Multicancer Detection Assays Remain Largely Elusive for Early-Stage Disease Detection

Detection and treatment of cancer in earlier stages remain a key strategy for improving outcomes; however, typical screening methods are commonly ineffective or nonexistent for some types of cancer. The long-desired "holy grail" of cancer detection would be a single test that could seamlessly detect cancer during a routine health check-up. This aspiration is closer to a reality with multicancer early detection (MCED) assays, which offer the potential to revolutionize screening by detecting multiple cancer types from a single blood test.

MCED was the topic of an education session presented at the 2025 American Society of Clinical Oncology (ASCO) annual meeting. The session, which was titled “The Future of Cancer Detection Is Coming,” featured new research and discussion, covering 2 abstracts that were presented at the meeting.

Scott David Ramsey, MD, PhD

Image credit: Fred Hutchinson Cancer Center

“Currently we have good quality screening tests but together they only represent half of the cancer burden in the United States,” Scott David Ramsey, MD, PhD, Public Health Sciences Division, Fred Hutchinson Cancer Center, said during the presentation at ASCO. “But more than half of cancer deaths are at sites with no screening tests.”

MCED tests utilize circulating tumor DNA (ctDNA), methylation patterns, RNA, and protein biomarkers present in blood to identify cancer signals at earlier stages than conventional methods. By leveraging advances in machine learning and artificial intelligence, these assays can also predict the tissue of origin, guiding follow-up diagnostics. This technology could expand early detection beyond the limited cancer types covered by current screening recommendations.

Patients have expressed optimism about the potential of MCED testing. A cross-section population-based survey conducted in England revealed that most patients appreciate the convenience and promise of earlier cancer detection, with more than 93.8% expressing that they would “probably” or “definitely” would have MCED screening.¹ Such favorable perceptions underscore the importance of patient-centered screening approaches that prioritize ease of use and timely information.

Screening Is a Multistep Journey

Importantly, Ramsey noted, MCED testing represents only the first step in a complex, multistep screening pathway. For MCED to realize its full impact, positive test results must trigger rapid, safe, and effective follow-up diagnostics and treatments. This process involves evaluating positive findings promptly to confirm or rule out cancer while minimizing harm from false positives, overdiagnosis, and unnecessary interventions.

Unlike diagnostic tests used in symptomatic patients, screening tests are applied to asymptomatic individuals, making the risk-benefit calculation more stringent. High specificity is essential to reduce false positives and the resulting patient anxiety and healthcare costs. Yet increasing specificity often comes at the expense of sensitivity, highlighting the delicate balance manufacturers must navigate in assay design.

Though initial findings on MCED assays are encouraging, the evidence base remains limited. Clinical validation requires large-scale, prospective, randomized controlled trials to demonstrate safety, efficacy, and clinical utility. Such studies are resource-intensive and time-consuming but critical to ensure that MCED testing improves cancer-related outcomes without unintended harms.

Retrospective analyses and single-arm studies show MCED assays detecting cancers at earlier stages, which could translate to improved survival. However, these studies do not yet prove that MCED-guided screening reduces mortality or improves quality of life compared to standard care. Moreover, long-term data on potential harms are lacking.

Latest Data From ASCO Highlighted

The session drew attention to 2 abstracts that were presented at ASCO for MCED assays. The first study, which was labeled CORE-HH (NCT05435066), assessed a blood-based methylated circulating DNA (ctDNA) test specifically in individuals with obesity.² These participants were selected as obesity is now the second most common cause of cancer in the United States, according to presenter Dax Kurbegov, MD, FASCO, from the Sarah Cannon Research Institute.

Dax Kurbegov, MD, FASCO

Image credit: Sarah Cannon Research Institute

This study included a cancer arm of individuals with confirmed cancer and a control arm of individuals not suspected of having cancer at enrollment or having a diagnosis in the past 5 years. The study looked at conventional sensitivity, which was the probability of a positive test regardless of the tumor of origin (TOO). It also assessed intrinsic accuracy, which was the probability of a correct TOO readout. Finally, it analyzed the TOO-specific positive predictive value (PPV), which was the probability of correct case type among individuals of a given TOO readout.

For the study, there were 762 samples that underwent primary testing, of which 408 were from those with cancer and 354 were from non-cancer participants. The primary screening test achieved 60.5% sensitivity at 80% target specificity. When a cancer signal was detected in the first test, reflex testing was completed. The reflex testing had 98.3% specificity. The conventional sensitivity was 43.4%. The sensitivity for stages I and II was 25.8%, and the sensitivity for stages III and IV was 80.3%.

For cancers without a current screening program, the sensitivity was 50.9%. The overall accuracy for the TOO was 36% (95% CI, 30.9%-40.9%). The highest PPV is seeing upper gastrointestinal, lung, and colorectal cancers. In a statistical model containing 100,000 people, the test identified 51 of 86 pancreas and gallbladder cancers, of which 8 of 31 were early stage.

"The reflex ctDNA-methylation MCED test data achieved clinically meaningfulness for cancer intrinsic accuracy and per-TTO PPV across multiple cancer types," said Kurbegov. "High performance was observed for cancers lacking organized screening programs."

The second abstract spotlighted by ASCO looked at data from a 5-year analysis of a blood-based ctDNA test from the circulating cell-free genome atlas (CCGA) study (NCT02889978).³ This study looked at observed survival in patients tested with the MCED assay compared with their expected survival rates from the SEER database. It broke down the results by those with no cancer signal detect (NCSD) and those with a cancer signal detect (CSD).

For those with a CSD observed, the survival was 43% vs an expected survival of 40% (HR, 0.72; 95% CI, 0.67-0.78). For the NCSD group, the observed survival was 88% compared with 81% for the expected survival (HR, 0.42; 95% CI, 0.35-0.50). There was a marked difference between the NCSD and CSD groups for survival, with NCSD faring far better (HR, 0.60; 95% CI, 0.50-0.72).

Survival was similar between CSD and SEER and NCSD and SEER across stages. For stage I the survival rate was 66% vs 71% for CSD and SEER, respectively, and 90% and 85% for NCSD vs SEER. For those with stage IV, the survival rate was 22% vs 16% for CSD and SEER, respectively, and 56% and 32% for NCSD vs SEER.

"Survival differences between detected and undetected cases [were] largely explained by clinical factors, specifically stage," Alan Bryce, MD, from the City of Hope Cancer Center Phoenix, said during a presentation of the findings. "Importantly, while CSD cancers had a meaningful risk of death, survival was similar to cases detected by conventional means, even at early stages."

Discussants Describe Potential but Warn of Limitations

"These abstracts highlight the promise of MCED testing," Marie Wood, MD, FASCO, FACP, University of Colorado, said during a discussion of the abstracts. "They provide insight into testing in high-risk populations and demonstrate that overdiagnosis is not likely an issue with MCED testing."

Both studies of methylation-based MCED tests showed high specificity but consistently low sensitivity for early-stage cancers, with detection rates for such cancers hovering near 25%, said abstract discussant Maximilian Diehn, MD, PhD, FASCO.

This pattern was observed across multiple case-control studies using different, but technically similar, methylation assays, he noted. The limited sensitivity is attributed to inherent biological and technical factors, such as the low concentration of tumor-derived DNA in early-stage disease. While these tests may effectively identify advanced cancers, they miss many early cases, which are most critical for improving long-term outcomes and reducing treatment costs.

"Methylation-based MCED tests have high specificity but low sensitivity for early-stage cancers," said Diehn from Stanford University. "Performance of MCED tests in case-control studies may be overly optimistic, and randomized trials with survival end points are needed to prove clinical utility."

Health Equity and Access Considerations

A key concern is that new technologies like MCED could inadvertently exacerbate existing health disparities if access barriers persist. Financial, geographic, and systemic obstacles must be addressed through thoughtful policy and practice to ensure equitable uptake. Otherwise, underserved populations may remain underrepresented in screening programs, limiting the overall public health benefit.

“MCED could save lives, but people must be screened, and positive tests must receive rapid and excellent follow-up,” said patient advocate Jane Perlmutter, PhD, MBA, FASCO, from the Gemini Group. “Most patients are positive about the potential of MCED, but unfortunately, I think MCED is likely to increase health disparities unless we take the appropriate policy decisions.”

Managed care organizations and policy makers play a crucial role in shaping coverage and reimbursement frameworks that support widespread and equitable MCED implementation. Designing programs that reduce patient out-of-pocket costs, integrate culturally competent education, and streamline follow-up care pathways will be essential to maximize impact.

References

1. Schmeising-Barnes N, Waller J, Marlow LAV. Intention to have blood-based multi-cancer early detection (MCED) screening: a cross-sectional population-based survey in England. Br J Cancer. 2024;131:1202-1211. doi:10.1038/s41416-024-02822-4

2. Kurbegov D, Massaad E, DiRienzo AG, et al. Performance evaluation of a reflex blood-based methylated ctDNA multi-cancer early detection test in individuals with obesity. J Clin Oncol. 2025;43 (suppl 17; abstr 100). doi:10.1200/JCO.2025.43.16_suppl.100

3. Swanton R, Cohn A, Margolis M, et al. Prognostic significance of blood-based multi-cancer detection in circulating tumor DNA (ctDNA): 5-year outcomes analysis. J Clin Oncol. 2025;43 (suppl 17; abstr 101). doi:10.1200/JCO.2025.43.16_suppl.101