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| Genetic Test: Multicancer Early Detection Testing | |
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| Description: |
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.
Cancer is the second leading cause of death in the United States following heart disease, causing 1 in every 6 deaths (Cancer Statistics, 2024). Excluding non-melanoma skin cancers, approximately 2.1 million new cancer cases are expected to be diagnosed in the US in 2026, and more than 626,000 people will die from the disease (Siegel, 2026). 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 (WHO, 2025).
Cancer screening tests such as ‘liquid biopsies’ that are minimally invasive have been called multicancer early detection (MCED) tests (NCI, 2025). 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.
Regulatory Status
No MCED tests have been approved or cleared by the U.S. Food and Drug Administration (FDA). Several tests, including Galleri (GRAIL), CanScan (Geneseeq), and OverC Multi-Cancer Detection Blood Test (Burning Rock) have been granted breakthrough device designated by the FDA. CancerGuard (Abbott) is commercially available as a laboratory-developed test (LDT) but has not been cleared or approved by the FDA (Exact Sciences, 2025).
On January 29, 2026, GRAIL submitted a Premarket Approval (PMA) application to the FDA for the Galleri MCED test, which holds Breakthrough Device Designation (2018). The application is currently under FDA review (GRAIL, 2026). See below for further details.
Regulatory Status of the Galleri MCED Test
In February 2024, the National Cancer Institute (NCI) launched the Cancer Screening Research Network (CSRN) to evaluate emerging technologies for cancer screening (NCI, 2024; NCI, 2025). As part of this initiative, the CSRN began the Vanguard Study, which aims to enroll up to 24,000 participants to evaluate the feasibility and benefits of MCED tests. This study will focus on diverse populations across eight US sites led by the Fred Hutchinson Cancer Center, with further participation from the US Department of Defense and the Department of Veterans Affairs. Participants will be randomly assigned to a control group or one of two MCED test groups. The control group will have blood drawn without further testing, while the MCED test groups will receive assays - Avantect from ClearNote Health and Shield from Guardant Health - at no cost. The study objectives include assessing participant willingness, adherence to testing, diagnostic follow-up, and evaluating the feasibility of diagnostic processes. Enrollment in the Vanguard Study began in 2025, and the study is actively recruiting participants.
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 (CLIA). Galleri is available under the auspices of the CLIA.
Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.
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Policy/ Coverage: |
Effective October 2023
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
The use of multicancer early detection (MCED) tests (e.g., Galleri) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without Primary Coverage Criteria, the use of multicancer early detection (MCED) tests (e.g., Galleri) is considered Not Medically Necessary or is investigational and is not covered. Not Medically Necessary or investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
This evidence review was created in June 2023 with a search of the PubMed database. The most recent literature update was performed through March 01, 2023.
Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.
The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.
Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.
Multicancer Early Detection Screening of Asymptomatic Populations
Clinical Context and Test Purpose
The purpose of multicancer early detection (MCED) testing in individuals being screened for cancer is to inform a decision about whether to refer the individual for further screening or diagnostic testing.
Different cancers are vastly heterogeneous in their natural histories, invasiveness of diagnostic work-up, prognoses, and responses to treatment, and therefore have distinct screening recommendations. Population-based cancer screening is currently recommended for a few select cancers.
To evaluate an MCED test, an explication of how the test would be integrated into current screening and diagnostic pathways is needed. Positive screening tests set off a chain of cascading events that can lead to benefit or harm. This cascade varies depending on whether the MCED is positioned as a triage, replacement, or add-on for existing screening and diagnostic tools, periodicity of the MCED test, as well as invasiveness and effectiveness of diagnostic work-up and treatments (Bossuyt, 2006).
To demonstrate that a screening test is useful:
The following PICO was used to select literature to inform this review.
Populations
The relevant population of interest are individuals who are being screened for cancer. Screening is the identification of pre-clinical cancer or precursor lesions in apparently healthy, asymptomatic populations.
A person’s risk of developing cancer depends on risk factors related to genetics, demographics, environmental or other exposures and the interaction between these risk factors. Several risk factors are associated with an increased risk of cancer in general (e.g., older age, family history, smoking, diet, obesity, physical activity, exposure to certain viruses, hormones or radiation) (Cancer.Net Editorial Board, 2023). Additional risk factors are specific to cancer type (e.g., sunlight exposure and skin cancer, radon exposure and lung cancer, occupational chemical exposures and respiratory cancers, viral exposures (e.g., cervical or liver cancer).
Cancer survival rates are lower for Black individuals than for White individuals for almost every cancer type. The survival disparity is partially explained by the later stage at diagnosis for Black individuals; however, Black individuals also have lower survival within specific stages for most cancers (Siegel, 2022).
The National Cancer Institute convened a panel of experts in 2021 to discuss initial design concepts for trials evaluating MCED assays for cancer screening (Minasian, 2023). The panel suggested that trials should target the general population in the age range of 50 to 75years.
Interventions
The tests being considered are MCED tests. This review will not discuss tests that are used to screen for 1 cancer.
Several MCED tests are in development. Most MCED tests being developed are 'liquid biopsies' that detect altered DNA from cancer-causing genes that has been shed into circulation, called circulating-tumor DNA (ctDNA). ctDNA is only a small proportion of the total circulating-free DNA (cfDNA), particularly in patients with early-stage cancer.
Screening is not usually a single event. Screening tests may be applied repeatedly over time with a specified frequency. The screening interval or periodicity is normally determined by the growth rate of a cancer; for example, in average-risk adults of appropriate ages, breast cancer screening is performed approximately every 1 to 2 years whereas colon cancer screening is performed approximately every 5 to 10 years. The National Cancer Institute panel on MCED assays also made recommendations regarding periodicity of screening for trials of MCED tests (Minasian, 2023). The panel proposed trials should consist of annual screening for 3 to 5 years.
Many of the MCED tests in development predict the overall likelihood of cancer and the tissue of origin.
Standardized diagnostic pathways for each of the cancers included in an MCED test are needed, including specification of follow-up of positive and negative test results.
Galleri
According to the manufacturer's website, the Galleri® MCED test is 'a qualitative, next-generation sequencing-based, in vitro diagnostic test intended for the detection of DNA methylation patterns using cell-free DNA (cfDNA) isolated from human peripheral whole blood (Grail, 2023). It is unclear how the Galleri test would fit into existing clinical pathways for screening; the website FAQs offer the following information (Grail, 2023):
The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study included assay discovery, development, and refinement for the Galleri MCED test (Jamshidi, 2022; Liu, 2020). The CCGA clinical validation substudy of the marketed version of the test will be discussed in the following section on Clinical Validity.
Comparators
The comparator of interest is standard of care cancer screenings. The U.S. Preventive Services Task Force (USPSTF) supports screening for breast, cervical, colorectal, and lung cancers.
Outcomes
The National Cancer Institute panel on MCED assays made recommendations regarding randomized controlled trial (RCT) outcomes for trials of MCED tests (Minasian, 2023). The panel concluded that the primary outcome of trials should be either cancer mortality (all cancers) or cancer mortality from the subset of cancers included in each assay. Key secondary efficacy outcomes identified by the panel were all-cause mortality and incidence of advanced stage disease. Key safety outcomes identified by the panel were false-positives, invasive procedures, serious adverse events, and overdiagnosis. The panel proposed trials should include follow-up of at least 7 years.
Potential Benefits
The primary benefit of screening for cancer is the potential to diagnose cancer at an earlier stage or detect precursor lesions that can be treated with less aggressive or more effective treatment, thereby theoretically improving the length or quality of life. Thus, cancer-specific mortality and quality of life are the primary outcomes of interest for assessing benefit. However, mortality is a demanding outcome that requires long follow-up times and a large number of participants in order to produce reliable and precise estimates.
Longitudinal examination of the population-based, age-standardized stage distribution of all cancers may give early information on the likelihood of a survival benefit. However, it is possible for screening to increase the proportion of early-stage cancers that are detected without reducing the absolute incidence of advanced cancer because of overdiagnosis.
Shift in stage-specific incidence (stage-shift) has been validated as a surrogate for mortality for screening of breast cancer with mammography, and colorectal cancer with flexible sigmoidoscopy (Duffy, 2021; Cuzick, 2007). However, in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) trial of postmenopausal women without increased familial ovarian cancer risk, while annual screening with biomarker CA125 and transvaginal ultrasound scans did reduce stage III or IV disease incidence compared to no screening, it did not improve survival with a median follow-up of over 16 years (Menon, 2021).
Owens et al developed a mathematical model for the relationship between stage shift and disease-specific mortality and compared results to those from published screening trials. The authors concluded that the expected reduction in mortality given a specific stage-shift will likely vary substantially across cancer types and that stage-shift is unlikely to be a reliable basis for inference about mortality reduction for many cancer types (Owens, 2022).
As such, stage-shift is not a validated surrogate for cancer-specific mortality across a wide range of cancers.
Stage-shift could also be related to health outcomes of interest other than mortality, such as functional or quality of life outcomes, by affecting intensity or timing of future treatment for recurrence or metastasis. Use of stage-shift as a surrogate for other health outcomes requires validation.
Potential Harms
Population-based screening is applied to asymptomatic people without signs of disease. The prevalence of any given cancer is generally low. Therefore, the majority of those screened for a particular cancer are not destined to develop clinically significant cancer that needs treatment and therefore do not benefit from screening. However, all persons screened are at risk of harm from either the screening test or the cascade of events following from a positive screening test.
Direct Harms
For many screening tests, there are relatively few direct medical harms of the actual screening tests. For example, screening tests that rely on blood draws are associated with minor discomfort.
Downstream Harms
The majority of harms from cancer screening come from downstream cascading events. The harms may arise from the diagnostic work-up of false positive screens, from diagnosis and treatment of over diagnosed cancers, and from false negative screens for those cancers where screens are already part of standard care.
The harms from the diagnostic work-up of false positives depends on the false positive rate and on the nature of the work-up.
The false positive rate per screening test may be low but given that many screening strategies include repeated screening tests over many years or a lifetime, the absolute number of people with complications as a result of a false-positive diagnostic work-up can be considerable. In addition, in the context of a test for multiple cancers, false positives can occur across several diseases.
Overdiagnosis of cancer that would not have become burdensome during an individual’s lifetime leads to unnecessary treatments along with their associated risks.
False-negative test results of a new cancer screening test also have the potential to cause harm. For those cancers that already have established screening recommendations as part of standard care (e.g., breast, prostate), the new cancer screening test might alter individuals’ adherence to existing recommendations which could lead to missed early diagnoses.
Performance characteristics should be provided for the overall population and stratified by demographic characteristics, stage, grade, and by cancer categorized by median time to recurrence or metastasis (e.g., less than 2 years versus 2 to 4 years versus greater than 4 years).
Cumulative risk
The periodicity of the screening test affects the overall rate of true and false positive results of the screening strategy. A screening strategy in which a test is performed frequently has several opportunities to detect a preclinical cancer. However, it also has a higher cumulative risk of at least 1 false positive test.
The ‘prevalent screen’ is the first time a screening test is applied. In the prevalent screen, cases of cancer will have been present for varying lengths of time. The subsequent screens are called ‘incident screens’. During incident screens, most cases found will have had their onset between rounds of screening, although some will have been missed by the previous screens (false negatives). The yield of a single screening test is higher for the prevalent screen, but the incident screenings are more likely to detect aggressive cancer.
Performance characteristics of the MCED test are needed for a single use of the test and cumulatively over repeated use corresponding to the proposed periodicity of the test.
Study Selection Criteria
The review will focus on MCED tests that are available in the US. The Galleri test is the only commercially available MCED test in the US at this time.
For the evaluation of clinical validity of the Galleri test, studies that meet the following eligibility criteria will be considered:
Clinically Valid
No studies met the study selection criteria.
Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if individuals receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for individuals managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCT).
No RCTs have been published.
An RCT (NHS-Galleri; NCT05611632) is underway in the United Kingdom, conducted within the National Health Service (NHS),to test whether Galleri can reduce the number of late-stage cancers (Neal, 2022). The trial has enrolled over 140,000 people, from the general population of England ages 50 to 77 years who did not have or were not being investigated for cancer. Participants were randomized to have their blood tested using Galleri or to the control group who will have their blood stored. Blood is being collected up to 3 times annually. Follow-up is underway. The study registration indicates that estimated study completion date is in 2026.
Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. The evidence is insufficient to demonstrate test performance so no inferences can be made about clinical utility through a chain of evidence.
Section Summary: Multicancer Early Detection Screening of Asymptomatic Populations
The Galleri test is the only commercially available MCED test in the US at this time. Specifics of how the test should be used in practice, including the appropriate at-risk target populations, frequency of testing, and follow-up of positive and negative test results, have not been fully described. Available estimates of clinical validity are from a case-control study and likely overestimate performance characteristics for the target population. Results from the PATHFINDER study have been presented at a conference and summarized in a press release but have not been published in full. Performance characteristics, including sensitivity, specificity and predictive values, for the prediction of risk of cancer and for tissue of origin should be provided for the overall intended-use population and stratified by demographic characteristics, stage, grade, and by cancer. Performance characteristics are needed for a single use of the test and cumulatively over repeated use corresponding to the proposed periodicity of the test.
There are no studies demonstrating clinical utility of the Galleri test. An RCT testing whether Galleri can reduce the number of late-stage cancers is underway in the UK. No data are available on cancer-related mortality, quality of life or functional outcomes, or rates of overdiagnosis and overtreatment.
Supplemental Information
The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.
Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.
National Comprehensive Cancer Network
NCCN Guidelines on Genetic/Familial High-risk Assessment: Breast, Ovarian, and Pancreatic (v.3.2023) make the following statement regarding screening with ctDNA tests (NCCN, 2023):
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below
Ongoing
NCT02889978a The Circulating Cell-free Genome Atlas Study (CCGA)
Planned enrollment: 15254
Completion Date: Mar 2024
NCT03085888a The STRIVE Study: Breast Cancer Screening Cohort for the Development of Assays for Early Cancer Detection
Planned enrollment: 99481
Completion Date: May 2025
NCT05611632a A Randomized, Controlled Trial to Assess the Clinical Utility of a Multi-cancer Early Detection (MCED) Test for Population Screening in the United Kingdom (UK) When Added to Standard of Care
Planned Enrollment: 140000
Completion Date: Feb 2026
NCT03934866a The SUMMIT Study: Cancer Screening Study With or Without Low Dose Lung CT to Validate a Multi-cancer Early Detection Test
Planned Enrollment: 13035
Completion Date: Aug 2030
Unpublished
NCT04213326a Detecting Cancers Earlier Through Elective Plasma-based CancerSEEK Testing - Ascertaining Serial Cancer Patients to Enable New Diagnostic
Planned Enrollment: 6400
Completion Date: Jan 2021
NCT04241796a The PATHFINDER Study: Assessment of the Implementation of an Investigational Multi-Cancer Early Detection Test Into Clinical Practice
Planned Enrollment: 6662
Completion Date: Jan 2022
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Schrag et al reported results of the PATHFINDER prospective study of the Galleri test. PATHFINDER enrolled 6662 adults aged 50 years or older without signs or symptoms of cancer from oncology and primary care outpatient clinics at seven US health networks between 2019 and 2020 (Schrag, 2023). 6621 participants had analyzable results and were included in the analysis. 64% of participants were women and 92% were White. The reference standard was a cancer diagnosis established by pathological, laboratory, or radiographic confirmation. Diagnostic assessments were coordinated by, and at the discretion of, the participant's doctor. Participants were followed for 12 months. A cancer signal was detected by the Galleri test in 92 (1.4%) of participants. In 2 of those participants, diagnostic assessments began before Galleri test results were reported. 35 of the participants with a positive Galleri test were diagnosed with cancer; 57 of the participants with a positive Galleri test had no cancer diagnosis. The median time to diagnostic resolution was 79 days (IQR, 37 to 219). 76 of the 90 participants with positive Galleri results had laboratory tests, 83 (92%) had at least one imaging test, 44 (53%) had more than 1 imaging study, and 44 (49%) had at least one procedure. Within 12 months of enrollment, 122 cancers were diagnosed in 121 participants: 35 (29%) detected by Galleri; 38 (31%) detected through other screening tests; 48 (40%) clinically detected. Overall positive predictive value (PPV) was 35/92 (38%; 95% CI, 29 to 48). Negative predictive value (NPV) was 6235/6321 (99%; 95% CI, 98 to 99). Specificity was 6235/6290 (99%; 95% CI, 99 to 99). Sensitivity was not reported in the publication but is 35/121 (29%; 95% CI, 21 to 38) based on the values provided. A correct first or second prediction of tissue of origin was returned for 33 (97%) of 34 true positives.
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2025. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Wade et al undertook a systematic review commissioned by the UK National Institute for Health and Care Research (NIHR) Health Technology Assessment programme to evaluate the clinical efficacy of MCED tests for screening purposes (Wade, 2025). The literature search identified studies on MCED tests targeting individuals aged 50–79 without cancer suspicion. Key outcomes included test accuracy, cancer detection rates, diagnostic resolution time, mortality, harms, quality of life, and satisfaction. Thirty-six studies published through September 2023 met the review inclusion criteria: 1 ongoing RCT, 13 cohort studies, 17 case-control studies, and 5 ongoing cohort/case-control studies. MCED tests claimed to detect 3 to over 50 cancer types. Diagnostic accuracy varied widely among available tests. For US-based tests, Galleri showed sensitivity 20.8 to 66.3% and specificity 98.4 to 99.5%, while CancerSEEK (now called Cancerguard currently undergoing further assessment by Exact Sciences) had sensitivity 27.1 to 62.3% and specificity 98.9 to 99.1%. The sensitivity of several non-US based-tests ranged from 40% to 100%, and specificity 96.4 to 99.9%. Sensitivity for detecting early-stage cancers (stages I-II) was generally lower than for later-stage cancers (stages III-IV). Study selection was complex due to unclear development stages of MCED tests. The evidence was limited, with no completed RCTs and high risk of bias in most studies, primarily due to limited follow-up of negative test results. Only one Galleri study recruited asymptomatic US individuals over 50, but it did not report patient-relevant outcomes like mortality or quality of life. High specificity (greater than 96%) was consistent across MCED tests, while sensitivity varied based on study design, population, reference tests used, and follow-up duration.
2026 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2026. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Kahwati et al undertook a systematic review commissioned by the Agency for Healthcare Research and Quality (AHRQ) to assess the benefits, accuracy, and harms of blood-based multicancer screening tests (MCSTs) in asymptomatic adults (AHRQ Publication No. 25-EHC033) (Kahwati, 2025). The literature search identified studies on MCSTs across a broader range of analytes than Wade et al (2025), including cell-free DNA, proteins, RNA, and metabolites, with a search date through December 2024 (literature surveillance conducted through March 2025). Twenty studies (N=109,177) evaluating 19 MCSTs met the review inclusion criteria, limited to external validation populations: 13 case-control studies reporting diagnostic performance and 7 studies reporting prediagnostic performance. For Galleri test specifically, the review included the CCGA case-control substudy by Klein et al, assessed as high risk of bias due to its design, and the PATHFINDER study by Schrag et al; the latter is the only Galleri study reporting prediagnostic performance in the intended-use screening population. The systematic review noted that sensitivity estimates from case-control designs overestimate real-world prediagnostic performance. Across all MCSTs, sensitivity ranged from 9.5% to 99.8% and specificity from 65.7% to 100%, with sensitivity lower in prediagnostic performance designs. No completed studies were identified reporting on benefits of screening including mortality, cancer detection, or quality of life. Strength of evidence was graded as insufficient for accuracy and harms. The systematic review concluded that evidence is insufficient to determine whether MCSTs improve health outcomes.
Nadauld et al reported psychosocial outcomes from the PATHFINDER study (Nadauld, 2025). Although anxiety scores increased transiently in participants with a cancer signal detected result at the time of result disclosure, scores returned toward baseline by end of study, suggesting that MCED testing is not associated with significant sustained psychosocial harm.
Nabavizadeh et al reported initial results of the PATHFINDER 2 prospective study (NCT05155605), conducted under FDA investigational device exemption with use of a commercial version of the Galleri test, to address the limitations of PATHFINDER including small sample size, limited diversity, and use of a pre-commercial test version. In a pre-specified analysis of the first 25,578 participants with 12 months of follow-up, the Galleri test demonstrated specificity of 99.6%, PPV of 61.6%, and overall episode sensitivity of 40.4%. Adding this test to U.S. Preventive Services Task Force (USPSTF) A and B recommended screenings led to a more than seven-fold increase in cancer detection (Nabavizadeh, 2025). Full results of the PATHFINDER 2 study are pending publication.
An RCT (NHS-Galleri; NCT05611632) is underway in the United Kingdom, conducted within the National Health Service (NHS), to test whether Galleri can reduce the number of late-stage cancers (Neal, 2022). The primary objective of the NHS-Galleri trial is to show a reduction in late-stage (III-IV) cancers in people who received the Galleri test compared with those who did not. This will be measured in three clinical groups of cancers, focusing first in a pre-specified group of 12 cancer types that together represent approximately two-thirds of cancer deaths in England and the United States. Secondary objectives include reduction in stage IV cancer; performance of the Galleri test, including PPV and FPR; cancer detection rate; safety; and healthcare resource utilization. The trial has enrolled over 140,000 people from the general population of England ages 50 to 77 years who did not have or were not being investigated for cancer. Participants were randomized to have their blood tested using Galleri or to the control group who will have their blood stored. Blood is being collected up to 3 times annually for over 2 years. Follow-up is underway. The study registration indicates that estimated study completion date is in 2030. Preliminary results announced by GRAIL in February 2026 indicated the trial did not meet its prespecified primary endpoint; however, a favorable trend toward reduction in Stage IV diagnoses was observed (Grail, 2026). Full results are pending publication.
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| References: |
American Cancer Society (ACS).(2025) Cancer Facts & Figures 2025. Accessed May 20, 2025.
Bossuyt PM, Irwig L, Craig J, et al.(2006) Comparative accuracy: assessing new tests against existing diagnostic pathways. BMJ. May 06 2006; 332(7549): 1089-92. PMID 16675820 Cancer Statistics.(2024) Cancer Statistics 2024. Accessed, May 21, 2025. Cancer.Net Editorial Board.(2023) Understanding Cancer Risk. 2018; https://www.cancer.net/navigating-cancer-care/prevention-and-healthy-living/understanding-cancer-risk. Accessed April 12, 2023. Cuzick J, Cafferty FH, Edwards R, et al.(2007) 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 Duffy MJ, Diamandis EP, Crown J.(2021) 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 Exact Sciences.(2025) Exact Sciences Launches Cancerguard, First-of-Its-Kind Multi-Cancer Early Detection Blood Test (September 10, 2025). https://www.exactsciences.com/news-events/press-releases/exact-sciences-launches-cancerguard-first-of-its-kind-multi-cancer-early-detection-blood-test. Accessed May 12, 2026. GRAIL, LLC.(2023) Frequently asked questions for healthcare providers interested in ordering the Galleri test. https://www.galleri.com/hcp/support/provider-faqs. Accessed April 12, 2023. GRAIL, LLC.(2023) GRAIL Announces Significant Progress with Multi-Cancer Early Detection Test Including FDA Breakthrough Device Designation. https://grail.com/press-releases/grail-announces-significant-progress-with-multi-cancer-early-detection-test-including-fda-breakthrough-device-designation/. Accessed April 12, 2023. 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