Policy

BCBSNC will provide coverage for gene expression profiling and protein biomarkers for prostate cancer when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy. 

When Gene Expression Profiling and Protein Biomarkers for Prostate Cancer is covered

1. For individuals with low-risk or favorable intermediate-risk disease, as defined by the NCCN (See Note 1), the one-time use of Prolaris^®, Oncotype DX Genomic Prostate Score^®, or Decipher^® tumor-based assays to guide management of prostate cancer is considered medically necessary when all the following criteria are met: 
   1. When pathological examination showed localized adenocarcinoma of the prostate with no clinical evidence of metastasis or lymph node involvement.
   2. When the individual has no significant co-morbidities, including advanced age, to suggest they have an estimated life expectancy of less than 10 years.
2. For individuals with unfavorable intermediate-risk and high-risk disease, as defined by the NCCN (see Note 1), the one-time use of Prolaris^® or Decipher^® tumor-based assays to guide management of prostate cancer is considered medically necessary when all of the following conditions are met:
   1. A needle biopsy showed localized adenocarcinoma of the prostate with no clinical evidence of metastasis or lymph node involvement.
   2. The individual has no significant co-morbidities, including advanced age, to suggest they have an estimated life expectancy of less than 10 years.
3. For individuals for whom there is a potential need for a prostate biopsy, the one-time use of the ExoDx Prostate (IntelliScore) (EPI) biomarker test either once prior to prostate biopsy or once prior to repeat biopsy is considered medically necessary when all of the following conditions are met:
   1. The individual has confirmed (See Note 2) moderately elevated PSA levels: 
      1. For individuals ages 50 – 75 years, PSA levels between 3 – 10 ng/mL 
      2. For individuals over the age of 75, PSA levels between 4 – 10 ng/mL
   2. The individual has none of the following conditions for which a prostate biopsy is already indicated:
      1. DRE suspicious for cancer. 
      2. Persistently elevated PSA. 
      3. Positive multiparametric MRI, if performed. 
      4. Known to have a high-penetrance prostate cancer risk gene(s) per NCCN guidelines (See Note 3)
   3. The individual has no other relative contraindication for prostate biopsy including any of the following:
      1. A less than 10-year life expectancy. 
      2. Benign disease not ruled out.
4. For individuals with a prostate, the one-time use of the 4Kscore test (either once prior to initial biopsy or once prior to repeat biopsy) is considered medically necessary when all the following conditions are met: 
   1. The individual has confirmed (see Note 2), moderately elevated PSA levels
      1. .For individuals ages 45 – 75 years, PSA levels greater than 3 and less than 10 ng/mL. 
      2. For individuals over the age of 75, PSA levels greater than or equal to 4 and less than 10 ng/mL.
   2. The individual has none of the following conditions for which a prostate biopsy is already indicated:
      1. DRE suspicious for cancer. 
      2. Persistently elevated PSA. 
      3. Positive multiparametric MRI (if performed). 
      4. Ethnicity at higher risk for prostate cancer (see Note 4).
      5. First-degree relative (see Note 5) with prostate cancer.
      6. Known to have a high-penetrance prostate cancer risk gene(s) per NCCN guidelines (see Note 3).
   3. The individual has no other relative contraindication for prostate biopsy including any of the following: 
      1. A less than 10-year life expectancy. 
      2. Benign disease not ruled out.
5. For individuals with a prostate, the one-time use of the IsoPSA^® test (either once prior to initial biopsy or once prior to repeat biopsy) is considered medically necessary when all the following conditions are met: 
   1. For individuals 50 years of age or older who have confirmed (see Note 2) PSA levels greater than 4 and less than or equal to 25 ng/mL. 
   2. The individual has no other relative contraindication for prostate biopsy, including any of the following: 
      1. A less than 10- year life expectancy. 
      2. Benign disease not ruled out.

When Gene Expression Profiling and Protein Biomarkers for Prostate Cancer is not covered

1. For the assessment and/or monitoring of prostate cancer, the following tests are considered not medically necessary: 
   1. Ki-67 immunohistochemistry 
   2. PTEN loss 
2. The following tests are considered not medically necessary:

• All other urine testing for gene expression profile and/or protein biomarkers designed to assess prostate cancer.
• Other screening tests for prostate cancer, (alpha-methylacyl coenzyme A racemase (AMACR), ConfirmMDx, early prostate cancer antigen, endoglin, E twenty-six (ETS) gene fusions, human kallikrein 2, analysis of prostatic fluid electrolyte composition, interleukin-6, transforming growth factor-beta 1, TMPRSS2:ERG gene fusion, MyProstateScore, gene hypermethylation, PCA3/KLK3 ratio, Prostate Health Index (PHI), PCA3 score.
• All other tests not described above that use cellular and biologic features of a tumor (e.g., those that are used to predict risk of recurrence in patients with prostate cancer).

Reimbursement is not allowed for other screening tests for prostate cancer that are not listed in the “when covered” section, including, but not limited to, alpha-methylacyl coenzyme A racemase (AMACR). 

Notes:

Note 1: NCCN Prostate Cancer Initial Risk Stratification and Staging Workup for Clinically Localized Disease (NCCN, 2024a).

Policy Guidelines

Prostate cancer (PCa) is the most common cancer in American individuals who have a prostate and the second leading cause of death in the same group. In 2024, the American Cancer Society estimates that approximately 299,010 new prostate cancer diagnoses and approximately 35,250 prostate cancer deaths will occur; although, the five-year survival rate between 2012-2018 was 97%. About one individual in eight among those who have a prostate will be diagnosed with prostate cancer during their lifetime in the United States (ACS, 2024a, 2024b).

Many cases of prostate cancer do not become clinically evident, as indicated in autopsy studies, where prostate cancer is detected in approximately 30 percent of individuals with a prostate aged 55 or older and approximately 60 percent of individuals with a prostate by age 80 (Bell et al., 2015). These data suggest that prostate cancer often grows so slowly that most individuals die of other causes before the disease becomes clinically advanced (Hoffman, 2023).

Prostate cancer survival is related to many factors, especially the extent of tumor at the time of diagnosis. The five-year relative survival among individuals with cancer localized to the prostate or with regional spread is 100%, compared with 31% among those diagnosed with distant metastases (Hoffman, 2023). Gene expression profiling has been proposed as a method of risk stratification for prostate cancer. Several tests evaluating the expression levels of various genes have been produced to be used in conjunction with other tools such as Gleason score and PSA assessment. The Gleason score is a scoring system used to categorize a prostate cancer biopsy based on risk assessment.

Tissue-based gene expression classifiers (GEC) are now widely used to assist in prostate cancer prognosis. These tests are RNA-based prognostic biomarkers that analyze a distinct multigene panel to predict cancer progression, from the chance of having the disease to the probability of death at ten years due to prostate cancer. Genomic tests can predict prostate cancer aggressiveness, detect potentially dangerous prostate cancer-related genomic activity, and utilize biopsy samples to deliver prognostic information via immunofluorescence imaging. Additionally, researchers have identified the potential of microRNAs as human prostate cancer biomarkers (Song et al., 2018). While several types of biomarker tests exist, the NCCN specifically recommends Prolaris, Oncotype DX Genomic Prostate Score^® (GPS^™), and Decipher, as tumor-based molecular assays to consider during initial risk stratification (NCCN, 2024a). Ki-67 and PTEN are also listed in NCCN guidelines, but are not recommended (NCCN, 2024a).

Proprietary Testing, Clinical Utility and Analytical Validity

Hu et al. (2018) evaluated the utility of three genomic expression classifiers (GEC), including Decipher, Oncotype, and Prolaris. 747 patients underwent GEC testing. The authors found that “Among patients with clinical favorable risk of cancer, the rate of active surveillance (AS) differed significantly among patients with a GEC result above the threshold (46.2%), those with a GEC result below the threshold (75.9%), and those who did not undergo GEC (57.9%)”. The authors further estimated that “for every nine individuals with favorable risk of cancer who undergo GEC testing, one additional patient may have their disease initially managed with AS” (Hu et al., 2018).

Prolaris

The test “Prolaris” (created by Myriad Genetics) has been used to inform decision making on active surveillance (AS) and whether to proceed to a treatment option, such as radiation or surgery. Prolaris is an assessment of the average expression of 31 cell-cycle progression (CCP) genes compared to 15 reference genes. This score is combined with the patient’s age, PSA, percent positive cores, clinical stage, Gleason score, and AUA risk category and is intended to provide a 10-year prostate cancer-specific mortality risk. Scores range from zero to ten, with each unit increase representing a doubling of disease-risk progression. Prolaris may also be used to assess risk post-prostatectomy, and the same scale of zero to ten is used. Each unit increase represents a doubling of risk of biochemical recurrence (BCR) (Alford et al., 2017).

Cell cycle progression (CCP) expression has found to correlate with mortality rate of prostate cancer and can provide important pretreatment prognostic information. Cuzick et al. (2015) found that not only was there a relationship between CCP expression and mortality rate, the increased expression of CCP was predictive of BCR after 10 years. Even after adjusting for factors such as PSA and Gleason score, the CCP was both “highly significant” and “independent” of prostate cancer mortality rate. The authors noted that the CCP score could be created from minimal tumor mass (as little as 0.5 mm), with a 90% success rate with >0.5 mm visible tumor, as well as Prolaris’ objective criteria compared to the Gleason score (Cuzick et al., 2015).

Prolaris may be used to lower unnecessary treatment by providing a molecular indication of the disease’s progression. Radical treatments, such as prostatectomies, are often unnecessary, and there is utility in a biomarker metric than can reliably inform providers of a course of treatment or condition. An AS status is preferable to treatment. Hu et al. (2018) used data provided by the CCP score (along with two other biomarker tests) to perform risk stratification and assess whether further treatment was needed or if the condition could be managed by active surveillance. Lin et al. (2018) clearly separated high- and low-risk patients using the CCP score. The study combined the CCP score as well as a clinical assessment from CAPRA into a cell-cycle risk (CCR) score. This CCR score was used to select patients for an AS status. The threshold created from both the molecular measures and the clinical measures has the advantage of including higher-risk patients whose clinical features may be lowerrisk. Furthermore, the patients that fell below the threshold were found to have a mortality risk of 2.5%, and the probability of survival of patients with scores under the threshold was 100% (Hu et al., 2018; Lin et al., 2018). Finally, Prolaris has been used by providers to inform clinician decision making. A survey by Carneiro et al found that the course of treatment for prostate cancer patients was influenced by Prolaris’ results. About 65% of cases were reported to have shifted in the intended treatment based on the test results, and about 40% were reported to have opted for the AS choice (a “decrease” in treatment) (Carneiro et al., 2018). 

Tward et al. (2020) studied the ability of CCR to predict prostate cancer metastasis using Prolaris. According to a CCR threshold of 2.112, 29.5% patients were hypothesized to be high risk metastasis (CCR>2.112) and 70.5% were unfavorable intermediate risk patients (CCR < 2.112). Patients were followed five years later to determine if CCR accurately predicted metastasis in those undergoing multimodality therapy (androgen deprivation with surgery) or radiation therapy. According to the results, the CCR score does provide a clinically meaningful different risk of metastasis for patients receiving multimodality therapy or radiation therapy. Multimodality therapy reduced patients' risk of metastasis and treatment benefit can be evaluated as a function of the CCR score. For those with CCR scores below the threshold of 2.112 (27% of high-risk group and 73% of the unfavorable intermediate group), radiation therapy was considered after assessing the difference in the risk of metastasis (Tward et al., 2020).

Oncotype DX Genomic Prostate Score^® (GPS^™) is similar to Prolaris in that it assesses levels of gene expression, could be used for lower-risk patients, and could inform clinicians about the possible course of treatment. The primary difference is that Oncotype DX only tests 12 genes, with five reference genes (compared to 31 and 15, respectively, for Prolaris) (Exact Sciences, 2021). These expression levels are combined into an algorithm to produce a genomic prostate score (GPS) score of 0-100. This GPS score correlated with prediction of cancer aggression (outcomes such as death or recurrence) (Cullen et al., 2015).

Cullen et al. (2015) found that the GPS score correlated well with BCR. The researchers noted that OncoType DX is a good predictor of both early and late BCR and is validated for adverse pathology whereas Prolaris is validated for 10-year mortality or BCR after radical prostatectomy (Alford et al., 2017; Cullen et al., 2015; Davis, 2014; NCCN, 2024a). Oncotype DX was recently validated in a group of individuals separated by race, showing that this tool is an independent predictor of adverse pathology with similar predictive accuracy in both African American (n=96) and European American (n=76) populations (Murphy et al., 2020).

AR-V7 Nucleus Detect Test 

The AR-V7 Nucleus detect test is available through Epic Sciences. This test evaluates the Androgen Receptor Splice Variant-7 (AR-V7) protein in the nucleus of circulating tumor cells and is intended to identify metastatic castration-resistant prostate cancer patients who will not respond to androgen-receptor targeted therapies (Epic Sciences, 2023).

Scher et al. (2016) examined 161 patients with progressive metastatic castration-resistant prostate cancer (mCRPC) to assess its association with AR-V7. Out of 191 samples (128 pre-ARS inhibitor and 63 pretaxane), the investigators found AR-V7-positive circulating tumor cells in 34 samples, and those samples were found to have worse clinical outcomes and overall survival than those without AR-V7. Scher et al. (2016) concluded that “the results validate CTC nuclear expression of AR-V7 protein in individuals with mCRPC as a treatment-specific biomarker that is associated with superior survival on taxane therapy over ARS-directed therapy in a clinical practice setting” (Scher et al., 2016).

Further, Chen et al. (2018) studied the overexpression of the nuclear AR-V7 protein in prostate cancer cases. A total of 401 individuals participated in this study. Participants were split into two cohorts: cohort I included those who were high-risk (n=238), and cohort II included those who were not considered high-risk (n=238). Analyses showed that high nuclear AR-V7 protein expression was detected in approximately 30-40% of participants, and a “High baseline expression of nuclear AR-V7 protein was associated with an unfavorable BCR-free survival in the high-risk patient cohort I but not in the unselected consecutive cohort II. Remarkably, AR-V7 was an independent negative prognostic factor in high-risk prostate cancer patients of cohort I who were selected to receive adjuvant treatment” (Chen et al., 2018).

Graf et al. (2020) studied the clinical utility of AR-V7 as a biomarker for patients with progressing metastatic castration-resistant prostate cancer (mCRPC). The results were used by physicians to make a second line of therapy choice of either an androgen receptor signaling inhibitor (ARSI) or taxane chemotherapy. There were 255 samples of circulating tumor cells (CTCs) tested for AR-V7. Patients with detectable AR-V7 in the CTCs had superior survival with taxane treatment over ARSIs and patients who were AR-V7- negative had superior survival on ARSIs over taxanes. These results showed that individuals who tested AR-V7- positive were more likely to survive longer on taxane chemotherapy. Overall, the authors suggest that the use of AR-V7 CTC test "to inform treatment choice can improve patient outcomes relative to decisions based solely on standard-of-care measures” (Graf et al., 2020).

Decipher

Decipher is a genomic prognostic test that is used to predict cancer outcomes in patients that have undergone a radical prostatectomy (RP). It relies on the expression levels of 22 RNA markers in the RP specimen and is primarily used to predict likeliness of metastases or mortality. The algorithm score ranges from zero to one, where a higher score corresponds with higher chance of metastasis. This algorithm was shown to have outperformed the traditional assessment of clinical and pathological features in predicting metastasis (0.75 accuracy compared to 0.69) as well as 17 other genetic tests (0.54 to 0.68 accuracy) (Alford et al., 2017; Dalela, et al., 2016).

Van den Broeck et al. (2019) aimed to validate the Decipher test in the prediction of distant metastatic recurrence in individuals with high-risk nonmetastatic prostate cancer 10 years after the surgery was completed. A total of 298 people participated in this study. Results showed that “the median Decipher scores were higher in the population that developed metastases” suggesting that this study “validates Decipher as a predictor for metastatic recurrence even in patients with high-risk, nonmetastatic PC [prostate cancer] within 10-yr follow-up” (Van den Broeck et al., 2019). Specifically, the data showed that each 10% increase in Decipher score resulted in an increased risk of distant metastatic prostate cancer recurrence.

In a prospective trial by Marascio et al. (2020), the clinical utility of the Decipher tumor test on postoperative management of prostate cancer post prostatectomy was discussed. There were 3,455 individuals with prostates enrolled in the study and the change in treatment decision-making was recorded. In the cohort, 61% of the patients had high-risk tumors with a two-year prostate cancer reoccurrence. As a result of genome classifier testing, providers’ recommendations changed for 39% of the patients, translating to a number needed to test of three to change one treatment decision. This study demonstrated that genome classifier testing favorably impacts treatment decision making post radical prostatectomy, promoting more post-operative radiotherapy. This translated to improved patient reported quality of life (Marascio et al., 2020).

Nguyen et al. (2023) published a meta-analysis examining the prognostic ability of the Decipher Genomic Classifier for distant metastases, prostate cancer-specific mortality, and overall survival within the context of three randomized phase three high-risk definitive radiation therapy trials. The total cohort consisted of 265 individuals whose median age was 69 years and median pretreatment PSA of 25.8 ng/mL. The authors report that upon metaanalysis, the Decipher Genomic Classifier score was statistically significantly associated with time to distant metastasis, prostate cancer–specific mortality, and overall survival (Nguyen et al., 2023).

Spratt et al. (2023) reported on the Decipher Genomic Classifier’s performance in the context of intermediate-risk prostate cancer. Through multivariable analysis of 215 individual samples, it was determined that the test was “independently prognostic for disease progression (subdistribution hazard ratio [sHR], 1.12; 95% confidence interval [CI], 1.00-1.26; P = .04), biochemical failure (sHR, 1.22; 95% CI, 1.10-1.37; P < .001), distant metastasis (sHR, 1.28; 95% CI, 1.06-1.55; P = .01), and prostate cancer-specific mortality (sHR, 1.45; 95% CI, 1.20-1.76; P < .001).” Beyond prognostic utility, the authors argue that the data herein support the predictive value of the Decipher Genomic Classifier for individuals with intermediate risk prostate cancer; among individuals with a test score of intermediate-high, radiation dose-escalation showed greater absolute benefit, with 10-year metastasis-free survival of 75% (95% CI, 55-95) compared with 54% (95% CI, 31-77) for standard dose (Spratt et al., 2023).

ExoDX Prostate (IntelliScore (EPI)

ExoDX is a urinary test that detects the expression level of three genetic biomarkers (ERG, PCA3, and SPDEF) (ExoSome, 2024a, 2024b). This test integrates the expression levels of these three biomarkers and assigns an individualized risk score to predict the risk of high-grade prostate cancer (Gleason score ≥seven). This test is intended for individuals 50 or over with a PSA level of two to ten ng/mL presenting for an initial biopsy (prior to a DRE) and as a useful test in the post-biopsy setting for patients thought to be higher risk despite a negative prostate biopsy (ExoSome, 2024a, 2024b; NCCN, 2024b).

McKiernan et al. (2016) used ExoDX to discriminate between benign prostate cancer (Gleason score 6 and under) and high-risk cancer (Gleason score ≥7). The prognostic score was derived from a sample of 499 patients with PSA levels of two to twenty ng/mL; it was then validated in a sample of 1064 patients and evaluated in a population of 255. The test was compared to the standard of care practices (SOC), and the area under the curve (AUC) of the test was 0.77 compared to the SOC’s 0.66. An independent validation found the AUC of the test to be 0.73 compared to the SOC’s 0.63. The authors calculated that 138 of 519 biopsies (27%) would have been avoided and that the test only missed five percent of patients with high-risk disease (McKiernan et al., 2016). Within a second phase of the long-term study, McKiernan and colleagues report that using the EPI validated cut-point of 15.6 results in avoiding 26% of unnecessary prostate biopsies and a 20% decrease in all biopsies. If the EPI cut-point is raised to 20, then 31% of total biopsies would be avoided, including 40% of unnecessary biopsies (McKiernan et al., 2018).

A study published in 2018 did a cost-effectiveness analysis and comparison of not only ExoDx (EPI), but also Prostate Health Index (PHI), 4Kscore, and SelectMDx to current standard care of care. Using 2017 US dollars for their calculations, the cost and quality adjusted life-years (QALY) for the current standard of care—transrectal ultrasound guided biopsy (TRUS biopsy)—was $3,863 and 18.0865, respectively. The authors of the study note that EPI, PHI, and SelectMDx cost less than performing TRUS biopsy. They note, “The EPI provided the highest QALY with an incremental cost-effectiveness ratio of $58,404 per QALY. The use of biomarkers could reduce the number of unnecessary biopsies by 24% to 34% compared to the current standard of care… Using SelectMDx or the EPI following elevated prostate specific antigen but before proceeding to biopsy is a cost-effective strategy in this setting” (Sathianathen Niranjan et al., 2018).

A randomized, blinded, two-armed clinical utility study was published in 2020 using ExoDx (EPI) in individuals presenting for initial biopsy with PSA values in the intermediate range (two to ten ng/mL). This large study (n = 1,094) included 72 urologists from 24 different practices. All patients had an EPI test performed, but the patients were divided into two different groups (control and experimental) where only the experimental group received results prior to their biopsy decision. Of the individuals within the experimental group who received negative EPI scores, 74% deferred biopsy. For individuals within the experimental group who received positive EPI scores, 87% were recommended by their urologists to undergo the biopsy, and ultimately 72% did. As compared to the control arm of the study, there is a 30% increase in the detection of high-grade prostate cancer [HGPC], and the authors “estimate that 49% fewer HGPC were missed due to deferrals compared to standard of care (SOC). Overall, 68% of urologists reported that the EPI test influenced their biopsy decision” (Tutrone et al., 2020).

McKiernan et al. (2020) investigated the use of the EPI test in a prospective clinical validation study of 229 individuals who were undergoing repeat biopsy. The EPI test demonstrated an NPV of 92% and results evidenced avoidance of 26% of unnecessary biopsies while missing 2.1% of the incidences of high-grade prostate cancer (a total of five patients) (McKiernan et al., 2020).

4Kscore

4Kscore is intended to assess the risk for “aggressive” prostate cancer. The test incorporates total PSA, free PSA, “intact” PSA, and “hk2” [human kallikrein 2] (NCCN, 2024a; OPKO, 2021). These biomarkers, along with other patient clinical information (such as age and prior biopsy status) are evaluated by the 4Kscore algorithm, which generates a risk score for aggressive cancer (% percent risk of Gleason seven or higher, if a biopsy were to be performed).

Zappala et al. (2017) performed a meta-analysis of 4kScore validation studies. A total of 12 studies encompassing 11134 patients were included, and the pooled area under curve (AUC) for the test to “discriminate for high-grade PCa [prostate cancer] was found to be 0.81 (Zappala et al., 2017).

Two key prospective and blinded investigations were completed in 2015 and 2018, attempting to validate 4Kscore in a total of 937 patients, defined as the “intended use” population. The test demonstrated an overall sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of 96.9%, 27.4%, 95.9%, and 33.7%, respectively. These metrics showed little variation between African American and non-African American individuals, with the exception of PPV (46.7% compared to 28.1%, respectively) (Parekh et al., 2015; Punnen et al., 2018).

Wysock et al. (2020) compared the performance of 4K score to SelectMDx in detecting prostate cancer in 114 patients who received both tests. These tests were analyzed to provide guidance on whether to perform biopsy. Based on the results, the two scores lead to different biopsy recommendations. A total of 50 of 144 patients underwent biopsy based on the test results. Of the 50 patients, 22 (44%) were found to have clinically significant prostate cancer. In addition, the specificity of 4K score was significantly greater compared to SelectMDx while sensitivity was similar. The area under the curve for 4K score was 0.830 and SelectMDx was 0.672. The authors state that "the 4Kscore when combined with magnetic resonance imaging was superior to the SelectMDx" in detecting prostate cancer (Wysock et al., 2020).

Mi et al. (2021) completed a meta-analysis to help inform the diagnostic accuracy of 4Kscore in detecting high-grade prostate cancer, covering a total of nine studies and 1,689 patients. The investigators reported a pooled sensitivity, specificity, and AUC of 0.90 (95%CI: 0.86-0.92), 0.44 (95%CI: 0.36-0.52), and 0.81 (95%CI: 0.77- 0.84), respectively, and concluded that “4Kscore can be used as a model for the diagnosis of high-grade CaP [prostate cancer]. However, we detected significant heterogeneity among studies that was not explained by subgroup or meta-regression analysis, thus lowering our confidence in these results.”

Further validation of the test will be useful; however, to date, 4Kscore has demonstrated relatively high sensitivity and AUC compared to other molecular testing for the assessment of high-grade prostate cancer risk.

ConfirmMDX 

ConfirmMDX uses methylation-specific polymerase chain reaction (PCR) to identify methylation of three genes (GSTP1, APC, and RASSF1), and determine whether a patient with a previously negative prostate biopsy should undergo a repeat biopsy (MDx_Health, 2023a). This test has been evaluated by Van Neste, Partin, et al. (2016) and was found to have a negative predictive value (NPV) of 96% for high-grade prostate cancer. A total of 7899 prostate core biopsies from 803 patients were assessed, and the NPV of finding low levels of DNA methylation was 89.2% for all cancers. The positive predictive value (PPV) of the genetic assay was found to be 28.2% (for detection of any cancer on a repeat biopsy), and this was calculated to be “significantly higher” than the PPV of standard of care practices. The final algorithm was optimized to a maximum of 0.742 AUC (Van Neste, Partin, et al., 2016). Wojno et al. (2014) evaluated the utility of this test and found that out of 138 patients that the test had been performed on, only six with a negative result had undergone a repeat biopsy.

SelectMDX

SelectMDX evaluates two mRNA cancer-related biomarkers (HOXC6 and DLX1 with KLK3 as a reference gene) to assist a clinician in deciding to continue routine screening or to order a prostate biopsy. This test is considered a “non-invasive urine test” and reports a binary result of “increased risk” or “very low-risk” (MDxHealth, 2023b). Van Neste, Hendriks, et al. (2016) evaluated this test at a 0.90 AUC in a validation cohort. The authors concluded that the mRNA signature was one of the most significant components of the validation results (Van Neste, Hendriks, et al., 2016). Shore (2018) assessed the effect of SelectMDX results on clinical decision making and found that out of 253 patients that SelectMDX evaluated as “negative,” only 12% underwent a biopsy (Shore, 2018).

IsoPSA^®

IsoPSA^® is a blood test indicated for use in individuals with a prostate who are over 50 years of age with elevated PSA, to help inform the likelihood of having high-grade prostate cancer. Utilizing a proprietary, 2-phase aqueous polymer and salt mixture, PSA isoforms separate between the two aqueous phases, where the discriminatory power between benign and cancerous clinical phenotypes purportedly resides primarily in the top phase. The PSA isoform content in the top layer is then measured with conventional, FDA-approved PSA ELISA immunoassays, and a single numerical score (IsoPSA Index) that is either above or below an established cutoff is generated, providing a binary positive or negative result.

The clinical validity of IsoPSA^® was demonstrated in several studies. Stovsky et al. (2019) performed a multicenter, prospective validation in 271 individuals scheduled for prostate biopsy, and found that the test yielded an area under the receiver operating characteristic curve of 0.784 for high grade cancer. Klein et al. (2022) completed an additional multicenter study of 888 individuals scheduled for prostate biopsy and found similar results, establishing an AUC of 0.783 for IsoPSA^®. These investigators further reported a sensitivity, specificity, NPV, and PPV of 0.902, 0.455, 0.893, and 0.477, respectively.

To investigate the clinical utility of IsoPSA^®, Scovell et al. (2022) performed a “real-world” observational study engaging 38 providers across the Cleveland Clinic health system. The authors examined whether an IsoPSA^® result changed the number of biopsy and magnetic resonance imaging recommendations for a cohort of 734 individuals with total serum prostate specific antigen [PSA] ≥4 and <100 ng/ml and no history of prostate cancer. The authors determined that “IsoPSA testing resulted in a 55% (284 vs 638) net reduction in recommendations for prostate biopsy for those with total PSA ≥four ng/ml.”

Progensa PCA3

Progensa PCA3 is an FDA-approved assay that examines the concentration of the prostate cancer gene 3 (PCA3) and compares it to the amount of prostate-specific antigen RNA. This test is intended for assistance in decision making for a repeat biopsy in individuals with a prostate who are 50 years or older, and a PCA3 score under 25 was associated with a decreased likelihood of a positive biopsy. However, the manufacturer states this test should not be used for those with atypical small acinar proliferation on their most recent biopsy (Hologic, 2024). A total of 466 samples were provided, and 102 of these samples were evaluated to require a repeat biopsy. This assay was evaluated at a 77.5% sensitivity, a 57.1% specificity, a 33.6% positive predictive value, and a 90.0% negative predictive value (Gittelman et al., 2013).

Rodríguez and García-Perdomo (2020) performed a systematic review and meta-analysis of the diagnostic accuracy of PCA3 prior to a patient’s first prostate biopsy. They found that with a cutoff of 35, the sensitivity of the diagnostic tests was 0.69 (95% confidence interval 0.61-0.75), specificity was 0.65 (95% confidence interval 0.553-0.733), the diagnostic odds ratio was 4.244 (95% confidence interval 3.487-5.166), and the AUC was 0.734 (95% confidence interval 0.674-0.805). This study suggests that there may be a greater clinical utility with 35 as the cutoff as opposed to the 25 approved by the FDA, and ultimately urinary PCA3 can “be used as a guide for directing the performance of the first prostate biopsy and decreasing unnecessary biopsies” (Matuszczak et al., 2021; Rodríguez & García-Perdomo, 2020).

MyProstateScore

MyProstateScore is a panel that measures urinary prostate cancer antigen three (PCA3), urinary TMPRSS2:ERG gene fusion (T2:ERG), and serum PSA, to predict the likelihood of prostate cancer in biopsy-naïve patients. Validating the test in a cohort of 1225 patients, Tomlins et al. (2016) found that MyProstateScore was superior to PSA alone, yielding an AUC of 0.693 (compared to 0.585 for PSA). Tosoian et al. (2021) aimed to validate an optimal MyProstateScore threshold for ruling out clinically significant (grade group ≥two) cancer finding that a threshold of 10 resulted in 97% sensitivity and 98% NPV. The investigators further concluded that use of the test could have prevented about one out of three of the biopsies that patients received.

ProMark

Another test that may have utility is ProMark. It measures the levels of eight proteins through quantitative immunofluorescence of a biopsy specimen. It is used to predict cancer aggression in patients with a Gleason score of 3+3 or 3+4. The proteins chosen have roles in cell proliferation, signaling, or stress response, and the score is reported from one to 100. This score represents individualized risk. Blume-Jensen et al. (2015) narrowed down the eight primary protein biomarkers used (down from the 12 proposed by an earlier study) as well as assessed its ability to predict clinical endpoints of favorable and nonfavorable disease. They recommended a cutoff of 0.33 (on a scale of zero to one) for “nonfavorable” pathology (83.6% of patients with favorable disease fell below this cutoff). Conversely, a cutoff of 0.8 was recommended for favorable pathology as 76.9% of patients with nonfavorable pathology were above this cutoff. The authors concluded that this assay provided useful information, especially when differentiating between Gleason scores (Alford et al., 2017; Blume-Jensen et al., 2015). 

Prostate Health Index

Prostate Health Index (PHI) measures total PSA, fPSA (free non-protein bound PSA), and p2PSA (an isoform of fPSA). Levels of these three proteins are combined and calculated, implying that individuals with a higher total PSA and p2PSA and a lower fPSA have a higher risk of presenting with prostate cancer (Couñago et al., 2020). PHI is clinically used to reduce the number of unnecessary biopsies in those with border-line PSA levels, predict biochemical recurrence after radical prostatectomy, and enhance the predictive value of multi-parametric MRI. PHI is not recommended in primary screening for prostate cancer (Duffy, 2020).

Jia et al. (2020) compared the diagnostic value of PCA3 and PHI for detection of prostate cancer at initial biopsy in a meta-analysis of 10,376 patients from 20 studies. The pooled sensitivity for PCA3 and PHI was 0.55 and 0.88, respectively. The pooled specificity for PCA3 and PHI was 0.74 and 0.36. The area under the curve, measuring overall quality of the diagnostic test, was 0.72 for PCA3 and 0.76 for PHI. The combination use of PCA3 and PHI resulted in a higher area under the curve of 0.79. Overall, this study suggests that both PCA3 and PHI show acceptable results and a "combination of these two diagnostic tests may be more helpful than the use of either test alone in prostate cancer management” (Jia et al., 2020). 

White et al. (2018) evaluated the clinical utility of the PHI on “biopsy decision management” among patients with “non-suspicious DRE findings and tPSA in the four to ten ng/mL range” in an observational study at several large urology group practices. They found that there was a “significant reduction in biopsy procedures performed” in individuals receiving a PHI test when comparing to the control group (36.4% biopsy vs 60.3% biopsy), and that the “PHI score impacted physician’s patient management plan in 73% of cases, including biopsy deferrals when the PHI score was low, and decisions to perform biopsies when the PHI score indicated an intermediate or high probability of prostate cancer,” defined as a score greater than or equal to 36. This altogether conveyed the importance of the PHI score in clinical decision making in terms of how to proceed with individual patient circumstances (Matuszczak et al., 2021; White et al., 2018).

Ki-67 and PTEN

Finally, the NCCN specifically recommends against two particular tests in assessment of prostate cancer; Ki-67 staining and PTEN loss (NCCN, 2024a).

Ki-67 is a nuclear protein involved in cell cycle proliferation and is intended to provide prognostic information on metastasis and prostate cancer-specific mortality (NCCN, 2024a; Ross et al., 2022). Ki-67 staining has shown some promising results. However, the primary limitation with these studies is that most active surveillance populations will have a Gleason Score of 6 or less, which is considered “low-risk”. This population will most likely have low Ki-67 levels, clouding its utility in populations trying to decide between immediate and deferred treatment (Ross et al., 2022).

PTEN loss is a relatively early event in the course of prostate cancer. PTEN is a tumor suppressor gene on chromosome 10q and is involved in cell cycle regulation. PTEN is intended to provide prognostic information on prostate cancer-specific mortality, biochemical recurrence, and cancer progression (NCCN, 2024a; Ross et al., 2022). Data on prognostic value of PTEN loss post-treatment have been conflicting. It is possible that active treatments contribute to the disruption of the PTEN pathway or the high correlation between PTEN loss and clinicopathologic factors. Lotan et al. (2011) found that when clinicopathologic factors, such as Gleason Score and surgical margin status, were included in their multivariable analysis, PTEN’s association with metastasis and prostate cancer-specific mortality decreased significantly.

ArteraAI Prostate

Cancer ArteraAI Prostate Cancer is a multimodal artificial intelligence (MMAI) digital pathology-based post-radical prostatectomy biomarker test that stratifies the risk of metastasis as well as identifies the potential benefits of additional hormone therapy. It is for patients who have been diagnosed with localized prostate cancer who have not yet received radiation therapy (RT) or androgen-deprivation therapy (ADT) before getting a biopsy. The current standard for individuals with intermediate-risk localized prostate cancer includes treatment with ST-ADT in combination with radiation therapy, but a clinical study of the predictive biomarker used in the ArteraAI Prostate test showed that only 34% of patients require radiation therapy. The AI portion of the test “learns” from digital pathology images and clinical data inputs to then predict the likelihood of additional therapy being beneficial, as well provides details as to the prognosis of the patient. Test results do not require tissue, but rather a validated algorithm is used to assess the “digital image” from a patient’s biopsy and clinical data.

The development of the ArteraAI model relied on two trials and utilized clinical data and digital pathology. The 5-year DM area under the curve was 0.83 for ArteraAI, compared with 0.72 for NCCN risk group (P < .001). Results show promising risk stratification for hormonal therapy (Results identified 40% of biochemical recurrence (BCR) patients who benefited from therapy intensification vs. 60% of patients who did not) indicating potential benefits for high-risk patients; this tool is purported to be of use with both newly-diagnosed patients and those that show biochemical recurrence (ArteraAI, 2024; Hannah Clarke, 2024).

Esteva et al. (2022) performed a study to demonstrate the usage of multimodal deep learning architecture to personalize therapy for prostate cancer by predicting long-term outcomes using clinical data and digital histopathology from prostate biopsies. The models, trained and validated on data from the five phase III randomized trials, outperformed the National Cancer Center Network (NCCN) risk groups in terms of discriminatory performance on all endpoints. The AI-based tool (ArteraAI) provided superior prognostication with a relative improvement over these current risk group tools (based on digital rectal exam, serum prostate-specific antigen (PSA) level, and tumor biopsy grade) of between 9.2% to 14.6% in a held-out validation set (Esteva et al., 2022).

Guidelines and Recommendations

National Cancer Coalition Network (NCCN)

Patients with low or favorable intermediate-risk disease and life expectancy ≥10 y may consider the use of the following tumor-based molecular assays: Decipher, Oncotype DX Prostate, and Prolaris. Patients with unfavorable intermediate- and high-risk disease and life expectancy ≥10 y may consider the use of Decipher and Prolaris tumor-based molecular assays. Retrospective studies have shown that molecular assays performed on prostate biopsy or RP specimens provide prognostic information independent of NCCN or CAPRA risk groups. These include, but are not limited to, “likelihood of death with conservative management, likelihood of biochemical recurrence after radical prostatectomy, and likelihood of developing metastasis after operation, definitive EBRT, or post-recurrence EBRT” (NCCN, 2024a). Furthermore, they note that clinicians may consider testing patients with metastatic prostate cancer and regional prostate cancer for alterations in homologous recombination DNA repair genes BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, and CDK12; “Post-test genetic counseling is recommended if pathogenic/likely pathogenic somatic mutations in any gene that has clinical implications if also identified in germline (e.g, BRCA2, BRCA1, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, PMS2) (NCCN, 2024a).” The NCCN noted that somatic tumor testing of the aforementioned genes has potential for early use of platinum chemotherapy, use of PARP inhibitors, or eligibility for clinical trials. Lastly, they recommend that individuals with regional disease, metastatic castration-resistant disease, or castration-naïve metastatic disease should additionally consider tumor testing for microsatellite instability or mismatch repair deficiency. The NCCN also specifically does not recommend either Ki-67 or PTEN testing” (NCCN, 2024a).

The NCCN does include available tissue-based tests for prostate cancer prognosis within their table of possible testing as indicated in the Table below. Regarding Decipher testing, NCCN states that Decipher “may be considered to inform adjuvant treatment if adverse events are found to occur after radical prostatectomy”. Decipher testing can also be used to inform counseling for risk stratification in patients with PSA resistance or reoccurrence after radical prostatectomy. NCCN discourages repeat molecular tumor analysis (NCCN, 2024a, 2024b):

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81313, 81479, 81539, 81541, 81542, 81551, 0005U, 0113U, 0021U, 0047U, 0053U, 0228U, 0339U, 0403U, 0359U, 0403U, 0424U, 0433U, 0495U, 0497U, 0558U, 0559U

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

For Policy Titled: Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management

ACS. (2024a). Key Statistics for Prostate Cancer. Retrieved 5/10/2024 from https://www.cancer.org/cancer/types/prostate-cancer/about/key-statistics.html

ACS. (2024b). Survival Rates for Prostate Cancer. https://www.cancer.org/cancer/types/prostate-cancer/detection-diagnosis-staging/survival-rates.html

Alford, A. V., Brito, J. M., Yadav, K. K., Yadav, S. S., Tewari, A. K., & Renzulli, J. (2017). The Use of Biomarkers in Prostate Cancer Screening and Treatment. Rev Urol, 19(4), 221-234. https://pubmed.ncbi.nlm.nih.gov/29472826/

ArteraAI. (2024). New Data Validating the First AI-Based Biomarker to Stratify Risk of Metastasis in Radical Prostatectomy Patients with Biochemical Recurrence. https://www.businesswire.com/news/home/20240506052855/en/New-Data-Validating-the-First-AI-Based-Biomarker-to-Stratify-Risk-of-Metastasis-in-Radical-Prostatectomy-Patients-with-Biochemical-Recurrence

Bell, K. J., Del Mar, C., Wright, G., Dickinson, J., & Glasziou, P. (2015). Prevalence of incidental prostate cancer: A systematic review of autopsy studies. Int J Cancer, 137(7), 1749-1757. https://doi.org/10.1002/ijc.29538

Benedettini, E., Nguyen, P., & Loda, M. (2008). The pathogenesis of prostate cancer: from molecular to metabolic alterations. Diagn Histopathol (Oxf), 14(5), 195-201. https://doi.org/10.1016/j.mpdhp.2008.03.001

Blume-Jensen, P., Berman, D. M., Rimm, D. L., Shipitsin, M., Putzi, M., Nifong, T. P., . . . Saad, F. (2015). Development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer. Clin Cancer Res, 21(11), 2591-2600. https://doi.org/10.1158/1078-0432.Ccr-14- 2603

Carneiro, A., Priante Kayano, P., Gomes Barbosa, Á. R., Langer Wroclawski, M., Ko Chen, C., Cavlini, G. C., . . . Bianco, B. (2018). Are localized prostate cancer biomarkers useful in the clinical practice? Tumor Biology, 40(9), 1010428318799255. https://doi.org/10.1177/1010428318799255

Chen, X., Bernemann, C., Tolkach, Y., Heller, M., Nientiedt, C., Falkenstein, M., . . . Duensing, S. (2018). Overexpression of nuclear AR-V7 protein in primary prostate cancer is an independent negative prognostic marker in men with high-risk disease receiving adjuvant therapy. Urol Oncol, 36(4), 161.e119-161.e130. https://doi.org/10.1016/j.urolonc.2017.11.001

Couñago, F., López-Campos, F., Díaz-Gavela, A. A., Almagro, E., Fenández-Pascual, E., Henríquez, I., . . . Del Cerro, E. (2020). Clinical Applications of Molecular Biomarkers in Prostate Cancer. Cancers (Basel), 12(6). https://doi.org/10.3390/cancers12061550

Cullen, J., Rosner, I. L., Brand, T. C., Zhang, N., Tsiatis, A. C., Moncur, J., . . . McLeod, D. G. (2015). A Biopsy-based 17-gene Genomic Prostate Score Predicts Recurrence After Radical Prostatectomy and Adverse Surgical Pathology in a Racially Diverse Population of Men with Clinically Low- and Intermediate-risk Prostate Cancer. Eur Urol, 68(1), 123-131. https://doi.org/10.1016/j.eururo.2014.11.030

Cuzick, J., Stone, S., Fisher, G., Yang, Z. H., North, B. V., Berney, D. M., . . . Scardino, P. (2015). Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. Br J Cancer, 113(3), 382-389. https://doi.org/10.1038/bjc.2015.223

Dalela, D., Löppenberg, B., Sood, A., Sammon, J., & Abdollah, F. (2016). Contemporary Role of the Decipher^® Test in Prostate Cancer Management: Current Practice and Future Perspectives. Rev Urol, 18(1), 1-9.

Davis, J. W. (2014). Novel commercially available genomic tests for prostate cancer: a roadmap to understanding their clinical impact. BJU International, 114(3), 320-322. https://doi.org/10.1111/bju.12695

Duffy, M. J. (2020). Biomarkers for prostate cancer: prostate-specific antigen and beyond. Clin Chem Lab Med, 58(3), 326-339. https://doi.org/10.1515/cclm-2019-0693

Eggener, S. E., Rumble, R. B., Armstrong, A. J., Morgan, T. M., Crispino, T., Cornford, P., . . . Beltran, H. (2020). Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline. J Clin Oncol, Jco1902768. https://doi.org/10.1200/jco.19.02768 

Epic Sciences. (2023). AR-V7 by Epic Sciences. https://www.epicsciences.com/ar-v7-test/

Esteva, A., Feng, J., van der Wal, D., Huang, S.-C., Simko, J. P., DeVries, S., Chen, E., Schaeffer, E. M., Morgan, T. M., Sun, Y., Ghorbani, A., Naik, N., Nathawani, D., Socher, R., Michalski, J. M., Roach, M., Pisansky, T. M., Monson, J. M., Naz, F., . . . Consortium, N. R. G. P. C. A. (2022). Prostate cancer therapy personalization via multi-modal deep learning on randomized phase III clinical trials. npj Digital Medicine, 5(1), 71. https://doi.org/10.1038/s41746-022-00613-w

Exact Sciences. (2021). A Tailored Report for Clinically Low Risk Prostate Cancer Patients https://d2ft3j3kbsqj8w.cloudfront.net/-/media/Project/PrecisionOncology/PrecisionOncology/OIQ-Reports/Prostate/GPS-Interactive-Report-Tool/GPSRE_GPS_Annotated_Report-2- Pager_M_US_GPS_00374.pdf?rev=50c0c67b355241178c9deba9609ded65

ExoSome. (2024a). ExoDx^™ Prostate Test. Retrieved 2/8/21 from http://www.exosomedx.com/physicians/exodx-prostate-test

ExoSome. (2024b). Prostate Cancer. http://www.exosomedx.com/prostate-cancer-0

Gittelman, M. C., Hertzman, B., Bailen, J., Williams, T., Koziol, I., Henderson, R. J., . . . Ward, J. F. (2013). PCA3 molecular urine test as a predictor of repeat prostate biopsy outcome in men with previous negative biopsies: a prospective multicenter clinical study. J Urol, 190(1), 64-69. https://doi.org/10.1016/j.juro.2013.02.018

Graf, R. P., Hullings, M., Barnett, E. S., Carbone, E., Dittamore, R., & Scher, H. I. (2020). Clinical Utility of the Nuclear-localized AR-V7 Biomarker in Circulating Tumor Cells in Improving Physician Treatment Choice in Castration-resistant Prostate Cancer. Eur Urol, 77(2), 170-177. https://doi.org/10.1016/j.eururo.2019.08.020

Hannah Clarke. (2024). ArteraAI Prostate Test included in NCCN guidelines. Urology Times. https://www.urologytimes.com/view/arteraai-prostate-cancer-test-included-in-nccn-guidelines

Hoffman, R. (2023). Screening for prostate cancer. https://www.uptodate.com/contents/screening-for-prostate-cancer

Hologic. (2024). Progensa Brochure. https://stage.hologic.com/sites/default/files/package-insert/Progensa%20PCA3%20Physician%20Brochure-USA.pdf

Hu, J. C., Tosoian, J. J., Qi, J., Kaye, D., Johnson, A., Linsell, S., . . . Morgan, T. M. (2018). Clinical Utility of Gene Expression Classifiers in Men With Newly Diagnosed Prostate Cancer. (2), 1-15. https://doi.org/10.1200/po.18.00163

Jia, W., Wu, B., Shao, Y., Cao, X., & Wang, D. (2020). Diagnostic performance of prostate cancer antigen 3 and the Prostate Health Index in detecting overall and clinically significant prostate cancer in men at first biopsy: A meta-analysis. International Journal of Urology, n/a(n/a). https://doi.org/10.1111/iju.14464

Klein, E. A., Partin, A., Lotan, Y., Baniel, J., Dineen, M., Hafron, J., Manickam, K., Pliskin, M., Wagner, M., Kestranek, A., & Stovsky, M. (2022). Clinical validation of IsoPSA, a single parameter, structure-focused assay for improved detection of prostate cancer: A prospective, multicenter study. Urol Oncol, 40(9), 408 e409-408 e418. https://doi.org/10.1016/j.urolonc.2022.06.002

Lin, D. W., Crawford, E. D., Keane, T., Evans, B., Reid, J., Rajamani, S., . . . Cuzick, J. (2018). Identification of men with low-risk biopsy-confirmed prostate cancer as candidates for active surveillance. Urologic Oncology: Seminars and Original Investigations, 36(6), 310.e317-310.e313. https://doi.org/10.1016/j.urolonc.2018.03.011 

Lotan, T. L., Gurel, B., Sutcliffe, S., Esopi, D., Liu, W., Xu, J., . . . De Marzo, A. M. (2011). PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res, 17(20), 6563-6573. https://doi.org/10.1158/1078-0432.Ccr-11-1244

Marascio, J., Spratt, D. E., Zhang, J., Trabulsi, E. J., Le, T., Sedzorme, W. S., . . . Den, R. B. (2020). Prospective study to define the clinical utility and benefit of Decipher testing in men following prostatectomy. Prostate Cancer and Prostatic Diseases, 23(2), 295-302. https://doi.org/10.1038/s41391-019-0185-7

Matuszczak, M., Schalken, J. A., & Salagierski, M. (2021). Prostate Cancer Liquid Biopsy Biomarkers' Clinical Utility in Diagnosis and Prognosis. Cancers (Basel), 13(13). https://doi.org/10.3390/cancers13133373

McKiernan, J., Donovan, M. J., Margolis, E., Partin, A., Carter, B., Brown, G., . . . Carroll, P. (2018). A Prospective Adaptive Utility Trial to Validate Performance of a Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer in Patients with Prostate-specific Antigen 2-10ng/ml at Initial Biopsy. Eur Urol, 74(6), 731-738. https://doi,org/10.1016/j.eururo.2018.08.019

McKiernan, J., Donovan, M. J., O’Neill, V., Bentink, S., Noerholm, M., Belzer, S., . . . Carroll, P. (2016). A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer at Initial BiopsyUrine Exosome Signature to Predict High-Grade Prostate CancerUrine Exosome Signature to Predict High-Grade Prostate Cancer. JAMA Oncology, 2(7), 882-889. https://doi.org/10.1001/jamaoncol.2016.0097

McKiernan, J., Noerholm, M., Tadigotla, V., Kumar, S., Torkler, P., Sant, G., Alter, J., Donovan, M. J., & Skog, J. (2020). A urine-based Exosomal gene expression test stratifies risk of high-grade prostate Cancer in men with prior negative prostate biopsy undergoing repeat biopsy. BMC Urol, 20(1), 138. https://doi.org/10.1186/s12894-020-00712-4

MDxHealth. (2023a). ConfirmMDx for Prostate Cancer. https://mdxhealth.com/confirm-mdx-for-physicians/

MDxHealth. (2023b). SelectMDx for Prostate Cancer. https://mdxhealth.com/select-mdx-for-physicians/

Mi, C., Bai, L., Yang, Y., Duan, J., & Gao, L. (2021). 4Kscore diagnostic value in patients with high-grade prostate cancer using cutoff values of 7.5% to 10%: A meta-analysis. Urol Oncol, 39(6), 366 e361-366 e310. https:doi.org/10.1016/j.urolone.2020.11.001

Mottet, N., Cornford, P., van den Bergh, R. C. N., Briers, E., Eberli, D., De Meerleer, G., De Santis, M., Gillessen, S., Grummet, J., Henry, A. M., van der Kwast, T. H., van Leenders, G. J. L. H., Mason, M. D., O'Hanlon, S., van Oort, I. M., Oprea-Lager, D. E., Ploussard, G., Rouvière, O., Schoots, I. G., . . . Willemse, P.-P. (2023). Guidelines on Prostate Cancer. https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-EANM-ESTRO-ESUR-ISUP-SIOG-Guidelines-on-Prostate-Cancer-2023_2023-06-13-141145.pdf

Murphy, A. B., Carbunaru, S., Nettey, O. S., Gornbein, C., Macias, V., Sharifi, R., . . . Gann, P. (2020). A 17- Gene Panel Genomic Prostate Score has Similar Predictive Accuracy for Adverse Pathology at Radical Prostatectomy in African American and European American Men. Urology. https://doi.org/10.1016/j.urology.2020.01.052

NCCN. (2024a). NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 4.2024—May 17, 2024. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf 

NCCN. (2024b). Prostate Cancer Early Detection Version 2.2024—March 6, 2024. https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf

Nguyen, P. L., Huang, H. R., Spratt, D. E., Davicioni, E., Sandler, H. M., Shipley, W. U., Efstathiou, J. A., Simko, J. P., Pollack, A., Dicker, A. P., Roach, M., Rosenthal, S. A., Zeitzer, K. L., Mendez, L. C., Hartford, A. C., Hall, W. A., Desai, A. B., Rabinovitch, R. A., Peters, C. A., . . . Feng, F. Y. (2023). Analysis of a Biopsy-Based Genomic Classifier in High-Risk Prostate Cancer: Meta-Analysis of the NRG Oncology/Radiation Therapy Oncology Group 9202, 9413, and 9902 Phase 3 Randomized Trials. Int J Radiat Oncol Biol Phys, 116(3), 521-529. https://doi.org/10.1016/j.ijrobp.2022.12.035

OPKO. (2021). OPKO Health Receives U.S. FDA Approval for the 4Kscore^® Test. https://www.opko.com/news-media/press-releases/detail/454/opko-health-receives-u-s-fda-approval-for-the-4kscore

Parekh, D. J., Punnen, S., Sjoberg, D. D., Asroff, S. W., Bailen, J. L., Cochran, J. S., Concepcion, R., David, R. D., Deck, K. B., Dumbadze, I., Gambla, M., Grable, M. S., Henderson, R. J., Karsh, L., Krisch, E. B., Langford, T. D., Lin, D. W., McGee, S. M., Munoz, J. J., . . . Zappala, S. M. (2015). A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur Urol, 68(3), 464-470. https://doi.org/10.1016/j.eururo.2014.10.021

Parker, C., Castro, E., Fizazi, K., Heidenreich, A., Ost, P., Procopio, G., Tomball, B., & . Gillessen, S. (2020). Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up^†. Annals of Oncology, 31(9), 1119-1134. doi:10.1016/j.annonc.2020.06.011

Punnen, S., Freedland, S. J., Polascik, T. J., Loeb, S., Risk, M. C., Savage, S., Mathur, S. C., Uchio, E., Dong, Y., & Silberstein, J. L. (2018). A Multi-Institutional Prospective Trial Confirms Noninvasive Blood Test Maintains Predictive Value in African American Men. J Urol, 199(6), 1459-1463. https://doi.org/10.1016/j.juro.2017.11.113

Rodríguez, S. V. M., & García-Perdomo, H. A. (2020). Diagnostic accuracy of prostate cancer antigen 3 (PCA3) prior to first prostate biopsy: A systematic review and meta-analysis. Can Urol Assoc J, 14(5), E214-e219. https://doi.org/10.5489/cuaj.6008

Ross, A. E., D'Amico, A. V., & Freedland, S. J. (2022). Molecular prognostic tests for prostate cancer. Wolters Kluwer. Retrieved 10/10/2023 from https://www.uptodate.com/contents/molecular-prognostic-tests-for-prostate-cancer

Sathianathen Niranjan, J., Kuntz Karen, M., Alarid-Escudero, F., Lawrentschuk Nathan, L., Bolton Damien, M., Murphy Declan, G., . . . Konety Badrinath, R. (2018). Incorporating Biomarkers into the Primary Prostate Biopsy Setting: A Cost-Effectiveness Analysis. Journal of Urology, 200(6), 1215-1220. doi:10.1016/j.juro.2018.06.016

Scher, H. I., Lu, D., Schreiber, N. A., Louw, J., Graf, R. P., Vargas, H. A., . . . Dittamore, R. (2016). Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate CancerAR-V7 Expression in Circulating Tumor Cells and Castration-Resistant Prostate Cancer OutcomesAR-V7 Expression in Circulating Tumor Cells and Castration-Resistant Prostate Cancer Outcomes. JAMA Oncology, 2(11), 1441-1449. doi:10.1001/jamaoncol.2016.1828

Scovell, J. M., Hettel, D., Abouassaly, R., Almassi, N., Berglund, R., Breaux, T., Weight, C., Isac, W., Zampini, A., Stark, E., Rochelle, R., Kestranek, A., Stovsky, M., & Klein, E. (2022). IsoPSA^® Reduces Provider Recommendations for Biopsy and Magnetic Resonance Imaging in Men with Total Prostate Specific Antigen ≥4 ng/ml: A Real-World Observational Clinical Utility Study. https://doi.org/10.1097/UPJ.0000000000000291 

Shore, N. (2018). SelectMDx Impacts Prostate Biopsy Decision-making in Routine Clinical Practice.

Song, C. J., Chen, H., Chen, L. Z., Ru, G. M., Guo, J. J., & Ding, Q. N. (2018). The potential of microRNAs as human prostate cancer biomarkers: A meta-analysis of related studies. J Cell Biochem, 119(3), 2763- 2786. doi:10.1002/jcb.26445

Spratt, D. E., Liu, V. Y. T., Michalski, J., Davicioni, E., Berlin, A., Simko, J. P., Efstathiou, J. A., Tran, P. T., Sandler, H. M., Hall, W. A., Thompson, D. J. S., Parliament, M. B., Dayes, I. S., Correa, R. J. M., Robertson, J. M., Gore, E. M., Doncals, D. E., Vigneault, E., Souhami, L., . . . Feng, F. Y. (2023). Genomic Classifier Performance in Intermediate-Risk Prostate Cancer: Results From NRG Oncology/RTOG 0126 Randomized Phase 3 Trial. International Journal of Radiation Oncology, Biology, Physics, 117(2), 370-377. https://doi.org/10.1016/j.ijrobp.2023.04.010

Steiling, K., & Christenson, S. (2023, 10/10/2023). Tools for genetics and genomics: Gene expression profiling. Retrieved from https://www.uptodate.com/contents/tools-for-genetics-and-genomics-gene-expression-profiling

Stovsky, M., Klein, E. A., Chait, A., Manickam, K., Stephenson, A. J., Wagner, M., Dineen, M., Lotan, Y., Partin, A., Baniel, J., Kestranek, A., Gawande, P., & Boris, Z. (2019). Clinical Validation of IsoPSA, a Single Parameter, Structure Based Assay for Improved Detection of High Grade Prostate Cancer. J Urol, 201(6), 1115-1120. https://doi.org/10.1097/JU.0000000000000185

Taplin, M.-E., & Smith, J. A. (2024, 3/22/2024). Clinical presentation and diagnosis of prostate cancer. https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-prostate-cancer

Tomlins, S. A., Day, J. R., Lonigro, R. J., Hovelson, D. H., Siddiqui, J., Kunju, L. P., Dunn, R. L., Meyer, S., Hodge, P., Groskopf, J., Wei, J. T., & Chinnaiyan, A. M. (2016). Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk Assessment. Eur Urol, 70(1), 45-53. https://doi.org/10.1016/j.eururo.2015.04.039

Tosoian, J. J., Trock, B. J., Morgan, T. M., Salami, S. S., Tomlins, S. A., Spratt, D. E., Siddiqui, J., Kunju, L. P., Botbyl, R., Chopra, Z., Pandian, B., Eyrich, N. W., Longton, G., Zheng, Y., Palapattu, G. S., Wei, J. T., Niknafs, Y. S., & Chinnaiyan, A. M. (2021). Use of the MyProstateScore Test to Rule Out Clinically Significant Cancer: Validation of a Straightforward Clinical Testing Approach. J Urol, 205(3), 732-739. https://doi.org/10.1097/JU.0000000000001430

Tutrone, R., Donovan, M. J., Torkler, P., Tadigotla, V., McLain, T., Noerholm, M., Skog, J., & McKiernan, J. (2020). Clinical utility of the exosome based ExoDx Prostate(IntelliScore) EPI test in men presenting for initial Biopsy with a PSA 2-10 ng/mL. Prostate Cancer Prostatic Dis. doi:10.1038/s41391-020-0237-z

Tward, J. D., Schlomm, T., Bardot, S., Freedland, S. J., Lenz, L., Cohen, T., . . . Bishoff, J. (2020). Ability of the combined clinical cell-cycle risk score to identify patients that benefit from multi versus single modality therapy in NCCN intermediate and high-risk prostate cancer. Journal of Clinical Oncology, 38(6_suppl), 346-346. doi:10.1200/JCO.2020.38.6_suppl.346

Van den Broeck, T., Moris, L., Gevaert, T., Tosco, L., Smeets, E., Fishbane, N., . . . Joniau, S. (2019). Validation of the Decipher Test for Predicting Distant Metastatic Recurrence in Men with High-risk Nonmetastatic Prostate Cancer 10 Years After Surgery. Eur Urol Oncol, 2(5), 589-596. doi:10.1016/j.euo.2018.12.007 

Van Neste, L., Hendriks, R. J., Dijkstra, S., Trooskens, G., Cornel, E. B., Jannink, S. A., . . . Schalken, J. A. (2016). Detection of High-grade Prostate Cancer Using a Urinary Molecular Biomarker-Based Risk Score. Eur Urol, 70(5), 740-748. doi:10.1016/j.eururo.2016.04.012

Van Neste, L., Partin, A. W., Stewart, G. D., Epstein, J. I., Harrison, D. J., & Van Criekinge, W. (2016). Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies. Prostate, 76(12), 1078-1087. doi:10.1002/pros.23191

White, J., Shenoy, B. V., Tutrone, R. F., Karsh, L. I., Saltzstein, D. R., Harmon, W. J., Broyles, D. L., Roddy, T. E., Lofaro, L. R., Paoli, C. J., Denham, D., & Reynolds, M. A. (2018). Clinical utility of the Prostate Health Index (phi) for biopsy decision management in a large group urology practice setting. Prostate Cancer Prostatic Dis, 21(1), 78-84. https://doi.org/10.1038/s41391-017-0008-7

Wojno, K. J., Costa, F. J., Cornell, R. J., Small, J. D., Pasin, E., Van Criekinge, W., . . . Van Neste, L. (2014). Reduced Rate of Repeated Prostate Biopsies Observed in ConfirmMDx Clinical Utility Field Study. Am Health Drug Benefits, 7(3), 129-134. https://pubmed.ncbi.nlm.nih.gov/24991397/

Wysock, J. S., Becher, E., Persily, J., Loeb, S., & Lepor, H. (2020). Concordance and Performance of 4Kscore and SelectMDx for Informing Decision to Perform Prostate Biopsy and Detection of Prostate Cancer. Urology, 141, 119-124. doi:10.1016/j.urology.2020.02.032

Zappala, S. M., Scardino, P. T., Okrongly, D., Linder, V., & Dong, Y. (2017). Clinical performance of the 4Kscore Test to predict high-grade prostate cancer at biopsy: A meta-analysis of us and European clinical validation study results. Rev Urol, 19(3), 149-155. doi:10.3909/riu0776

Medical Director review 4/2020

Medical Director review 7/2020

Specialty Matched Consultant Panel 8/2020

Medical Director review 1/2021

For Policy Titled: Gene Expression Profiling and Protein Biomarkers for Prostate Cancer

Medical Director review 4/2021

Specialty Matched Consultant Panel 8/2021

Medical Director review 4/2022

Medical Director review 1/2023

Medical Director review 1/2024

Medical Director review 7/2024

Policy Implementation/Update Information

For Policy Titled: Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management 

10/1/19 New policy developed. Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management is considered investigational. See Related Policy: Prostate Cancer Screening AHS-G2008. Medical Director review 8/2019. (lpr)

10/29/19 No change to policy statements. Minor reformatting and edits. (hb)

5/12/20 Off cycle review to align with CMP Prostate Cancer Screening AHS-G2008. Removed references to the following tests and transferred them to AHS-G2008: ExoDX Prostate, Intelliscore, Select MDX, PCA3, KLK3, ConfirmDX, PPCA. Removed CPT codes 0005U, 81313, 81551 and transferred to AHS-G2008. Updated Policy Guidelines. Medical Director review 4/2020. (lpr)

7/28/20 Reviewed by Avalon 2nd Quarter 2020 CAB. References updated. Medical Director review 7/2020. (lpr)

9/8/20 Specialty Matched Consultant Advisory Panel review 8/19/2020. No change to policy statement. (lpr)

2/9/21 Added PLA code 0005U to Billing/Coding section. Off-cycle review per Avalon, No change to policy statement. (lpr)

For Policy Titled: Gene Expression Profiling and Protein Biomarkers for Prostate Cancer

5/18/21 Reviewed by Avalon 1st Quarter 2021 CAB. Medical Director review 4/2021. Revised “When Covered” section to include tests to assess and/or monitor prostate cancer which were relocated from AHS-G2008 Prostate Specific Antigen (PSA) Testing policy. These tests remain investigational. Updated Policy Guidelines, Billing/Coding sections as well as References. Changed related policy AHS-G2008 Prostatic Specific Antigen (PSA) Testing title. Policy Title changed from: Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management to: Gene Expression Profiling and Protein Biomarkers for Prostate Cancer. (lpr)

9/7/21 Specialty Matched Consultant Advisory Panel review 8/18/2021. No change to policy statement. (lpr)

2/8/22 Reviewed by Avalon Q4 2021 CAB. Removed PLA code 0244U from Billing/Coding section. Medical Director review 1/2022. No change to policy statement. (lpr)

5/31/22 Reviewed by Avalon Q1 2022 CAB. Extensive revisions to policy. Added coverage criteria under “When Covered” section. Updated policy guidelines and references. Medical Director review 4/2022. (lpr)

9/30/22 Added CPT code 0339U to Billing/Coding section. Corrected typo in policy statement. No change to intent of policy statement. (lpr)

12/30/22 Added PLA code 0359U to Billing/Coding section for effective date 1/1/2023. (lpr)

3/31/23 Off cycle review by Avalon. Updated policy guidelines and references. Deleted related policies section. Clarified “when covered” section and added coverage criteria for 4Kscore. Clarified and edited notes 2-5. Added PLA codes 0339U, 0359U to Billing/Coding section. Medical Director review 1/2023. (lpr)

9/29/23 Added PLA code 0403U to Billing/Coding section for 10/1/23 code update. (lpr)

12/29/23 Added PLA codes 0424U and 0433U to Billing/Coding section for 1/1/2024 code update. (lpr)

2/21/24 Reviewed by Avalon Q4 2023 CAB. Medical Director review 1/2024. Updated policy guidelines and references. Added related policies section. Added coverage criteria for IsoPSA in “when covered” section. (lpr)

9/4/24 Reviewed by Avalon 2nd Quarter 2024 CAB. Medical Director review 7/2024. Updated related policies, policy guidelines and references. Edited “when covered” statement #3 for clarification and Note 4. Added PLA codes 0113U and 0403U to Billing/Coding section. (lpr)

10/1/24 Added PLA code 0495U to Billing/Coding section for 10/1/24 code update. (lpr)

10/30/24 Added PLA code 0497U to Billing/Coding section for 10/1/24 code update. (lpr)

7/1/25 Added PLA codes 0558U, 0559U to Billing/Coding section for 7/1/25 code update. (lpr)