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Proposed LCD for Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis (DL37733)

Coverage for EPI test has been added. Only the addition of coverage for EPI test is open for Official Comment.


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LCD Information

Document Information

Source LCD ID

L37733

Proposed LCD ID

DL37733

Proposed LCD Title

Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis

AMA CPT / ADA CDT / AHA NUBC Copyright Statement

CPT codes, descriptions and other data only are copyright 2018 American Medical Association. All Rights Reserved. Applicable FARS/HHSARS apply.

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CMS National Coverage Policy

Language quoted from Centers for Medicare and Medicaid Services (CMS), National Coverage Determinations (NCDs) and coverage provisions in interpretive manuals is italicized throughout the policy. NCDs and coverage provisions in interpretive manuals are not subject to the Local Coverage Determination (LCD) Review Process (42 CFR 405.860[b] and 42 CFR 426 [Subpart D]). In addition, an administrative law judge may not review an NCD. See Section 1869(f)(1)(A)(i) of the Social Security Act.

Unless otherwise specified, italicized text represents quotation from one or more of the following CMS sources:

Title XVIII of the Social Security Act (SSA):
Section 1862(a)(1)(A) excludes expenses incurred for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

Section 1833(e) prohibits Medicare payment for any claim which lacks the necessary information to process the claim.

Section 1862(a)(7) excludes routine physical examinations, unless otherwise covered by statute.

CMS Publications:
CMS Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 80.1 – Laboratory services must meet applicable requirements of CLIA

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 16, Section 40.7 Billing for Noncovered Clinical Laboratory Tests Section and 120.1 Clarification of the Use of the Term “Screening” or “Screen”

CMS Publication 100-04, Medicare Claims Processing Manual, Chapter 30, Section 50 Advance Beneficiary Notice of Noncoverage (ABN)

CMS Publication 100-08, Medicare Program Integrity Manual, Chapter 13, Local Coverage Determinations

CMS National Correct Coding Initiative (NCCI) Policy Manual for Medicare Services, Chapter 10, Pathology/Laboratory Services, (A) Introduction

CMS Publication 100-02, Medicare Benefit Policy Manual, Chapter 15, Section 80.6. 5 which describes the Surgical/Cytopathology Exception.

CMS National Correct Coding Initiative (NCCI) Policy Manual for Medicare Services, Chapter 10 Pathology/Laboratory Services which addresses reflex testing.

Code of Federal Regulations:

42 CFR, Section 410.32, indicates that diagnostic tests may only be ordered by the treating physician (or other treating practitioner acting within the scope of his or her license and Medicare requirements) who furnishes a consultation or treats a beneficiary for a specific medical problem and who uses the results in the management of the beneficiary's specific medical problem. Tests not ordered by the physician (or other qualified non-physician provider) who is treating the beneficiary are not reasonable and necessary (see Sec. 411.15(k)(1) of this chapter).


Coverage Guidance

Coverage Indications, Limitations, and/or Medical Necessity

ONE biomarker test (%fPSA, PHI, 4Kscore, or EPI) is covered ONCE in men 45 years old (≥ 50 years old for EPI) prior to initial biopsy, with confirmed* moderately elevated PSA (>3 and <10 ng/mL; ≥4 and <10 ng/mL in men >75 years old) with BOTH the following:  

  1. No other relative indication for prostate biopsy including ANY of the following:

    1. DRE suspicious for cancer
    2. Persistently elevated PSA
    3. Positive multiparametric MRI (if done)
    4. Other major risk factor for prostate cancer including:
      1. Ethnicity at higher risk for prostate cancer
      2. First-degree relative with prostate cancer
      3. High-penetrance prostate cancer risk gene(s) per NCCN (if known)
  2. No other relative contraindication for prostate biopsy including ANY of the following:

    1. <10 year life expectancy
    2. Benign disease not ruled out

*PSA elevation should be confirmed after a few weeks under standardized conditions (i.e., no ejaculation, manipulations, and urinary tract infections) in the same laboratory before considering a biopsy (1).

Summary of Evidence

Prostate cancer is the most diagnosed, non-cutaneous malignancy, and the third leading cause of cancer-related deaths in American men (behind lung and colorectal cancer). Approximately 165,000 men are expected to be diagnosed with prostate cancer in 2018, with approximately 18% dying of the disease (2). However, prostate cancer is a heterogeneous disease with a clinical course ranging from indolent to life-threatening. Prostate-specific antigen (PSA) screening, introduced around 1990 (3), resulted in a marked drop in the incidence of metastatic disease at diagnosis, and probably, but not definitely, reduced prostate cancer-specific mortality (1,4). However, a concomitant over-diagnosis (via prostate biopsy) and over-treatment of early-stage and indolent disease occurred as well (5-9). Only about 25% of men with PSA in the 4-10 ng/mL range have prostate cancer on biopsy, and of those, about 20-50% are indolent, disease that would not be a problem if undetected or untreated (10,11). As noted in a recent editorial, “in a biological sense, of course, screening does not cause prostate cancer, but in a practical sense, it does (12).” The results of three major PSA screening trials involving hundreds of thousands of men, the US Prostate, Lung, Colorectal and Ovarian Cancer Screening (PCLO) trial, the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, and the Cluster Randomized Trial of PSA Testing or Prostate Cancer (CAP), all show the risk-benefit ratio to be a close call (6,13,14). Because screening seemed to be doing more harm than good, the US Preventive Services Task Force (USPSTF) advised against PSA testing in 2012, though this is under reconsideration for men aged 55 to 69 years (10,15).

However, ample evidence has shown survival benefits associated with treatment of intermediate- and high-risk, early-stage prostate cancer (6,16). A Gleason score of 2 to 5 is regarded as normal prostate tissue; 6 is low-grade prostate cancer that usually grows slowly; 7 is an intermediate grade; 8 to 10 is high-grade cancer that grows more quickly. Ten-year survival rates stratified by Gleason score have been estimated from the Surveillance, Epidemiology, and End Results registry to be about 98% for scores 2 through 6, 92% for a score of 7 with primary pattern 3 and secondary pattern 4 (3+4), 77% for a score of 7 (4+3), and 70% for scores between 8 and 10 (17).

Unfortunately, PSA is not even specific to prostate cancer, much less clinically significant prostate cancer. Therefore, the current focus is on finding a more nuanced approach (beyond PSA and digital rectal exam (DRE)), by reserving biopsy and treatment for men with clinically significant, higher-grade (Gleason ≥ 7) prostate cancer (HGPCa). Such testing would represent secondary or reflex testing, rather than screening, effectively allowing for risk stratification and a more targeted response to PSA screening results (18). This strategy has the potential to not only decrease biopsies (and associated risks), but also of reducing detection of indolent disease (and the attendant risks of overtreatment). The primary aim is to increase specificity compared with PSA without decreasing the sensitivity to diagnose high-risk prostate cancer.

This Local Coverage Determination (LCD) will focus on biomarker testing used to refine selection of patients for initial (not repeat) biopsy.

Percent Free PSA (%fPSA)

Unbound or free PSA (fPSA), expressed as a ratio of total PSA (tPSA), is significantly lower in men with prostate cancer. In 1998, a large, prospective, multicenter study showed that a 25% %fPSA cutoff detected 95% of prostate cancers (of any grade) while avoiding 20% of unnecessary biopsies (11).

In 2003, the FDA approved %fPSA for use “as an aid in distinguishing prostate cancer from benign prostate conditions in men 50 years or older with total PSA 4-10 ng/mL, and DRE findings not suspicious for cancer (19).”

In a recent publication, among 417 men with a PSA>2, using a 25% cutoff, 83 (20%) would have avoided a biopsy (20). %fPSA has since become widely adopted more for active surveillance post prostate biopsy (1).

Prostate Health Index (PHI)

The PHI adds [-2]proPSA (p2PSA) (a fPSA isoform associated with PCa) to tPSA and fPSA in an algorithm that calculates a score that has demonstrated a correlation with HGPCa. The test was initially validated in 2011 in a multi-institutional, prospective trial evaluating 892 men (with no history of PCa, a normal DRE, and PSA of 2-10 ng/mL) for the presence of Gleason ≥4+3 prostate cancer (21). The receiver-operating characteristic curve (AUC) for PHI (0.724) exceeded that of %fPSA (0.670) in discriminating between Gleason ≥4+3 vs. lower Gleason grade PCa or negative biopsies. No optimal PHI cutoff was defined, however. Shortly thereafter, in 2012, PHI was FDA approved with identical indications to %fPSA (22).

A subsequent, prospective multi-center study of 658 men with a PSA of 4-10 ng/mL and normal DRE showed AUCs of 0.707 for PHI, 0.661 for %fPSA, and 0.551 for PSA, potentially sparing 30.1% of unnecessary biopsies with a PHI cutpoint of 28.6 (23). Another prospective multi-center studied two independent cohorts of 561 (primary) and 395 (validation) biopsy naive men (24). The primary and validation cohorts demonstrated an AUC for the detection of high-grade (GS ≥7) prostate cancer of 0.815 and 0.783, respectively. The study determined the optimal cutoff of PHI to be a score of 24, reducing unnecessary biopsies by 36% and only missing 2.5% of high-grade cancers. A subsequent publication by the same group showed that PHI significantly improved the performance of the Prostate Cancer Prevention Trial (PCPT) and ERSPC risk calculators in men with a PSA 2-10 ng/mL for predicting HGPCa (25).

In a prospective, single-center observational study in 188 men with elevated PSA (> 2ng/mL) and negative DRE, PHI had a higher discriminative ability for clinically significant PCa (AUC 0.76) compared to PSA (AUC 0.52) or %fPSA (AUC 0.75%) (51). However, the authors focus seems to be on something called PHI density rather than PHI.

In another prospective observational study, 506 men over 50 years old, with PSA in the 4-10 ng/mL range, a negative DRE, and receiving a PHI test, were compared with a historical control group of 683 similar men (52). Men receiving a PHI test showed nearly a 24% reduction in biopsy procedures performed compared to the historical control group (36.4% versus 60.3%, respectively, p<0.0001). “Based on questionnaire responses, the phi score impacted the 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 (phi ≥36).” The authors conclude that the study “supports the routine use of PHI testing for men presenting with elevated serum total PSA and non-suspicious DRE findings.”

Of note, there is conflicting data on the optimal PHI cutoff, with another study claiming poor results using a cutoff of 25-30 (26). The study, comparing 4K and PHI, is described in more detail in the 4Kscore section.

4Kscore

The 4Kscore combines data from serum levels of four kallikrein proteins (fPSA, tPSA, iPSA, human kalilkrein 2 (hK2)), along with clinical information (age, DRE, prior negative biopsy) to estimate the percent likelihood of HGPCa on biopsy using a proprietary algorithm.

In a population-based study involving 2914 men with elevated PSA >3 ng/mL, addition of free PSA, intact PSA, and hK2 to a model containing total PSA and age improved the AUC from 0.64 to 0.76 and 0.70 to 0.78 for models without and with digital rectal examination results, respectively (P <.001 for both) (27). The authors claim application of the panel could reduce biopsies by 51.3% and miss 12% of high-grade cancers.

In a multi-center prospective study of 1012 subjects scheduled for prostate biopsy, the predictive accuracy of the 4Kscore was compared to a modified Prostate Cancer Prevention Trial (PCPT) Risk Calculator 2.0 and showed superior discrimination in detecting HGPCa (AUC 0.82 versus 0.74, p < 0.0001) (28). It was estimated that, depending on the 4Kscore cutoff (≥6% to ≥15%), biopsies avoided would range from 30% to 58%, and the number of HGPCa missed would range from 1.3% to 4.7%.   

In a study of 6129 men with elevated PSA (≥ 3 ng/mL), the 4Kscore AUC for predicting HGPCa was 0.820 (95% CI = 0.802 to 0.838) vs 0.738 (95% CI = 0.716 to 0.761) for PSA and age alone (29). Using a 6% risk of high-grade cancer as a cutoff, the model would reduce biopsies by 42.8% and delay diagnosis in 14 of 133 (10.5%) of HGPCa.

A multi-institutional clinical utility study was performed to evaluate the effect of the 4Kscore test in lieu of prostate biopsy for males referred to urologists for atypical PSA and/or DRE results (30). The study involved 611 subjects in 35 United States academic and community settings. Results for the patients were stratified into low risk (< 7.5%), intermediate risk (7.5%-19.9%), and high risk (≥ 20%) for aggressive prostate cancer. Performing the 4Kscore Test resulted in a 64.6% reduction in prostate biopsies in patients; the actual percentage of cases not proceeding to biopsy were 94.0%, 52.9%, and 19.0% for men who had low-, intermediate-, and high-risk 4Kscore results, respectively.

When comparing PHI and the 4K score, the two tests appear to demonstrate similar discriminatory ability in predicting high-risk prostate cancer in men with a PSA between 3 and 15 ng/mL (AUC 4Kscore 0.718 vs. PHI 0.711); both tests had a higher AUC than PSA and age alone (p<0.0001 for both) (26). Of note, the 4K panel showed net benefit when the cutoff for biopsy exceeds 8% risk for HGPCa. The clinical utility of PHI was also strongly dependent on the cut-off used. PHI cutoffs of 25–30 had poor clinical utility compared to higher cutoffs (30-40). According to the study authors, the tests save almost 30% of the biopsies to the cost of missing 10% high grade cancers if using 10% risk of high grade cancer as predicted by the 4K panel or a PHI cutoff of 39.

However, a subsequent meta-analysis of twelve 4Kscore studies (N = 11,134), yielded an overall AUC of 0.81 (0.79-0.83), and found the Nordstrom study to be an outlier (AUC 0.72 vs. around 0.8 for others) (45). Excluding Nordstrom (a possible methodological flaw was admitted to by the Nordstrom authors (46)) increased this to 0.82 (0.80-0.84), and heterogeneity was no longer significant (p = 0.08). Interestingly, the authors also cite the lack of a specific “arbitrary” cutoff as a positive, saying “a continuous risk score from <1% to >90% that allows the physician and patient to act according to their own desired risk threshold.”

A prospective, multi-institutional study of 366 men (56% African American) showed better discrimination (AUC 0.81 vs. 0.74, p <0.01) than SOC (age, PSA, DRE) (47). There was no significant AUC difference for detecting clinically significant prostate cancer between African American and non-African Americans. In a retrospective study of 749 men referred for biopsy due to elevated PSA (≥3 ng/mL), low %fPSA (<20%), or suspicious DRE, the use of the 4Kscore (in conjunction with age and DRE) improved discrimination compared with SOC (age and PSA) for high-grade cancer (0.78 vs. 0.72; p = 0.002) (48). At a threshold of > 8%, 24% of biopsies would have been avoided and 13 high-grade cancers missed.

Two similarly designed retrospective, case-control studies address the question of whether biopsy outcome is a good proxy for long-term prostate cancer morbidity and mortality. A case-control studied 12,542 men enrolled at ages 40-60 and followed for >15yr; 1,423 developed incident PCa, 235 with distant metastasis (49). PSA and 4Kscore were measured in cryopreserved blood. Among those with a PSA ≥3ng/mL (2,432), 62% had a 4Kscore ≥7.5% and a 16.36% (95% CI: 12.44-20.74) risk at 20 years of distant metastasis, versus a 1.82% (95% CI: 0.47-4.99) risk among the 38% with a 4Kscore <7.5%. The authors conclude that the 4Kscore “can be used as a reflex test to aid biopsy decisions.” Another case-control studied 11,506 men enrolled at ages 45-73 and followed for >15yr; 1,223 developed incident PCa, 235 prostate cancer deaths (50). PSA and 4Kscore were measured in cryopreserved blood. Among men aged 60-73 with a PSA ≥2ng/mL (1,822), 54% had a 4Kscore ≥7.5% and a 24.21% (95% CI: 20.62-27.98) risk at 20 years of prostate cancer death, versus a 4.24% (95% CI: 2.64-6.40) risk among the 38% with a 4Kscore <7.5%. The authors conclude that “men with elevated PSA but low 4Kscores can be monitored rather than being subject to biopsy.”

The 4K score is not FDA approved, but rather a Laboratory Developed Test (LDT) through one CLIA-accredited testing laboratory in Nashville, TN.

ExoDx Prostate IntelliScore (EPI) 

EPI is a urine-based 3-gene exosomal RNA expression assay. The EPI gene signature and score incorporates levels of PCA3 (PCa antigen 3), ERG (v-ets erythroblastosis virus E26 oncogene homologs) and SPDEF (SAM-pointed domain-containing Ets transcription factor). EPI uses a proprietary algorithm to translate the level of expression of these three genes into an individualized risk score that predicts the presence of HGPCa, with a higher EPI score indicative of a higher probability of high-grade disease. It is intended to be used in conjunction with other standard-of-care (SOC) elements such as age, family history, PSA level and DRE results.

A study in men over 50 years without a prior biopsy and a PSA 2-10 ng/mL demonstrated a correlation with HGPCa significantly better than SOC alone (31). In 255 men in the training target population (median age 62 years and median PSA level 5.0 ng/mL, and initial biopsy), EPI plus SOC was associated with improved discrimination of HGPCa: AUC 0.77 (95%CI, 0.71-0.83) vs SOC AUC 0.66 (95%CI, 0.58-0.72) (P <.001). Results were similar in the independent validation of 519 patients; EPI plus SOC AUC 0.73 (95%CI, 0.68-0.77) was superior to SOC AUC 0.63 (95%CI, 0.58-0.68) (P <.001). Using a predefined cut point, 138 of 519 (27%) biopsies would have been avoided, missing 8% of HGPCa cases, but only 5% of patients with dominant pattern 4 high-risk GS7 disease. An accompanying editorial indicates EPI has the advantage over other biomarkers in being the least invasive (requires neither DRE or phlebotomy) (32).

In a second prospective, nonrandomized, controlled clinical study of 503 men 50 years or older with a PSA between 2-10 ng/mL, EPI AUC 0.70 (95%CI, 0.65-0.75) was superior to both the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC2.0) AUC 0.63 (95%CI, 0.58-0.68) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculator AUC 0.59 (95%CI, 0.54-0.64) (53). Using the test’s predefined cut point (15.6), 101 of 503 (20%) biopsies would have been avoided, missing 7% of HGPCa cases (11 ≥ GG2, of which 7 were ≥ GG3). The authors concluded “EPI is a noninvasive, easy-to-use, gene expression urine assay, which has now been successfully validated in over 1000 patients across two prospective validation trials to stratify risk of ≥GG2 from GG1 cancer and benign disease. The test improves identification of patients with higher grade disease and would reduce the total number of unnecessary biopsies.” A prospective utility and outcomes study has been completed and results are being prepared for publication (33).

Mi-Prostate Score (MiPS)

The MiPS assay measures tPSA and post-DRE urine expression of PCA3 and the TMPRSS2:ERG fusion gene. A validation study of 1244 men with planned biopsy (80% initial) found the AUC for the prediction of HGPCa was 0.772 for MiPS compared with 0.651 for PSA alone (34). Using a predicted risk cutoff of ≥30%, 35% of biopsies could have been avoided, and only 1% of HGPCa missed.

A multicenter prospective validation study of 561 men found a sensitivity and specificity for HGPCa of 93% and 33%, respectively (35). The authors calculate that 42% of unnecessary biopsies could be avoided at the cost of only 7% missed HGPCa.

SelectMDx

SelectMDx is a gene expression assay measuring mRNA levels of homeobox C6 (HOXC6) and distal-less hemeobox 1 (DLX1) in post-DRE urine; both HOXC6 and DL1 may be involved in the onset of prostate cancer and are associated with HGPCa (36). A prospective, multicenter study involved a training cohort (n=519) and validation cohort (n=386) in men scheduled for prostate biopsy (PSA ≥ 3ng/mL, abnormal DRE, or family history of prostate cancer) (37). Using a cut-off of 27.5 for the prediction of HGPCa, the expression of DLX1 and HOXC6 alone resulted in an AUC of 0.76 and 0.73 for the two cohorts, respectively. Combined with other SOC risk factors, the AUC increased to 0.90 in the training set and 0.86 in the validation set.

Analysis of Evidence
(Rationale for Determination)

The number of assays purported to serve as a useful adjunct to PSA in HGPCa prediction is mounting rapidly. There is some guideline consensus, if tepid, around the clinical utility of four: %fPSA, PHI, 4Kscore, and EPI. NCCN currently recommends “consideration” of certain reflex biomarker testing (%fPSA <10%, PHI >35, EPI score > 15.6, or 4Kscore), in patients with PSA levels >3 ng/mL who have never undergone a biopsy, “but for whom the patient and/or the physician wish to further define the probability of high-grade cancer (1).” Other organizations also seem to imply some support for certain of these biomarkers when the PSA is 4-10 ng/mL, including the American Cancer Society (ACS), (38) as well as the European Association of Urology (EAU), European Society for Radiotherapy & Oncology (ESTRO), and International Society of Geriatric Oncology (SIOG) (39).

The Canadian Urological Association (CUA) distinguishes %fPSA from both 4Kscore and PHI, concluding that “percent free PSA can be useful in estimating the risk of underlying disease in men with elevations in PSA (Level of evidence: 2; Grade of recommendation: C) (40).” In contrast, 4Kscore and PHI “in men with moderately elevated PSA…may improve the prediction of clinically significant prostate cancer and provide additional information over PSA alone; however, … At the present time, based upon the available data, the CUA does not encourage the widespread use of these tests.”

Other biomarkers (specifically, MiPS, and SelectMDx) are deemed investigational by NCCN (and presumably the others) due to lack of independent validation, false negatives, short follow-up, lack of randomized trials, lack of cut-point standardization, undetected cancers (up to 25%) with a single negative prostate biopsy, and the potential for upgrading (32%-49) that occurs in patients with Gleason 6 at biopsy. The concern implicit in the last two issues is that biomarker validations studies, which correlate biomarker test results only with initial biopsy findings, may be underestimating the risk of missing clinically significant cancer, hence the need for longer follow-up.

The American Urological Association (AUA) state that biomarkers “can be used as adjuncts for informing decisions about the need for a prostate biopsy –or repeat biopsy- after PSA screening, but emphasizes the lack of evidence that these tests will increase the ratio of benefit to harm (41).”

The American Society of Clinical Oncology (ASCO) considers ancillary radiologic and genomic tests (during active surveillance) investigational, noting that “prospective validation of these tests is needed to assess their impact on patient outcomes such as survival”, but may have a role in patients with discordant clinical and/or pathologic findings (42). While a different patient population, the concerns would apply equally to the pre-initial biopsy biomarker literature. An ASCO guideline on “Molecular and Cellular Diagnostics in Localized Prostate Cancer” is in development.

In addition, the case against early diagnosis of low risk prostate cancer is weakening. There is increasing uncoupling of over-diagnosis and over-treatment due to the emerging use of active surveillance. The most recent AUA/ASTRO/SUO, ASCO, and NICE guidelines recommend active surveillance (serial PSA, DRE, prostate biopsy) for most low risk localized prostate cancer patients (PSA <10, Gleason score ≤ 7, and clinical stage T1-T2a) (42-44). This trend toward active surveillance (instead of treatment) of low risk prostate cancer could lower the harm associated with diagnosis. Active surveillance of low risk cancer also ameliorates the risks associated with misclassification on initial biopsy.

In summary, while the results of the mostly industry-sponsored validation studies are promising, benefits remain theoretical, namely, that fewer biopsies of men with moderately elevated PSA is inherently a good thing. Certainly, it is good in the short term for men who avoid an “unnecessary” prostate biopsy. Not good, however, are necessary biopsies missed due to false negatives. Moreover, even the definition of “unnecessary” may be evolving. Also, some studies overrepresented men for whom the information is less likely to be helpful (a positive DRE, PSA levels outside the gray zone, or older men not candidates for surgery), or underrepresented others (e.g., high risk groups such as African Americans, etc.). Comparative studies of the many biomarkers are lacking and it is unclear how to use the tests in practice, particularly when test results are contradictory. For all these reasons, the long-term benefit of these tests to net health outcomes (i.e., mortality, morbidity, or quality of life) is not yet clear.

Given the state of flux of PSA screening in general, combined with only vague and lukewarm guideline support (secondary to the absence of Level I studies), of even certain adjunctive biomarker testing, NGS will provide very circumscribed coverage. Coverage will be limited to patients with moderately elevated PSA levels, but with no other, even relative, indication for or against biopsy (largely based on NCCN guidelines). These are men for whom the decision about whether to proceed with prostate biopsy is most ambiguous, and therefore for whom the information is most likely to impact clinical decision making (see the Indications and Limitations section for details).


Proposed Process Information

Changes Fields Changes
Coverage for EPI test was added to the Indications and Limitations section, based on the review of recently published literature (53).
Coverage Indications Limitations and/or Medical Necessity
Sources of Information and Basis for Decision

Associated Information

N/A

Sources of Information

N/A

Bibliography

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  12. Barry MJ. Screening for Prostate Cancer: Is the Third Trial the Charm? JAMA. 2018;319(9):868-869.
  13. Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012;104(2):125-132.
  14. Martin RM, Donovan JL, Turner EL, et al. Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial. JAMA. 2018;319(9):883-895.
  15. Moyer VA, Force USPST. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120-134.
  16. Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med. 2014;370(10):932-942.
  17. Wright JL, Salinas CA, Lin DW, et al. Prostate cancer specific mortality and Gleason 7 disease differences in prostate cancer outcomes between cases with Gleason 4 + 3 and Gleason 3 + 4 tumors in a population based cohort. J Urol. 2009;182(6):2702-2707.
  18. Carter HB, Albertsen PC, Barry MJ, et al. Early detection of prostate cancer: AUA Guideline. J Urol. 2013;190(2):419-426.
  19. FDA Approval-Percent Free PSA assay. 2004; https://www.accessdata.fda.gov/cdrh_docs/pdf2/P020027A.pdf.
  20. Ankerst DP, Gelfond J, Goros M, et al. Serial Percent Free Prostate Specific Antigen in Combination with Prostate Specific Antigen for Population Based Early Detection of Prostate Cancer. J Urol. 2016;196(2):355-360.
  21. Catalona WJ, Partin AW, Sanda MG, et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol. 2011;185(5):1650-1655.
  22. FDA approval- Prostate Health Index (PHI).  https://www.accessdata.fda.gov/cdrh_docs/pdf9/P090026A.pdf.
  23. Loeb S, Sanda MG, Broyles DL, et al. The prostate health index selectively identifies clinically significant prostate cancer. J Urol. 2015;193(4):1163-1169.
  24. de la Calle C, Patil D, Wei JT, et al. Multicenter Evaluation of the Prostate Health Index to Detect Aggressive Prostate Cancer in Biopsy Naive Men. J Urol. 2015;194(1):65-72.
  25. Loeb S, Shin SS, Broyles DL, et al. Prostate Health Index improves multivariable risk prediction of aggressive prostate cancer. BJU Int. 2017;120(1):61-68.
  26. Nordstrom T, Vickers A, Assel M, Lilja H, Gronberg H, Eklund M. Comparison Between the Four-kallikrein Panel and Prostate Health Index for Predicting Prostate Cancer. Eur Urol. 2015;68(1):139-146
  27. Vickers A, Cronin A, Roobol M, et al. Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol. 2010;28(15):2493-2498.
  28. Parekh DJ, Punnen S, Sjoberg DD, et al. A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur Urol. 2015;68(3):464-470.
  29. Bryant RJ, Sjoberg DD, Vickers AJ, et al. Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study. J Natl Cancer Inst. 2015;107(7).
  30. Konety B, Zappala SM, Parekh DJ, et al. The 4Kscore(R) Test Reduces Prostate Biopsy Rates in Community and Academic Urology Practices. Rev Urol. 2015;17(4):231-240.
  31. McKiernan J, Donovan MJ, O'Neill V, et al. A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer at Initial Biopsy. JAMA Oncol. 2016;2(7):882-889.
  32. Patel HD, Chalfin HJ, Carter HB. Improving Prostate Cancer Screening and Diagnosis: Health Policy and Biomarkers Beyond PSA. JAMA Oncol. 2016;2(7):867-868.
  33. Tutrone RF. A Prospective, Randomized Blinded, Shared Decision Impact Trial of the ExoDx Prostate (IntelliScore), EPI Test, in Men Presenting for Initial Biopsy. (https://clinicaltrials.gov/ct2/show/NCT03235687).
  34. Tomlins SA, Day JR, Lonigro RJ, et al. Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk Assessment. Eur Urol. 2016;70(1):45-53.
  35. Sanda MG, Feng Z, Howard DH, et al. Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer. JAMA Oncol. 2017;3(8):1085-1093.
  36. Leyten GH, Hessels D, Smit FP, et al. Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer. Clin Cancer Res. 2015;21(13):3061-3070.
  37. Van Neste L, Hendriks RJ, Dijkstra S, et al. Detection of High-grade Prostate Cancer Using a Urinary Molecular Biomarker-Based Risk Score. Eur Urol. 2016;70(5):740-748.
  38. American Cancer Society. What Tests Can Detect Prostate Cancer Early.  https://www.cancer.org/cancer/prostate-cancer/early-detection/tests.html.
  39. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2017;71(4):618-629.
  40. Rendon RA, Mason RJ, Marzouk K, et al. Recommandations de l'Association des urologues du Canada sur le depistage et le diagnostic precoce du cancer de la prostate. Can Urol Assoc J. 2017;11(10):298-309.
  41. AUA Guideline: Early Detection of Prostate Cancer (2013; Reviewed and Validity Confirmed 2015).  https://www.auanet.org/guidelines?q=&ContentType=&filters=785|.
  42. Chen RC, Rumble RB, Loblaw DA, et al. Active Surveillance for the Management of Localized Prostate Cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement. J Clin Oncol. 2016;34(18):2182-2190.
  43. Sanda MG, Cadeddu JA, Kirkby E, et al. Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. Part I: Risk Stratification, Shared Decision Making, and Care Options. J Urol. 2017.
  44. NICE Clinical Guideline: Prostate cancer: diagnosis and management. 2014; https://www.nice.org.uk/guidance/cg175.
  45. Zappala SM, Scardino PT, Okrongly D, Linder V, Dong Y. 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. 2017;19(3):149-155.
  46. Vickers A, Nordstrom T, Assel M, Lilja H, Gronberg H, Eklund M. Re: Tobias Nordstrom, Andrew Vickers, Melissa Assel, Hans Lilja, Henrik Gronberg, Martin Eklund. Comparison Between the Four-kallikrein Panel and Prostate Health Index for Predicting Prostate Cancer. Eur Urol 2015;68:139-46. Eur Urol. 2018;74(2):e35-e36.
  47. Punnen S, Freedland SJ, Polascik TJ, et al. A Multi-Institutional Prospective Trial Confirms Noninvasive Blood Test Maintains Predictive Value in African American Men. J Urol. 2018;199(6):1459-1463.
  48. Braun K, Sjoberg DD, Vickers AJ, Lilja H, Bjartell AS. A Four-kallikrein Panel Predicts High-grade Cancer on Biopsy: Independent Validation in a Community Cohort. Eur Urol. 2016;69(3):505-511.
  49. Stattin P, Vickers AJ, Sjoberg DD, et al. Improving the Specificity of Screening for Lethal Prostate Cancer Using Prostate-specific Antigen and a Panel of Kallikrein Markers: A Nested Case-Control Study. Eur Urol. 2015;68(2):207-213.
  50. Sjoberg DD, Vickers AJ, Assel M, et al. Twenty-year Risk of Prostate Cancer Death by Midlife Prostate-specific Antigen and a Panel of Four Kallikrein Markers in a Large Population-based Cohort of Healthy Men. Eur Urol. 2018;73(6):941-948.51.
  51. Tosoian JJ, Druskin SC, Andreas D, et al. Prostate Health Index density improves detection of clinically significant prostate cancer. BJU Int. 2017;120(6):793-798.
  52. White J, Shenoy BV, Tutrone RF, et al. Clinical utility of the Prostate Health Index (phi) for biopsy decision management in a large group urology practice setting. Prostate Cancer Prostatic Dis. 2018;21(1):78-84.
  53. McKiernan J, Donovan MJ, Margolis E, et al. 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. 2018.

Open Meetings

Meeting Date Meeting State(s) Meeting Information
06/27/2019 Connecticut
Illinois
Maine
Massachusetts
Minnesota
New Hampshire
New York - Downstate
New York - Entire State
New York - Queens
New York - Upstate
Rhode Island
Vermont
Wisconsin
12:00-1:30 p.m. CT
Illinois State Medical Society
20 N. Michigan Avenue Suite
700 Michigan Room
Chicago, IL. 60602

Contractor Advisory Committee (CAC) Meetings

N/A

MAC Meeting Information URL(s)

N/A

Proposed LCD Posting Date

06/06/2019

Comment Period Start Date

06/06/2019

Comment Period End Date

07/20/2019

Released to Final LCD Date

Please Note: This is not the LCD Effective Date.

N/A

Reason for Proposed LCD

    • Provider Education/Guidance
    • Public Education/Guidance
    • Request for Coverage by a Practitioner (Part B)

Proposed Contact

Virginia Muir
LCD Comments
P.O. Box 7108
Indianapolis, IN 46207-7108
PartBLCDComments@anthem.com


Coding Information

Bill Type Codes:

Contractors may specify Bill Types to help providers identify those Bill Types typically used to report this service. Absence of a Bill Type does not guarantee that the policy does not apply to that Bill Type. Complete absence of all Bill Types indicates that coverage is not influenced by Bill Type and the policy should be assumed to apply equally to all claims.

N/A

Revenue Codes:

Contractors may specify Revenue Codes to help providers identify those Revenue Codes typically used to report this service. In most instances Revenue Codes are purely advisory. Unless specified in the policy, services reported under other Revenue Codes are equally subject to this coverage determination. Complete absence of all Revenue Codes indicates that coverage is not influenced by Revenue Code and the policy should be assumed to apply equally to all Revenue Codes.

N/A

CPT/HCPCS Codes

Group 1 Paragraph:
Refer to Coding Article A56609

Group 1 Codes:

Code Description
XX000 Not Applicable

ICD-10 Codes that Support Medical Necessity

Group 1 Paragraph:
Refer to Coding Article A56609

Group 1 Codes:

ICD-10 Code Description
XX000 Not Applicable

ICD-10 Codes that DO NOT Support Medical Necessity

Group 1 Paragraph: N/A

Group 1 Codes:

ICD-10 Code Description
XX000 Not Applicable

Additional ICD-10 Information

N/A


Associated Documents

Attachments

N/A

Related Local Coverage Documents

Article(s)
A56609 - Billing and Coding: Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis

Related National Coverage Documents

N/A


Keywords

N/A

Proposed LCD for Biomarker Testing (Prior to Initial Biopsy) for Prostate Cancer Diagnosis (DL37733)
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