@article{3eeaf7fc0ab949a0a1ddd7e71ef98003,
title = "Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set",
abstract = "Background: A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. Patients and methods: This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. Results: Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). Conclusion: In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. Clinical trial number: NCT02889978.",
keywords = "cancer, cell-free nucleic acids, liquid biopsy, machine learning, methylation, multi-cancer early detection",
author = "Klein, {E. A.} and D. Richards and A. Cohn and M. Tummala and R. Lapham and D. Cosgrove and G. Chung and J. Clement and J. Gao and N. Hunkapiller and A. Jamshidi and Kurtzman, {K. N.} and Seiden, {M. V.} and C. Swanton and Liu, {M. C.}",
note = "Funding Information: This work was supported by GRAIL, Inc., and GRAIL, Inc. was involved in the study{\textquoteright}s design, conduct, data collection, analysis and interpretation, and reporting (no grant number). Funding Information: The authors thank the following GRAIL, Inc. colleagues for critical input and help with manuscript development: Eric Fung, Earl Hubbell, and Ruhi Ubale. The following GRAIL, Inc. colleagues are acknowledged for significant contributions to the assay design: Farnaz Absalan, Leila Bazargan, Jen Berman, Jeremy Carter, Chenlu Hou, Byoungsok Jung, and Kristan Steffen. The following GRAIL, Inc. colleagues are acknowledged for biostatistical support: Gregory Alexander, Lane Eubank, Tony Wu, Lori (Quan) Zhang, and Nan Zhang. Authors also thank the members of the GRAIL, Inc. Data Sciences group: Hamed Amini, Siddhartha Bagaria, John Beausang, Joerg Bredno, Jackie Brooks, Robert Calef, Daniel Civello, Soleil Damangir, Konstantin Davydov, Zhao Dong, Alexander Fields, Peter Freese, Sam Gross, Earl Hubbell, Payam Khodabakhshi, Ting-Chin Liu, Ting Ma, Cyrus Maher, Collin Melton, Patriss Mordi, Josh Newman, Costanza Rojo, Neda Ronaghi, Onur Sakarya, Jan Schellenberger, Eric Scott, Avinash Shanmugam, Nima Shojajee, Pranav Singh, Archana Shenoy, Oliver Venn, Sharon Wootton, and Chris Yakym. The following GRAIL, Inc. colleagues are acknowledged for clinical development: Jason Carlson, Xiaoji Chen, Beth Chang, Kalyani Chilukuri, Clarice Grant-Coles, Jordan Frisbie, Neelima Gandepally, Nathan Gliner, David Jones, Smit Shah, Robert Shortt, Jessica Quan, Jennifer Woo, and Dave Nguyen. Editorial and writing support was funded by GRAIL, Inc. and provided by Jennifer Hepker and Merrilee R. Johnstone from Prescott Medical Communications Group (Chicago, IL). This work was supported by GRAIL, Inc. and GRAIL, Inc. was involved in the study's design, conduct, data collection, analysis and interpretation, and reporting (no grant number). EAK is a consultant for GRAIL, Inc.; DC is a consultant for Pfizer and Merck; AJ and KNK are full-time employees of GRAIL, Inc. and have stock in Illumina and GRAIL, Inc.; JG and NH are full-time employees of GRAIL Inc. and own stock in GRAIL, Inc. MVS has stock in McKesson Corporation, is a clinical adviser for GRAIL, Inc. and a director of Next Oncology and Nemucore Medical Innovations; CS has stock in GRAIL, Inc. Epic Biosciences and Apogen Biotech, grants from Pfizer and AstraZeneca, received honoraria or consultant fees from Roche Ventana, Celgene, Pfizer, Novartis, Genentech, and BMS, and is a co-founder of Achilles Therapeutics; MCL participated as an advisory board member for GRAIL, Inc. All other authors have declared no conflicts of interest. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = sep,
doi = "10.1016/j.annonc.2021.05.806",
language = "English (US)",
volume = "32",
pages = "1167--1177",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "9",
}