TY - JOUR
T1 - Validation of a Novel Multitarget Blood Test Shows High Sensitivity to Detect Early Stage Hepatocellular Carcinoma
AU - Chalasani, Naga P.
AU - Porter, Kyle
AU - Bhattacharya, Abhik
AU - Book, Adam J.
AU - Neis, Brenda M.
AU - Xiong, Kong M.
AU - Ramasubramanian, Tiruvidaimarudur S.
AU - Edwards, David K.
AU - Chen, Irene
AU - Johnson, Scott
AU - Roberts, Lewis R.
AU - Kisiel, John B.
AU - Reddy, K. Rajender
AU - Singal, Amit G.
AU - Olson, Marilyn C.
AU - Bruinsma, Janelle J.
N1 - Funding Information:
The authors would like to thank the participants in the clinical trial, along with the investigators and collaborators at the study sites around the world, without whom these studies would not have been possible. In addition, the authors want to acknowledge the invaluable contribution of the following individuals (all are from Exact Sciences): Martin Krockenberger (statistical programming assistance for algorithm development study and quality-control data checks for clinical validation); Nishitha Therala and Varun Sama (statistical programming for clinical validation study); Marina Pavlova (clinical validation data management and organization); Audrey Ford and Rory O'Brien (planning and oversight of clinical validation study execution); Hannah Paspulati, Stephanie Saccardi, Lucy Chow, Adrian Chan, Kathleen Yapyuco, Shirley de la Rama, and Nicola Lin (clinical validation study execution); Amanda Adams, Callie Busse, Ashley Daugherty, Jeanne Dudek, Elisabeth Enghofer, Miranda Ortman, Laura Pauers, Alycia Riehl, and Becky Rosenow (assay development and algorithm development study execution); James Light, Gary Choncholas, Will Ault, Brock Shilling, Nick Balge, Jared Ness, Kevin Menningen, Rick Campbell, Pat Flanagan, John Ruprecht, Paul Tisdel, Carly Swiftney, Peter Chance, Bill Rosholt, and Alexis Krueger (system development); Theran Meyers, Anthony Nguyen, Adan Carrera, and Cory Jonet (laboratory information system engineering); Peter Leahy and Jemma Iano-Fletcher (business analysis and quality assurance); Kevin Allred (project management); Feyza Sancar and Elle Grevstad (manuscript feedback and guidance); Bonnie Gulley and Rob Fisher (sample collection study); Laura Strong (clinical validation protocol development); Chris Upjohn (clinical validation program management); and Betsy Mulligan and Betsy Kleba (program team leadership). Conceptualization: Janelle J. Bruinsma, John B. Kisiel, Marilyn C. Olson, Methodology and Design: Janelle J. Bruinsma, John B. Kisiel, Marilyn C. Olson, Tiruvidaimarudur S. Ramasubramanian, Naga P. Chalasani, Kyle Porter, Adam J. Book, Brenda M. Neis, Abhik Bhattacharya, Formal Analysis: Tiruvidaimarudur S. Ramasubramanian, Abhik Bhattacharya, Kyle Porter, Investigation: Janelle J. Bruinsma, Marilyn C. Olson, Lewis R. Roberts, Naga P. Chalasani, Adam J. Book, Brenda M. Neis, Kong M. Xiong, Resources: Naga P. Chalasani, K. Rajender Reddy, Lewis R. Roberts, Amit G. Singal, Data Curation: Janelle J. Bruinsma, Tiruvidaimarudur S. Ramasubramanian, Abhik Bhattacharya, Kyle Porter, Adam J. Book, Kong M. Xiong, Writing – Original Draft: Kyle Porter, Tiruvidaimarudur S. Ramasubramanian, Abhik Bhattacharya, David K. Edwards V, Janelle J. Bruinsma, Marilyn C. Olson, Writing – Review and Editing: Kyle Porter, Naga P. Chalasani, Tiruvidaimarudur S. Ramasubramanian, Abhik Bhattacharya, Marilyn C. Olson, David K. Edwards V, Irene Chen, Lewis R. Roberts, John B. Kisiel, K. Rajender Reddy, Adam J. Book, Amit G. Singal, Scott Johnson, Janelle J. Bruinsma, Brenda M. Neis, Kong M. Xiong, Visualization: Janelle J. Bruinsma, Marilyn C. Olson, Tiruvidaimarudur S. Ramasubramanian, David K. Edwards V, Kyle Porter, Abhik Bhattacharya, Supervision: Janelle J. Bruinsma, Marilyn C. Olson, Naga P. Chalasani Project Administration: Janelle J. Bruinsma Conflicts of interest These authors disclose the following: Kyle Porter, Abhik Bhattacharya, Adam J. Book, Brenda M. Neis, Kong M. Xiong, Tiruvidaimarudur S. Ramasubramanian, David K. Edwards V, Irene Chen, Scott Johnson, Marilyn C. Olson, and Janelle J. Bruinsma are employees of Exact Sciences; Naga P. Chalasani has consulting agreements and research grants from several pharmaceutical companies, but these are not directly or significantly related to this publication; Lewis R. Roberts has served on advisory boards for AstraZeneca, Bayer, Eisai, Exact Sciences, Gilead Sciences, GRAIL, QED Therapeutics, and TAVEC, and has received research support from Ariad Pharmaceuticals, Bayer, Boston Scientific, Gilead Sciences, Glycotest, RedHill BioPharma, TARGET PharmaSolutions, and FUJIFILM Medical Systems; K. Rajender Reddy has served as an ad hoc advisor to Mallinckrodt, Deciphera, and Pfizer, on Data and Safety Monitoring Board for Novartis, and has received research support (paid to the University of Pennsylvania) from Mallinckrodt, Intercept, BMS, Merck, Gilead, Sequana, Grifols, HCC-TARGET, and NASH-TARGET; John B. Kisiel is listed as an inventor of intellectual property owned by Mayo Clinic and Exact Sciences and may receive royalties in accordance with Mayo Clinic policy; and Amit G. Singal has served as a consultant or on advisory boards for FUJIFILM Medical Systems, Glycotest, Exact Sciences, GRAIL, and Bayer. The remaining author discloses no conflicts. Funding Supported by grants from Exact Sciences to Indiana University, Mayo Clinic, and the University of Pennsylvania (Naga P. Chalasani, Lewis R. Roberts, and K. Rajender Reddy). The funding agreement with Exact Sciences ensured author independence when interpreting and analyzing the data and in writing and submitting the publication.
Funding Information:
Funding Supported by grants from Exact Sciences to Indiana University, Mayo Clinic, and the University of Pennsylvania (Naga P. Chalasani, Lewis R. Roberts, and K. Rajender Reddy). The funding agreement with Exact Sciences ensured author independence when interpreting and analyzing the data and in writing and submitting the publication.
Publisher Copyright:
© 2022 The Authors
PY - 2022/1
Y1 - 2022/1
N2 - Background & Aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although biannual ultrasound surveillance with or without α-fetoprotein (AFP) testing is recommended for at-risk patients, sensitivity for early stage HCC, for which potentially curative treatments exist, is suboptimal. We conducted studies to establish the multitarget HCC blood test (mt-HBT) algorithm and cut-off values and to validate test performance in patients with chronic liver disease. Methods: Algorithm development and clinical validation studies were conducted with participants in an international, multicenter, case-control study. Study subjects had underlying cirrhosis or chronic hepatitis B virus; HCC cases were diagnosed per the American Association for the Study of Liver Diseases criteria and controls were matched for age and liver disease etiology. Whole blood and serum were shipped to a central laboratory and processed while blinded to case/control status. An algorithm was developed for the mt-HBT, which incorporates methylation biomarkers (HOXA1, TSPYL5, and B3GALT6), AFP, and sex. Results: In algorithm development, with 136 HCC cases (60% early stage) and 404 controls, the mt-HBT showed 72% sensitivity for early stage HCC at 88% specificity. Test performance was validated in an independent cohort of 156 HCC cases (50% early stage) and 245 controls, showing 88% overall sensitivity, 82% early stage sensitivity, and 87% specificity. Early stage sensitivity in clinical validation was significantly higher than AFP at 20 ng/mL or greater (40%; P < .0001) and GALAD (gender, age, Lens culinaris agglutinin-reactive AFP, AFP, and des-γ-carboxy-prothrombin score) of -0.63 or greater (71%; P = .03), although AFP and GALAD at these cut-off values had higher specificities (100% and 93%, respectively). Conclusions: The mt-HBT may significantly improve early stage HCC detection for patients undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality. ClinicalTrials.gov number NCT03628651.
AB - Background & Aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although biannual ultrasound surveillance with or without α-fetoprotein (AFP) testing is recommended for at-risk patients, sensitivity for early stage HCC, for which potentially curative treatments exist, is suboptimal. We conducted studies to establish the multitarget HCC blood test (mt-HBT) algorithm and cut-off values and to validate test performance in patients with chronic liver disease. Methods: Algorithm development and clinical validation studies were conducted with participants in an international, multicenter, case-control study. Study subjects had underlying cirrhosis or chronic hepatitis B virus; HCC cases were diagnosed per the American Association for the Study of Liver Diseases criteria and controls were matched for age and liver disease etiology. Whole blood and serum were shipped to a central laboratory and processed while blinded to case/control status. An algorithm was developed for the mt-HBT, which incorporates methylation biomarkers (HOXA1, TSPYL5, and B3GALT6), AFP, and sex. Results: In algorithm development, with 136 HCC cases (60% early stage) and 404 controls, the mt-HBT showed 72% sensitivity for early stage HCC at 88% specificity. Test performance was validated in an independent cohort of 156 HCC cases (50% early stage) and 245 controls, showing 88% overall sensitivity, 82% early stage sensitivity, and 87% specificity. Early stage sensitivity in clinical validation was significantly higher than AFP at 20 ng/mL or greater (40%; P < .0001) and GALAD (gender, age, Lens culinaris agglutinin-reactive AFP, AFP, and des-γ-carboxy-prothrombin score) of -0.63 or greater (71%; P = .03), although AFP and GALAD at these cut-off values had higher specificities (100% and 93%, respectively). Conclusions: The mt-HBT may significantly improve early stage HCC detection for patients undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality. ClinicalTrials.gov number NCT03628651.
KW - Early Cancer Detection
KW - Hepatocellular Carcinoma Surveillance
KW - Liquid Biopsy
KW - Multitarget Hepatocellular Carcinoma Blood Test
KW - mt-HBT
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UR - http://www.scopus.com/inward/citedby.url?scp=85116925922&partnerID=8YFLogxK
U2 - 10.1016/j.cgh.2021.08.010
DO - 10.1016/j.cgh.2021.08.010
M3 - Article
C2 - 34391922
AN - SCOPUS:85116925922
SN - 1542-3565
VL - 20
SP - 173-182.e7
JO - Clinical Gastroenterology and Hepatology
JF - Clinical Gastroenterology and Hepatology
IS - 1
ER -