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Observational Study
. 2024 Aug:8:e2400269.
doi: 10.1200/PO.24.00269.

A Targeted Methylation-Based Multicancer Early Detection Blood Test Preferentially Detects High-Grade Prostate Cancer While Minimizing Overdiagnosis of Indolent Disease

Brandon A Mahal  1 , Matthew Margolis  2 , Earl Hubbell  2 , Cheng Chen  2 , Jeffrey M Venstrom  2 , John Abran  2 , Jordan J Kartlitz  2 , Alexander W Wyatt  3 , Eric A Klein  2
Affiliations
Observational Study

A Targeted Methylation-Based Multicancer Early Detection Blood Test Preferentially Detects High-Grade Prostate Cancer While Minimizing Overdiagnosis of Indolent Disease

Brandon A Mahal et al. JCO Precis Oncol. 2024 Aug.

Erratum in

Abstract

Purpose: Indolent prostate cancer (PCa) is prevalent in the intended use population (adults age 50-79 years) for blood-based multicancer early detection (MCED) tests. We examined the detectability of PCa by a clinically validated, targeted methylation-based MCED test.

Methods: Detectability by Gleason grade group (GG), clinical stage, association of detection status with tumor methylated fraction (TMeF), and overall survival (OS) were assessed in substudy 3 of Circulating Cell-Free Genome Atlas (CCGA; ClinicalTrials.gov identifier: NCT02889978) and PATHFINDER (ClinicalTrials.gov identifier: NCT04241796) studies.

Results: Test sensitivity for PCa in substudy 3 of CCGA was 11.2% (47/420). The test detected 0 (0%) of 58 low-grade (GG1), 3 (1.9%) of 157 favorable intermediate-grade (GG2), 4 (5.1%) of 78 unfavorable intermediate-grade (GG3), and 36 (31.9%) of 113 high-grade (GG4 and 5) cancers and 3 (3.2%) of 95 stage I, 11 (4.7%) of 235 stage II, 7 (14.9%) of 47 stage III, and 22 (81.5%) of 27 stage IV cases. The median TMeF was higher for detected than nondetected cases (2,106.0 parts per million [PPM]; IQR, 349.8-24,376.3 v 24.4 PPM; IQR, 17.8-38.5; P < .05). Nondetected cases had better OS (P < .05; hazard ratio [HR], 0.263 [95% CI, 0.104 to 0.533]) and detected cases had similar survival (P = .2; HR, 0.672 [95% CI, 0.323 to 1.21]) compared with SEER adjusted for age, GG, and stage. Performance was similar in PATHFINDER, with no detected GG1/2 (0/13) or stage I/II (0/16) cases.

Conclusion: This MCED test preferentially detects high-grade, clinically significant PCa. Use in population-based screening programs in addition to standard-of-care screening is unlikely to exacerbate overdiagnosis of indolent PCa.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
Sensitivity of prostate cancer detection by (A) GG and (B) clinical stage in substudy 3 of CCGA. The number of MCED-detected cases out of total cases in each grade or stage group is reported. Error bars designate 95% CIs. CCGA, Circulating Cell-Free Genome Atlas study; GG, Gleason grade group; MCED, multicancer early detection.
FIG 2.
FIG 2.
Relationship between cancer detectability, TMeF, and PSA. Red = cases not detected; blue = cases detected. Triangles indicate GG3-5, stage I-III cases. GG, Gleason grade group; MCED, multicancer early detection; PPM, parts per million; PSA, prostate-specific antigen; TMeF, tumor methylated fraction.
FIG 3.
FIG 3.
TMeF of prostate cancer cases in substudy 3 of CCGA by MCED test detection status. CCGA, Circulating Cell-Free Genome Atlas study; MCED, multicancer early detection; PPM, parts per million; TMeF, tumor methylated fraction.
FIG 4.
FIG 4.
Observed versus expected OS of prostate cancer cases in substudy 3 of CCGA compared with SEER adjusted for age, stage, and grade. Nondetected cases had better OS (P < .05; HR, 0.263 [95% CI, 0.104 to 0.533]), and detected cases had similar survival (P = .2; HR, 0.672 [95% CI, 0.323 to 1.21]) compared with SEER estimates adjusted for age, GG, and clinical stage. CCGA, Circulating Cell-Free Genome Atlas study; GG, Gleason grade group; HR, hazard ratio; OS, overall survival.
FIG A1.
FIG A1.
Age-adjusted PCa incidence in the United States overlaps with the MCED intended use population. Observed SEER PCa incidence rates by age at diagnosis, years 2016-2020. Figure generated with SEER. MCED, multicancer early detection; PCa, prostate cancer.
See this image and copyright information in PMC

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