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

Multi-cancer early-detection blood tests represent a new paradigm for cancer screening and are being developed for use in addition to standard-of-care single-cancer screening tests. As for all screening tests, there is the potential that MCED test adoption could contribute to the overdiagnosis of indolent cancers that would be unlikely to cause harm during a person’s lifetime. This is particularly relevant for prostate cancer, for which there is a high population prevalence of low-grade, indolent cancers. The current prostate cancer screening modality, prostate-specific antigen (PSA) testing, has notoriously low specificity, and as a result, an estimated 23 to 42% of prostate cancers detected by screening are considered overdiagnosed.1 Considering the significant age-related incidence of prostate cancer in the intended use population for MCED testing, it is important to evaluate the performance of MCED tests in identifying both indolent and aggressive forms of this disease.

We assessed the prostate cancer detection performance of the MCED test Galleri® (GRAIL, Inc., Menlo Park, CA), which is commercially available and has been previously assessed in two large-scale clinical studies (substudy 3 of Circulating Cell-Free Genome Atlas [CCGA; NCT02889978] and PATHFINDER [NCT04241796]). Looking at the prostate cancer cases in these two trials, we found low test sensitivity (11.2%, 47/420 in substudy 3 of CCGA) and episode sensitivity (5.6%, 1/18 in PATHFINDER) for prostate cancer. Breaking down detection by Gleason grade (GG) and stage reveals that the overall sensitivity for prostate cancer is influenced by the test’s low sensitivity for low-grade and early-stage prostate cancers. The test detected no low-grade GG1 cancers, 1.9% of favorable intermediate-grade GG2 cancers, and 4.2% of stage I/II cancers across both studies.

Although it is desirable for single-cancer screening tests to have high sensitivity, multi-cancer tests are optimized for specificity; as such, a lower sensitivity for low-grade, early-stage prostate cancers means the test will be unlikely to contribute to overdiagnosis of indolent disease. Accordingly, the prostate cancer cases that were not detected by the MCED test had better overall survival than would be expected based on SEER control data adjusted for age, GG, and stage. This result suggests that detection and intervention may not have benefited these cases.

We also found that cell-free DNA shedding, estimated by the tumor methylated fraction (TMeF), was lower for non-detected than detected prostate cancer cases. As TMeF positively correlates with biologic aggressiveness,2 this result further supports the observation that non-detected cases are unlikely to be clinically significant cancers.3

Conversely, a key clinical takeaway from this analysis is that when prostate cancers were detected, they were more likely to be high grade or stage (93% were GG3-5 and 67% were stage III or IV). This preferential detection of clinically significant prostate cancers indicates that a cancer signal detected MCED test result with a prediction of prostate origin strongly suggests aggressive disease that warrants prompt diagnostic workup.

Written by:

Brandon A. Mahal, MD, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL
Eric A. Klein, MD, GRAIL, Inc, Menlo Park, CA

References:

Loeb S, Bjurlin M, Nicholson J, et al: Overdiagnosis and overtreatment of prostate cancer. Eur Urol 65:1046-1055, 2014
Bredno J, Lipson J, Venn O, et al: Clinical correlates of circulating cell-free DNA tumor fraction. PLoS One 16:e0256436, 2021
Chen X, Dong Z, Hubbell E, et al: Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA. Clin Cancer Res. 27:4221-4229, 2021

Read the Abstract

Login