@article{81db68533aa54eb188400072920b02b4,
title = "Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA",
abstract = "Background: Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. Participants and methods: The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. Results: Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. Conclusions: cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.",
keywords = "cancer, cell-free DNA, methylation, next-generation sequencing",
author = "{STRIVE investigators} and {GRAIL, Inc.} and Advisors and Liu, {M. C.} and Oxnard, {G. R.} and Klein, {E. A.} and C. Swanton and Seiden, {M. V.} and Liu, {Minetta C.} and Oxnard, {Geoffrey R.} and Klein, {Eric A.} and David Smith and Donald Richards and Yeatman, {Timothy J.} and Cohn, {Allen L.} and Rosanna Lapham and Jessica Clement and Parker, {Alexander S.} and Tummala, {Mohan K.} and Kristi McIntyre and Sekeres, {Mikkael A.} and Bryce, {Alan H.} and Robert Siegel and Xuezhong Wang and Cosgrove, {David P.} and Abu-Rustum, {Nadeem R.} and Jonathan Trent and Thiel, {David D.} and Carlos Becerra and Manish Agrawal and Garbo, {Lawrence E.} and Giguere, {Jeffrey K.} and Michels, {Ross M.} and Harris, {Ronald P.} and Richey, {Stephen L.} and McCarthy, {Timothy A.} and Waterhouse, {David M.} and Couch, {Fergus J.} and Wilks, {Sharon T.} and Krie, {Amy K.} and Rama Balaraman and Alvaro Restrepo and Meshad, {Michael W.} and Kimberly Rieger-Christ and Travis Sullivan and Lee, {Christine M.} and Greenwald, {Daniel R.} and William Oh and Tsao, {Che Kai} and Neil Fleshner and Kennecke, {Hagen F.} and Khalil, {Maged F.} and Spigel, {David R.} and Manhas, {Atisha P.} and Ulrich, {Brian K.} and Kovoor, {Philip A.} and Christopher Stokoe and Courtright, {Jay G.} and Yimer, {Habte A.} and Larson, {Timothy G.} and Seiden, {Michael V.} and Cummings, {Steven R.} and Farnaz Absalan and Gregory Alexander and Brian Allen and Hamed Amini and Aravanis, {Alexander M.} and Siddhartha Bagaria and Leila Bazargan and Beausang, {John F.} and Jennifer Berman and Craig Betts and Alexander Blocker and Joerg Bredno and Robert Calef and Gordon Cann and Jeremy Carter and Christopher Chang and Hemanshi Chawla and Xiaoji Chen and Chien, {Tom C.} and Daniel Civello and Konstantin Davydov and Vasiliki Demas and Mohini Desai and Zhao Dong and Saniya Fayzullina and Fields, {Alexander P.} and Darya Filippova and Peter Freese and Fung, {Eric T.} and Sante Gnerre and Samuel Gross and Meredith Halks-Miller and Hall, {Megan P.} and Hartman, {Anne Renee} and Chenlu Hou and Earl Hubbell and Nathan Hunkapiller and Karthik Jagadeesh and Arash Jamshidi and Roger Jiang and Byoungsok Jung and Kim, {Tae Hyung} and Klausner, {Richard D.} and Kurtzman, {Kathryn N.} and Mark Lee and Wendy Lin and Jafi Lipson and Hai Liu and Qinwen Liu and Margarita Lopatin and Tara Maddala and Maher, {M. Cyrus} and Collin Melton and Andrea Mich and Shivani Nautiyal and Jonathan Newman and Joshua Newman and Virgil Nicula and Cosmos Nicolaou and Ongjen Nikolic and Wenying Pan and Shilpen Patel and Prins, {Sarah A.} and Richard Rava and Neda Ronaghi and Onur Sakarya and Satya, {Ravi Vijaya} and Jan Schellenberger and Eric Scott and Sehnert, {Amy J.} and Rita Shaknovich and Avinash Shanmugam and Shashidhar, {K. C.} and Ling Shen and Archana Shenoy and Seyedmehdi Shojaee and Pranav Singh and Steffen, {Kristan K.} and Susan Tang and Toung, {Jonathan M.} and Anton Valouev and Oliver Venn and Williams, {Richard T.} and Tony Wu and Xu, {Hui H.} and Christopher Yakym and Xiao Yang and Jessica Yecies and Yip, {Alexander S.} and Jack Youngren and Jeanne Yue and Jingyang Zhang and Lily Zhang and Zhang, {Lori (Quan)} and Nan Zhang and Christina Curtis and Berry, {Donald A.}",
note = "Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = jun,
doi = "10.1016/j.annonc.2020.02.011",
language = "English",
volume = "31",
pages = "745--759",
journal = "Annals of Oncology",
issn = "0923-7534",
number = "6",
}