Prostate Cancer Screening

Number: 0521

Policy

1. Aetna considers prostate-specific antigen (PSA) screening a medically necessary preventive service for men 45 years of age and older who are considered average-risk for prostate cancer, and for men 40 years of age and older who are considered at high-risk for prostate cancer.  Risk groups include African-American men and men with a family history of prostate cancer. Note: Routine prostate cancer screening for members 75 years of age or older is considered not medically necessary unless life expectancy is greater than or equal to 10 years.
   
   
2. When used for routine screening, annual PSA screening is considered medically necessary, but additional PSA tests may be considered medically necessary in men with previously elevated PSAs or signs or symptoms of disease.
    
3. Aetna considers diagnostic PSA testing medically necessary for men of all ages with signs or symptoms of prostate cancer, and for follow-up of men with prostate cancer.
    
4. Aetna considers annual digital rectal examination (DRE) a medically necessary preventive service.
   
   
5. Aetna considers measurement of selenium in the blood or in tissues (such as toenail clippings) experimental and investigational to assess the risk of developing prostate cancer because it has no proven value for this indication.
   
   
6. Aetna considers the following experimental and investigational for prostate cancer screening because they have no proven value for this indication (not an all-inclusive list):
    
   • Alpha-methylacyl coenzyme A racemase (AMACR)
   • Analysis of prostatic fluid electrolyte composition (e.g., citrate, zinc; not an all inclusive list)
   • Apifiny non-PSA blood test (Armune BioScience)
   • BRAF mutations
   • Early prostate cancer antigenE
   • Endoglin
   • E twenty-six (ETS) gene fusions
   • Genetic-based screening
   • Human glandular kallikrein 2 (hK2) (also known as kallikrein-related peptidase 2 [KLK2])
   • Interleukin-6
   • MicroRNAs in prostatic fluid/tissue
   • Neutrophil gelatinase-associated lipocalin (NGAL)
   • Prostate cancer gene 3 (PCA3)
   • TMPRSS2:ERG gene fusion
   • Transforming growth factor-beta 1.

   See also

   • CPB 0001 - Transrectal Ultrasound and
   • CPB 0352 - Tumor Markers.

Note: Some plans exclude coverage of preventive services.  Please check benefit plan descriptions for details.  Medically necessary diagnostic PSA testing is covered regardless of whether the member has preventive service benefits.

Background

The decision to perform routine prostate cancer screening with digital rectal examination (DRE) or prostate-specific antigen (PSA) is left to the discretion of the clinician.  Patients who request screening should be given objective information about the potential benefits and harms of early detection and treatment.

The American Cancer Society (ACS) recommends PSA screening for all men over age 50 and at age 45 for men at higher risk (e.g., men with a family history of prostate cancer and African-American men).  Similar recommendations have been issued by the American Urological Association (AUA) and the American College of Radiology.  The ACS, however, acknowledges that currently there is no clinical trial evidence that screening for prostate cancer is associated with a reduction in mortality.

The updated ACS guideline for the early detection of prostate cancer (Wolf et al, 2010) recommends both the PSA blood test and DRE should be offered annually, beginning at age 50, to men who have at least a 10-year life expectancy.  Men at high-risk (African-American men and men with a strong family of 1 or more first-degree relatives (father, brothers) diagnosed at an early age) should begin testing at age 45.  Men at even higher risk, due to multiple first-degree relatives affected at an early age, could begin testing at age 40.  Depending on the results of this initial test, no further testing might be needed until age 45.  The ACS states that information should be provided to all men about what is known and what is uncertain about the benefits and limitations of early detection and treatment of prostate cancer so that they can make an informed decision about testing.  Men who ask their doctor to make the decision on their behalf should be tested.  The ACS states that discouraging testing is inappropriate.  Furthermore, not offering testing is also inappropriate.

In a review on prostate cancer screening, Ilic and colleagues (2011) concluded that prostate cancer screening did not significantly decrease all-cause or prostate cancer-specific mortality in a combined meta-analysis of 5 randomized controlled trials.  Any benefits from prostate cancer screening may take greater than 10 years to accrue; therefore, men who have a life expectancy of less than 10 to 15 years should be informed that screening for prostate cancer is not beneficial and has harms.

The American Urological Association (AUA, 2013) recommends against PSA screening in men under age 40 years (Grade C) and does not recommend routine screening in men between ages 40 to 54 years at average risk (Grade C). AUA state that the greatest benefit of screening appears to be in men ages 55 to 69 years. "For men younger than age 55 years at higher risk, decisions regarding prostate cancer screening should be individualized. Those at higher risk may include men of African American race; and those with a family history of metastatic or lethal adenocarcinomas (e.g., prostate, male and female breast cancer, ovarian, pancreatic) spanning multiple generations, affecting multiple first-degree relatives, and that developed at younger ages."

The National Comprehensive Cancer Network (NCCN, v.2.2018) recommends baseline screening beginning at age 45. "African-American men and men with a family history of prostate cancer represent high-risk groups. However, the panel believes that current data are insufficient to definitively inform the best strategy for prostate cancer screening in these populations, and also notes that a baseline PSA value is a stronger predictive factor than a positive family history or race. Overall, the panel believes that it is reasonable for African-American men and those with a strong family history to begin discussing PSA screening with their providers earlier than those without such risk factors and to consider screening at annual rather than less frequent screening intervals." Panelists uniformly agreed that PSA testing should only be offered to men with a 10 or more year life expectancy. The panel supports screening in men until age 75. The panel recommends that PSA testing to be considered only in very healthy patients older than 75 years (category 2B); however, the panel uniformly discourage PSA testing in men unlikely to benefit from prostate cancer diagnosis based on age and/or comorbidity. The panel recommends that frequency of testing be 2 to 4 years for men aged 45 to 75 years with serum PSA values below 1 ng/mL, and at 1 to 2 year intervals for men with PSA of 1 to 3 ng/mL.

Most professional societies do not recommend routine screening for prostate cancer with DRE or serum tumor markers (e.g., PSA).  These include the American Academy of Family Physicians, the U.S. Preventive Services Task Force (USPSTF), the Institute for Clinical Systems Improvement, the Canadian Task Force on the Periodic Health Examination, the American College of Preventive Medicine, the U.S. Office of Technology Assessment, the American Society for Internal Medicine and American College of Physicians, the National Cancer Institute, the Centers for Disease Control and Prevention, and the technology assessment agencies of Canada, England, Sweden, and Australia.

The USPSTF (2018) recommends individualized decision-making about prostate cancer screening for men aged 55 to 69, thus providing a grade C recommendation for prostate cancer screening for men in that age group. The USPSTF systematically reviewed evidence on prostate-specific antigen (PSA)-based prostate cancer screening, treatments for localized prostate cancer, and prebiopsy risk calculators, concluding that although screening offers a small potential benefit of reducing chance of death from prostate cancer in some men, many men will experience potential harms of screening (i.e., false-positives results that require additional testing and possible prostate biopsy, overdiagnosis, overtreatment, and treatment complications such as erectile dysfunction and urinary difficulties). In regard to age and the effectiveness of PSA-based screening and prostate cancer mortality, outcomes from randomized clinical trials showed that randomization to screening was not associated with statistically significant reductions in prostate cancer mortality among men aged 65 to 74 years at baseline in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial (RR, 1.02 [95% CI, 0.77-1.37]) or among men aged 70 to 74 years at baseline in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (RR, 1.17 [95% CI, 0.82-1.66]). The systematic review revealed that across all studies, relatively few men older than 70 years were enrolled, and there is limited evidence about the differential benefits or harms of screening for men at higher risk. The USPSTF concluded that the evidence is limited on the benefit of screening among men older than 70 years, thus, providing a grade D recommendation against PSA-based screening for prostate cancer in men 70 years and older. The USPSTF further concluded that the evidence was insufficient to make a specific recommendation regarding screening discussions for higher-risk groups: African-American men and those with a family history of prostate cancer.

The American Academy of Family Physicians (AAFP, 2018) makes the recommendation against routine screening (i.e., PSA test or DRE) for prostate cancer. For men who desire PSA screening, it should only be performed after engaging in shared decision making. Furthermore, PSA-based prostate cancer screening should not be performed in men over 70 years of age.

An UpToDate review on "Screening for prostate cancer" (Hoffman, 2018) recommend prostate cancer screening beginning at age 40 to 45 years for men at high risk (e.g., black men, men with family history of prostate cancer, particularly in relatives younger than age 65, and men who are known or likely to have the BRCA1 or BRCA2 mutations) and have a life expectancy greater than or equal to 10 years (Grade 2C). For men at "average risk", the authors recommend prostate screening discussions with their healthcare provider starting at the age of 50, and who also have a life expectancy greater than or equal to 10 years. The authors recommend discontinuing the screening after age 69, or earlier when comorbidities limit life expectancy to less than 10 years, or patient decides against screening (Grade 2B). The authors further note that stopping screening at age 65 may be appropriate if the PSA level is less than 1 ng/mL.

If screening is to be performed, the generally accepted approach is to screen with DRE and PSA and to limit screening to men with a life expectancy of greater than 10 years.  There is currently insufficient evidence to determine the need and optimal interval for repeat screening or whether PSA thresholds must be adjusted for density, velocity, or age.

Schenk-Braat and Bangma (2006) noted that PSA is currently the most important biochemical marker for the diagnosis of prostate cancer.  Because of the limited specificity of PSA, clinically irrelevant tumors and benign abnormalities are also detected that can potentially lead to over-treatment and the associated physical as well as emotional burden for the patient.  Furthermore, PSA is used as an indicator of progression or clinical response following prostate cancer therapy, but the prognostic value of this marker is limited.  Ongoing research is examining several alternative markers (e.g., osteoprotegerin, human kallikrein 2, and the gene DD3(PCA3)) that may improve the specificity of current PSA-based diagnostics and the prognostic value of PSA.

Prostate-specific antigen velocity, the yearly rate of increase of PSA, has not been proven to improve the test characteristics of PSA, Schroder and colleagues (2006) stated that PSA-driven screening has been applied to a large part of the male population in many countries.  An elevated PSA in secondary screens may indicate benign enlargement of the prostate rather than prostate cancer.  In such cases the yearly rate of increase of PSA (PSA velocity [PSAV]) may improve the test characteristics of PSA.  These investigators examined if PSAV predict prostate cancer in pre-screened populations.  Data from the European Randomized Study of Screening for Prostate Cancer Rotterdam were used to study the issue.  Relative sensitivity, relative specificity, and positive predictive value (PPV) were calculated.  Logistic regression analysis was used to compare odds ratios for positive biopsies.  The relationship between PSAV and parameters of tumor aggressiveness was investigated.  A total of 588 consecutive participants were identified who presented at their first screening with PSA values less than 4.0 and who progressed to PSA values greater than 4.0 ng/ml 4 years later were included in this study.  None was biopsied in round-1, all were biopsied in round-2.  Relative sensitivity and specificity depend strongly on PSAV cut-offs of 0.25 to 1.0 ng/ml/year.  The use of PSAV cut-offs did not improve the PPV of the PSA cut-off of 4.0 ng/ml, nor did any of the PSAV cut-offs improve the odds ratio (OR) for identifying prostate cancer with respect to the cut-off value of 4.0 ng/ml.  The rate of aggressive cancers seems to increase with increasing PSAV.  The authors concluded that PSAV did not improve the detection characteristics of a PSA cut-off of 4.0 ng/ml in secondary screening after 4 years.

Wolters et al (2009) evaluated the value of PSAV in screening for prostate cancer.  Specifically, the role of PSAV in lowering the number of unnecessary biopsies and reducing the detection rate of indolent prostate cancer was evaluated.  All men included in the study cohort were subjects in the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam section.  During the first and second screening round, a PSA test was performed on 2,217 men, and all underwent a biopsy during the second screening round 4 years later.  Prostate specific antigen velocity was calculated and biopsy outcome was classified as benign, possibly indolent prostate cancer, or clinically significant prostate cancer.  A total of 441 cases of prostate cancer were detected, 333 were classified as clinically significant and 108 as possibly indolent.  The use of PSAV cut-offs reduced the number of biopsies but led to important numbers of missed (indolent and significant) prostate cancer; PSAV was predictive for prostate ancer (OR: 1.28, p < 0.001) and specifically for significant prostate cancer (OR: 1.46, p < 0.001) in uni-variate analyses.  However, multi-variate analyses using age, PSA, prostate volume, DRE and transrectal ultrasonography outcome, and previous biopsy (yes/no) showed that PSAV was not an independent predictor of prostate cancer (OR: 1.01, p = 0.91) or significant prostate cancer (OR: 0.87, p = 0.30).  The authors concluded that the use of PSAV as a biopsy indicator would miss a large number of clinically significant cases of prostate cancer with increasing PSAV cut-offs.  In this study, PSAV was not an independent predictor of a positive biopsy in general or significant prostate cancer on biopsy.  Thus, PSAV does not improve the ERSPC screening algorithm.

The role of selenium in cancer prevention has been the subject of recent study and debate.  Population studies suggest that people with cancer are more likely to have low selenium levels (measured in the blood or in tissues such as toenail clippings) than healthy matched individuals.  However, in most cases it is not clear if low selenium levels are a cause or merely a consequence of disease.  Initial evidence from the Nutritional Prevention of Cancer (NPC) trial suggests that selenium supplementation reduces the risk of prostate cancer among men with normal baseline PSA levels and low selenium blood levels.  The ongoing Selenium and Vitamin E Cancer Prevention Trial (SELECT) aims to definitively address the role of selenium in prostate cancer prevention.  The study, which spans from 2001 to 2013, will include 32,400 men.  Currently, it is unclear if selenium is beneficial in the treatment of prostate cancer or any type of cancer.  Measurement of body selenium (e.g., in serum, toenail clippings) has no proven value in the prevention of prostate cancer.

Costello and Franklin (2009) proposed that changes in prostatic fluid composition could provide accurate and reliable biomarkers for the screening of prostate cancer.  Most notable is the consistent and significant decrease in citrate and zinc that is associated with the development and progression of prostate cancer.  These researchers provided the clinical and physiological basis and the evidence in support of the utility of prostatic fluid analysis as an effective approach for screening/detection of prostate cancer, especially early stage and "at-risk" subjects.  The problem of interference from benign prostatic hypertrophy that hampers PSA testing is eliminated in the potential prostatic fluid biomarkers.  The potential development of rapid, simple, direct, accurate clinical tests would provide additional advantageous conditions.  The authors stated that further exploration and development of citrate, zinc and other electrolytes as prostatic fluid biomarkers are needed to address this critical prostate cancer issue.

A long-term randomized controlled clinical trial found prostate cancer screening had no effect on mortality (Andriole et al, 2009).  From 1993 through 2001, investigators randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects).  Men in the screening group were offered annual PSA testing for 6 years and DRE for 4 years.  The subjects and health care providers received the results and decided on the type of follow-up evaluation.  Usual care sometimes included screening, as some organizations have recommended.  The numbers of all cancers and deaths and causes of death were ascertained.  In the screening group, rates of compliance were 85 % for PSA testing and 86 % for DRE.  Rates of screening in the control group increased from 40 % in the first year to 52 % in the sixth year for PSA testing and ranged from 41 to 46 % for DRE.  After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2,820 cancers) in the screening group and 95 (2,322 cancers) in the control group (rate ratio, 1.22; 95 % confidence interval [CI]: 1.16 to 1.29).  The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95 % CI: 0.75 to 1.70).  The data at 10 years were 67 % complete and consistent with these overall findings.  An important limitation of this study is that subjects in the control group underwent considerable screening outside of the clinical trial.  An accompanying editorial (Barry, 2009) commented that serial PSA screening has at best a modest effect on prostate cancer mortality during the first decade of follow-up, and that this benefit comes at the cost of substantial over-diagnosis and over-treatment.

Available evidence shows that the majority of men with low-risk prostate tumors receive aggressive treatment, despite the risk of complications. Shao and colleagues (2010) used the Surveillance, Epidemiology and End Results (SEER) database to study the records of 123,934 men over the age of 25 who had newly diagnosed prostate cancer from 2004 to 2006.  About 14 % of the men had PSA values lower than 4, generally younger men.  In that group, 54 % had low-risk disease that could be safely monitored for progression with little risk.  Nonetheless, 75 % of them received aggressive treatment, including a radical prostatectomy and radiation therapy.  Among men in that group over the age of 65, in which "watchful waiting" is generally advised for low-risk disease, 66 % had aggressive therapy.  In both cases, the percentages were similar to those in the group with PSA levels between 4 and 20.

Mazzola et al (2011) stated that the introduction and widespread adoption of PSA has revolutionized the way prostate cancer is diagnosed and treated.  However, the use of PSA has also led to over-diagnosis and over-treatment of prostate cancer resulting in controversy about its use for screening.  Prostate specific antigen also has limited predictive accuracy for predicting outcomes after treatment and for making clinical decisions about adjuvant and salvage therapies.  Thus, there is an urgent need for novel biomarkers to supplement PSA for detection and management of prostate cancer.  A plethora of promising blood- and urine-based biomarkers have shown promise in early studies and are at various stages of development (human kallikrein 2, early prostate cancer antigen, transforming growth factor-beta 1, interleukin-6, endoglin, prostate cancer gene 3 (PCA3), alpha-methylacyl coenzyme A racemase (AMACR) and E twenty-six (ETS) gene fusions).

Pettersson et al (2012) stated that whether the genomic re-arrangement trans-membrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (ERG) has prognostic value in prostate cancer is unclear.  Among men with prostate cancer in the prospective Physicians' Health and Health Professionals Follow-Up Studies, these researchers identified re-arrangement status by immunohistochemical assessment of ERG protein expression.  They used Cox models to examine associations of ERG over-expression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality).  In a meta-analysis including 47 additional studies, these investigators used random-effects models to estimate associations between re-arrangement status and outcomes.  The cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and 2005.  During a median follow-up of 12.6 years, 266 men experienced recurrence and 85 men developed lethal disease.  These researchers found no significant association between ERG over-expression and biochemical recurrence [hazard ratio (HR), 0.99; 95 % CI: 0.78 to 1.26] or lethal disease (HR, 0.93; 95 % CI: 0.61 to 1.43).  The meta-analysis of prostatectomy series included 5,074 men followed for biochemical recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events). TMPRSS2:ERG was associated with stage at diagnosis [risk ratio (RR)(≥T3 vs. T2), 1.23; 95% CI, 1.16-1.30) but not with biochemical recurrence (RR, 1.00; 95 % CI: 0.86 to 1.17) or lethal disease (RR, 0.99; 95 % CI: 0.47 to 2.09).  The authors concluded that the findings of this meta-analysis suggested that TMPRSS2:ERG, or ERG over-expression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy.

Salagierski et al (2012) stated that widespread PSA screening together with the increase in the number of biopsy cores has led to increased prostate cancer incidence.  Standard diagnostic tools still cannot unequivocally predict prostate cancer progression, which often results in a significant over-treatment rate.  These investigators presented recent findings on PCA3 and TMPRSS:ERG fusion, and described their clinical implications and performance.  The PubMed^® database was searched for reports on PCA3 (130 articles), TMPRSS:ERG and ETS fusion (180 publications) since 1999.  In recent years advances in genetics and biotechnology have stimulated the development of non-invasive tests to detect prostate cancer.  Serum and urine molecular biomarkers have been identified, of which PCA3 has already been introduced clinically.  The identification of prostate cancer specific genomic aberrations, i.e., TMPRSS2:ERG gene fusion, might improve diagnosis and affect prostate cancer treatment.  The authors concluded that although several recently developed markers are promising, often showing increased specificity for prostate cancer detection compared to that of PSA, their clinical application is limited.

Choudhury et al (2012) noted that despite widespread screening for prostate cancer and major advances in the treatment of metastatic disease, prostate cancer remains the second most common cause of cancer death for men in the Western world.  In addition, the use of PSA testing has led to the diagnosis of many potentially indolent cancers, and aggressive treatment of these cancers has caused significant morbidity without clinical benefit in many cases.  The recent discoveries of inherited and acquired genetic markers associated with prostate cancer initiation and progression provide an opportunity to apply these findings to guide clinical decision-making.  In this review, these investigators discussed the potential use of genetic markers to better define groups of men at high risk of developing prostate cancer, to improve screening techniques, to discriminate indolent versus aggressive disease, and to improve therapeutic strategies in patients with advanced disease.  PubMed-based literature searches and abstracts through January 2012 provided the basis for this literature review.  These researchers also examined secondary sources from reference lists of retrieved articles and data presented at recent congresses.  Cited review articles were only from the years 2007 to 2012, favoring more recent discussions because of the rapidly changing field.  Original research articles were curated based on favoring large sample sizes, independent validation, frequent citations, and basic science directly related to potentially clinically relevant prognostic or predictive markers.  In addition, all authors on the manuscript evaluated and interpreted the data acquired.  These investigators addressed the use of inherited genetic variants to assess risk of prostate cancer development, risk of advanced disease, and duration of response to hormonal therapies.  The potential for using urine measurements such as PCA3 RNA and TMPRSS2-ERG gene fusion to aid screening was discussed.  Multiple groups have developed gene expression signatures from primary prostate tumors correlating with poor prognosis, and attempts to improve and standardize these signatures as diagnostic tests were presented.  Massive sequencing efforts are underway to define important somatic genetic alterations (amplifications, deletions, point mutations, translocations) in prostate cancer, and these alterations hold great promise as prognostic markers and for predicting response to therapy.  These researchers provided a rationale for assessing genetic markers in metastatic disease for guiding choice of therapy and for stratifying patients in clinical trials, and discussed challenges in clinical trial design incorporating the use of these markers. The authors concluded that the use of genetic markers has the potential to aid disease screening, improve prognostic discrimination, and prediction of response to treatment. However, most markers have not been prospectively validated for providing useful prognostic or predictive information or improvement upon clinicopathologic parameters already in use. They stated that significant efforts are underway to develop these research findings into clinically useful diagnostic tests in order to improve clinical decision making.

Measurement of MicroRNAs in Prostatic Fluid/Tissue

Schubert et al (2016) noted that defining reliable biomarkers is still a challenge in patients with urological tumors. Because short non-coding RNAs known as microRNAs (miRNAs) regulate diverse important cellular processes, these non-coding RNAs are putative molecular candidates.  These researchers provided a critical overview about the current state of miRNAs as biomarkers in urological cancers with respect to prognostic stratification as well as for individual treatment selection.  They performed a comprehensive review of the published literature focusing at the clinical relevance of miRNAs in tissues and body fluids of prostate, bladder and kidney cancer.  Using electronic database, a total of 91 articles, published between 2009 and 2015, were selected and discussed regarding the robustness of miRNAs as valid biomarkers.  A number of miRNAs have been identified with prognostic and predictive relevance in different urologic tumor types.  However, the inconsistency of the published results and the lack of multivariate testing in independent cohorts do not allow an introduction into clinical decision making at present.  The authors concluded that miRNA-based biomarkers are a promising tool for future personalized risk stratification and response prediction in urological cancers.

Fabris et al (2016) stated that miRNAs control protein expression through the degradation of RNA or the inhibition of protein translation. The miRNAs influence a wide range of biologic processes and are often deregulated in cancer.  This family of small RNAs constitutes potentially valuable markers for the diagnosis, prognosis, and therapeutic choices in prostate cancer (PCa) patients, as well as potential drugs (miRNA mimics) or drug targets (anti-miRNAs) in PCa management.  These investigators reviewed the currently available data on miRNAs as biomarkers in PCa and as possible tools for early detection and prognosis.  A systematic review was performed searching the PubMed database for articles in English using a combination of the following terms: microRNA, miRNA, cancer, prostate cancer, miRNA profiling, diagnosis, prognosis, therapy response, and predictive marker.  The authors summarized the existing literature regarding the profiling of miRNA in PCa detection, prognosis, and response to therapy.  The articles were reviewed with the main goal of finding a common recommendation that could be translated from bench to bedside in future clinical practice.  The authors concluded that the miRNAs are important regulators of biologic processes in PCa progression.  A common expression profile characterizing each tumor subtype and stage has still not been identified for PCa, probably due to molecular heterogeneity as well as differences in study design and patient selection.  Moreover, they stated that large-scale studies that should provide additional important information are still missing; further studies, based on common clinical parameters and guidelines, are needed to validate the translational potential of miRNAs in PCa clinical management.  Such common signatures are promising in the field and emerge as potential biomarkers.  The authors noted that the literature showed that microRNAs hold potential as novel biomarkers that could aid prostate cancer management, but additional studies with larger patient cohorts and common guidelines are needed before clinical implementation.

Furthermore, an UpToDate review on "Screening for prostate cancer" (Hoffman, 2013) does not mention the use of microRNAs as a screening tool for prostate cancer.

BRAF Mutations

Cohn and colleagues (2017) stated that mutations in the BRAF gene have been implicated in several human cancers.  The objective of this screening study was to identify patients with solid tumors (other than metastatic melanoma or papillary thyroid cancer) or multiple myeloma harboring activating BRAFV600 mutations for enrollment in a vemurafenib clinical study.  Formalin-fixed, paraffin-embedded tumor samples were collected and sent to a central laboratory to identify activating BRAFV600 mutations by bi-directional direct Sanger sequencing.  Overall incidence of BRAFV600E mutation in evaluable patients (n = 548) was 3 % (95 % CI: 1.7 to 4.7): 11 % in colorectal tumors (n = 75), 6 % in biliary tract tumors (n = 16), 3 % in non-small cell lung cancers (n = 71), 2 % in other types of solid tumors (n = 180), and 3 % in multiple myeloma (n = 31).  There were no BRAFV600 mutations in this cohort of patients with ovarian tumors (n = 68), breast cancer (n = 86), or PCa (n = 21).  The authors noted that BRAF mutations have been identified in up to 10 % of Asian patients with PCa, but appeared to be rare among Caucasian patients.  The finding of no mutations among 21 patients with PCa is also consistent with data from the COSMIC database, showing documented BRAF mutations in approximately 1 % of almost 2,500 sequenced samples.

Neutrophil Gelatinase-Associated Lipocalin

Muslu and colleagues (2017) noted that PSA with DRE is used for diagnosis of PCa, where definite diagnosis can only be made by prostate biopsy. Recently neutrophil gelatinase-associated lipocalin (NGAL), a lipocalin family member glycoprotein, come into prominence as a cancer biomarker.  In a prospective study, these researchers tested serum NGAL as a diagnostic biomarker for PCa and for differentiation of PCa from benign prostatic hyperplasia (BPH).  A total of 90 patients who underwent trans-rectal ultrasound (TRUS)-guided 12-core prostate biopsy between May 2015 and September 2015 were evaluated.  Histopathologically diagnosed 45 PCa and 45 BPH patients were enrolled in this study.  Serum NGAL and PSA levels of all participants were measured, then these data were evaluated by statistical programs.  When sensitivity fixed to 80 % specificity of NGAL was better than PSA (49 % and 31 %, respectively).  Receiver operating characteristic (ROC) curve analysis showed that NGAL alone or its combined use with PSA exhibited better area under curve (AUC) results than PSA alone (0.662, 0.693, and 0.623, respectively).  The authors concluded that NGAL gave promising results such as increased sensitivity and a better AUC values in order to distinguish PCa from BPH.  They stated that NGAL showed a potential to be a non-invasive biomarker which may decrease the number of unnecessary biopsies; more studies are needed to define more accurate cut-off values for both NGAL alone and PSA-NGAL combination; and more accurate results can be achieved by increasing the number of cases.

Non-PSA Blood Test

Apifiny (Armune BioScience, Inc., Kalamazoo, MI) is a non-PSA blood test that measures eight prostate-cancer-specific autoantibodies in human serum (i.e.,  ARF 6, NKX3-1, 5’-UTR-BMI1, CEP 164, 3’-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2) (AMA, 2017; Armune BioScience, 2017). In essence, The Apifiny measures the body’s immune-system response to cancerous activity in prostate tissue. Per Armune BioScience, Inc., autoantibodies are produced and replicated (amplified) by the immune system in response to the presence of prostate-cancer cells. The autoantibodies are stable and, because of their amplification, are likely to be abundant and easy to detect, especially during the early stages of cancer. The methodology involves immunoassay, flow cytometry, and algorithmic analysis to derive at a score that indicates a potential risk of having prostate cancer. The use of Apifiny results may supplement other information about prostate-cancer risks, and may therefore aid in earlier diagnosis of prostate cancer and potentially increase survival rates. It is not known if Apifiny scores are affected by age, race, or other factors. The Apifiny non-PSA blood test is not FDA approved (Armune BioScience, 2017).

Schipper et al (2016) discuss novel prostate cancer biomarkers derived from autoantibody signatures. The authors used T7 phage-peptide detection to identify a panel eight biomarkers for prostate cancer (PCA) on a training set. The estimated receiver-operating characteristic (ROC) curve had an area under the ROC curve of 0.69 when applied to the validation set. Spearman correlations were high, within 0.7 to 0.9, indicating that the biomarkers have a degree of inter-relatedness. They noted that the  identified biomarkers play a role in processes such as androgen response regulation and cellular structural integrity and are proteins that are thought to play a role in prostate tumorigenesis. The authors concluded that autoantibodies against PCA can be developed as biomarkers for detecting PCA. The scores from the algorithm they developed can be used to indicate a relative high or low risk of PCA, particularly for patients with intermediate (4.0 to 10 ng/ml) PSA levels. Since most commercially available assays test for PSA or have a PSA component, this novel approach has the potential to improve diagnosis of PCA using a biologic measure independent of PSA.

Wang et al (2005) discussed autoantibody signature biomarkers in prostate cancer. The authors constructed phage-protein microarrays in which peptides derived from a prostate-cancer cDNA library were expressed as a prostate-cancer – phage fusion protein. They used the phage protein microarrays to analyze serum samples from 119 patients with prostate cancer, along with 138 controls.  A phage-peptide detector that was constructed from the training set was evaluated on an independent validation set of 128 serum samples (60 from patients with prostate cancer and 68 from controls). The authors note the 22-phage-peptide detector had 88.2 percent specificity (95 percent confidence interval, 0.78 to 0.95) and 81.6 percent sensitivity (95 percent confidence interval, 0.70 to 0.90) in discriminating between the group with prostate cancer and the control group. This panel of peptides performed better than did prostate-specific antigen (PSA) in distinguishing between the group with prostate cancer and the control group (area under the curve for the autoantibody signature, 0.93; 95 percent confidence interval, 0.88 to 0.97; area under the curve for PSA, 0.80; 95 percent confidence interval, 0.71 to 0.88). Logistic-regression analysis revealed that the phage-peptide panel provided additional discriminative power over PSA (P<0.001). Among the 22 phage peptides used as a detector, 4 were derived from in-frame, named coding sequences. The remaining phage peptides were generated from untranslated sequences. The authors concluded that autoantibodies against peptides derived from prostate-cancer tissue could be used as the basis for a screening test for prostate cancer. However, they note that they have not tested the phage-microarray system for screening for prostate cancer. They state that this would require extension and confirmation in community-based screening cohorts. Furthermore, the authors state that although promising, how it will perform in prospective and multi-institutional studies remains to be determined.

The National Comprehensive Cancer Network Biomarkers Compendium does not mention Apifiny, non-PSA test, as a diagnostic or screening option.

Genetic-Based Screening

Benafif and Eeles (2016) noted that PCa is the commonest non-cutaneous cancer in men in the United Kingdom.  Epidemiological evidence as well as twin studies points towards a genetic component contributing to etiology.  A family history of PCa doubles the risk of disease development in 1st-degree relatives.  Linkage and genetic sequencing studies identified rare moderate-high-risk gene loci, which predispose to PCa development when altered by mutation.  Genome-wide association studies (GWAS) have identified common single-nucleotide polypmorphisms (SNPs), which confer a cumulative risk of PCa development with increasing number of risk alleles.  There are emerging data that castrate-resistant disease is associated with mutations in DNA repair genes.  Linkage studies investigating possible high-risk loci leading to PCa development identified possible loci on several chromosomes, but most have not been consistently replicated by subsequent studies.  Germline SNPs related to PSA levels and to normal tissue radio-sensitivity have also been identified though not all have been validated in subsequent studies.  Utilizing germline SNP profiles as well as identifying high-risk genetic variants could target screening to high-risk groups, avoiding the drawbacks of PSA screening.  The authors concluded that incorporating genetics into PCa screening is being investigated currently using both common SNP profiles and higher risk rare variants.  Knowledge of germline genetic defects will allow the development of targeted screening programs, preventive strategies and the personalized treatment of PCa.

Eeles and Ni Raghallaigh (2018) noted that PCa is the second most common malignancy affecting men worldwide, and the commonest affecting men of African descent.  Significant diagnostic and therapeutic advances have been made in the past 10 years.  Improvements in the accuracy of PCa diagnosis include the uptake of multi-parametric magnetic resonance imaging (MRI) and a shift towards targeted biopsy.  There are also more life-prolonging systemic and hormonal therapies for men with advanced disease.  However, the development of robust screening tools and targeted screening programs has not followed at the same pace.  Evidence to support population-based screening remains unclear, with the use of PSA as a screening test limiting the ability to discriminate between clinically significant and insignificant disease.  Since PCa has a large heritable component and given that most men without risk factors have a low lifetime risk of developing lethal PCa, much work is being done to further the knowledge of how clinicians can best screen men in higher risk categories, such as those with a family history (FH) of the disease or those of African ancestry.  These men have been reported to carry upwards of a 2-fold increased risk of developing the disease at an earlier age, with evidence suggesting poorer survival outcomes.  In men with a FH of PCa, this is felt to be due to rare, high-penetrance mutations and the presence of multiple, common low penetrance alleles, with men carrying specific germline mutations in the BRCA and other DNA repair genes at particularly high risk.  To-date, large scale GWAS have led to the discovery of approximately 170 SNPs associated with PCa risk, allowing over 30 % of PCa risk to be explained.  Genomic tests, utilizing somatic (prostate biopsy) tissue can also predict the risk of unfavorable pathology, biochemical recurrence and the likelihood of metastatic disease using gene expression.  Targeted screening studies are currently under way in men with DNA repair mutations, men with a FH and those of Afro-Caribbean ethnicity that will greater inform the understanding of disease incidence and behavior in these men, treatment outcomes and developing the most appropriate screening regime for such men.  Incorporating a patient's genetic mutation status into risk algorithms allows clinicians an opportunity to develop targeted screening programs for men in whom early cancer detection and treatment will positively influence survival, and in the process offer male family members of affected men the chance to be counselled and screened accordingly.  The authors concluded that advances in the field of uro-oncology such as the diagnostic performance of multi-parametric MRI and genomic interrogation have led to a position of potentially use these as screening tools in the right populations.

Furthermore, an UpToDate review on "Screening for prostate cancer" (Hoffman, 2018) does not mention genetic-based screening.

MRI-Targeted or Standard Biopsy in Prostate Cancer Screening

Eklund et al (2021) stated that high rates of over-diagnosis are a critical barrier to organized PCa screening; MRI with targeted biopsy has shown the potential to address this challenge.  However, the implications of its use in the context of organized PCa screening are unknown.  These investigators carried out a population-based non-inferiority trial of PCa screening in which men 50 to 74 years of age from the general population were invited by mail to participate; participants with PSA levels of 3 ng/ml or higher were randomly assigned, in a 2:3 ratio, to undergo a standard biopsy (standard biopsy group) or to undergo MRI, with targeted and standard biopsy if the MRI results suggested PCa (experimental biopsy group).  The primary outcome was the proportion of men in the intention-to-treat (ITT) population in whom clinically significant cancer (Gleason score greater than or equal to 7) was diagnosed.  Akey secondary outcome was the detection of clinically insignificant cancers (Gleason score of 6).  Of 12,750 men enrolled, 1,532 had PSA levels of 3 ng/ml or higher and were randomly assigned to undergo biopsy: 603 were assigned to the standard biopsy group and 929 to the experimental biopsy group.  In the ITT analysis, clinically significant cancer was diagnosed in 192 men (21 %) in the experimental biopsy group, as compared with 106 men (18 %) in the standard biopsy group (difference, 3 percentage points; 95 % CI: -1 to 7; p < 0.001 for non-inferiority).  The percentage of clinically insignificant cancers was lower in the experimental biopsy group than in the standard biopsy group (4 % [41 participants] versus 12 % [73 participants]; difference, -8 percentage points; 95 % CI: -11 to -5).  The authors concluded that MRI with targeted and standard biopsy in men with MRI results suggestive of PCa was non-inferior to standard biopsy for detecting clinically significant PCa in a population-based screening-by-invitation trial and resulted in less detection of clinically insignificant cancer.

The authors stated that the STHLM3-MRI trial was carried out in Stockholm, Sweden, with centralized radiologic and pathological assessment, which may limit generalizability to other health care settings.  In addition, only a single round of screening was conducted, so whether the reduction in over-diagnosis will be retained via multiple rounds of screening is unknown.  However, subjects in this trial will be invited for subsequent screening, and men with negative MRI results will be followed to ensure that clinically significant cancers were not overlooked.  These researchers also could not draw definitive conclusions regarding the equivalency of MRI-targeted and standard biopsy approaches with respect to PCa mortality, although equivalency appeared plausible since the Gleason score distributions across clinically significant cancers were similar in the 2 trial groups.  Although consensus is lacking on the definition of clinically significant PCa, these researchers used Gleason scores of 7 or higher, a common definition used in previous studies, while also reporting outcomes for other scores (Gleason Score of greater than or equal to 4+3).  In the STHLM3-MRI trial, men with negative MRI results but Stockholm3 scores of 25 % or greater were recommended to undergo standard biopsy as a safety mechanism.  Recognizing that Stockholm3 testing is not widely available, these investigators included sensitivity analyses in which the biopsy outcomes of these participants were omitted.  The effect on the results was small.  Other safety mechanisms could be used -- for example, biopsy on the basis of PSA alone (e.g., PSA greater than or equal to 10 ng/ml) or PSA combined with free PSA, prostate volume (i.e., PSA density), or both.  These researchers stated that in a trial of population-based screening by invitation, these findings showed that among men with elevated PSA levels, combined biopsy performed only in men who had positive results on MRI was non-inferior to standard biopsy for detecting clinically significant PCa.  The markedly reduced incidences of unnecessary biopsy and diagnosis of clinically insignificant cancer address key barriers impeding implementation of population-based screening for PCa.  When normalized to a population of 10,000 men 50 to 74 years of age in which those with elevated PSA levels (greater than or equal to 3 ng/ml) were referred for biopsy, the combined biopsy approach in men with positive MRI scans would result in 409 fewer men undergoing biopsy, 366 fewer biopsies with benign findings, and 88 fewer clinically insignificant cancers detected than with the standard biopsy approach.  These numbers represent 48 %, 73 %, and 62 % lower incidences, respectively, with the use of MRI and the combined biopsy approach.  These investigators stated that the reduced biopsy rate and potential down-stream savings that resulted from less over-treatment offer potential cost savings that may offset the additional costs of MRI.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
84152	Prostate specific antigen (PSA); complexed (direct measurement)
84153	total
84154	free
CPT codes not covered for indications listed in the CPB :
Genetic based screening for prostate cancer - no specific code:
0021U	Oncology (prostate), detection of 8 autoantibodies (ARF 6, NKX3-1, 5'-UTR-BMI1, CEP 164, 3'-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2), multiplexed immunoassay and flow cytometry serum, algorithm reported as risk score
84255	Chemistry, Selenium [PCA3]
TMPRSS2:ERG gene fusion, Measurement of microRNAs in prostatic fluid/tissue:
No specific code
CPT codes not covered for indications listed in the CPB:
81210	BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)
81313	PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen]) ratio (eg, prostate cancer)
81539	Oncology (high-grade prostate cancer), biochemical assay of four proteins (Total PSA, Free PSA, Intact PSA, and human kallikrein-2 [hK2]), utilizing plasma or serum, prognostic algorithm reported as a probability score
83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified [neutrophil gelatinase-associated lipocalin (NGAL)]
Other CPT codes related to the CPB:
88271	Molecular cytogenics; DNA probe, each (eg, FISH)
88272	chromosomal in situ hybridization, analyze 3-5 cells (eg, for derivatives and markers)
88273	chromosomal in situ hybridization, analyze 10-30 cells (eg, for microdeletions)
88274	Interphase in situ hybridization, analyze 25-99 cells
88275	Interphase in situ hybridization, analyze 100-300 cells
88291	Cytogenics and molecular cytogenics, interpretation and report
Modifier 0Z	Solid tumor gene, not otherwise specified
HCPCS codes covered if selection criteria are met:
G0102	Prostate cancer screening; digital rectal examination
G0103	Prostate cancer screening; prostate specific antigen test (PSA)
ICD-10 codes covered if selection criteria are met:
C61	Malignant neoplasm of prostate
D07.5	Carcinoma in situ of prostate
D29.1	Benign neoplasm of prostate
D40.0	Neoplasm of uncertain behavior of prostate
N40.0 - N40.3	Enlarged prostate
N42.30 - N42.39	Dysplasia of prostate
R97.20 - R97.21	Elevated prostate specific antigen [PSA]
Z12.5	Encounter for screening for malignant neoplasm of prostate
Z15.03	Genetic susceptibility to malignant neoplasm of prostate
Z80.42	Family history of malignant neoplasm of prostate
Z85.46	Personal history of malignant neoplasm of prostate

The above policy is based on the following references: