Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma.

Details

Serval ID
serval:BIB_FF3E25E6BFAE
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma.
Journal
Oncogene
Author(s)
von Felden J., Craig A.J., Garcia-Lezana T., Labgaa I., Haber P.K., D'Avola D., Asgharpour A., Dieterich D., Bonaccorso A., Torres-Martin M., Sia D., Sung M.W., Tabrizian P., Schwartz M., Llovet J.M., Villanueva A.
ISSN
1476-5594 (Electronic)
ISSN-L
0950-9232
Publication state
Published
Issued date
01/2021
Peer-reviewed
Oui
Volume
40
Number
1
Pages
140-151
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Little is known about the mutational landscape of advanced hepatocellular carcinoma (HCC), and predictive biomarkers of response to systemic therapies are lacking. We aimed to describe the mutational landscape of advanced HCC and to identify predictors of primary resistance to systemic therapies using circulating tumor DNA (ctDNA). We prospectively enrolled 121 patients between October 2015 and January 2019. We performed targeted ultra-deep sequencing of 25 genes and Digital Droplet PCR of TERT promoter, including sequential samples throughout treatment. Primary endpoint was progression-free survival (PFS) stratified by mutation profiles in ctDNA. Secondary endpoints were overall survival and objective response rate. The most frequent mutations in ctDNA of advanced HCC were TERT promoter (51%), TP53 (32%), CTNNB1 (17%), PTEN (8%), AXIN1, ARID2, KMT2D, and TSC2 (each 6%). TP53 and CTNNB1 mutations were mutually exclusive. Patients with mutations in the PI3K/MTOR pathway had significantly shorter PFS than those without these mutations after tyrosine kinase inhibitors (2.1 vs 3.7 months, p < 0.001), but not after immune checkpoint inhibition (CPI). WNT pathway mutations were not associated with PFS, overall survival, or objective response after CPI. Serial profiling of ctDNA in a subset correlated with treatment response. Mutation profiling of ctDNA in advanced HCC shows similar mutation frequencies for known HCC drivers compared to early stages and identifies predictive biomarkers of response to systemic therapies.
Keywords
Aged, Biomarkers, Tumor/genetics, Carcinoma, Hepatocellular/genetics, Circulating Tumor DNA/genetics, Drug Resistance, Neoplasm, Female, High-Throughput Nucleotide Sequencing, Humans, Immune Checkpoint Inhibitors/therapeutic use, Liver Neoplasms/genetics, Male, Middle Aged, Mutation, PTEN Phosphohydrolase/genetics, Promoter Regions, Genetic, Prospective Studies, Protein Kinase Inhibitors/pharmacology, Protein Kinase Inhibitors/therapeutic use, Sequence Analysis, DNA/methods, Survival Analysis, Telomerase/genetics, beta Catenin/genetics
Pubmed
Web of science
Create date
02/11/2020 13:15
Last modification date
02/12/2023 7:16
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