Retired Local Coverage Determination (LCD)

MolDX: Prolaris™ Prostate Cancer Genomic Assay

L36787

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Document Information

LCD ID
L36787
LCD Title
MolDX: Prolaris™ Prostate Cancer Genomic Assay
Proposed LCD in Comment Period
N/A
Source Proposed LCD
DL36787
Original Effective Date
For services performed on or after 02/16/2017
Revision Effective Date
For services performed on or after 11/01/2019
Revision Ending Date
10/28/2021
Retirement Date
10/28/2021
Notice Period Start Date
01/01/2017
Notice Period End Date
02/15/2017
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CMS National Coverage Policy

Title XVIII of the Social Security Act (SSA), §1862(a)(1)(A), states that no Medicare payment shall be made for items or services that “are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”

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

Coverage Guidance

Coverage Indications, Limitations, and/or Medical Necessity

WPS GHA will provide limited coverage for the Prolaris™ prostate cancer assay (Myriad, Salt Lake City, UT) to help determine which patients with early stage, needle biopsy proven prostate cancer, can be conservatively managed rather than treated with definitive surgery or radiation therapy.

Summary of Evidence

In 2014, nearly 233,000 men in the U.S. will be diagnosed with prostate cancer, which accounts for 14% of all new cancer diagnosis. More than 29,000 men will die from this disease representing 5% of all cancer deaths. Gratefully 98.9% of men are surviving at 5 years.

Many individuals do not need treatment for their prostate cancer in as much as their prognosis is excellent even without treatment. However, physicians and patients struggle to know who can safely be observed versus the subgroup that needs more aggressive treatment to achieve cure and recognize that definitive treatment for localized prostate cancer can have lifelong morbidities.

Traditionally, clinicopathologic characteristics are utilized to determine risk and subsequent treatment. Several nomograms have been introduced to try to determine who is at risk of developing metastatic disease and who, if treated early, could avoid this outcome. A representative one taken from NCCN (and AUA), divides early prostate cancer into several groups based initially on life expectancy, with a second stratification using clinical exam, reassessment of life expectancy, biopsy (Gleason score), PSA and imaging.

These groups are detailed below:

Risk Category
  Very Low Low Intermediate High
Clinicopathologic Findings

T1c AND

  • Gleason score ≤ 6
    AND
  • PSA ≤ 10 ng/mL
    AND
  • < 3 prostate
    cores with tumor
    AND
  • ≤ 50% tumor in
    any core

        AND

  • PSA density of <
    0.15 ng/mL/g
  •  T1-T2a

         AND

  • Gleason
    score ≤ 6 Gleason grade group 1
    AND
  • PSA ≤ 10
    ng/mL
T2b-T2c OR

  • Gleason score 3+4= 7/Gleason grade group 2 OR
  • Gleason score 4+3=7/Gleason grade group 3 OR
  • PSA 10-20
    ng/mL
T3a OR
  • Gleason
    Score 8/Gleason grade group 4 

     OR

  • Gleason score 9-10 Gleason grade group 5 OR
  • PSA > 20
    ng/mL
Treatment Options        
≥ 20 y life
expectancy
  • Active
    Surveillance
  • RT or Brachy
  • RP (± LND)
     
≥ 10 y life
expectancy
  • Active
    Surveillance
  • Active
    Surveillance
  • RT or Brachy
  • RP (± LND
  • RP (± LND)
  • RT or Brachy

     ± Adj Horm

  • RT + Adj
    Horm
  • RT +
    Brachy
  • RP + LND
    ± RT, ADT
< 10 y life
expectancy
  • Observation
  • Observation
  • RT or Brachy
    ± Adj Horm
  • Observation
  • NA


Table 1: NCCN 2017. V2 - Localized Prostate Cancer Risk Stratification and Treatment (PSA – Prostate Specific Antigen; RT – Radiation Therapy; RP – Radical Prostatectomy; LND – lymph node dissection; Adj Horm –Adjuvant Androgen Deprivation)

Use of these stratification and treatment approaches has led to high cure rates for early stage prostate cancer. Yet it is widely accepted that many men are over-treated to achieve this cure rate. In the PIVOT trial men with early prostate cancer, initially randomized to radical prostatectomy or observation, showed that over 12 years there was no difference in absolute mortality between the groups. However, this study was hampered by several factors including:

  • Only 731 of 5023 eligible patients chose to participate in the study based on randomization criteria.
  • In the group randomized to RP: only 85% of the men received definitively therapy (79% surgery; 6% other).
  • In the observational group: 10% of the observation group received RP initially and additional 20% eventual received definitive treatment.
  • Despite broad inclusion criteria, >50% of patients had a PSA of = 7 (25%), 40% of men were classified initially as being low risk; and 30% were intermediate.

Although subgroups were small, it appears that high-risk groups (including those with PSA > 10) benefitted from RP. Furthermore, there was a trend for the intermediate risk patients to benefit from RP as well. The small number of participants willing to enter the study, and the high rate of crossover (both initially and subsequently) demonstrate the difficulty of doing observation trials in the United States.

Prolaris™ Prostate Cancer Assay

Test Description
Prolaris™ is an RNA based assay measuring the expression of 31 cell cycle progression (CCP) genes and 15“housekeeping” genes that act as internal controls and normalization standards in each patient sample. The assay is performed on formalin fixed paraffin-embedded (FFPE) prostate cancer blocks. The assay results are reported as a numerical score along with accompanying interpretive information.

Test Performance
The clinical performance of this assay was assessed in several retrospective validation studies. These include two British cohorts of men diagnosed with prostate cancer on biopsy and then treated conservatively; and an additional cohort of men diagnosed by TURP and conservatively managed. Further validation was performed in various other cohorts including men who underwent radical prostatectomy, and men treated with definitive radiotherapy. The Prolaris™ cell cycle progression score (CCP) was found to be an independent and more robust prognostic factor for disease related death than traditional clinicopathologic factors although disease stage and Gleason score consistently portended a more negative prognostic picture.

Due to the difficulty in obtaining prospective data in early prostate cancer (outcomes take decades to develop, hard to accrue patients to a conservatively managed arm in the U.S.), and given the unmet need, clinical utility can be extrapolated from this retrospective data. Doing so is not without shortcomings. It is unclear how the British cohorts were followed or who went on to receive definitive therapy inside the observation groups. The U.K. standard of care for treating these prostate cancer patients is different. In the U.S. conservatively managed patients is not the common occurrence. Furthermore, the long time period to determine outcomes and the lack of tissue specimens make review of a U.S. cohort unlikely if not impossible for many years.

In several of the published cohorts including the conservatively managed patients, multivariate analysis identified CCP score and Gleason score as the only values that consistently identify increased risk of death from prostate cancer. It also should be noted that the cancer related death rate in these retrospective studies of conservatively managed patients was much greater than would be expected in the United States with 19.3% of the patients with the lowest CCP succumbing to disease. Subset analysis suggests that if the patients with higher risk disease
(Gleason score > 7; higher stage) had received definitive treatment (like the current standard in the U.S.) the rate succumbing to disease would likely be substantially better.

The potential usefulness of this test is that it allows physicians to determine which patients with early prostate cancer are candidates for active surveillance or observation and are more likely to have a good outcome without needing to receive definitive treatment.NA

Analysis of Evidence (Rationale for Determination)

Level of Evidence
Quality – Moderate
Strength – Moderate
Weight – Limited to moderate

The Prolaris™ assay is covered only when the following clinical conditions are met:

  • Needle biopsy with localized adenocarcinoma of prostate (no clinical evidence of metastasis or lymph node involvement), and
  • FFPE prostate biopsy specimen with at least 0.5 mm of cancer length, and
  • Patient stage as defined by one of the following:
    • Very Low Risk Disease (T1c AND Gleason Score ≤ 6 AND PSA ≤ 10 ng/mL AND <3 prostate cores with tumor AND ≤ 50% cancer in any core AND PSA density of < 0.15 ng/mL/g) OR
    • Low Risk Disease (T1-T2a AND Gleason Score ≤ 6 AND PSA ≤ 10 ng/mL), Patient has an estimated life expectancy of ≥ 10 years, and
  • Patient has an estimated life expectancy of greater than or equal to 10 years, and,
  • Patient is a candidate for and is considering conservative therapy and yet and would be eligible for definitive therapy (radical prostatectomy, radiation therapy or brachytherapy), and
  • Result will be used to determine treatment between definitive therapy and conservative management, and
  • Patient has not received pelvic radiation or androgen deprivation therapy prior to the biopsy, and
  • Test is ordered by a physician certified in the in the Myriad Prolaris™ Certification and Training Registry (CTR), and
  • Patient is monitored for disease progression according to established standard of care, and
  • Physician must report the development of metastasis or prostate cancer deaths in patients not treated definitively who were deemed low risk by the assay.

Certification and Training Registry (CTR) Program
Because of the complicated nature of management decisions utilizing the Prolaris™ assay and the potential for adverse harm to patients if the test is not used appropriately, testing must be furnished only by physicians who are enrolled in a MolDX approved Myriad Prolaris™ CTR program. This serves to assure the appropriate selection of patients, compliance with management decisions and stringent follow up to ensure the benefits of the test outweigh its risks. As part of this requirement Myriad will provide the MolDx Contractor reports every 6 months in a mutually agreed upon format.

The goals of the Myriad Prolaris™ CTR program are as follows:

  • To ensure that physicians understand the limitation of the test based on its validation through retrospective and non-U.S. standards of care studies, and
  • To inform prescribers and patients on the safe-use conditions for Prolaris™, and
  • Make a good faith effort to identify any safety concerns from the use of the test.

WPS GHA and the MolDx Contractor expect Myriad to:

  • Establish and maintain the Prolaris™ Certification and Training Registry (CTR);
  • Ensure that healthcare providers who order the Prolaris™ score are registered and certified in the Prolaris™ CTR program and that the Prolaris™ assay is available only through these providers;
  • Maintain a secure registry database of Myriad Prolaris™ CTR providers;
  • Report utilization data by clinicopathologic staging;
  • Immediately report any distant metastases or prostate cancer related deaths in patients who did not receive definitive therapy and were Prolaris™ low risk;
  • Share all required data and reports in a HIPAA complaint fashion.

Changes/Expectations for Coverage
Expanded coverage to higher risk cohorts (intermediate or high) would require inclusion of the Prolaris™ assay in a widely accepted treatment guideline (such as AUA, NCCN or ASCO), or through successful development of outcome data through published prospective or prospective-retrospective trials showing a favorable clinical outcome (i.e. non-inferiority of non-definitively treated patients).

General Information

Associated Information

Documentation Requirements
The patient's medical record must contain documentation that fully supports the medical necessity for services included within this LCD. (See “Coverage Indications, Limitations, and/or Medical Necessity") This documentation includes, but is not limited to, relevant medical history, physical examination, and results of pertinent diagnostic tests or procedures.

Documentation supporting the medical necessity should be legible, maintained in the patient's medical record, and must be made available to the MAC upon request.

Sources of Information
N/A
Bibliography
  1. Bishoff JT, Freedland SJ, Gerber L, et al. Prognostic utility of the CCP score generated from biopsy in men treated with prostatectomy. J Urol. 2014 Aug; 192(2):409-14.
  2. Cuzick J, Berney DM, Fisher G, et al. Transatlantic Prostate Group. Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer. 2012 Mar 13; 106(6):1095-9.
  3. Cuzick J, Stone S, Yang ZH, et al. Validation of a 46-gene cell cycle progression (CCP) RNA signature for predicting prostate cancer death in a conservatively managed watchful waiting needle biopsy cohort.
    Presentation at the American Urological Association meeting May 16-21, 2014 in Orlando FL.
  4. Cuzick J, Swanson GP, Fisher G, et al. Transatlantic Prostate Group. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol. 2011 Mar; 12(3):245-55.
  5. Freedland SJ, Gerber L, Reid J, et al. Prognostic Utility of Cell Cycle Progression Score in Men With Prostate Cancer After Primary External Beam Radiation Therapy. Int J Radiat Oncol Biol Phys. 2013 Aug 1; 86(5):848-53.
  6. National Cancer Institute (U.S.), Surveillance and Epidemiology End Results (SEER), 2010. http://seer.cancer.gov/statfacts/html/
  7. NCCN Prostate Cancer Guideline 2017.V2
  8. Resnick MJ et al. Long-Term Functional Outcomes after Treatment for Localized Prostate Cancer. N Engl J Med 2013; 368:436-445.
  9. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367:203-13.

Revision History Information

Revision History DateRevision History NumberRevision History ExplanationReasons for Change
10/28/2021 R6

10/28/2021 - LCD is being retired. Information has been incorporated into our LCD L38433 MolDX: Prostate Cancer Genomic Classifier Assay for Men with Localized Disease.

  • LCD Being Retired
11/01/2019 R5

Change Request 10901 Local Coverage Determinations (LCDs): it will no longer be appropriate to include Current Procedure Terminology (CPT)/Health Care Procedure Coding System (HCPCS) codes or International Classification of Diseases Tenth Revision-Clinical Modification (ICD-10-CM) codes in the LCDs. All CPT/HCPCS, ICD-10 codes, and Billing and Coding Guidelines have been removed from this LCD and placed in the Billing and Coding Article related to this LCD. Consistent with Change Request 10901, if any language from IOMs and/or regulations was present in the LCD, it has been removed and the applicable manual/regulation has been referenced. Review completed 10/23/2019.

  • Other (Compliance with CR 10901)
10/01/2018 R4

10/01/2018-Annual review completed 09/05/2018.

  • Other (Annual Review)
01/01/2018 R3

05/01/2018-Removed CDD from the title of the LCD. Added CPT code 81541 & removed CPT code 81479.

  • Revisions Due To CPT/HCPCS Code Changes
12/01/2017 R2

 

12/01/2017-Updated the analysis of evidence information, added “OR” back into table for Intermediate and High-Risk Categories & corrected typo.

 

  • Other
11/01/2017 R1

11/01/2017: Added Gleason grade score to the low, intermediate and high risk table. Updated NCCN guideline in the source of information section. Annual review completed 10/06/2017. At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination; and, therefore not all the fields included on the LCD are applicable as noted in this policy.

  • Other (Annual Review)

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Updated On Effective Dates Status
10/28/2021 11/01/2019 - 10/28/2021 Retired You are here
11/19/2019 11/01/2019 - N/A Superseded View
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