Over the course of the 1-year follow-up period after MCED testing, 121 patients had a cancer diagnosis. There were 73 patients whose cancer was detected via screening — 35 by the MCED test, 29 by USPSTF-recommended screening tests, and 9 by other screening tests. An additional 48 patients had cancers detected because of signs or symptoms (n= 28), via routine imaging (n= 14), or due to incidental findings (n=6).
Therefore, of the 121 cancers diagnosed within the first year after MCED testing, 29% were diagnosed by the MCED test.
Overall, the test’s specificity was 99.1% (6253/6290), the positive predictive value was 38% (35/92), and the negative predictive value was 98.6% (6235/6321). The number of screenings needed to detect 1 cancer was 189 (6621/35), and the MCED test yield was 0.5% (35/6621).
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The researchers also evaluated a refined version of the MCED test using the patients’ banked specimens and did not disclose those results to patients or clinicians.
With this refined test, 0.9% of patients had a cancer signal detected (58/6578), the specificity was 99.5% (6216/6249), the positive predictive value was 43.1% (25/58), and the negative predictive value was 98.5% (6216/6311). The number needed to screen was 263 (6578/25), and the yield was 0.38% (25/6578).
An Important First Step but Far From Perfect
The results of PATHFINDER “are an important first step for early cancer detection tests,” Dr Schrag said in a statement.3
In her presentation, Dr Schrag acknowledged the importance of determining whether MCED testing reduces cancer mortality and the importance of assessing the test’s performance in racially and ethnically diverse populations. That information could be forthcoming soon.
The randomized NHS-Galleri trial is designed to compare the incidence of advanced cancer diagnoses in 140,000 adults who undergo annual MCED screening for 3 years vs adults who receive usual care. The trial recently completed accrual.4
In another trial, PATHFINDER2 (ClinicalTrials.gov Identifier: NCT05155605), researchers expect to screen an additional 20,000 individuals in North America and employ a refined version of the MCED test.
The results of the current PATHFINDER study are “far from being perfect,” said ESMO discussant Federica Di Nicolantonio, PhD, of the University of Turin in Italy.5 She expressed reservations about the psychological impact of months-long diagnostic uncertainty for patients with false-positive results.
Dr Di Nicolantonio speculated that the false-positive results could be due to inflammatory conditions or benign/preneoplastic lesions that shed cell-free DNA. She noted that, even with further refinements of the MCED test, technical artifacts will likely remain problematic to some degree.
With regard to the patients who were diagnosed with cancer over a 1-year follow-up period after a negative MCED test, Dr Di Nicolantonio suggested that such individuals could have nonshedding tumors or rare, potentially fast-growing malignancies that were not identified by the MCED assay or that developed during the follow-up interval.
She expressed optimism that refined versions of the MCED test and other techniques — including assays of cell-free DNA fragments (ie, “fragmentomics”) — may demonstrate even better performance in future trials.6
While MCED tests are being refined and validated for cancers such as pancreatic, small bowel, and stomach cancers — for which there are currently no approved screening options — Dr Schrag stressed the importance of continued guideline-concordant screening for cancers such as breast and colorectal cancers.
Disclosures: PATHFINDER was supported by GRAIL, LLC, a subsidiary of Illumina, Inc. Dr Di Nicolantonio disclosed a relationship with Pierre Fabre. Dr Schrag and colleagues declared affiliations with a range of biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
References
1. Schrag D, McDonnell III CH, Nadauld L, et al. A prospective study of a multi-cancer early detection blood test. Presented at ESMO 2022; September 9-13, 2022. Abstract 903O.
2. Klein EA, Richards D, Cohn A, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol. Published online June 24, 2021. doi:10.1016/j.annonc.2021.05.806
3. A new era of early cancer detection with blood test may change cancer screening paradigms. ESMO. News Release. Published September 11, 2022. Accessed October 17, 2022.
4. Grail and National Health Service (NHS) England complete enrollment of 140,000 participants in largest study of multi-cancer early detection test. Businesswire. News Release. Published July 18, 2022. Accessed October 17, 2022.
5. Di Nicolantonio F. Invited Discussant 903O, 1696O and 66O. Presented at ESMO 2022; September 9-13, 2022.
6. Ding SC, Lo YMD. Cell-free DNA fragmentomics in liquid biopsy. Diagnostics. Published online April 13, 2022. doi:10.3390/ diagnostics12040978
