Detection of Gastrointestinal Cancer in Individuals Without Clinical Suspicion of Cancer Using a Multi-Cancer Early Detection Test in the PATHFINDER Study

Introduction: Colorectal cancer (CRC) is the only gastrointestinal (GI) cancer with USPSTF-recommended screening guidelines. Other GI cancer (eg, esophageal, liver) screening guidelines are based on predisposing risk factors; however, not all patients who develop cancer would have met the clinical criteria for screening described in the guidelines. A blood-based multi-cancer early detection (MCED) test was evaluated in the prospective PATHFINDER study (NCT04241796; n=6,662). MCED test detection of GI cancers in PATHFINDER is reported here. Methods: The MCED test uses machine learning to detect cancer-specific methylation patterns in tumor cell-free DNA and predict a cancer signal origin (CSO). Participants in PATHFINDER were age ≥50 years with/without additional cancer risk factors (eg, smoking), not under clinical investigation for cancer, and consented to one year of follow-up surveillance. Participants with a confirmed GI cancer diagnosis were reviewed for cancer signal detected (CSD)/not detected (CSND) result, CSO prediction accuracy, cancer type and stage, and time to diagnostic resolution. Results: Among 8 participants diagnosed with a GI cancer, 6 were detected by the MCED test (Table 1). CSO prediction was accurate for 5/6 diagnoses, and the sixth case was a diagnosis of small intestine cancer that was obtained after a CSO-directed workup utilizing upper and lower endoscopy. All cases with a CSD result achieved diagnostic resolution in < 2 months from test result. Notably, 3/6 had early-stage, non-metastatic cancer and 4/6 had cancer without USPSTF-recommended screening (small intestine, liver, bile duct, pancreatic). All 6 were detected prior to clinical presentation, including the stage IV CRC (n=2). The 2 participants diagnosed with GI cancer after a CSND result had a circulating tumor fraction below the clinical limit of detection; these include a stage I CRC (n=1) and a stage III pancreatic cancer (n=1) diagnosed 6 months after MCED testing due to new symptom development. Conclusion: This blood-based MCED test detected 75% of GI cancers in PATHFINDER. The majority were in GI cancer types that have no current USPSTF screening recommendations, and half were detected at early stages (I/II). These data support the utility of an MCED test that predicts a CSO as time to diagnosis was rapid (< 2 months), prediction accuracy was high (83%), and the cancers were diagnosed in participants not under clinical investigation for cancer, even those diagnosed with stage IV CRC. Table 1. - Gastrointestinal Cancer Cases in the PATHFINDER Study With a Cancer Signal Detected Result Age (y) Sex Top predicted CSO Cancer Type Stage Time to diagnostic resolution (d) 65-69 M Liver/Bile-duct Liver I 57 65-69 F Colon/Rectum Small intestine I 60 75-79 M Pancreas/Gallbladder Pancreas II 38 75-79 M Liver/Bile-duct Intrahepatic bile duct III 36 80-84 F Colon/Rectum Colon or rectum IV 26 ≥85 F Colon/Rectum Colon or rectum IV 54 CSO, cancer signal origin; d, days; F, female; m, male; y, years.