Multicancer Early Detection Testing Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM

EFFECTIVE DATE: 01|01|2024 POLICY LAST REVIEWED: 09|03|2025

OVERVIEW
Many cancers appear to have a better prognosis if diagnosed early in their natural history. This has led to efforts to detect preclinical cancers in asymptomatic individuals through screening. Cancer screening tests such as ‘liquid biopsies’ that are minimally invasive and can simultaneously detect multiple types of cancer have been called multicancer early detection (MCED) tests.

MEDICAL CRITERIA Not applicable.

PRIOR AUTHORIZATION
No applicable.

POLICY STATEMENT Medicare Advantage Plans
The use of multicancer early detection (MCED) tests (e.g., Galleri) is not covered for cancer screening as the evidence is insufficient to determine that the technology results in an improvement in net health outcome.

Commercial Products
The use of multicancer early detection (MCED) tests (e.g., Galleri) is not medically necessary as the evidence is insufficient to determine that the technology results in an improvement in net health outcome.

Some genetic testing services are not covered and a contract exclusion for any self-funded group that has excluded the expanded coverage of biomarker testing related to the state mandate, R.I.G.L. §27-19-81 described in the Biomarker Testing Mandate policy. For these groups, a list of which genetic testing services are covered with prior authorization, are not medically necessary or are not covered because they are a contract exclusion can be found in the Coding section of the Genetic Testing Services or Proprietary Laboratory Analyses policies. Please refer to the appropriate Benefit Booklet to determine whether the member’s plan has customized benefit coverage. Please refer to the list of Related Policies for more information.

COVERAGE Benefits may vary between groups and contracts. Please refer to the appropriate Benefit Booklet, Evidence of Coverage or Subscriber Agreement for applicable not medically necessary/not covered benefits/coverage.

BACKGROUND Cancer is the second leading cause of death in the US following heart disease. Cancer is the cause of death in 1 of every 5 deaths in the US. In the US, more than 1.7 million new cases of cancer were reported in 2019, and almost 600,000 people died of cancer. Many cancers appear to have a better prognosis if diagnosed early in their natural history. This has led to efforts to detect preclinical cancers in asymptomatic persons through screening. However, screening tests have associated benefits and harms that must be considered when evaluating whether a test should be used in a population.

Early detection of cancer has 2 components: early diagnosis and screening. Early diagnosis is the early identification of cancer in symptomatic individuals with the aim of reducing the proportion of individuals diagnosed at a late stage. Screening is the identification of preclinical cancer or precursor lesions in apparently healthy, asymptomatic populations by tests that can be applied rapidly and widely in the target population. This review focuses on tests for screening indications. Medical Coverage Policy | Multicancer Early Detection Testing

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

Cancer screening tests such as ‘liquid biopsies’ that are minimally invasive and can simultaneously detect multiple types of cancer have been called multicancer early detection (MCED) tests. MCED tests are distinct from traditional cancer screening tests due to two main factors. Firstly, they employ a single blood test rather than x-rays, imaging tests like mammography, or procedures like colonoscopy. Secondly, they simultaneously screen for multiple types of cancer from various organs, including those not checked by existing methods. MCED tests predict the presence of cancer, rather than diagnose it. Depending on the biological signals measured, they may screen for multiple cancer types. Current development focuses on measuring signals in blood plasma, such as changes in DNA/RNA sequences, DNA methylation patterns, DNA fragmentation patterns, protein biomarker levels, and antibodies against cancer cell components. Researchers are continually developing new technological approaches to expand the range of measurable biological signals, such as those identified by immune cells.

No MCED tests have been approved or cleared by the U.S. Food and Drug Administration (FDA). Several tests, including Galleri® (GRAIL), CanScanTM (Genesseeq), OverCTM Multi-Cancer Detection Blood Test (Burning Rock) have been granted breakthrough device designation by the FDA.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Galleri is available under the auspices of the Clinical Laboratory Improvement Amendments.

Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

For individuals who are being screened for cancer who receive multicancer early detection (MCED) testing, the relevant published evidence includes a systematic review, and one US-based prospective study. Relevant outcomes are overall survival, disease-specific survival, functional outcomes, quality of life, treatment-related mortality, and treatment-related morbidity. A systematic review of 36 studies on MCED tests highlighted variability in diagnostic accuracy. Evidence was limited, with no completed RCTs. While the tests exhibited high specificity, sensitivity varied depending on study design, population, reference tests, and follow-up duration. Insufficient follow-up for negative results led to high risk of bias across studies. Currently, the Galleri test is the only commercially available MCED test in the United States. One prospective study of the Galleri test reported a positive predictive value of 38% (95% CI, 29 to 48) and specificity and negative predictive value of approximately 99%. The specifics regarding the practical application of the test, including the appropriate at-risk target populations, frequency of testing, and follow-up for positive and negative results, have not been fully described. There is a need for performance characteristics for both the prediction of overall cancer likelihood and the tissue of origin. No clinical utility studies have been published to date, and estimates of changes in cancer-specific mortality, quality of life, functional outcomes, and rates of overdiagnosis and overtreatment remain unknown. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

CODING Medicare Advantage Plans and Commercial Products
CPT codes have not been assigned to the test(s) addressed in this policy. Therefore, an Unlisted code(s) should be used.

RELATED POLICIES Biomarker Testing Mandate
Genetic Testing Services
Proprietary Laboratory Analysis (PLA) and Multianalyte Assays with Algorithmic Analyses (MAAA) Unlisted Procedures

PUBLISHED

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM

Provider Update, November 2025 Provider Update, September 2024 Provider Update, November 2023

REFERENCES

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2. American Cancer Society. Cancer Facts & Figures 2025. Accessed May 20, 2025.
3. World Health Organization. Screening and early detection. Accessed May 16, 2025.
4. National Cancer Institute. Questions and Answers about Multi-Cancer Detection Tests. Accessed May 22, 2025.
5. National Cancer Institute. NIH launches research network to evaluate emerging cancer screening technologies 2024. Accessed, May 19, 2025.
6. National Cancer Institute. Vanguard Study. Accessed May 10, 2025.
7. American Cancer Society. Cancer Risk and Prevention. Accessed May 12, 2025.
8. GRAIL, LLC. Frequently asked questions for healthcare providers interested in ordering the Galleri test. Accessed May 13, 2025.
9. Bossuyt PM, Irwig L, Craig J, et al. Comparative accuracy: assessing new tests against existing diagnostic pathways. BMJ. May 06 2006; 332(7549): 1089-92. PMID 16675820
10. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin. Jan 2022; 72(1): 7-33. PMID 35020204
11. Minasian LM, Pinsky P, Katki HA, et al. Study design considerations for trials to evaluate multicancer early detection assays for clinical utility. J Natl Cancer Inst. Mar 09 2023; 115(3): 250-257. PMID 36458902
12. Jamshidi A, Liu MC, Klein EA, et al. Evaluation of cell-free DNA approaches for multi-cancer early detection. Cancer Cell.Dec 12 2022; 40(12): 1537-1549.e12. PMID 36400018
13. Liu MC, Oxnard GR, Klein EA, et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. Jun 2020; 31(6): 745-759. PMID 33506766
14. Duffy MJ, Diamandis EP, Crown J. Circulating tumor DNA (ctDNA) as a pan-cancer screening test: is it finally on the horizon?. Clin Chem Lab Med. Jul 27 2021; 59(8): 1353-1361. PMID 33856748
15. Cuzick J, Cafferty FH, Edwards R, et al. Surrogate endpoints for cancer screening trials: general principles and an illustration using the UK Flexible Sigmoidoscopy Screening Trial. J Med Screen. 2007; 14(4): 178-85. PMID 18078562
16. Menon U, Gentry-Maharaj A, Burnell M, et al. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. Jun 052021; 397(10290): 2182-2193. PMID 33991479
17. Owens L, Gulati R, Etzioni R. Stage Shift as an Endpoint in Cancer Screening Trials: Implications for Evaluating Multicancer Early Detection Tests. Cancer Epidemiol Biomarkers Prev. Jul 01 2022; 31(7): 1298-1304. PMID 35477176
18. Feng X, Zahed H, Onwuka J, et al. Cancer Stage Compared With Mortality as End Points in Randomized Clinical Trials of Cancer Screening: A Systematic Review and Meta-Analysis. JAMA. Apr 07 2024. PMID 38583868
19. Klein EA, Richards D, Cohn A, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol. Sep 2021; 32(9): 1167-1177. PMID 34176681
20. Tang WHW, Yimer H, Tummala M, et al. Performance of a targeted methylation-based multi-cancer early detection test by race and ethnicity. Prev Med. Feb 2023; 167: 107384. PMID 36495927
21. Shao SH, Allen B, Clement J, et al. Multi-cancer early detection test sensitivity for cancers with and without current population-level screening options. Tumori. Jun 2023; 109(3): 335-341. PMID 36316952
22. Nicholson BD, Oke J, Virdee PS, et al. Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study. Lancet Oncol. Jul 2023; 24(7):733-743. PMID 37352875
23. Wade R, Nevitt S, Liu Y, et al. Multi-cancer early detection tests for general population screening: a systematic literature review. Health Technol Assess. Jan 2025; 29(2): 1-105. PMID 39898371

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 4 (401) 274-4848 WWW.BCBSRI.COM

24. Schrag D, Beer TM, McDonnell CH, et al. Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study. Lancet. Oct 07 2023; 402(10409): 1251-1260. PMID 37805216
25. Neal RD, Johnson P, Clarke CA, et al. Cell-Free DNA-Based Multi-Cancer Early Detection Test in an Asymptomatic Screening Population (NHS-Galleri): Design of a Pragmatic, Prospective Randomised Controlled Trial. Cancers (Basel).Oct 01 2022; 14(19). PMID 36230741

26. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic; Version 3.2025. Accessed May 16, 2025.

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    This medical policy is made available to you for informational purposes only. It is not a guarantee of payment or a substitute for your medical judgment in the treatment of your patients. Benefits and eligibility are determined by the member's subscriber agreement or member certificate and/or the employer agreement, and those documents will supersede the provisions of this medical policy. For information on member-specific benefits, call the provider call center. If you provide services to a member which are determined to not be medically necessary (or in some cases medically necessary services which are non-covered benefits), you may not charge the member for the services unless you have informed the member and they have agreed in writing in advance to continue with the treatment at their own expense. Please refer to your participation agreement(s) for the applicable provisions. This policy is current at the time of publication; however, medical practices, technology, and knowledge are constantly changing. BCBSRI reserves the right to review and revise this policy for any reason and at any time, with or without notice. Blue Cross & Blue Shield of Rhode Island is an independent licensee of the Blue Cross and Blue Shield Association. CLICK THE ENVELOPE ICON BELOW TO SUBMIT COMMENTS