Diagnostic workup following a multicancer early detection test with a cancer signal origin prediction.
Authors: McDonnell Charles H. , Hudnut Andrew G. , Behl Deepti , Ang Roger , Spinelli Barbara , Jacobs Debbie , Kim Ina , Bobolis Kristie 
Published: June 2022

e15037 Background: A blood-based multi-cancer early detection (MCED) test is available for use as a complement to single cancer screening modalities, though clinical experience is limited. PATHFINDER (NCT04241796; enrollment complete, n = 6662) is a prospective study in asymptomatic adults ≥50 y that returns MCED test results (‘signal not detected’ or ‘signal detected’) with ≥1 cancer signal origin (CSO) prediction to direct diagnostic workup. MCED testing is a novel approach to cancer screening, so clinical guidance on how to best utilize MCED test findings is critical. To review follow-up testing required to achieve a definitive diagnosis after a signal detected result and corresponding CSO prediction, the diagnostic workups of PATHFINDER trial participants are summarized. Methods: Participants from the interim PATHFINDER data set (data cutoff Mar-19-2021) with a confirmed new cancer identified by the MCED test and post-diagnosis clinical notes were included. Participants with a predicted or confirmed heme-related cancer were excluded as were those for whom a determinate CSO or staging information was unavailable. Key diagnostic steps from signal detected (Day 1) to resolution were summarized. A multidisciplinary review board guided initial diagnostic follow-up. Results: Five individuals met the eligibility criteria for consideration; three with gastrointestinal cancers have been described elsewhere and are therefore not summarized here. Of the remaining two participants identified, the first was a male smoker > 60y (CSO prediction = Head and Neck). Based on the CSO, laryngoscopy and head and neck CT were performed. Laryngoscopy was negative, but CT revealed necrotic lymph nodes suggestive of metastases. A subsequent PET-CT found an incidental T1N0M0 stage I renal cell carcinoma and an FDG-avid base of tongue lesion, which was biopsied (moderately differentiated squamous cell carcinoma). A stage II (T2N2M0) head and neck cancer was diagnosed at Day 81. The patient underwent radiation therapy, chemotherapy, and nephrectomy and is alive with no evidence of cancer ≥502 days post-diagnosis. The second was a female smoker > 60y (CSO prediction = Lung). Based on the CSO, she received a non-contrast chest CT, revealing a 2.1 cm spiculated mass highly suspicious for primary lung malignancy. PET-CT confirmed the mass was FDG-avid, and core biopsy revealed well to moderately differentiated adenocarcinoma. The participant was diagnosed with Stage IIIB (T1N3M0) lung cancer (Day 22). She underwent subsequent radiation, chemo, and immunotherapy. She is alive ≥683 days post-diagnosis, but metastatic disease has subsequently developed. Conclusions: The MCED test detected cancer signals and accurately predicted CSO for these participants, both of whom achieved diagnostic resolution < 3 months. Clinical insight from the CSO prediction was used to direct the workup required to achieve a definitive diagnosis.