Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study

Abstract

Background: Multicancer early detection (MCED) blood tests can detect a cancer signal from circulating cell-free DNA (cfDNA). PATHFINDER was a prospective cohort study investigating the feasibility of MCED testing for cancer screening.

Methods: In this prospective cohort study done in oncology and primary care outpatient clinics at seven US health networks, a convenience sample of adults aged 50 years or older without signs or symptoms of cancer consented to MCED testing. We collected blood, analysed cfDNA, and returned results to participants' doctors. If a methylation signature indicative of cancer was detected, predicted cancer signal origin(s) informed diagnostic assessment. The primary outcome was time to, and extent of, diagnostic testing required to confirm the presence or absence of cancer. This trial is registered at ClinicalTrials.gov, NCT04241796, and is completed.

Findings: Between Dec 12, 2019, and Dec 4, 2020, we recruited 6662 participants. 4204 (63·5%) of 6621 participants with analysable results were women, 2417 (36·5%) were men, and 6071 (91·7%) were White. A cancer signal was detected in 92 (1·4%) of 6621 participants with analysable results. 35 (38%) participants were diagnosed with cancer (true positives) and 57 (62%) had no cancer diagnosis (false positives). Excluding two participants whose diagnostic assessments began before MCED test results were reported, median time to diagnostic resolution was 79 days (IQR 37-219): 57 days (33-143) in true-positive and 162 days (44-248) in false-positive participants. Most participants had both laboratory tests (26 [79%] of 33 with true-positive results and 50 [88%] of 57 with false-positive results) and imaging (30 [91%] of 33 with true-positive results and 53 [93%] of 57 with false-positive results). Fewer procedures were done in participants with false-positive results (17 [30%] of 57) than true-positive results (27 [82%] of 33) and few had surgery (one with a false-positive result and three with a true-positive result).

Interpretation: This study supports the feasibility of MCED screening for cancer and underscores the need for further research investigating the test's clinical utility.

Funding: GRAIL.

Figure 1:

Trial profile Participant flow diagram, including true positive analysis sets for outcomes with variable participant numbers to the left. CSO=cancer signal origin. EOS=end of study. TP=true positives.

Figure 2:

Time to diagnostic resolution for participants with cancer signal detected (n=90)

Figure 3.

Extent of diagnostic testing in participants with cancer signal detected

Figure 4:

Cancer diagnosed after a positive MCED result The 36 cancers diagnosed in the 35 true positive participants are depicted by a dot in the organ/system in which the cancer was found. Histology details are given when available. Of the 29 participants with new cancers, 14 (48%) were Stage I or II. Overall 74% cancers detected lack current USPSTF-recommendations for screening tests. c=clinical staging/diagnosis. c/w=consistent with. MCED=multi-cancer early detection. R(L)=recurrent local cancer. R(M)=recurrent metastatic cancer. USPSTF=United States Preventive Services Task Force.