70MO - Cell-free DNA indicates potential preclinical detectability of cancer signals up to 30 months prior to diagnosis

Background

Multi-cancer early detection (MCED) tests measuring cell-free DNA (cfDNA) in blood are being developed for use along with single-cancer screening. To evaluate detectability of cancer signals using a methylation-based assay in individuals without known cancer at the time of blood draw, we assessed the time between preclinical signals and future cancer diagnosis (Dx) in a mammography screening cohort (STRIVE NCT03085888).

Methods

STRIVE is a multicenter, prospective, observational cohort study of 99,252 women who underwent screening mammography and were followed for cancer Dx via medical records up to 30 months after a baseline (BL) mammogram and blood draw. A subset of incident cancers and non-cancers was assessed for tumor methylated fraction (TMeF). Non-cancer samples were used to determine background TMeF level; TMeFs > 98th percentile of TMeFs in non-cancers were considered indicative of preclinical cancer detectability. Time to Dx was assessed in 6-month intervals for all cancers and for a subset of the 12 most fatal cancer types accounting for ⅔ US cancer deaths.

Results

In the overall study, 2436 cancers (2.6%) were diagnosed–1078 (44.3%) breast and 1358 (55.7%) non-breast cancers. The analysis subset included 1519 cancers and 1616 non-cancers. As the time between BL blood draw and cancer Dx shortened, the percent of detectable cancers by BL TMeF level increased: 32% (113/351) within 1-6 months, 23% (65/283) in 7-12, 13% (49/365) in 13-18, 7% (16/223) in 19-24, and 6% (18/297) in 25-30. For the subset of 12 deadliest cancers, the percent of detectable cancers by BL TMeF was higher at each time interval: 53% (67/127) in 1-6 months, 37% (43/117) in 7-12, 26% (25/95) in 13-18, 13% (11/88) in 19-24, and 10% (10/97) in 25-30. Among cancers with detectable BL TMeF, the mean time from BL to Dx was 275 days.

Conclusions

In this cohort, TMeF levels suggest that MCED screening can potentially identify cancers up to 30 months before clinical presentation. TMeF levels were consistently higher in the deadliest cancers compared to all cancer types. The mean time of 275 days between detectable BL TMeF and cancer Dx suggests that the average preclinical detectable window by MCED is within a year, supporting MCED screening on an annual interval.

Clinical trial identification

NCT03085888.

Editorial acknowledgement

Editorial assistance provided by Alexandra L. Thomas and Merrilee Johnstone of Prescott Medical Communications Group, a Citrus Health Group, Inc. Company (Chicago, IL).

Legal entity responsible for the study

GRAIL, LLC.

Funding

GRAIL, LLC.

Disclosure

C.M. Vachon: Financial Interests, Institutional, Research Funding: GRAIL, LLC. R. Jiang, J. Youngren, E.T. Fung, E. Hubbell: Financial Interests, Personal, Full or part-time Employment: GRAIL, LLC; Financial Interests, Personal, Stocks or ownership: Illumina, Inc. O. Venn: Financial Interests, Personal, Full or part-time Employment: GRAIL, LLC; Financial Interests, Personal, Stocks or ownership: Illumina, Inc, GRAIL, LLC. X. Hou: Financial Interests, Personal, Full or part-time Employment: GRAIL, LLC. K.V. Giridhar: Financial Interests, Institutional, Advisory Board: Eli Lilly, Novartis, AstraZeneca, Tersera Therapeutics, Gilead Sciences, Puma Biotechnology, Exact Sciences, NeoGenomics; Financial Interests, Institutional, Trial Chair, ACT-MBC: Menarini Silicon Biosystems; Financial Interests, Institutional, Other, TBCRC041: Guardant Health. F.J. Couch: Financial Interests, Institutional, Research Funding: GRAIL, LLC; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca. R.L. Korn: Other, Personal, Other, Adjunct Faculty: TGEN/City of Hope; Financial Interests, Personal, Stocks or ownership, Owner: Imaging Endpoints Core Lab; Financial Interests, Personal, Stocks/Shares: Globavir, Renibus, Verve, Tru-Life; Other, Personal, Other, PCT/US2017/047026; US10854338B2; US10332634B2: Patents. All other authors have declared no conflicts of interest.