New England Journal of Medicine32.0·22 Sept 2026·3 citations
Peter Sasien, Peter Johnson, Thomas Round +10
Colorectal Cancer Screening and Detection · Oncology
BACKGROUND: Whether screening with blood-based early-detection tests for multiple cancers in addition to usual care has clinical utility is unknown. METHODS: In a randomized, controlled trial conducted in England, we obtained peripheral blood from persons 50 to 77 years of age at up to three annual visits. After baseline blood collection, participants were randomly assigned in a 1:1 ratio to the intervention group (participants whose blood was tested) or the control group (participants whose blood was stored). Participants and trial personnel were initially unaware of the group assignments. The primary end point was stage III or IV cancer among 12 prespecified types of cancer, and a key secondary end point was stage IV cancer among the 12 prespecified types. The differences between the groups in the incidence rate (the number of first eligible events divided by person-years at risk) were measured after three screening rounds and at least 12 months of follow-up after the last participant's third visit. RESULTS: Overall, 71,122 participants were randomly assigned to the intervention group and 71,128 to the control group. The incidence rate of stage III or IV cancer (primary end point) did not differ significantly between the groups (incidence rate ratio [intervention vs. control], 1.03; 95% confidence interval [CI], 0.92 to 1.14, P = 0.63). The incidence rate ratio for stage IV cancer (a key secondary end point) after 3 screening rounds was 0.86 (95% CI, 0.74 to 1.00). Less than 1% of participants had trial-related adverse events; none were serious. CONCLUSIONS: In this trial, we did not observe a lower incidence rate of stage III or IV cancers across 12 prespecified cancers after three screening rounds with multicancer early-detection testing plus usual care than with usual care alone. Further follow-up is warranted to assess the way in which findings for stage III or IV cancers and the between-group difference in stage IV cancers evolve over time. (Funded by Grail; NHS-Galleri ClinicalTrials.gov number, NCT05611632; ISRCTN number, ISRCTN91431511.).
Nima Nabavizadeh, Charles McDonnell, Dax Kurbegov +17
Global Cancer Incidence and Screening · Oncology
Early cancer detection improves survival; however, most cancer types do not have guideline-recommended screening. We previously reported the first PATHFINDER study that established feasibility of cancer screening with a blood-based multi-cancer early detection (MCED) test that predicts cancer signal origin (CSO) to guide diagnostic workup. The prospective, interventional PATHFINDER 2 study expands clinical evidence for the MCED test by evaluating co-primary endpoints of MCED performance metrics and safety in participants aged 50 years or older without clinical suspicion of cancer. Performance measures included cancer detection rate, positive and negative predictive values, episode sensitivity, specificity and CSO prediction accuracy. Safety was evaluated in terms of number and type of invasive procedures performed and adverse events due to diagnostic testing, after 12 months of follow-up. Endpoints were analyzed descriptively; no hypothesis testing was performed. Between December 2021 and July 2024, 35,878 participants were enrolled. Among 32,007 performance-analyzable participants, cancer detection rate was 0.54% (95% confidence interval (CI): 0.47-0.63%), positive predictive value was 60.3% (95% CI: 54.5-65.8%), negative predictive value was 99.2% (95% CI: 99.1-99.3%) and specificity was 99.64% (95% CI: 99.57-99.70%). Episode sensitivity was 39.3% (95% CI: 34.9-44.0%; all cancers) and 69.8% (95% CI: 62.8-76.0%; prespecified 12-cancer subgroup). Positive and negative likelihood ratios were 108.9 (95% CI: 87.6-135.2) and 0.61 (95% CI: 0.56-0.66), respectively, and the number needed to screen to detect one cancer was 185 (95% CI: 159-215). CSO prediction accuracy was 91.3%. Among 35,335 safety-analyzable participants, 213 (0.6%) had invasive procedure(s) after a positive MCED test; 90.5% were nonsurgical. No serious study-related adverse events were reported by the time of this analysis. These results provide insights into performance and safety of the MCED test in an intended-use population. Randomized trials and longer follow-up are needed to assess the clinical utility of MCED tests. ClinicalTrials.gov identifier: NCT05155605 .
New England Journal of Medicine32.0·16 Sept 2026·2 citationsOA
Rodrigo Jover, Michael Bretthauer, Joaquín Cubiella +34
Colorectal Cancer Screening and Detection · Oncology
BACKGROUND: More evidence is needed to inform recommendations for intervals of colonoscopy surveillance after polyp removal. METHODS: In this ongoing noninferiority trial conducted in eight European countries, we randomly assigned patients with high-risk adenomas (defined as ≥1 adenoma with a diameter of ≥10 mm, high-grade dysplasia, or villous growth or 3 to 10 adenomas of any kind) to undergo a first colonoscopy at 5 years after polyp removal or at 3 years; surveillance at 3 years is currently recommended in guidelines. The 3-year group also underwent colonoscopy at 5 years. The primary end point is the cumulative incidence of colorectal cancer at 10 years, with a prespecified noninferiority margin of 0.7 percentage points for the upper boundary of the confidence interval for the difference between the two groups. Here, we report the results of an interim analysis conducted after 5.5 years of follow-up. Inverse probability weighting was used to account for missing data owing to nonparticipation in surveillance colonoscopy at 5 years. In this analysis, the incidence of colorectal cancer is reported with a one-sided 99.12% confidence interval; for the final analysis at 10 years, the plan is to calculate a 95.33% confidence interval to maintain an overall type I error of 5%. RESULTS: A total of 10,799 patients underwent randomization: 5398 patients were assigned to the 5-year group and 5401 to the 3-year group. The 5-year cumulative incidence of colorectal cancer was 0.77% with less-frequent surveillance and 0.82% with more-frequent surveillance (difference, -0.05 percentage points); the upper boundary of the 99.12% confidence interval was 0.68, which met the criterion for noninferiority. The distribution of cancer stage at diagnosis did not appear to differ substantially between the two groups. A total of 5 patients died of colorectal cancer: 3 patients (0.06%) in the 5-year group and 2 (0.04%) in the 3-year group. CONCLUSIONS: In this interim analysis of a 10-year noninferiority trial, beginning surveillance colonoscopy at 5 years after polyp removal was noninferior to beginning at 3 years with respect to the cumulative incidence of colorectal cancer at 5 years among patients with high-risk adenomas. (Funded by the Research Council of Norway and others; EPoS II ClinicalTrials.gov number, NCT02319928.).