well as the limitations and risks associated with prostate biopsy. On the whole, use of these biomarker tests can better detect cancer or high-grade cancer, and can reduce the performance of unnecessary prostate biopsies and their associated risks. It should be noted that mpMRI is also a consideration in these same patients and, though data is emerging that combining biomarkers with mpMRI results in improved diagnostic accuracy, it is not yet known how biomarker tests can be optimally used in conjunction with MRI.