Search

Objectives: Designing cancer screening trials for multi-cancer early detection (MCED) tests presents a significant methodology challenge, as natural histories of cell-free DNA-shedding cancers are not yet known. A microsimulation model was developed to project the performance and utility of an MCED test in cancer screening trials. Methods: Individual natural history of preclinical progression through cancer stages for 23 cancer classes was simulated by a stage-transition model under a broad range of cancer latency parameters. Cancer incidences and stage distributions at clinical presentation in simulated trials were set to match the data from Surveillance, Epidemiology, and End Results program. One or multiple rounds of annual screening using a targeted methylation-based MCED test (Galleri Ⓡ) was conducted to detect preclinical cancers. Mortality benefit of early detection was simulated by a stage-shift model. Results: In simulated trials, accounting for healthy volunteer effect and varying test sensitivity, positive predictive value in the prevalence screening round reached 48% to 61% in 6 natural history scenarios. After 3 rounds of annual screening, the cumulative proportions of stage I/II cancers increased by approximately 9% to 14%, the incidence of stage IV cancers was reduced by 37% to 46%, the reduction of stages III and IV cancer incidences was 9% to 24%, and the reduction of mortality reached 13% to 16%. Greater reductions of late-stage cancers and cancer mortality were achieved by five rounds of MCED screening. Conclusions: Simulation results guide trial design and suggest that adding this MCED test to routine screening in the United States may shift cancer detection to earlier stages, and potentially save lives. [ABSTRACT FROM AUTHOR]

Background: Currently recommended cancer screening programs address only part of the overall population cancer burden. Even populations deemed high‐risk for certain individual cancers experience a considerable potential burden of other cancers. However, few published cancer screening trials report the incidence of untargeted cancers. Methods: The National Lung Screening Trial (NLST), initiated in 2002–2004, was a randomized controlled trial of lung cancer screening in adults with ≥30 pack‐years of smoking. Active follow‐up for incident invasive cancers continued through 2009. Results: Among 53,229 NLST subjects (median follow‐up 6.5 years after randomization), the incidence of lung cancer was 615 per 100,000 person‐years (32% of 6142 overall first primary incident invasive cancers), and that of non‐lung cancer was 1327 per 100,000 (68%). Non‐lung cancer incidence exceeded that for lung cancer in all 5‐year age categories and all quintiles of smoking pack‐years. Besides lung cancer, the most common cancers were prostate, breast, colon/rectum, bladder, and head/neck; 23% were smoking‐related cancers, and 54% were cancer types lacking recommended population‐based screening modalities (32% excluding prostate). Non‐lung cancer comprised 48% of 1793 cancer deaths. Conclusions: In the NLST, only 32% of first primary cancer incidence after study entry was lung, compared with 68% non‐lung. Even in a population at high risk for lung cancer, a single‐cancer screening test misses most cancers. Thus, in combination with existing single‐cancer screening modalities, multi‐cancer screening tests—which address many of the incident non‐lung cancers in this trial—have potential to address a currently inaccessible portion of cancer morbidity and mortality. [ABSTRACT FROM AUTHOR]

Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA-white blood cell sequencing for accurate variant interpretation. Ultra-sensitive cell-free DNA (cfDNA) sequencing uncovers clonal hematopoiesis as a major source of somatic cfDNA variants in healthy individuals and patients with cancer, and underscores the importance of matched white blood cell DNA sequencing in liquid biopsy procedures., Author(s): Pedram Razavi [sup.1] [sup.2] , Bob T. Li [sup.1] , David N. Brown [sup.3] , Byoungsok Jung [sup.4] , Earl Hubbell [sup.4] , Ronglai Shen [sup.5] , Wassim Abida [...]

Background: Cure fraction--the proportion of persons considered cured of cancer after long-term follow-up--reflects the total impact of cancer control strategies, including screening, without lead-time bias. Previous studies have not reported stage-stratified cure fraction across the spectrum of cancer types. Methods: Using a mixture cure model, we estimated cure fraction across stages for 21 cancer types and additional subtypes. Cause-specific survival for 2.4 million incident cancers came from 17 US Surveillance, Epidemiology, and End Results registries for adults 40 to 84 years at diagnosis in 2006 to 2015, followed through 2020. Results: Across cancer types, a substantial cure fraction was evident at early stages, followed by either a sharp drop from stages III to IV or a steady decline from stages I to IV. For example, estimated cure fractions for colorectal cancer at stages I, II, III, and IV were 62% (95% confidence interval: 59%-66%), 61% (58%-65%), 58% (57%-59%), and 7% (7%-7%), respectively. Corresponding estimates for gallbladder cancer were 50% (46%-54%), 24% (22%-27%), 22% (19%-25%), and 2% (2%-3%). Differences in 5-year cause-specific survival between early-stage and stage IV cancers were highly correlated with between-stage differences in cure fraction, indicating that survival gaps by stage are persistent and not due to lead-time bias. Conclusions: A considerable fraction of cancer is amenable to cure at early stages, but not after metastasis. [ABSTRACT FROM AUTHOR]

Background: Positive results of a multi‐cancer early detection (MCED) test require confirmatory diagnostic workup. Here, residual current cancer risk (RR) during the process of diagnostic resolution, including situations where the initial confirmatory test does not provide resolution, was modeled. Methods: A decision‐tree framework was used to model conditional risk in a patient's journey through confirmatory diagnostic options and outcomes. The diagnostic journey assumed that cancer signal detection (a positive MCED test result) had already led to a transition from screening to diagnosis and began with an initial positive predictive value (PPV) from the positive result. Evaluation of a most probable (top) predicted cancer signal origin (CSO) and then a second–most probable predicted CSO followed. Under the assumption that the top‐ and second‐predicted CSOs were each followed by a targeted confirmatory test, the RR was estimated for each subsequent scenario. Results: For an initial MCED test result with typical performance characteristics modeled (PPV, 40%; top‐predicted CSO accuracy, 90%), after a negative initial confirmatory test (sensitivity, 70%, 90%, or 100%) the RR ranged from 6% to 20%. A second‐predicted CSO (accuracy, 50%), after a negative second confirmatory test, still provided a significant RR (3%–18%) in comparison with the National Institute for Health and Care Excellence–recommended cancer risk threshold warranting investigation in symptomatic individuals (3%). With a 40% PPV for an MCED test and 90% specificity for a confirmatory test, the risk of incidental findings after one or two confirmatory tests was 6% and 12%, respectively. Conclusions: These results may illustrate the impact of a positive MCED test on follow‐up decision‐making. A positive result of a multicancer early detection (MCED) test is followed by confirmatory diagnostic workup. This article reports the potential impact of a positive MCED test on follow‐up decision‐making by quantifying the residual current cancer risk during the process of diagnostic resolution, including situations where the initial confirmatory test does not provide resolution. [ABSTRACT FROM AUTHOR]