Abstract
Simple SummaryPATHFINDER is an interventional study that will examine how well a multi-cancer early detection test can be integrated into clinical practice. This test looks at DNA methylation patterns in patient blood samples to detect cancer and also predict cancer origin. The PATHFINDER study will include ~6200 study participants from 31 sites in the United States. The study will return tests results to participants and their health care providers and will evaluate how test results affect the clinical pathway to confirm or rule out a cancer diagnosis. Results of this study could help determine how a blood-based multi-cancer early detection test will fit into clinical practice.To examine the extent of the evaluation required to achieve diagnostic resolution and the test performance characteristics of a targeted methylation cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test, ~6200 participants ≥50 years with (cohort A) or without (cohort B) ≥1 of 3 additional specific cancer risk factors will be enrolled in PATHFINDER (NCT04241796), a prospective, longitudinal, interventional, multi-center study. Plasma cfDNA from blood samples will be analyzed to detect abnormally methylated DNA associated with cancer (i.e., cancer “signal”) and a cancer signal origin (i.e., tissue of origin). Participants with a “signal detected” will undergo further diagnostic evaluation per guiding physician discretion; those with a “signal not detected” will be advised to continue guideline-recommended screening. The primary objective will be to assess the number and types of subsequent diagnostic tests needed for diagnostic resolution. Based on microsimulations (using estimates of cancer incidence and dwell times) of the typical risk profiles of anticipated participants, the median (95% CI) number of participants with a “signal detected” result is expected to be 106 (87–128). Subsequent diagnostic evaluation is expected to detect 52 (39–67) cancers. The positive predictive value of the MCED test is expected to be 49% (39–58%). PATHFINDER will evaluate the integration of a cfDNA-based MCED test into existing clinical cancer diagnostic pathways. The study design of PATHFINDER is described here.
Highlights
There are a limited number of cancer screening programs in the UnitedStates (US), Europe, and other countries
“signal detected” test results and the number of cancers diagnosed at the diagnostic resolution by modeling the natural history of cancer for a set of participants aged 50 and older with and without a history of cancer
Cancer incidence was estimated to be approximately 1.41% based on data from the Surveillance, Epidemiology, and End Results Program (SEER) database [35], National Institutes of Health–American Association of Retired Persons cohort for current and former smokers [36], and National Health Interview Survey (2001–2014) for current and former smokers [37]
Summary
There are a limited number of cancer screening programs in the UnitedStates (US), Europe, and other countries. The United States Preventive Services Task Force recommendations are limited to screening for breast, cervical, colon, lung (in high-risk individuals), and, on an individual basis, prostate cancer [1,2,3,4,5]. In the US, approximately three-quarters of all new cancer cases and cancer-related deaths in 2020 will be due to cancers without established screening paradigms [14]. These cancers tend to be diagnosed at later stages [15] when a cure is less likely, and treatment is less effective, more burdensome, and costly [16,17]. Undergoing multiple single-cancer detection tests results in a cumulative risk of false positives [18]
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