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

Oncogene volume 40, pages 140–151 (2021)Cite this article

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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.

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Fig. 1: ctDNA mutation profiling in advanced HCC.
Fig. 2: ctDNA mutation profiles and response to TKI.
Fig. 3: ctDNA mutation profiles and response to CPI.
Fig. 4: Molecular monitoring using ctDNA.

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Data availability

Raw data for the sequencing analysis included in this article will be made available upon publication via Sequence Read Archive of the NCBI (accession number PRJNA626404).

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Acknowledgements

The authors thank the ISMMS Cancer Center Biorepository for providing some of the samples, as well as the office of Scientific Computing for providing computational resources and staff expertise.

Funding

JvF is supported by the German Research Foundation (FE1746/1-1). AJC is supported by the National Cancer Institute Ruth L. Kirschstein NRSA Institutional Research Training Grant (CA078207). IL is supported by a grant from the Swiss National Science Foundation, from Foundation Roberto & Gianna Gonella and Foundation SICPA. PKH is supported by the German Research Foundation (HA8754/1–1). DD is supported by the Grant for Studies Broadening from the Spanish Association for the Study of the Liver (Asociación Española para el Estudio del Hígado, AEEH) and the Cancer Research Grant from Nuovo Soldati Foundation. JML is supported by the European Commission (EC)/Horizon 2020 Program (HEPCAR, Ref. 667273-2), U.S. Department of Defense (CA150272P3), an Accelerator Award (CRUCK, AECC, AIRC) (HUNTER, Ref. C9380/A26813), National Cancer Institute, Tisch Cancer Institute (P30-CA196521), Samuel Waxman Cancer Research Foundation, Spanish National Health Institute (SAF2016-76390) and the Generalitat de Catalunya/AGAUR (SGR-1358). AV is supported by the U.S. Department of Defense (CA150272P3).

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Authors and Affiliations

  1. I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Johann von Felden

  2. Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Johann von Felden, Amanda J. Craig, Teresa Garcia-Lezana, Ismail Labgaa, Philipp K. Haber, Delia D’Avola, Amon Asgharpour, Douglas Dieterich, Miguel Torres-Martin, Daniela Sia, Josep M. Llovet & Augusto Villanueva

  3. Department of Visceral Surgery, Lausanne University Hospital CHUV, Lausanne, Switzerland

    Ismail Labgaa

  4. Liver Unit and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Clínica Universidad de Navarra, Pamplona, Spain

    Delia D’Avola

  5. Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Antoinette Bonaccorso, Parissa Tabrizian & Myron Schwartz

  6. Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Max W. Sung & Augusto Villanueva

  7. Liver Cancer Translational Research Laboratory, IDIBAPS, Hospital Clinic, Universitat de Barcelona, Catalonia, Spain

    Josep M. Llovet

  8. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain

    Josep M. Llovet

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Contributions

Study design: JvF, JML, AV. Patient enrollment/sample collection: JvF, AJC, TGL, IL, PKH, DDA, AA, DD, AB, MWS, PT, MS, AV. Experiments/analysis/data collection: JvF, AJC, TGL, IL, PKH, MTM, DS, JML, AV. Drafting of the manuscript: JvF, AV. All authors gave intellectual input to the manuscript and have approved its final version.

Corresponding author

Correspondence to Augusto Villanueva.

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Conflict of interest

AA reports financial activities for consulting from Gilead, Genfit, Sterotherapeutics, and Connect, for consulting and speaking from Intercept, for advisory board membership from SanyalBio, all outside the submitted work. DD reports grants and personal fees from Gilead, grants and personal fees from Abbvie, grants and personal fees from Intercept, outside the submitted work. MWS reports advisory board fees from Bayer, Eisai, Exelixis, all outside the submitted work; JML reports grants and personal fees from Bayer Pharmaceuticals, Eisai Inc., Bristol Myers Squibb, Boehringer-Ingelheim, and Ipsen, personal fees from Merck, Celsion, Eli Lilly, Roche, Genentech, Glycotest, Nucleix, Can-Fite Biopharma, Exelixis, and Astrazeneca, all outside the submitted work. AV reports personal fees from NGM Pharmaceuticals, Gilead, Nucleix, Fuji Wako, Guidepoint, Exact Sciences, all outside the submitted work. All remaining authors have nothing to declare in regard to this manuscript.

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von Felden, J., Craig, A.J., Garcia-Lezana, T. et al. Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma. Oncogene 40, 140–151 (2021). https://doi.org/10.1038/s41388-020-01519-1

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