Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma

Philipp K Haber; Florian Castet; Miguel Torres-Martin; Carmen Andreu-Oller; Marc Puigvehí; Maeda Miho; Pompilia Radu; Jean-Francois Dufour; Chris Verslype; Carolin Zimpel; Jens U Marquardt; Peter R Galle; Arndt Vogel; Melanie Bathon; Tim Meyer; Ismail Labgaa; Antonia Digklia; Lewis R Roberts; Mohamed A Mohamed Ali; Beatriz Mínguez; Davide Citterio; Vincenzo Mazzaferro; Fabian Finkelmeier; Jörg Trojan; Burcin Özdirik; Tobias Müller; Moritz Schmelzle; Anthony Bejjani; Max W Sung; Myron E Schwartz; Richard S Finn; Swan Thung; Augusto Villanueva; Daniela Sia; Josep M Llovet

doi:10.1053/j.gastro.2022.09.005

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma

Gastroenterology. 2023 Jan;164(1):72-88.e18. doi: 10.1053/j.gastro.2022.09.005. Epub 2022 Sep 12.

Authors

Philipp K Haber¹, Florian Castet², Miguel Torres-Martin², Carmen Andreu-Oller³, Marc Puigvehí⁴, Maeda Miho³, Pompilia Radu⁵, Jean-Francois Dufour⁶, Chris Verslype⁷, Carolin Zimpel⁸, Jens U Marquardt⁸, Peter R Galle⁹, Arndt Vogel¹⁰, Melanie Bathon¹⁰, Tim Meyer¹¹, Ismail Labgaa¹², Antonia Digklia¹³, Lewis R Roberts¹⁴, Mohamed A Mohamed Ali¹⁴, Beatriz Mínguez¹⁵, Davide Citterio¹⁶, Vincenzo Mazzaferro¹⁶, Fabian Finkelmeier¹⁷, Jörg Trojan¹⁷, Burcin Özdirik¹⁸, Tobias Müller¹⁸, Moritz Schmelzle¹⁹, Anthony Bejjani²⁰, Max W Sung³, Myron E Schwartz³, Richard S Finn²⁰, Swan Thung³, Augusto Villanueva³, Daniela Sia³, Josep M Llovet²¹

Affiliations

¹ Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York, New York, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, Department of Surgery, Recanti/Miller Transplant Institute at the Icahn School of Medicine at Mount Sinai, New York, New York, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Surgery, Campus Charité Mitte and Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
² Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Catalonia, Spain.
³ Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York, New York, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, Department of Surgery, Recanti/Miller Transplant Institute at the Icahn School of Medicine at Mount Sinai, New York, New York, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
⁴ Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York, New York, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, Department of Surgery, Recanti/Miller Transplant Institute at the Icahn School of Medicine at Mount Sinai, New York, New York, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Hepatology Section, Gastroenterology Department, Parc de Salut Mar, IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, Barcelona, Spain.
⁵ University Clinic for Visceral Surgery and Medicine, University of Bern, Inselspital, Bern, Switzerland.
⁶ University Clinic for Visceral Surgery and Medicine, University of Bern, Inselspital, Bern, Switzerland; Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland.
⁷ Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.
⁸ Department of Medicine I, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany; Department of Medicine I, University of Lübeck, UKSH - Campus Lübeck, Lübeck, Germany.
⁹ Department of Medicine I, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany.
¹⁰ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
¹¹ Department of Oncology, University College London Cancer Institute, London, United Kingdom.
¹² Department of Visceral Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹³ Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁴ Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
¹⁵ Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain, Liver Diseases Research Group, Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain, CIBERehd, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹⁶ Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Department of Oncology, University of Milan, Milan, Italy.
¹⁷ Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany.
¹⁸ Department of Hepatology and Gastroenterology, Campus Virchow Klinikum and Campus Charité Mitte, Charité University Medicine Berlin, Berlin, Germany.
¹⁹ Department of Surgery, Campus Charité Mitte and Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany; Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
²⁰ Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, California.
²¹ Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York, New York, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, Department of Surgery, Recanti/Miller Transplant Institute at the Icahn School of Medicine at Mount Sinai, New York, New York, Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain. Electronic address: josep.llovet@mssm.edu.

PMID: 36108710
DOI: 10.1053/j.gastro.2022.09.005

Abstract

Background & aims: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1.

Methods: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response.

Results: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy.

Conclusion: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

Keywords: Biomarkers; Hepatocellular Carcinoma; Immunotherapy; Predictors of Response.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Biomarkers
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / metabolism
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
Liver Neoplasms* / metabolism
Programmed Cell Death 1 Receptor / metabolism
Prospective Studies

Substances

Programmed Cell Death 1 Receptor
Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding