Systematic review and meta-analysis of accuracy of tumor origin detection in blood cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) assays in the general population.

person Joo Hee Park Northwestern University, Chicago, IL info_outline Joo Hee Park, Youjin Oh, Liam Il-Young Chung, Richard Duan, Trie Arni Djunadi, Sung Mi Yoon, Zunairah Shah, Chan Mi Jung, Ilene Hong, Leeseul Kim, Horyun Choi, Young Kwang Chae

Authors person Joo Hee Park Northwestern University, Chicago, IL info_outline Joo Hee Park, Youjin Oh, Liam Il-Young Chung, Richard Duan, Trie Arni Djunadi, Sung Mi Yoon, Zunairah Shah, Chan Mi Jung, Ilene Hong, Leeseul Kim, Horyun Choi, Young Kwang Chae Organizations Northwestern University, Chicago, IL, Northwestern University Feinberg School of Medicine, Chicago, IL, Northwestern Memorial Hospital, Chicago, IL, Louis A Weiss Memorial Hospital, Chicago, IL, Northwestern University, Evanston, IL, Ascension Saint Francis Hospital, Evanston, IL, University of Hawaii Internal Medicine Residency Program, Honolulu, HI Abstract Disclosures Research Funding No funding received None. Background: Among recently developed blood-based MCED tests, the ability to determine the location of tumors is pivotal to guiding appropriate treatment. We systematically reviewed and statistically examined the accuracy of tumor of origin predictions among blood-based MCED tests. Methods: Original articles were searched from Pubmed, Cochrane, and Embase for blood-based screening tests, multiple cancer types, and asymptomatic human subjects. We excluded studies with small samples (n < 30), non-screening, and non-blood-based tests. For cfDNA-based assays, measurements of diagnostic accuracy were pooled for meta-analysis. Results: Of 1,074 records identified and screened, five case-control studies and one cohort study that used cfDNA-based diagnostic tests were analyzed. Accuracy of tissue-of-origin (TOO) prediction for 3,895 cancer samples across cancer types was 0.79 (95% CI 0.66 - 0.90). Among six cancer types, colorectal cancers had the highest accuracy and liver & bile duct cancers had the lowest, although the difference was statistically insignificant (0.89 (95% CI 0.79-0.97) vs. 0.68 (95% CI 0.40-0.90)). Additionally, cases were most frequently misclassified as colorectal cancer (Table 1). The information for localizing TOO was derived from methylation patterns of cfDNA in four studies, fragmentation profiles of cfDNA in another study, and combination of mutations in cfDNA and protein markers in the last study. Conclusions: Our results demonstrate that the primary site of cancers was accurately discerned in 79% of cases by MCED tests. However, performance varies across cancer types. Further research on performance based on cancer stages and in combination with other molecular profiling is warranted. Pooled accuracy of prediction of tissue-of-origin (TOO) and frequently ‘misclassified as’ cancer types. Events/Total Accuracy of prediction Misclassification Type Frequency Total 3,229/3,895 0.79 Colorectal 656/743 0.90 Upper GI 26/573 Breast 9/573 Breast 461/557 0.88 Colorectal 20/349 Pancreas & GB 4/349 Lung 4/349 Ovarian 136/164 0.85 Colorectal 16/147 Uterus 13/147 Pancreatic & GB 289/338 0.82 Colorectal 12/317 Upper GI 10/317 Upper GI 226/313 0.75 Colorectal 39/261 Lung 10/261 Lung 553/681 0.76 Colorectal 29/585 Head and neck 8/585 Liver & Bile duct 95/144 0.68 Colorectal 13/220 Pancreas & GB 8/220 Abbreviations: CI = confidence interval; GB = gallbladder, Upper GI = stomach and esophagus.