LCD L39005: MolDX: Molecular Biomarkers to Risk-Stratify Patients at Increased Risk for Prostate Cancer

There are two applications of molecular biomarkers to risk-stratify patients at increased risk for prostate cancer:

• A non-invasive or minimally invasive test, the results of which are obtained to inform the decision to perform an initial biopsy (pre-biopsy).

• A test performed to further refine risk when a biopsy has been performed but does not clearly indicate malignancy on histopathologic examination (post-biopsy). Such a test can potentially obviate the need for a repeat biopsy.

This contractor provides limited coverage for molecular Deoxyribonucleic acid/ribonucleic acid (DNA/RNA) biomarker tests for the diagnosis of prostate cancer that help differentiate men who may or may not benefit from a prostate biopsy when ALL of the following conditions are met:

• The patient must not have an established diagnosis of prostate cancer.

• The beneficiary is a candidate for prostate biopsy or repeat prostate biopsy, according to a consensus guideline [(i.e., National Comprehensive Cancer Network® (NCCN), American Society of Clinical Oncology®(ASCO), American Urological Association (AUA)].

• 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 75 years of age - PSA (or adjusted PSA in special populations, i.e., patients taking 5-alpha-reductase inhibitors) OR repeat PSA are ≥4 and

EXCEPTION: a molecular biomarker test may be performed in men with PSA levels >10 ng/mL who are being considered for repeat biopsy IF appropriate according to consensus guidelines AND according to the following: the specific biomarker test has been validated in men with PSA levels>10 ng/mL AND a Multiparametric MRI (mpMRI) is negative, if performed.

• 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 (ASAP) 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 as recommended by consensus guidelines

• The beneficiary would benefit from treatment of prostate cancer and patient management will be impacted by use of a biomarker in a manner already demonstrated in the peer-reviewed published literature to improve patient outcomes.

• The medical record supports the medical necessity for the biomarker test.

• Testing is performed according to the intended use of the test in the intended patient population for which the test was developed and validated.

• Testing must be performed according to Clinical Laboratory Improvement Amendments (CLIA) and/or Food and Drug Administration (FDA) regulations in an accredited laboratory.

• For a given clinical indication (pre-OR post-biopsy), only one molecular biomarker may be performed UNLESS a second test, meeting all the criteria established herein, is reasonable and necessary as an adjunct to the first test, according to criteria established in this policy.

• 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.

• 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.

• The test is ordered by a physician specialist in the management of prostate cancer, such as a urologist or oncologist. An exception may be made in geographic locations where the specialist(s) cannot be reasonably reached by the beneficiary and the ordering provider is located closer to the beneficiary’s place of residence than the nearest specialist. We would generally expect that beneficiaries for whom the test is ordered under this exception to be living in rural locations, islands, or some other location where access to care is limited.

NOTE: If the patient is considered higher risk (due to relevant family or personal cancer history, relevant high-risk genetic mutations, African ancestry, or other clinical parameters highly suspicious for cancer including a persistent and significant increase in PSA), 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 a 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 Services Program (MolDX®).

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 the PSA level has been an accepted approach to screening men for prostate cancer, and it is a statutorily covered Medicare benefit. The PSA level correlates with the risk of prostate cancer and the higher above the median PSA (for a given age group), the higher the risk for prostate cancer and aggressive prostate cancer. Approximately 30% of men with serum PSA levels between 4 and 10 ng/mL will be found to have prostate cancer, and total PSA levels >10 ng/mL confer a >67% likelihood of prostate cancer. 3,4 As such, NCCN guidelines recommend that patients with a PSA >10 ng/mL should be encouraged to undergo biopsy. 4 However, PSA is not a cancer-specific marker, and it is widely known that PSA values can be elevated and fluctuate for a variety of reasons other than cancer including inflammation, infection, and benign prostate hyperplasia. 5,6 While the test is sensitive, its negative predictive value (NPV) is relatively low and there are numerous false positives. 7,8 A cohort study of 1268 patients found that repeating the PSA resulted in normal ( with initial PSA levels between 4 and 10 ng/mL . 6 Moreover, compared with men who had an abnormal repeat PSA result, men with normal repeat PSA results were less likely to undergo biopsy and were approximately 80% less likely to have a diagnosis of prostate cancer and Gleason score of 7 or higher. 6 False negative PSA results also occur. In the Prostate Cancer Prevention Trial, 15% of men with PSA levels ≤4.0 ng/mL (and normal DREs) were diagnosed with prostate cancer; of these, 14.9% had a Gleason score of 7 or higher. 9 Therefore, there is not one particular value or cut-off with sufficiently high sensitivity and specificity for assessing prostate cancer risk.

Given the suboptimal ability of the PSA to accurately assess prostate cancer risk, there is ambiguity regarding its clinical value at various levels when reviewing associated outcomes subsequent to screening. 8 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. 10 After 7 to 13 years of follow-up, the mortality rates were low in both groups and not significantly different. 10,11 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). 12 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. 13,14

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. 12,15-18 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. 18 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. 19 Moreover, prostate biopsy is also prone to challenges such as sampling error, which may further lead to both over- and under-treatment, 20 with the false-positive and complication rates from biopsy being higher in older men. 7