I. Disclaimer

This document is intended to be used as a reference for non-VA providers and is not intended to replace clinical judgment when determining care pathways. These guidelines do not guarantee benefits or constitute medical advice. 

II. Clinical Determinations and Indications

1. Indications for Multicancer Detection Testing  
   Multicancer detection testing is considered investigational and experimental and therefore not medically necessary and not covered. 

There is insufficient evidence from peer-reviewed medical literature to support the safety and efficacy of multicancer detection (MCD) testing. 

III. Background and Supporting Information

The following information is for reference purposes only in accordance with the medical benefits package outlined in 38 C.F.R. § 17.38 (b). Each subsection supports VA’s determinations for medical necessity and alignment with generally accepted standards of medical practice. 

1. Background Information
   Cancer remains one of the most significant public health challenges in the United States and is the second leading cause of death, following heart disease. It accounts for approximately one in every six deaths. Despite advances in medical treatments, outcomes for many cancers remain closely tied to the stage at diagnosis. With considerably higher survival rates when cancers are detected earlier, this highlights the importance of early detection. 

Early detection strategies include early diagnosis and screening. Early diagnosis focuses on symptomatic individuals; while screening targets asymptomatic populations to identify pre-symptomatic disease. Recent advances in molecular diagnostics, high-throughput sequencing, and computational biology have enabled the development of multicancer detection (MCD) tests. These tests have been postulated to allow screening for multiple cancer types simultaneously using a blood sample. This contrasts with traditional screening methods such as mammography for breast cancer, colonoscopy for colon cancer, low-dose computed tomography (CT) for lung cancer, or Pap testing for cervical cancer.  

Multicancer detection tests evaluate biological signals associated with cancer across multiple organ sites simultaneously. Biological signals include cell-free tumor DNA (cfDNA), circulating tumor DNA (ctDNA), and antibodies. 

2. Research, Clinical Trials, and Evidence Summaries
   Current evidence from research evaluating MCD testing remains insufficient to establish clinical effectiveness for routine screening. Across multiple systematic reviews and evidence syntheses, MCD tests demonstrate high specificity but variable sensitivity across cancer types. In addition, current evidence has not demonstrated that MCD testing reduces cancer specific mortality, improves quality of life, or results in reductions in advanced cancers compared with standard guideline-recommended screening. Overall, current evidence is inadequate to establish clinical benefit. Leading authors conclude that MCD tests should not be adopted for population screening or coverage determination until robust randomized trials demonstrate beneficial, clear patient relevant outcomes, and the harms of testing and subsequent follow-up are also considered. 

Ghosh et al. (2025) conducted a review summarizing evidence from multiple large-scale studies evaluating MCD blood tests for early diagnosis of gastrointestinal (GI) malignancies. These studies, including the PATHFINDER trial, THUNDER study, and CancerSEEK, are primarily prospective cohort and validation studies that assess the feasibility, sensitivity, specificity, and clinical utility of MCD assays using advanced biomarker analysis and machine learning. For example, the THUNDER study retrospectively and prospectively validated cfDNA methylation-based MCD tests in over 2,700 participants, demonstrating sensitivity of 69.1% and specificity of 98.9% for detecting six cancer types, with high tissue origin accuracy. The CancerSEEK test showed median sensitivity of 70% and specificity greater than 99% for eight cancers, including several GI cancers lacking routine screening options. Outcomes from these studies indicate that MCD tests can identify cancers at earlier stages, potentially allowing for curative treatment, especially in cancers with no current screening tools such as cholangiocarcinoma and pancreatic cancer. However, the authors caution that MCD testing faces limitations including high costs, lack of FDA approval, risk of false positives, and limited data on reduction of cancer-specific mortality and insurance coverage. The authors recommend that MCD should not replace guideline-based, age-appropriate cancer screenings but may serve as a complementary tool, particularly for high-risk populations or cancers without established screening methods. They emphasize the need for further research, shared decision-making, and careful discussion of risks, benefits, and financial implications with patients before adoption into routine clinical practice. 

Kahwati et al. (2025) conducted a systematic review to evaluate the benefits, harms, and accuracy of blood-based MCD tests in asymptomatic adults. The review included 20 studies (N=109,177) assessing the accuracy of 19 different MCD tests but found no completed controlled studies evaluating whether these tests improve mortality, reduce advanced cancers, or enhance quality of life compared to standard screening or no screening. Accuracy results varied widely: sensitivity ranged from 9.5% to 99.8%, specificity from 65.7% to 100%, and area under the curve (AUC) from 0.52 to 1.0, with generally lower sensitivity and AUC in studies simulating real-world screening (pre-diagnostic designs) compared to case-control studies. Only one study reported on potential harms, finding no serious adverse events, but some unnecessary radiation exposure from follow-up imaging after false positives. The strength of evidence for both accuracy and harm was graded as insufficient due to high risk of bias, indirectness, and inconsistency across studies. The primary source of bias in these studies was the use of case-control design to estimate accuracy. Case-control trials cause selection bias by using different groups to estimate sensitivity and specificity, and spectrum bias that makes the test appear to perform better than it really is. This is compounded by additional biases such as unblinded study personnel, insufficient details on predefined test thresholds, and incomplete information on patient flow. The authors conclude that there is currently no direct evidence that MCD tests provide clinical benefit as a population screening tool and recommend that these tests not be adopted for routine screening or insurance coverage until ongoing randomized trials report on patient-relevant outcomes such as mortality, stage shift, and quality of life. They emphasize that robust evidence of clinical benefit through reductions in cancer mortality is required before considering coverage. Additionally, they highlight that implementation should be cautious given the potential for harms, costs, and uncertain impact on health outcomes. 

Wade et al. (2025) systematically reviewed 36 studies (including one ongoing randomized controlled trial, 13 cohort studies, and 17 case-control studies) evaluating blood-based MCD tests for population screening in adults aged 50–79 years without clinical suspicion of cancer. The review found that currently available MCD tests (such as Galleri, CancerSEEK, SPOT-MAS, Trucheck, CDA, and AICS) consistently demonstrated high specificity (greater than 96%), but sensitivity was highly variable (ranging from 20.8% to 100% depending on the test and study design) and was generally lower for early-stage cancers (stages I–II) compared to later stages (III–IV). While these tests can detect a broad range of cancers, their ability to identify early-stage, potentially more treatable cancers remains limited, and no completed randomized controlled trials were identified to support their impact on mortality, quality of life, or other patient-relevant outcomes. Most studies had a high risk of bias due to limited follow-up, particularly with participants with negative test results and poor applicability to general screening populations. The authors conclude that, although MCD tests are promising for ruling out cancer, currently there is insufficient high-quality evidence to support their use as a population screening tool. They recommend that further research, particularly randomized controlled trials reporting patient-relevant outcomes and cost-effectiveness, is needed before MCD tests can be recommended for routine screening. The authors caution that implementation should be carefully considered, balancing test accuracy, cost, and the likelihood of improving outcomes for patients, especially for cancers not currently covered by existing screening programs. 

Shrag et al. (2023) conducted the PATHFINDER study as a prospective cohort trial to evaluate the feasibility of a blood-based MCD test using cell-free DNA methylation patterns in adults aged 50 years and older without cancer symptoms. Among 6,621 participants, researchers detected a cancer signal in 1.4%, identifying 35 true positives and 57 false positives. The MCD test showed a positive predictive value of 38%, a negative predictive value of 98.6%, and a specificity of 99.1%. True positive participants reached diagnostic resolution in a median of 57 days, while false positive participants waited 162 days, leaving many to endure over five months of uncertainty. Clinicians performed extensive diagnostic workups for false positive participants: 88% had lab tests, 93% underwent imaging (often multiple PET-CT, CT, or MRI scans), and 30% underwent invasive procedures, with one participant even having surgery prompted by abnormal imaging. These prolonged evaluations imposed a significant psychological burden on patients and families, which the authors acknowledged by collecting anxiety and distress data for future reporting. The test identified cancers at early stages (48% stage I–II) and detected types lacking screening recommendations. The authors concluded that MCD testing is feasible in clinical practice, but emphasized the need for larger trials to establish clinical utility, mortality benefit, and strategies to mitigate false-positive harms before widespread adoption. 

The Department of Veterans Affairs National Oncology Program and Office of Research and Development through the Cooperative Studies Program Coordinating Center is actively participating in the National Cancer Institute’s VANGUARD Study which examines the feasibility of using MCD tests in upcoming randomized controlled trials. The study was launched in early 2025 and will enroll participants through 2027, following them for up to two years. VA serves as one of the nine ACCESS Hubs within the Cancer Screening Research Network.  

3. Medicare Coverage Determinations
4. There are no available Medicare national and local coverage determinations. VA and Medicare are governed by separate laws and regulations; thus, VA coverage determinations may be different. 

4. Health Care Procedural Coding Information
5. The following CPT^®/HCPCS codes listed in this section are provided for informational purposes only. Inclusion or exclusion of a code does not constitute or imply VA coverage or provider reimbursement. The list of codes may not be all-inclusive since the American Medical Association (AMA) and Centers for Medicare & Medicaid Services (CMS) code updates may occur more frequently than CDI updates. Please refer to section II.a. in this document to review indications and clinical criteria for medical necessity. 

The following CPT codes are considered not medically necessary/not covered when used to bill for the specific pathology procedure described in this CDI due to VA exclusion or because they are considered investigational and experimental. Additional codes may also apply. 

Note: Providers must complete the description of services when billing with an unlisted code.

CPT Code	Description
81479	Unlisted molecular pathology procedure

CPT copyright 2026 American Medical Association. All rights reserved. 

IV. Definitions

Term	Definition
Cell-free DNA	DNA that is circulating freely in bodily fluids, such as blood plasma, and is released from all types of cells
Circulating tumor DNA	Fragments of DNA that are released from a tumor and migrate into bodily fluids, such as blood plasma
High-throughput sequencing/Next Generation Sequencing	New sequencing techniques that can quickly analyze multiple sections of DNA at the same time. Older forms of sequencing analyzed one section of DNA at a time

V. References

American Cancer Society. (2025) Cancer Facts & Figures 2025. Retrieved December 22, 2025. 

Atlanta: American Cancer Society; 2025. Ghosh, A. K., Stephens, K. R., Kandiah, P. A., Hurt, R. T., & Gilman, E. A. (2025). Multicancer Detection (MCD) Testing in Gastrointestinal Cancers: An Evolving Tool for Early Diagnosis. Current gastroenterology reports, 27(1), 19.  

Kahwati, L. C., Avenarius, M., Brouwer, L., Crossnohere, N. L., Doubeni, C. A., Miller, C., Siddiqui, M., Voisin, C., Wines, R. C., & Jonas, D. E. (2025). Blood-Based Tests for Multiple Cancer Screening: A Systematic Review. Agency for Healthcare Research and Quality (US).  

National Cancer Institute. (2024). NIH launches research network to evaluate emerging cancer screening technologies. Retrieved December 22, 2025. 

National Cancer Institute. (2025). Questions and Answers about Multi-Cancer Detection Test. Retrieved December 22, 2025. 

National Cancer Institute. (2025). The Vanguard Study on Multi-Cancer Detection Tests. Retrieved February 12, 2026. 

National Cancer Institute. (2025). Vanguard Study. Retrieved February 12, 2026. 

Schrag, D., Beer, T. M., McDonnell, C. H., 3rd, Nadauld, L., Dilaveri, C. A., Reid, R., Marinac, C. R., Chung, K. C., Lopatin, M., Fung, E. T., & Klein, E. A. (2023). Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study. Lancet (London, England), 402(10409), 1251–1260.  

Wade, R., Nevitt, S., Liu, Y., Harden, M., Khouja, C., Raine, G., Churchill, R., & Dias, S. (2025). Multi-cancer early detection tests for general population screening: a systematic literature review. Health technology assessment (Winchester, England), 29(2), 1–105.  

VI. CDI History/Revision Information

Date	Summary of Updates
08/01/2026	New investigational/experimental CDI created

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