Abstract 1264: A targeted methylation-based multi-cancer early detection blood test preferentially detects high-grade prostate cancer and minimizes overdiagnosis
Bibliographic record
Abstract
Abstract Background: Indolent prostate cancer (PCa) is prevalent in men in the intended use population (adults aged 50-79 years) for blood-based multi-cancer early detection (MCED) tests. It is thus important to understand detectability of PCa by MCED tests across the spectrum of disease aggressiveness, including detection of indolent disease. Methods: PCa detectability by a targeted methylation-based MCED test that interrogates circulating cfDNA was assessed in 2 studies: 1) the Circulating Cell-free Genome Atlas (CCGA, NCT02889978), a case-control study (Substudy 3) that demonstrated detection of a shared cancer signal across > 50 cancer types and accurate prediction of cancer signal origin (CSO) with an observed false positive rate of 0.5%; and 2) PATHFINDER (PF, NCT04241796), a return of results cohort study in the intended use population without clinical suspicion of cancer. MCED test performance was assessed by Gleason grade group (GG) and clinical stage, and the association between tumor methylated fraction (TMeF) and cancer detectability was investigated. Results: The CCGA3 study included 420 recently diagnosed PCa cases with a median age of 65 years (IQR, 59-70). Test sensitivity for PCa was 11.2% (47/420), and CSO accuracy was 91.5% (43/47). Median PSA was higher in detected cases (14 ng/dL, IQR 7-38 vs 6 ng/dL, IQR 5-9, p < 0.05). The MCED test detected no low grade (GG1, 0/58), 1.9% (3/157) of favorable intermediate grade (GG2), 5.1% (4/78) of unfavorable intermediate grade (GG3), and 31.9% (36/113) of high grade (GG4 & GG5) cancers. Clinical staging showed detection of 3.2% (3/95) of Stage I, 4.7% (11/235) of Stage II, 14.9% (7/47) of Stage III, and 81.5% (22/27) of Stage IV cases. Non-detected cases had better overall survival (HR 0.263, CI 0.104 - 0.533, p<0.05), and detected cases had similar survival (HR 0.672, CI 0.323 - 1.21, p=0.2) compared to SEER estimates matched for age, stage and GG. Median TMeF was higher for detected cases (0.002106, IQR 0.000350 - 0.024376 vs 0.000024, IQR 0.00001 - 0.000038, p < 0.05). Performance was similar in PF (median age 66 years, IQR 58 -70) with overall sensitivity for PCa of 5.9% (1/17), including no (0/12) detected GG1-2 cases and one of five GG3-5 cases. No Stage I or II (0/15) and 1/2 (50%) Stage III & IV cases were detected. Conclusion: In two independent prospective studies, this MCED test preferentially detected high grade, clinically significant PCa. A cancer signal detected test result with a prostate CSO prediction generally indicates the presence of aggressive PCa and should lead to a prompt diagnostic work-up. Use of this test in population-based screening programs is unlikely to exacerbate overdiagnosis of indolent PCa. Citation Format: Brandan Mahal, Matthew Margolis, Earl Hubbell, Cheng Chen, Jeffrey M. Venstrom, John Abran, Jordan J. Karlitz, Alexander W. Wyatt, Eric A. Klein. A targeted methylation-based multi-cancer early detection blood test preferentially detects high-grade prostate cancer and minimizes overdiagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1264.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".