Gene Expression Profiling, Protein Biomarkers, and Multimodal Artificial Intelligence for Prostate Cancer Management

POLICY NUMBER

A.2.04.111

DESCRIPTION

Gene expression profile analysis and protein biomarkers have been proposed as a means to risk-stratify individuals with prostate cancer to guide treatment decisions.These tests are intended to be used either on prostate needle biopsy tissue to guide management decisions for active surveillance or therapeutic intervention, to guide radiotherapy use after radical prostatectomy (RP), or to guide medication selection after progression in metastatic castration-resistant prostate cancer.

Prostate Cancer

Prostate cancer is the most common cancer diagnosed among men in the U.S., and the second most common cancer overall. Autopsy studies in the era before the availability of prostate-specific antigen (PSA) screening have identified incidental cancerous foci in 30% of men 50 years of age, with incidence reaching 75% at age 80 years.

Localized prostate cancers may appear very similar clinically at diagnosis. However, they often exhibit diverse risk of progression that may not be captured by clinical risk categories (eg, D’Amico criteria) or prognostic tools based on clinical findings, including PSA titers, Gleason grade, or tumor stage. In studies of conservative management, the risk of localized disease progression based on prostate cancer-specific survival rates at 10 years may range from 15% to 20% to perhaps 27% at 20-year follow-up. Among older men (aged >70 years) with low-risk disease, comorbidities typically supervene as a cause of death; these men will die with prostate cancer present, rather than from cancer itself. Other very similar appearing low-risk tumors may progress unexpectedly rapidly, quickly disseminating and becoming incurable.

Risk Stratification in Newly Diagnosed Disease

In the United States, most prostate cancers are clinically localized at diagnosis due in part to the widespread use of PSA testing. Clinicopathologic characteristics are used to stratify patients by risk based on the extent of the primary tumor (T category), nearby lymph node involvement (N category), metastasis (M category), PSA level and Gleason score. The National Comprehensive Cancer Network and American Urological Association risk categories for clinically localized prostate cancer are similar, derived from the D’Amico criteria and broadly include low-, intermediate-, or high-risk as follows as well as subcategories within these groups:

• Low: T1-T2a and Gleason score ≤6/Gleason grade group 1 and PSA level ≤10 ng/mL;

• Intermediate: T2b-T2c or Gleason score 3+4=7/Gleason grade group 2 or Gleason score 4+3=7/Gleason grade group 3 or PSA level 10-20 ng/mL;

• High: T3a or Gleason score 8/Gleason grade group 4 or Gleason score 9-10/Gleason grade group 5 or PSA level >20 ng/mL.

Risk stratification is combined with patient age, life expectancy, and treatment preferences to make initial therapy decisions.

Principles of Risk Stratification and Biomarkers for Prostate Cancer

Predictive biomarkers and risk stratification methods are the primary tools within clinical practice that may aid in the treatment of individuals with localized and advanced prostate cancer. The NCCN uses multiple categories and subgroupings to capture prognostic risk and provide a method for risk-stratification to allow standardized treatment recommendations for individuals with localized and advanced prostate cancer. These tools are separated by type and category:

Type:

• "Standard Tools: These include clinical and/or pathologic variables routinely collected to assign a patient to an NCCN category and/or subgroup. Examples include TNM stage, Grade Group, PSA, and metastatic volume of disease."

• "Clinical and Pathologic Tools: These include clinical and/or pathologic tools that are generally derived from standard tools. Examples include multivariable models or nomograms, histologic variants, and PSA kinetics."

• "Advanced Tools: These involve an additional test above what is collected to assign an NCCN category or subgroup. These may include, but are not limited to, germline or somatic tests, gene expression tests, digital histopathology-based tests, imaging, and circulating markers."

Category:

• "Prognostic: Discriminates the risk of developing an oncologic endpoint (eg, distant metastasis). The relative benefit of a treatment (ie, the treatment effect or hazard ratio) is generally similar across a prognostic spectrum, although the absolute benefit of an intervention may vary by risk (ie, number needed to treat [NNT])."

  • "Prognostic biomarkers independently discriminate and are associated with a clinically meaningful endpoint above and beyond standard tools relevant to that disease setting that ultimately helps guide a therapeutic decision."

• "Predictive: Discriminates a difference in the relative benefit of a specific treatment for an oncologic endpoint."

  • "Predictive biomarkers have been demonstrated to measure a biomarker-treatment interaction that ultimately helps guide a therapeutic decision in the context of a randomized trial, specifically randomizing the treatment of interest."

Monitoring After Prostatectomy

All normal prostate tissue and tumor tissue are theoretically removed during radical prostatectomy (RP), so the serum level of PSA should be undetectable following RP. Detectable PSA post-RP indicates residual prostate tissue and presumably persistent or recurrent disease. Prostate-specific antigen is serially measured following RP to detect early disease recurrence. The National Comprehensive Cancer Network recommends monitoring serum PSA every 6 to 12 months for the first 5 years and annually thereafter. Many recurrences following RP can be successfully treated. The American Urological Association recommends that biochemical recurrence be defined as a serum PSA of 0.2 ng/mL or higher, which is confirmed by the second determination with a PSA level of 0.2 ng/mL or higher.

Castration-Resistant Prostate Cancer

Androgen deprivation therapy (ADT) is generally the initial treatment for patients with advanced prostate cancer. Androgen deprivation therapy can produce tumor response and improve quality of life but most patients will eventually progress on ADT. Disease that progresses while the patient is on ADT is referred to as castration-resistant prostate cancer. After progression, continued ADT is generally used in conjunction with other treatments. Androgen pathways are important in the progression of castration-resistant prostate cancer. Several drugs have been developed that either inhibit enzymes involved in androgen production or inhibit the androgen receptor, such as abiraterone and enzalutamide. Taxane chemotherapy with docetaxel or cabazitaxel may also be used after progression. Immunotherapy (sipuleucel-T) or radium 223 are options for select men.

Decision Framework for Evaluating Prostate Cancer Biomarkers

Many studies have investigated individual biomarkers or combinations of biomarkers associated with prostate cancer outcomes. Determining which studies constitute sufficient evidence that the test or biomarker is likely to be clinically useful depends on attributes of the test such as its performance and the quality of the study generating the results. Simon and colleagues (2009) have described a framework to evaluate prognostic biomarker evidence. Study designs, such as prospective clinical trials or previously conducted clinical trials with archived tumor samples, constitute stronger evidence than studies with less planned and systematic patient recruitment and data collection. Randomized trials allow the determination of treatment-biomarker interactions that may be clinically important. In some clinical scenarios, demonstration of a treatment-biomarker interaction is not critical, because the decision to withhold chemotherapy in a low-risk group (to avoid chemotherapy-related morbidity) does not require the presence of a biomarker-treatment interaction. The study must generate an absolute estimate of outcomes in the patient group of interest that would result in a change in management (eg, withholding of chemotherapy), and the study must have sufficient precision (narrow confidence intervals). Results of the same test across studies should show the consistency of results and more than 1 study demonstrating the desired result should be available. Simon and colleagues (2009) have proposed that at least 2 category B studies showing results consistent with clinical utility are necessary to demonstrate adequate evidence of a biomarker. Simon and colleagues (2009) also proposed that while "further confirmation in a separate trial of the results gained from a category A prospective trial is always welcome, compelling results from such a trial would be considered definitive and no other validating trial would be required."

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Prolaris® (Myriad Genetics), Oncotype Dx® Prostate and Oncotype DX AR-V7 Nuclear Detect (Genomic Health), Decipher gene expression profiling test (Decipher Corp), the ProMark™ protein biomarker test (Metamark Genetics), and Artera® Prostate Test are available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of these tests.

In November 2015, the FDA’s Office of Public Health Strategy and Analysis published a report suggesting FDA oversight of LDTs. The FDA argued that many tests need more FDA oversight than the regulatory requirements of the CLIA. The CLIA standards relate to laboratory operations, but do not address inaccuracies or unreliability of specific tests. Prolaris is among the 20 case studies in the document cited as needing FDA oversight. The report asserted that patients are potentially receiving inappropriate prostate cancer care because there is no evidence that results from the test meaningfully improve clinical outcomes.

POLICY

Use of gene expression analysis, protein biomarkers, and multimodal artificial intelligence (MMAI) to guide management of prostate cancer is considered investigational in all situations.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

04/01/2014: Approved by Medical Policy Advisory Committee.

01/12/2015: Policy reviewed; description updated. Policy statement unchanged.

07/20/2015: Code Reference section updated for ICD-10.

02/11/2016: Policy title changed from "Gene Expression Profile Analysis for Prostate Cancer Management" to "Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management." Policy description updated to add information regarding protein biomarkers. Policy statement updated to add protein biomarkers as investigational. Investigative definition updated in policy guidelines section.

06/07/2016: Policy number A.2.04.111 added.

12/05/2016: Policy description updated regarding estimated new cases for 2016 and FDA oversight of laboratory-developed tests. Policy statement unchanged.

12/22/2017: Code Reference section updated to add new 2018 CPT codes 81541 and 81551.

01/09/2018: Policy description updated regarding localized prostate cancers, risk stratification, and monitoring after prostatectomy. Policy statement unchanged.

02/16/2018: Code Reference section updated to add CPT code 0011M.

06/15/2018: Code Reference section updated to add CPT code 0005U and new codes 0047U and 0053U, effective 07/01/2018.

01/03/2019: Code Reference section updated to revise code description for CPT code 0011M, effective 01/01/2019.

01/24/2019: Policy description updated regarding castration-resistant prostate cancer and laboratory-developed tests. Policy statement unchanged.

09/17/2019: Code Reference section updated to add new CPT code 0133U, effective 10/01/2019.

12/19/2019: Policy description updated. Policy statement unchanged. Code Reference section updated to add new CPT code 81542 effective 01/01/2020.

12/17/2020: Code Reference section updated to add new CPT code 0228U, effective 01/01/2021.

01/14/2021: Policy reviewed. Minor edit made to policy statement.

02/03/2022: Policy reviewed; no changes.

12/16/2022: Policy reviewed; no changes.

07/01/2023: Code Reference section updated to make note of deleted CPT code.

12/14/2023: Policy reviewed; no changes.

07/01/2024: Code Reference section updated to add new CPT code 0475U.

10/01/2024: Code Reference section updated to add new CPT codes 0512U and 0513U.

11/11/2024: Policy description updated regarding studies for evaluating prostate cancer biomarkers. Policy statement unchanged. Code Reference section updated to remove deleted CPT code 0053U.

06/15/2025: Policy title changed from "Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management" to "Gene Expression Profiling, Protein Biomarkers, and Multimodal Artificial Intelligence for Prostate Cancer Management." Policy description updated regarding tests and principles of risk stratification and biomarkers for prostate cancer. Policy statement revised to add multimodal artificial intelligence to guide management of prostate cancer as investigational. Code Reference section updated to add CPT code 0376U.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.111

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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