MolDX: Biomarkers to Risk-Stratify Patients at Increased Risk for Prostate Cancer

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary.

42 Code of Federal Regulations (CFR) 410.32(a) Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests and §80.1.1 Certification Changes

This contractor provides limited coverage for prostate biomarker diagnostic tests that help differentiate men who may or may not benefit from a prostate biopsy when all of the following conditions are met:

1. The beneficiary is a candidate for prostate biopsy or repeat prostate biopsy, according to a consensus guideline [i.e., National Comprehensive Cancer Network^®(NCCN)].
   1. For men ≤ 75 years of age - Prostate Specific Antigen (PSA) (or adjusted PSA in special populations, i.e., patients taking 5alpha-reductase inhibitors) OR repeat PSA are >3 and <10ng/mL AND/OR Digital Rectal Exam (DRE) findings are very suspicious for cancer
   2. For men > 75 years of age - PSA (or adjusted PSA in special populations, i.e., patients taking 5alpha-reductase inhibitors) OR repeat PSA are ≥4 and <10ng/mL AND/OR DRE findings are very suspicious for cancer
2. The beneficiary has not had a prostate biopsy OR has had a previous negative or non-malignant but abnormal histopathology finding (i.e., atypical small acinar proliferation or high-grade prostatic intraepithelial neoplasia (HGPIN) on prostate biopsy)
   • Patients under consideration for a repeat biopsy have first undergone repeat PSA and/or DRE testing AND a repeat biopsy is considered within 24-months of the prior biopsy.
3. The beneficiary would benefit from treatment of prostate cancer.
4. The beneficiary is within the population for which the test was developed and validated. The lab providing the test is responsible for clearly indicating to treating clinicians the population and indication(s) for test use.
5. If the test relies on an algorithm (which may range in complexity from a threshold determination of a single numeric value to a complex mathematical or computational function), the algorithm must be validated in a cohort that is not a development cohort for the algorithm.
6. The analytes measured have demonstrated clinical validity and clinical utility (i.e., improved detection or discrimination of cancer or high-grade cancer or reduction in the need for biopsy) in the peer-reviewed published literature, establishing a clear and significant biological/molecular basis for stratifying patients and subsequently selecting (either positively or negatively) their clinical management decision within a clearly defined population.
7. The test is ordered by a physician specialist in the management of prostate cancer, such as a urologist or oncologist.

NOTE: If the patient is considered higher risk (due to family history, high-risk genetics, African ancestry, or other clinical parameters highly suspicious for cancer), a biopsy may still be warranted. These relative indications for biopsy should be taken into consideration as part of a shared decision-making process regarding whether to proceed with biopsy.

Analytical validity, clinical validity (of novel analytes), and clinical utility, will be assessed as part of a thorough and comprehensive technical assessment (TA) by the Molecular Diagnostic (MolDX^®) program.

Prostate cancer is the second leading cause of cancer deaths in American men. Estimates for 2020 have shown that over 191,000 men will be diagnosed in the United States.^1,2 Prostate cancer can be an indolent, non-aggressive disease or a fast-growing, aggressive disease with significant morbidity and mortality. Prostate cancer guidelines, therefore, aim to limit unnecessary detection and invasive procedures for indolent disease while maximizing the detection and treatment of aggressive cancer.

Prostate cancer screening with PSA level has been an accepted approach to screening older men for prostate cancer and it is a statutorily covered Medicare benefit. However, PSA is not a cancer-specific marker, and there is ambiguity regarding its clinical value at various levels when reviewing associated clinical outcomes subsequent to screening. While the test is sensitive, its negative predictive value (NPV) is relatively low and there are numerous false positives.^3,4 Therefore, there is not one particular value or cut-off with sufficiently high sensitivity and specificity for assessing prostate cancer risk.⁴ A large multi-center randomized controlled study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, was conducted involving over 76,000 men from 55 to 74 years of age who received either annual PSA measurements and digital rectal examinations or their usual care.⁵ After 7 to 13 years of follow-up, the mortality rates were low in both groups and not significantly different.^5,6 However, the study’s control arm included opportunistic screening for prostate cancer and therefore greatly confounded the results. Another large trial involving 8 European countries, the European Randomized study of Screening for Prostate Cancer (ERSPC), randomized 182,160 men between the ages of 50 and 74 to receive either screening for prostate cancer including PSA measurements or a ‘truer’ control arm (in which only a relatively small number of men had previously taken a PSA test).⁷ Patients received a prostate biopsy if there was a concern for cancer based on the screening data. This study subsequently followed patients for 16 years and found that the screening group had a significant relative reduction in prostate-cancer related mortality of 21% (reported at 13 years of follow-up) and an even larger absolute benefit and reduction in excess incidence with the longer follow-up time of 16 years.^8,9

Although PSA screening has been associated with a significant reduction in prostate-cancer related mortality, it has also led to the increased incidence of prostate cancer, resulting in the overdiagnosis and overtreatment of indolent tumors, considered to be clinically insignificant.^7,10-13 Autopsy studies have shown that among 70–79 year old men, more than one-third to one-half have indolent prostate cancer that would not have caused harm if undiagnosed and untreated.¹³ The performance of prostate biopsies, an invasive intervention, is currently the next step in diagnosis and management, and can involve significant complications, including hospitalization in approximately 1% of patients.¹⁴ Moreover, prostate biopsy is also prone to challenges such as sampling error, which may further lead to both over- and under-treatment,¹⁵ with the false-positive and complication rates from biopsy being higher in older men.³ The United States Preventative Services Task Force update on PSA screening most recently noted that the choice to undergo screening for prostate cancer with a PSA test should be an individualized decision, but cautioned that there is a significant risk of false positives and over treatment with possible significant complications such as erectile dysfunction (ED) and incontinence.¹⁶ Such guidance was similarly endorsed by the Choosing Wisely initiative, which also highlighted the American Urological Association’s (AUA) recommendation to consider a PSA test only after talking with one’s doctor about risk factors.^17,18 Guidelines from the NCCN recommend consideration of PSA testing to screen for prostate cancer in men age 45-75 years as a level 2A recommendation and in men age 75+ as a level 2B recommendation.¹⁹

Patient management may include active surveillance versus definitive therapy. From 1994 through 2002 a large study of men with localized prostate cancer diagnosed shortly after PSA screening randomized 731 subjects to radical prostatectomy vs observation. There was no significant difference in either prostate-cancer specific mortality or all-cause mortality through at least 12 years of follow-up,²⁰ although with longer follow-up, the mortality rate was lower in men who underwent prostatectomy, though this finding was not statistically significant.²¹ Additionally, urinary incontinence, ED, and bowel incontinence were significantly more common among those men who underwent a prostatectomy.²¹ In spite of these challenges, prostate cancer deaths have decreased by 50% since 1988, in large part due to enhanced screening measures.^2,22,23

It is evident that not all prostate cancers are the same, and detection and treatment should focus specifically on prostate cancers likely to contribute to morbidity and mortality. It is also evident that there are challenges with PSA testing, and a PSA -based screening strategy has not been proven to help differentiate low risk from aggressive prostate cancer. First-generation PSA derivative assays (e.g., free PSA, complexed PSA) were designed to increase PSA specificity for prostate cancer, but not necessarily specificity for clinically significant cancer. Additionally, a negative magnetic resonance imaging (MRI) does not exclude the possibility of cancer. As such, there is clinical utility for diagnostic tests that can better refine the implications of an elevated PSA test to help distinguish men with potentially life-threatening cancer from men who have indolent prostate cancer or no prostate cancer.

The most current NCCN recommendation reflects the growing body of evidence supporting the use of prostate biomarkers to further identify and risk stratify those patients at risk of high grade prostate cancer requiring further management from those with low grade or indolent cancer who might not benefit from further intervention and who may be spared unnecessary biopsies and interventions. Such biomarkers are non-invasive (typically blood- or urine- based) and may contribute to improved sensitivity and specificity of screening, surpassing the limitations of PSA testing. ^19,24-26

There are numerous biomarkers available for biopsy-naïve patients, including percent free PSA (%fPSA), which may improve detection of prostate cancer. Free PSA (fPSA) is an unbound form of PSA that is Food and Drug Administration (FDA)-approved for use in men with normal DRE and PSA levels of 4-10 ng/mL. At a cutoff of 25% in men with PSA values between 4–10ng/mL, fPSA has been shown to detect the majority of prostate cancers while avoiding approximately 20% of unnecessary biopsies.²⁷ There are additional biomarkers intended for use in biopsy-naïve patients which may help further refine the probability of higher risk cancer. One such test, the 4Kscore^®, measures kallikrein markers (including PSA and fPSA) in the blood and considers other clinical parameters including age and DRE, which together have been reported to better detect clinically significant cancer.^28-32 Studies have shown that use of the 4Kscore^®test is associated with reduced prostate biopsies,³³ in some cases up to 65%.³⁴ One study reported that the reduction in biopsies would not have resulted in missing a significant number of high-grade cancers.³⁴ However, there is no optimal cut-off threshold for the 4Kscore^®test. Further, some of these studies included patients outside of the intended use population (PSA > 10 ng/mL), were based on changing PSA thresholds, or were based on hypothetical analyses and short endpoints. Therefore, a reanalysis of the data was performed and found that the clinical utility of the panel was still supported using any reasonable combination of age or PSA in contemporary cohorts.³⁵ Another test, the Prostate Health Index (PHI) is a blood-based immunoassay that uses PSA, fPSA, and p2PSA (an isoform of fPSA) to calculate a score that categorizes a patient’s risk as low, moderate, or high. Studies have shown that the PHI significantly improves the sensitivity of prostate cancer detection^36,37, reliably discriminates high-grade cancer^36,38 and can significantly reduce the rate of prostate biopsies.³⁹ Other pre-biopsy biomarkers are performed using post-DRE urine, and measure the expression of genes associated with prostate cancer; some of these couple gene expression with other clinical and laboratory parameters in multimodal models, to optimize their clinical performance.^40-44 For example, SelectMDx^® evaluates messenger ribonucleic acid (mRNA) levels of HOXC6 and DLX1 relative to Kallikrein-related Peptidase 3 (KLK3). When combined with additional clinical risk factors in a multimodal approach, prospective multicenter studies found that the area under the curve (AUC) of the receiver operating characteristic (ROC) reached 0.90 in predicting detection of high-grade prostate cancer; importantly, the risk score remained a strong predictor (AUC 0.78) in men with PSA levels <10 ng/mL.⁴⁵ On the whole, use of these tests can better detect cancer or high-grade cancer, and can reduce the performance of unnecessary prostate biopsies and their associated risks.

A urine exosome gene expression assay, the ExoDx^™ Prostate IntelliScore (EPI), has also been reported to be statistically more predictive than standard of care (SOC) alone for predicting Gleason score of 7 (GS7) prostate cancer from GS 6 and benign disease.⁴³ A clinical utility study in men scheduled for initial biopsy found that, at a cutoff of 15.6, the test had a NPV of 89% and would reduce total biopsies by 20%; however, the test would miss 7% of high grade cancers.⁴² In men with a prior negative biopsy, a prospective clinical validation study found that the EPI test had a NPV of 92% and would have avoided 26% of unnecessary biopsies while missing 2% of high-grade cancers.⁴⁶ Importantly, these results were independent of SOC and other clinical features. In addition to the EPI test, there are other biomarkers that improve specificity in patients who have had at least 1 prior negative biopsy. Some of these are liquid biomarkers that overlap with those already discussed for use in biopsy-naïve patients, while others are tissue-based and should only be performed on a biopsy specimen. Some utilize gene expression data while others evaluate epigenetic markers such as hypermethylation in select genes thought to be associated with aggressive disease.^47-50 Progensa^® PCA3 is an mRNA expression assay that can be tested from post-DRE urine. In the repeat biopsy setting, it has been shown to improve the specificity of prostate cancer detection and determine which patients should undergo a repeat biopsy. One multi-center study evaluating men with at least 1 prior negative prostate biopsy reported that those with a score of <25 were more than 4 times as likely to have a negative repeat biopsy as men with a score of ≥25.⁵¹ Finally, ConfirmMDx^® is a multi-gene test that uses prostate biopsy tissue to assess the methylation status of 3 biomarkers (GSTP1, RASSF1, APC) associated with prostate cancer.^47,50 The performance of this assay in large, blinded clinical validation studies demonstrated a NPV of 90% for all prostate cancer and 96% for high-grade disease, considerably higher than that afforded by standard histopathology review.^47,49 A field observation study conducted in 138 patients with negative biopsies found a repeat biopsy rate of 4.3%,⁵² significantly lower than the 40% repeat biopsy rate reported in the PLCO trial, for patients with an initial negative biopsy.⁵³

In summary, use of biomarker tests may help overcome the limitations of screening by PSA as well as the limitations and risks associated with prostate biopsy. It is not yet known how these tests can be optimally used in conjunction with MRI. Importantly, they have shown that they can improve the probability of detecting high-grade cancer and/or reducing the performance of unnecessary (initial or repeat) biopsies.

Numerous prior Medicare coverage decisions have considered the evidence in the hierarchical framework of Fryback and Thornbury⁵⁴ where Level 2 addresses diagnostic accuracy, sensitivity, and specificity of the test; Level 3 focuses on whether the information produces change in the physician's diagnostic thinking; Level 4 concerns the effect on the patient management plan and Level 5 measures the effect of the diagnostic information on patient outcomes. To apply this same hierarchical framework to analyze an in vitro diagnostic test, we utilized the Association of Chamber of Commerce Executives (ACCE) Model Process for Evaluating Genetic Tests.⁵⁵  The practical value of a diagnostic test can only be assessed by taking into account subsequent health outcomes. When a proven, well established association or pathway is available, intermediate health outcomes may also be considered. For example, if a particular diagnostic test result can be shown to change patient management and other evidence has demonstrated that those patient management changes improve health outcomes, then those separate sources of evidence may be sufficient to demonstrate positive health outcomes from the diagnostic test.

Screening for prostate cancer using PSA is a statutorily covered benefit. However, PSA is a screening test, and is not diagnostic of either prostate cancer or of prostate cancer requiring immediate intervention. The diagnosis relies on a prostate biopsy, which is associated with a risk of significant post-operative complications.

NCCN Guidelines recognize the benefits of improving the identification of significant cancer while avoiding the detection of indolent disease, and recommend (as a level 2A recommendation) the consideration of a biomarker test (one that has been validated in peer-reviewed studies) to better define the probability of higher-grade cancer (Gleason score 3 + 4, Grade Group 2 or higher) in patients who meet PSA standards for consideration of prostate biopsy.¹⁹ For patients who have not yet had a biopsy, the guidelines include the use of %fPSA to improve cancer detection, and PHI, SelectMDx^®, 4Kscore^®, and ExoDx™ Prostate (EPI) tests to further define the probability of higher-grade cancer.¹⁹ They also include %fPSA, PHI, 4Kscore^®, EPI, PCA3 and ConfirmMDx^® to improve specificity for patients thought to be at higher risk despite a prior negative biopsy.¹⁹ However, as there is variation in the number and quality of clinical validity and clinical utility studies published, it is not always clear which biomarker test may be optimal in a particular setting.^19,56 For these reasons, the NCCN guidelines state that no biomarker test can be recommended over any other at this time.¹⁹ They also caution that these tests can be complex and should be interpreted carefully, and with referral to a specialist.¹⁹

Molecular biomarkers can help stratify men who have an elevated PSA into those more likely versus less likely to have aggressive disease. These non-invasive biomarker tests have demonstrated that they can (1) reduce the need for unnecessary biopsies in men unlikely to have prostate cancer or high-grade prostate cancer and/or (2) better define men at risk for higher-grade prostate cancer. There is adequate evidence to show that the incremental information provided by validated pre-biopsy molecular tests for prostate cancer in samples of patients whose findings can be generalized to the Medicare population, changes physician management in a way that improves outcomes. Tests that fulfill all criteria outlined in this policy will similarly be considered for coverage.

The reference to specific biomarkers in this document does not imply coverage by MolDX^®. This contractor will continue to evaluate biomarkers and will provide coverage based on the pertinent literature as well as professional society and nationally recognized guidelines (i.e., NCCN).

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• Creation of Uniform LCDs With Other MAC Jurisdiction
• Provider Education/Guidance