Early diagnosis of prostate cancer (PCa) is marred by a lack of consensus on the best screening strategy. Prostate specific antigen (PSA) had been in widespread use for routine PCa screening, until the U.S. Preventive Services Task Force (USPSTF) recommended against routine PSA screening in 2012. The USPSTF recommendation has cut screening rates, experts say, but its recommendation is not universally accepted and screening recommendations vary substantially among major medical societies in the United States.
"That there is still no clarity about the usefulness and desirability of routine PSA-based screening after 25 years and two large trials suggests that its net benefit is unlikely to be more than marginal, whereas the harms are proven and substantial."
—Paul F. Pinsky, Ph.D.
A benefit of PSA screening is a reduction in prostate-specific mortality. According to a review published March 30 in the New England Journal of Medicine (NEJM) such mortality is estimated based on a "reasonable summary of the evidence" to be approximately one prostate cancer death averted per 1,000 men screened several times each and followed for 10 to 15 years. Yet, common harms associated with PSA-based diagnosis and the treatment of PCa include: anxiety, urinary incontinence, and erectile dysfunction.
Benefits of early detection are thought to be far off, while harms occur nearly immediately with biopsy, radical prostatectomy, or radiation therapy. The main problem with PSA testing is its lack of specificity, which has been shown to lead to unnecessary, and often repeat biopsies and the overdiagnosis and overtreatment of nonaggressive disease.
"That there is still no clarity about the usefulness and desirability of routine PSAbased screening after 25 years and two large trials suggests that its net benefit is unlikely to be more than marginal, whereas the harms are proven and substantial," write the authors led by Paul F. Pinsky, Ph.D., from the National Institutes of Health in Bethesda, Md., in the NEJM. "Under the ‘first do no harm’ principle, it seems reasonable to forgo mass screening as a public health policy at this point but to continue to perform research on how to reduce the harms of PSA screening."
Markers Beyond PSA for Early Diagnosis
While interest in new promising biomarkers is high, to date, only a few have reached clinical practice. Below is a sampling of PCa markers of high interest.
Prostate cancer antigen 3 (PCA3) – PCA3, a prostatespecific noncoding messenger RNA, which is overexpressed in PCa tissue is available commercially as the U.S. Food and Drug Administration- (FDA-) approved Progensa PCA3 test (Hologic). The test, covered by insurance, costs approximately $385.
Prostate Health Index – This test, by Beckman Coulter, combines PSA, free PSA and p2PSA using an algorithm to predict the likelihood of finding prostate cancer on a repeat biopsy. The test, covered by insurance, costs less than $100.
Four-kallikrein panel – The combination of a four-kallikrein panel (4K; total PSA, freePSA, intact PSA, and human kallikrein-related peptidase) can predict biopsy outcome, potentially cutting back the number of men undergoing biopsy. It is available as the 4K laboratory-developed test (OPKO Health).
Mi-Prostate score – This test from University of Michigan MLabs combines PCA3 and TMPRSS2-ERG with serum PSA levels to predict biopsy outcome.
SelectMDx – A two-gene (HOXC6 and DLX1), urine-based panel can predict high-grade PCa. The risk score, SelectMDx (MDxHealth) can also potentially reduce the number of unnecessary biopsies.
Transmembrane protease serine 2-ERG (TMPRSS2-ERG) gene fusion – Gene fusions, often caused by genomic chromosomal rearrangements may initiate the oncogenic process. TMPRSS2-ERG gene fusion may be specific for PCa, but are not yet approved as predictive of prostate biopsy outcome or aggressiveness of disease.
- Exosome-based scoring – Scoring is derived from exosomal RNA (specifically the sum of normalized PCA3 and ERG exosomal RNA) and is associated with high-grade PCa. Two different scoring methods have been developed.
Adapted from: Hendriks RJ, van Oort IM, Schalken JA. Blood-based and urinary prostate cancer biomarkers: a review and comparison of novel biomarkers for detection and treatment decisions. Prostate Cancer and Prostatic Diseases. 2017; 20:12–19.
Narayan VM, Konety BR, Warlick C. Novel biomarkers for prostate cancer: An evidence-based review for use in clinical practice. International Journal of Urology. March 27, 2017 Accessed from http://onlinelibrary.wiley.com/ doi/10.1111/iju.13326/full.
Some screening strategies suggested by Pinsky, include less frequent screening intervals and discontinuing screening for men with very low PSA values. Additionally, though, there is great interest in identifying new biomarkers for diagnosing, staging, and risk-stratifying PCa to inform treatment decisions.
New markers would ideally be collected noninvasively; low enough in processing costs that they could be implemented in widespread screening programs; and differentiate clinically significant cancer from nonaggressive disease.
"Although many studies have shown that novel biomarkers outperform PSA, they are not yet part of daily clinical practice and guidelines," writes co-author R.J. Hendriks, from Radboud University Medical Center in the Netherlands, in a review published in the March issue of Prostate Cancer and Prostatic Diseases. "We would recommend that before using new biomarkers as tools for risk stratification, biopsy decisions, and treatment selection in patients with PCa, the biomarkers should be validated and prospectively compared with each other. … Longitudinal studies are required following men from initial investigation through to diagnosis and treatment of PCa to determine clinical effectiveness and cost-effectiveness to guide doctor and patient in decision-making regarding PCa diagnostics and treatment selection."
Much Interest in Genomic Markers
Better understanding the genetics behind PSA levels may be an important step in personalizing screening, according to a genome-wide association study published Jan. 31 in Nature Communications.
The California-based researchers used a discovery cohort (N=28,503) to search for genome-wide variants associated with PSA levels among non-Hispanic, white individuals who had not been diagnosed with PCa. Findings were validated in 11,825 additional men in the Kaiser Permanente cohort (non-cases of other race or ethnicity groups and PCa cases using their PSA levels at least two years before cancer diagnosis) and 5,603 external replication non-cases.
The researchers identified 40 genome- wide significant single-nucleotide polymorphisms (SNPs), of which 19 were novel, 15 were previously identified for PSA (14 of which were also PCa-associated), and six previously identified for PCa only. When incorporating PCa cases, analysis suggested that at least half of the 40 SNPs are PSA-associated independent of PCa. The authors note that existence of SNPs that influence PSA levels, but not PCa, and other SNPs that influence both highlights the difficulty of using conventional PSA levels as a screening tool.
"Determining the genetic basis of PSA levels, unrelated to cancer, may help increase both the sensitivity and specificity of screening for PCa by adjusting PSA levels for constitutive germline genetics," write the authors led by Thomas J. Hoffmann, from University of California San Francisco. "Clinicians could more accurately decide who should have a prostate biopsy, thereby reducing unnecessary procedures and their associated morbidities, as well as decreasing overdiagnosis."
NorthShore University Health System in Illinois is one of the first health systems to begin to personalize PCa screening. Last summer, the health system began estimating inherited risk of prostate, breast and colorectal cancer using genetics and providing modified screening schedules for patients based on their results.
Takeaway: While consensus regarding ideal PCa screening remains elusive, research continues to identify new markers or combinations of markers that can improve screening performance and ultimately better differentiate clinically relevant PCa from nonaggressive disease.