Multicancer early detection testing: Guidance for primary care discussions with patients

Abstract

Multicancer early detection (MCED) tests are an emerging technology for cancer screening. MCED tests can detect cancer signals from multiple cancers concurrently in biological samples such as blood, urine, saliva, or other bodily fluids. Some tests can suggest the most likely cancer origin, whereas others report cancer detected somewhere in the body. Although some MCED tests are currently commercially available, none are approved by the Food and Drug Administration or endorsed by any clinical practice guideline or recommendation. Most insurance companies do not currently cover MCED testing. MCED tests have not yet been evaluated for safety and effectiveness in randomized controlled trials. Because patients already are asking for MCED test prescriptions or for interpretation of results from tests acquired elsewhere, clinicians should be prepared to discuss what is known about the benefits, risks, and uncertainties of MCED testing, including performance characteristics in screening populations and preferred follow‐up strategies for positive test results. At this time, clinicians should not feel obligated to initiate discussions about MCED testing with their patients. However, clinicians should engage patients who inquire about getting tested or previous MCED test results in shared decision‐making, and take the opportunity to offer and help patients complete age‐ and sex‐appropriate guideline‐recommended cancer screenings. In this article, the current evidence and issues around MCED testing are summarized, and a framework for shared decision‐making discussions is provided.

Short abstract

Clinicians should be aware of the potential benefits, harms, and uncertainties around the use of multicancer early detection (MCED) blood tests for cancer screening to inform discussions with patients who inquire about these tests. Discussions should also note that MCED tests have limited insurance coverage, and are not approved by the Food and Drug Administration or endorsed by professional society guidelines.

INTRODUCTION

Multicancer early detection (MCED) tests are an emerging technology for cancer screening. ¹ , ² These tests, sometimes referred to as liquid biopsies, can detect cancer signals from multiple cancers concurrently in biological samples such as blood, urine, saliva, or other bodily fluids. ³ The tests can identify cell‐free DNA and RNA, DNA methylation and fragmentation patterns, protein markers, immune markers, and other analytes released or stimulated by tumor cells. Techniques such as genomics, epigenomics, transcriptomics, proteomics, and machine learning algorithms are used to analyze samples to identify the presence of cancer signals and sometimes to predict where in the body a cancer is located (referred to as the cancer signal origin [CSO] or tissue of origin). ⁴ , ⁵ A positive cancer signal requires further evaluation to confirm the presence and location of a cancer or to conclude that no cancer is clinically detectable at that time. As of November 2024, no MCED tests have yet been approved by the Food and Drug Administration (FDA). The FDA has granted a few MCED tests Breakthrough Device Designation status because these tests “provide for more effective diagnosis of life‐threatening diseases [compared to existing technologies]” such as cancer. ⁶ , ⁷ The designation is intended to expedite the processes leading to FDA approval. Currently, we are aware of one MCED liquid biopsy blood test (Galleri ⁸ ) that has undergone relevant clinical evaluation and is commercially available (at a cost of $949) via Clinical Laboratory Improvement Amendments (CLIA) regulations as a laboratory‐developed test. ³ This designation allows a single laboratory to design, manufacture, and perform high‐complexity diagnostic testing. However, MCED tests have not yet been evaluated for safety and effectiveness in randomized controlled trials (RCTs), a common prerequisite for coverage by commercial or public insurers, although some studies are underway. To our knowledge, few insurers currently cover MCED testing, and no clinical practice guideline developer, including the American Cancer Society or the US Preventive Services Task Force, recommends using MCED tests for cancer screening in any population. At this time, however, the lack of guideline recommendations is not surprising because test development, population‐based research, and preparatory processes for regulatory approval are still in progress. However, under CLIA regulations, some tests are currently or will be available; clinicians need to be prepared to discuss MCED tests with their patients.

This article provides clinicians with information about what is known and unknown about using MCED tests for cancer screening, and offers a framework for discussing MCED testing with patients who inquire about being tested.

BACKGROUND

Cancer is the second leading cause of death in the United States. An estimated 2,041,910 new cases of cancer and 618,120 cancer deaths are forecast for 2025. ⁹ The rationale for cancer screening is that early detection in asymptomatic persons allows the delivery of more effective and safer treatment, which can reduce cancer morbidity and mortality compared to treating persons with symptomatic cancers found at advanced stages. However, launching a successful population‐based screening program requires meeting 10 key principles outlined in a World Health Organization report from Wilson and Jungner ¹⁰ (Box 1). MCED tests do not currently fully meet these criteria, given the lack of data on the natural history of some of the detectable cancers, the economic impact of case finding, and the target population for screening.

BOX 1 Wilson–Jungner criteria for screening programs ¹⁰ .

Criteria	Met by MCED testing
1. The condition sought should be an important health problem.	Yes
2. There should be an accepted treatment for patients with recognized disease.	Yes
3. Facilities for diagnosis and treatment should be available.	Yes, although access to specialized cancer centers may be limited for rare cancers
4. There should be a recognizable latent or early symptomatic stage.	Not established for all cancers detected via MCED testing
5. There should be a suitable test or examination.	Yes
6. The test should be acceptable to the population.	Blood testing is generally very acceptable; however, given the currently limited number of insurers covering MCED testing, it is unaffordable for many individuals
7. The natural history of the condition, including development from latent to declared disease, should be adequately understood.	Not for all cancers detected by MCED testing
8. There should be an agreed policy on whom to treat as patients.	Uncertain whether the test is appropriate for the general population versus individuals at higher risk for cancer
9. The cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to the possible expenditure on medical care as a whole.	Currently unknown
10. Case finding should be a continuing process and not a “once and for all” project.	Uncertain—the interval for repeat testing is not yet determined

Existing screening programs target breast, cervical, colorectal, lung, and prostate cancers. ¹¹ , ¹² The standard‐of‐care screening programs recommended by the American Cancer Society (ACS) and other organizations, other than cervical cancer screening (for which there is incontrovertible observational evidence), have all first been evaluated in RCTs and shown to reduce cancer‐specific mortality. Additionally, screening for cervical and colorectal cancers leads to detecting and treating precancers, which can reduce cancer incidence. Although current cancer screening programs meet the criteria for population‐based screening, ¹⁰ they still face important implementation challenges that limit their ability to reduce cancer deaths, including low awareness of individual risk and the importance of screening, suboptimal uptake and adherence to regular screening, screening individuals with limited life expectancy or poor health status, inconsistent follow‐up of screen‐detected abnormalities, variable test accuracy, and inequitable access to screening and treatment due to capacity constraints in capital equipment or health care workforce as well as financial, cultural, geographic, and other barriers. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² Furthermore, even under optimal circumstances, not everyone who has a cancer detected by screening will avoid a cancer death. ²³ , ²⁴ , ²⁵ , ²⁶

Nearly half (1,016,900) of the cancer diagnoses and approximately three fifths (358,230) of the cancer deaths projected for 2025 are in cancers for which there are no recommended screening tests. ⁹ Such cancers are commonly diagnosed at an advanced stage, when the prognosis is poor. Both the absence of screening strategies for these cancers and the suboptimal uptake and adherence for the few recommended screening tests, which target specific age ranges, lead to diagnosing only a minority of some of the most lethal cancers at a localized stage. The former category includes pancreatic (13.7%), ovarian (17.5%), esophageal (21.6%), and liver (40.8%) cancers, whereas the latter includes lung (25.8%) and colorectal (36.5%) cancers. ²⁷

MCED testing represents a new approach for cancer screening. Unlike current screening programs, which aim to reduce cancer‐specific mortality in single cancers, the goal of MCED screening is to reduce cancer mortality across multiple cancers. If MCED screening leads to detecting and effectively treating multiple cancers, particularly those without recommended screening tests, these tests would be expected to reduce the population burden of cancer morbidity and mortality. In a study modeling the impact of reducing the overall incidence of late‐stage cancer, investigators from GRAIL (the company that manufactures Galleri, an MCED test currently available on the market) estimated that shifting all stage IV cancers to earlier stages could substantially reduce cancer‐related and all‐cause mortality. ²⁸ , ²⁹ Mortality reductions will depend on the natural histories of the individual cancers, the sensitivity of the MCED test for detecting each cancer at an earlier stage, ongoing adherence to regular screening, and the diagnostic pathways and patterns of care. ³⁰ , ³¹ , ³² , ³³

Clinicians should be aware of the important current gaps in evidence around MCED testing—gaps that would need to be filled before these tests could be recommended. The largest gap arises from the absence of RCTs, which are conventionally judged to provide the highest quality evidence for evaluating screening programs despite challenges to their implementation and interpretation. ³⁴ , ³⁵ Currently, there are no data from population‐based studies on whether MCED screening can reduce cancer‐related morbidity and/or cancer‐specific mortality, or lead to changes in early cancer indicators that would be accepted as predictive of mortality, either across multiple cancers or for individual cancers. There is also a paucity of data on conventional screening outcomes, including measures of sensitivity for any or specific cancers, true‐ and false‐positive rates, indeterminate findings, incidental findings, and the range of potential harms, including complications from diagnostic procedures, overdiagnosis (finding cancers that will never cause symptoms), and overtreatment (unnecessary treatment for indolent cancers). The impacts of MCED testing on adherence to recommended screening and costs to patients, payers, as well as health care systems are also unknown. Finally, the performance of MCED tests varies between and within tests because companies use different diagnostic algorithms and sets of measured analytes, which are continuously being refined. Invariably, some tests will have superior performance overall, and the performance will vary for individual cancers. Below, we discuss two emerging blood‐based MCED tests with published data on both diagnostic performance from cross‐sectional studies and clinical outcomes from prospective observational studies.

HOW ACCURATE ARE THESE NEW TESTS?

GRAIL Galleri

The commercially available GRAIL Galleri test, which is based on the Circulating Cell‐Free Genome Atlas (CCGA) study, has provided early cross‐sectional diagnostic accuracy data. ⁴ , ⁵ The Galleri test predicts a primary and secondary CSO. By adjusting detection thresholds, the specificity of the test has been set intentionally extremely high—99%—to reduce the occurrence of false positives and to avoid burdening the population with excess diagnostic testing. ³⁶ , ³⁷ The CCGA external validation case‐control study used an independent clinical validation set containing 2823 persons with cancer and 1254 persons without cancer. ⁵ The overall sensitivity was 51.5% (95% CI, 49.6%–53.35%) for detecting any cancer. Sensitivity varied widely across cancer types; for example, the sensitivity of the MCED test for cancers without recommended screening tests was 18.2% for kidney cancer and 34.8% for bladder cancer but 85.7% for head and neck cancers and 93.5% for liver/bile duct cancers. The sensitivities for cancers with recommended screening tests were 11.2% for prostate, 28.0% for breast, 74.8% for lung, 80.0% for cervical, and 82.0% for colorectal cancers. GRAIL has stated that Galleri should not replace conventional screening tests. ⁸ The overall accuracy of the primary cancer origin prediction in true positives was 88.7% (95% CI, 87.0%–90.2%). The Galleri test appears to preferentially detect aggressive cancers compared to indolent cancers; investigators suggest that this is because aggressive cancers are more likely to shed enough DNA to be detectable. ³⁸

Compared to recommended screening tests, the sensitivity of current MCED tests for detecting early‐stage cancers is markedly lower. The sensitivities reported in the CCGA study ranged from 16.8% (95% CI, 14.5%–19.5%) for stage I to 40.4% (95% CI, 36.8%–44.1%) for stage II, 77.0% (95% CI, 73.4%–80.3%) for stage III, and 90.1% (95% CI, 87.0%–90.2%) for stage IV. ⁵ Estimates of sensitivity and specificity for the CCGA study and other tests have been primarily derived from case‐control studies, which are commonly used in the early phases of test development and evaluation. ⁴ , ⁵ , ³⁹ However, these study cohorts are not representative of screening populations because they focus on already‐diagnosed, usually symptomatic cases, and oversample participants with advanced‐stage cancers. Notably, the CCGA data showed the test to have much lower sensitivity (18.0%; 95% CI, 15.5%–20.8%) among persons with cancers detected by conventional screening tests compared to those identified by clinical presentation (63.9%; 95% CI, 61.8%–66.0%), which were frequently detected at a more advanced stage, which is consistent with the assumption that more advanced/aggressive cancers have a higher rate of shedding. ⁵ Furthermore, the control groups in the CCGA study were not well matched to cases on demographic characteristics or risk factors. ⁵

An important statistic for population health is the positive predictive value (PPV), which is the probability of having disease given a positive test result. Clinically, it represents the proportion of individuals with positive screening tests who underwent further evaluations and were confirmed to have cancer. A low PPV implies that the majority of those facing the potential harms and costs of undergoing diagnostic evaluations will not be found to have cancer. The PPV is a function of the prevalence of the cancer as well as the sensitivity and specificity of the test; for given test performance characteristics, the PPV increases with increasing cancer prevalence. The CCGA investigators extrapolated their case‐control data on diagnostic performance (by applying it to Surveillance, Epidemiology, and End Results incidence and stage data in a 50‐ to 79‐year age group) to estimate that the overall PPV for detecting any cancer would be 44.4% (95% CI, 28.6%–79.9%) in population‐based screening. ⁵ This particularly high PPV for a cancer‐screening test is driven by the higher prevalence of multiple cancers as opposed to the lower prevalence of single cancers and by tests being designed to have an extremely high specificity.

The impact of the PPV on clinical practice has been more appropriately evaluated in prospective cohort studies where a diagnostic workup was used to define a true‐positive result. The PATHFINDER trial studied the GRAIL Galleri MCED test in a cohort of 6662 asymptomatic adults aged 50 years and older. The MCED test results reported whether a cancer signal was detected, and predicted the two most likely cancer sites of origin if a signal was detected. The diagnostic workup was at the discretion of the ordering physician. The MCED test was positive in 92 participants (1.4%). Within 12 months of enrollment, 35 participants with positive blood tests were diagnosed with cancer, 14 with early‐stage cancers (stage I or II), including seven types of cancers (liver, pancreas, smooth muscle, small intestine, uterine, head and neck, and lymphoma) with no recommended screening tests. The PPV of an abnormal test result for detecting a cancer was 38% (95% CI, 28.3%–48.3%). The PATHFINDER study also evaluated a refined MCED test version introduced after the study was launched. This version had a slightly higher PPV of 43.1% (95% CI, 31.2%–55.9%); the PPVs of both versions compare very favorably with the PPVs of current recommended screening tests. ³⁷

Exact Sciences CancerSEEK

The Exact Sciences CancerSEEK MCED test (now called Cancerguard), which is currently not commercially available to the public, was evaluated in the DETECT‐A study, which screened 10,006 women aged 65–75 years with no history of cancer, enrolled from a population with high adherence to recommended screening. ⁴⁰ Abnormalities in baseline tests were confirmed with more rigorous blood testing; if the confirmatory testing was positive, then the participant underwent a total‐body combined positron emission and computed tomography (PET‐CT) scan because this MCED test did not report a CSO. Participants with an abnormal PET‐CT scan were referred to specialists. Overall, 134 participants (1.34%) had a confirmed positive blood test, and 26 of these had a cancer diagnosed within 12 months of enrollment. A confirmed positive blood test (without a PET‐CT scan) had a PPV of 19.4% (95% CI, 13.1%–27.1%) for cancer detection. Eight cancers (30.8%) were detected at stage I or II, including three cancers (uterine, ovarian, and thyroid) with no recommended screening tests.

The PPVs for MCED tests are generally substantially higher than the PPVs for currently used single‐cancer tests (e.g., mammography, stool blood tests, and low‐dose CT scans) because the cancer prevalence is higher as a result of the aggregate detection of multiple cancers and because MCED test specificity is much higher than that seen with recommended screening tests. Given proof of efficacy, this would be a general benefit of multicancer detection relative to single‐cancer testing. However, the tradeoff is that the sensitivity for detecting localized cancers is much lower than for recommended screening tests, and precancers cannot be detected. Notably, more than two thirds of the cancers diagnosed in the two prospective observational studies were diagnosed clinically or with recommended screening tests. ⁴⁰ , ⁴¹

SHARED DECISION‐MAKING DISCUSSION POINTS

When queried in surveys, primary care patients indicate high levels of interest in MCED testing. ⁴² , ⁴³ Given that some MCED tests are commercially available via health care providers, patients are already requesting prescriptions for testing or sharing the results of testing performed outside of the clinician’s office. GRAIL reports establishing more than 100 commercial partnerships, surpassing 10,000 prescribers, and selling more than 180,000 Galleri tests as of April 2024. ⁴⁴ As more patients learn about MCED testing, demand is expected to grow. Below, we provide guidance for addressing patient questions about MCED testing.

WHAT ARE THE POPULATIONS THAT MIGHT BENEFIT FROM MCED TESTING?

The target populations for screening with MCED tests, the starting and ending ages, and the frequency of screening have not been determined. The prospective studies included older persons to increase the likelihood of finding cancer but an important limitation of these studies is that they conducted only one round of screening. The PATHFINDER study enrolled asymptomatic adults aged 50 years and older with or without additional cancer risk factors (having smoked >100 cigarettes, a genetic predisposition to cancer, or a history of cancer with no treatment for at least 3 years). ³⁷ The DETECT‐A study enrolled women aged 65–75 years with no history of cancer. ⁴⁰ The UK randomized National Health Service (NHS)–Galleri trial enrolled asymptomatic adults aged 55–77 years who had not been diagnosed or treated for cancer in the previous 3 years. Screening studies of colorectal, breast, and prostate cancers typically have targeted average‐risk persons and generally initiated screening between the ages of 40 and 55 years. Lung cancer screening trials, which target high‐risk individuals on the basis of their smoking history, have typically initiated screening at ages 50 or 55 years. ⁴⁵ , ⁴⁶

Current guidelines for breast, colorectal, and prostate cancer screening recommend earlier and more intensive screening strategies for those at increased risk, which is usually based on family history. Whether a family history of one or more cancers, particularly at an early age, should prompt early MCED testing is unknown at this time. Persons with high‐risk family histories should be encouraged to meet with genetic counselors. Additionally, MCED tests have not yet been trained or validated on younger populations, and therefore their role in detecting cancer in adolescents and young adults or testing pediatric cancer survivors for secondary cancers is unknown.

If MCED tests are shown to be efficacious, programs may vary in their starting and ending ages, screening intervals, and whether screening would apply to average‐risk adults and/or targeted at those at higher risk on the basis of known or yet‐to‐be‐determined risk factors.

HOW SHOULD MCED TESTING BE DISCUSSED WITH PATIENTS?

We believe that clinicians are not obligated to initiate discussions on MCED testing until more is known about their effectiveness. Given the many uncertainties surrounding MCED testing at this time, patients who initiate a discussion about MCED testing should engage in a shared decision‐making (SDM) process before undergoing testing. ⁴⁷ The goal of SDM is to inform a patient about the potential benefits, limitations, harms, and uncertainties around MCED testing to enable the patient to make decisions that align with their personal values and preferences. ⁴⁸ Factors to consider in ordering MCED tests include an individual’s reason for seeking an MCED test and their cancer risk factors, including age, sex, family history, and exposures, as well as life expectancy, and their willingness and ability to participate in the downstream evaluations of abnormal tests and, potentially, to undergo cancer treatment. ⁴⁷ , ⁴⁹ Some key discussion points are outlined in Box 2. Although not currently available, patient decision aids will likely play an important role in the SDM process.

BOX 2 Key points for shared decision‐making discussions on MCED testing.

What is an MCED test?	It is a test looking for traces of multiple cancers simultaneously. The test is offered for people who do not have signs or symptoms of cancer. Asymptomatic people aged 50 years and older typically have an approximately 1% chance of having a cancer at the time of testing. The test does not diagnose cancer; if it is positive, further diagnostic testing is required to confirm whether there is cancer and where the cancer is located. The optimal approach to managing positive results is uncertain.
What MCED tests are available?	One blood‐based screening test that detects cell‐free DNA is commercially available as of 2024: the GRAIL Galleri test.
Who is eligible for MCED testing?	The optimal age range of when to begin and end testing average‐risk individuals has not been established. There is currently no guidance for identifying the age to initiate testing for higher risk individuals. Patients should not have MCED testing unless they are willing to undergo diagnostic evaluations for positive tests. MCED tests should not replace standard‐of‐care screenings for breast, cervical, colorectal, lung, and prostate cancers.
How much does the test cost?	The list price of the GRAIL Galleri test is $949 as of 2024. MCED testing is currently covered by only a few insurance plans—patients should confirm coverage with their individual plan. There are additional costs for follow‐up evaluations of a positive test, which could range from hundreds to thousands of dollars depending on insurance coverage. Multiple diagnostic tests may be needed to confirm whether there is cancer.
What are the potential benefits of MCED testing?	A benefit is potentially detecting cancers that currently have no recommended screening tests at an earlier stage, when they may be treated more effectively and easily. Benefits are potentially reducing the risks of cancer mortality and morbidity and increasing life expectancy.
What are the potential limitations, harms, and uncertainties of MCED testing?	We do not yet know whether MCED testing reduces cancer mortality and morbidity. False‐positive results (false alarms): the risk is lower with MCED tests than with currently recommended screening tests. Approximately half of persons with positive tests are found not to have cancer after a diagnostic evaluation. Any positive result also can cause anxiety and distress. Although a negative test indicates a very low risk for having cancer at the time of testing, patients should not ignore new symptoms and signs that could indicate a cancer. Patients should continue with recommended screening tests. The optimal strategy for evaluating positive test results is uncertain. There is a risk of harm from diagnostic procedures done to evaluate positive MCED results; the magnitude of this risk is not yet established. Overdiagnosis and overtreatment: a detected cancer may be very slow growing, or the patient diagnosed with cancer may not benefit from earlier detection and treatment because of limited life expectancy. We are not yet able to estimate the degree of overdiagnosis and overtreatment associated with MCED tests. Incidental findings (unrelated to cancer) may be found during diagnostic workups of a positive MCED test, particularly from PET‐CT scans. These findings may lead to additional testing and treatments. We are not yet able to accurately characterize the benefits and harms of incidental findings associated with MCED testing.
How often to get the test?	The optimal testing interval is unknown but regular, repeat testing will be necessary to optimize any potential benefit of MCED testing.

WHAT IS THE FOLLOW‐UP FOR A POSITIVE MCED TEST?

Patients should be informed about and agree to undergo diagnostic testing to evaluate a positive test result before embarking on MCED testing. A positive MCED test indicates that the patient is at a high risk for having cancer given the test’s high specificity. The ordering clinician, working in concert with health systems and specialist colleagues, is responsible for ensuring that a complete diagnostic evaluation is conducted. The follow‐up of a positive MCED test depends on whether the test indicates a likely CSO. The predicted primary CSO reported by Galleri can be used to guide targeted evaluations toward a particular cancer, including imaging, laboratory testing, endoscopy, and, if indicated, tissue diagnoses. If that evaluation is unrevealing, a Galleri study protocol suggested that the next step could be either a targeted evaluation of the secondary predicted CSO or obtaining whole‐body imaging. ⁵⁰ For tests that do not predict a cancer site of origin, such as the Exact Sciences multianalyte blood test, the manufacturer recommends total‐body imaging with PET‐CT scans. ⁴⁰ Clinicians and patients should recognize that currently there are no specific consensus evidence‐based clinical guidelines for managing MCED positive results, and thus protocols for follow‐up of positive tests may vary across clinical settings. However, protocols for evaluating signs and symptoms suggestive of a particular cancer, or a known diagnosis, are available from the National Comprehensive Cancer Network. ⁵¹ The American College of Radiology also provides guidance for working up incidental findings detected by imaging examinations. ⁵² Primary care clinicians may also benefit from consulting with specialists in evaluating positive tests. ³⁰

WHAT SHOULD HAPPEN IF THE WORKUP IS NEGATIVE AFTER A POSITIVE MCED TEST?

A negative workup could suggest that the initial blood test result was a false positive and the risk of cancer could be low, although the sensitivity of PET‐CT scans as a second‐stage screen for general cancers is unknown. The DETECT‐A study reported that 95 of 98 participants with a false‐positive result remained cancer free during a median 3.6 years of follow‐up. ⁵³ However, a negative workup result could be misleading, particularly if the diagnostic evaluation was limited—or lacked the sensitivity to detect the cancer site of origin. This scenario could create enduring anxiety for many individuals. The next steps could be to repeat the MCED test, although the timing of subsequent testing after an apparent false‐positive test result is uncertain, or to watchfully wait for symptoms. ³ , ⁵⁴ GRAIL offers a free retest at 3–6 months if the initial diagnostic evaluation of a cancer signal is negative. ⁵⁵ Clinical trial and observational data will help inform evidence‐based approaches for these workups. Patients should continue with recommended cancer screening tests, be encouraged to make appropriate lifestyle changes to reduce cancer risk, and be followed for symptoms.

WHAT IS THE FOLLOW‐UP FOR AN INITIALLY NEGATIVE MCED TEST?

Given the low prevalence of cancer in the study populations, the negative predictive value exceeded 99% in clinical trials. ³⁷ , ⁴⁰ Patients can be reassured that they are at a low risk of cancer at the time of a negative test but they should not ignore new signs or symptoms that could be associated with cancer. The optimal timing for repeating MCED testing has not been determined. The ongoing UK NHS‐GRAIL trial and the proposed Vanguard trial are designed to have multiple rounds of annual testing. ⁵⁰ , ⁵⁶ Individuals who choose to undergo MCED testing should be aware that regular retesting is necessary to achieve any long‐term benefits. Patients should be counseled to continue with recommended screening tests, which perform better than MCED tests in identifying specific early‐stage cancers and, in the case of colorectal and cervical cancer tests, precancers that cannot be detected with MCED tests. The SDM discussion is also an opportunity to counsel and encourage patients to make lifestyle changes to reduce cancer risk. Appropriate patients can also be encouraged to participate in available clinical trials evaluating the clinical utility of MCED tests.

WHAT ABOUT INCIDENTAL FINDINGS?

Abnormal blood testing may lead to imaging studies, including PET‐CT scans, which may detect one or more incidental findings in some patients. Primary care clinicians will need to use their clinical judgment, ideally supported by professional practice guidelines and guidance from multidisciplinary teams, to determine the next steps in the diagnostic workup. Diagnosing and treating incidental findings may be beneficial to patients if they are clinically significant. Conversely, findings may be clinically inconsequential or consequential without any potential for successful intervention, which may lead to complications from testing and treatments, anxiety, overdiagnosis, and additional costs, which all represent potential harms from any cancer screening, including MCED testing.

MCED TESTING AND DISPARITIES

An important issue for MCED testing is its potential impact on cancer disparities. Some experts argue that being able to screen for multiple cancers with a single blood test obtained at a routine clinic visit may overcome cancer screening barriers such as transportation and increase initial uptake and long‐term adherence to screening, which may lead to detecting more treatable cancers. ⁵⁷ However, other experts are concerned about the potential adverse impacts of MCED testing on cancer disparities, particularly given the relative lack of insurance coverage for tests that cost hundreds to several thousands of dollars and uncertain coverage for subsequent diagnostic evaluations. ³ , ⁵⁸ Subsequent diagnostic evaluations are especially burdensome for individuals residing in geographic areas with a limited number of imaging facilities and workforce shortages. Populations that have the largest burden from cancer often face limited access to health care, lack health insurance, and have lower educational attainment and income. ⁵⁹ Uptake of recommended screening tests is already lower in these populations, as are rates of completing diagnostic evaluations and undergoing guideline‐concordant cancer treatment. ⁶⁰ , ⁶¹ Therefore, implementing MCED testing, especially if not covered by insurance, would be disproportionately burdensome to economically and socially marginalized populations. This would almost certainly increase disparities in cancer care, at least in the early stages of uptake. Ideally, health care systems should provide patient navigation when offering testing to persons who are at risk of not completing diagnostic evaluations or undergoing treatment as a result of social determinants of health such as education, socioeconomics, transportation, and other barriers. Payment reform would be necessary to address these underlying causes of disparities. Finally, more than 90% of the participants in the PATHFINDER and DETECT‐A observational studies were non‐Hispanic White; the diagnostic performance and outcomes of MCED testing in other populations are unknown. ⁵ , ³⁷ , ⁴⁰

FUTURE RESEARCH

The gold standard study design for evaluating a screening program is an RCT with cancer mortality as an end point. ²⁸ One ongoing RCT is the NHS‐Galleri study, which has collected blood from 140,000 asymptomatic participants in the United Kingdom. ⁵⁰ Half of the participants are being randomized to an intervention arm to have blood tested with an MCED test, and the other half are being randomized to the control arm to have blood stored. Intervention arm participants will be notified if a cancer signal is detected, and referred for further evaluation. Follow‐up is expected to be for up to 4 years, and the primary, surrogate end point is the overall reduction in the incidence rates of stage III and IV cancers. Cancer‐specific mortality is a secondary, delayed end point.

The National Cancer Institute is sponsoring the Vanguard Study on Multi‐Cancer Detection to assess the feasibility of implementing an MCED screening trial. ⁵⁸ As currently planned, this pilot study will enroll approximately 24,000 participants across seven sites, and randomly assign them to one of two different MCED test arms or to a control arm. All participants will be offered recommended cancer screening tests. The Vanguard Study will address recruiting strategies for enrolling participants from diverse populations, the diagnostic pathway after a positive test, and adherence to MCED testing and recommended screening tests. These results will be used to design a larger RCT to evaluate the efficacy of MCED testing in reducing cancer mortality.

Conclusions

MCED testing represents a potential paradigm shift in cancer screening that provides an opportunity to detect numerous cancers with a single test. Although tests are commercially available, they are being evaluated in clinical trials, and data are not yet available to determine whether MCED testing for cancer screening meets many of the criteria that have been adopted and recognized as the standards for population screening. ¹⁰ Because MCED testing is becoming increasingly available as new tests continue to be developed and evaluated, ³ , ⁵⁸ , ⁶² clinicians should be prepared to help patients make informed decisions about testing (Box 2). Clinicians should further inform patients that MCED testing does not replace recommended cancer screening tests, and encourage them to make appropriate lifestyle changes to reduce cancer risk. MCED testing offers the potential to reduce the burden of suffering and premature death from cancer, although it will be some time before we know whether this potential can be realized. In the meantime, this article offers guidance to health care providers in their discussions with patients who inquire about MCED testing

AUTHOR CONTRIBUTIONS

Richard M. Hoffman: Conceptualization, writing–original draft, and writing–review and editing. Andrew M. D. Wolf: Conceptualization and writing–review and editing. Sana Raoof: Conceptualization and writing–review and editing. Carmen E. Guerra: Conceptualization and writing–review and editing. Timothy R. Church: Conceptualization and writing–review and editing. Elena B. Elkin: Conceptualization and writing–review and editing. Ruth D. Etzioni: Conceptualization and writing–review and editing. Ya‐Chen Tina Shih: Conceptualization and writing–review and editing. Steven J. Skates: Conceptualization and writing–review and editing. Deana Manassaram‐Baptiste: Writing–review and editing, project administration, and conceptualization. Robert A. Smith: Conceptualization, writing–review and editing, and resources.

CONFLICT OF INTEREST STATEMENT

American Cancer Society (ACS) cancer prevention and screening guideline development is supported by ACS operational funds. BrightEdge LLC (“BrightEdge”), the Society’s philanthropic donor‐funded charitable impact fund, has made an investment in Freenome, a San Francisco–based corporation applying a multiomics platform to develop blood tests for early cancer detection. BrightEdge is a wholly owned subsidiary of the ACS. It operates under a charitable fund model that invests in companies developing novel, cancer‐focused therapies and technologies to advance the mission goal of accelerating market delivery of promising cancer‐related solutions. BrightEdge’s investment decisions are led by BrightEdge’s Investment Fiduciary Committee. Investment or another financial vehicle of BrightEdge in a company does not constitute an expressed or suggested endorsement of any products or services of the company by the ACS or BrightEdge. BrightEdge’s committee members do not have any approval rights over the content of the ACS’s screening guidelines. Deana Manassaram‐Baptiste and Robert A. Smith are employed by the ACS, which receives grants from private and corporate foundations, including foundations associated with companies in the health sector, for research and initiatives outside of the submitted work. These authors are not funded by any of these grants, and their salary is solely funded via ACS funds. Sana Raoof, Carmen E. Guerra, and Robert A. Smith report serving on the Multicancer Early Detection Consortium. Richard M. Hoffman reports professional activities for Wolters Kluwer. Sana Raoof reports serving as a scientific advisor to Grail, Exact Sciences, C the Signs, and Verily, and holding stock in Illumina. Carmen E. Guerra reports receiving research grants from the Genentech Foundation; owning stock in CRISPR Therapeutics, Beam Therapeutics, Intellia Therapeutics, and Editas Medicine; and serving on advisory boards for Freenome, Guardant Health, and Janssen Pharmaceuticals. Timothy R. Church reports consulting for Illumina. Elena B. Elkin reports professional activities for Pfizer. Ruth D. Etzioni reports holding stock in Seno Medical Instruments of San Antonio, Texas, an imaging device company, and receiving National Cancer Institute grants for research on cancer diagnostic tests. Ya‐Chen Tina Shih reports serving on the OncoCollective advisory board for Sanofi. Steven J. Skates reports consulting for Guardant Health and holding a patent with GENinCode. The other authors declare no conflicts of interest. The sources of funding described in this disclosure have not made any financial contribution, nor have they had any role or involvement in ACS prevention and screening guideline development or approval.

Hoffman RM, Wolf AMD, Raoof S, et al. Multicancer early detection testing: guidance for primary care discussions with patients. Cancer. 2025;e35823. doi: 10.1002/cncr.35823