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

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Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma
Gastroenterology ( IF 29.4 ) Pub Date : 2022-09-12 , DOI: 10.1053/j.gastro.2022.09.005
Philipp K Haber ₁ , Florian Castet ₂ , Miguel Torres-Martin ₂ , Carmen Andreu-Oller ₃ , Marc Puigvehí ₄ , Maeda Miho ₃ , Pompilia Radu ₅ , Jean-Francois Dufour ₆ , Chris Verslype ₇ , Carolin Zimpel ₈ , Jens U Marquardt ₈ , Peter R Galle ₉ , Arndt Vogel ₁₀ , Melanie Bathon ₁₀ , Tim Meyer ₁₁ , Ismail Labgaa ₁₂ , Antonia Digklia ₁₃ , Lewis R Roberts ₁₄ , Mohamed A Mohamed Ali ₁₄ , Beatriz Mínguez ₁₅ , Davide Citterio ₁₆ , Vincenzo Mazzaferro ₁₆ , Fabian Finkelmeier ₁₇ , Jörg Trojan ₁₇ , Burcin Özdirik ₁₈ , Tobias Müller ₁₈ , Moritz Schmelzle ₁₉ , Anthony Bejjani ₂₀ , Max W Sung ₃ , Myron E Schwartz ₃ , Richard S Finn ₂₀ , Swan Thung ₃ , Augusto Villanueva ₃ , Daniela Sia ₃ , Josep M Llovet ₂₁

Affiliation

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.
Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Catalonia, Spain.
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.
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.
University Clinic for Visceral Surgery and Medicine, University of Bern, Inselspital, Bern, Switzerland.
University Clinic for Visceral Surgery and Medicine, University of Bern, Inselspital, Bern, Switzerland; Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland.
Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.
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.
Department of Medicine I, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany.
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Department of Oncology, University College London Cancer Institute, London, United Kingdom.
Department of Visceral Surgery, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.
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.
Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Department of Oncology, University of Milan, Milan, Italy.
Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany.
Department of Hepatology and Gastroenterology, Campus Virchow Klinikum and Campus Charité Mitte, Charité University Medicine Berlin, Berlin, Germany.
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.
Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, California.
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.

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.

中文翻译：

晚期肝细胞癌抗 PD1 治疗反应的分子标志物

背景与目标

单药抗 PD1 检查点抑制剂在一小部分 (~20%) 晚期肝细胞癌 (aHCC) 患者中表现出显着的临床益处，但决定反应的分子机制尚不清楚。为了填补这一空白，我们在此分析了接受抗 PD1 治疗的患者中 aHCC 的分子和免疫特征。

方法

总体而言，在全身治疗之前，从 13 个中心获得了 aHCC 患者的 111 个肿瘤样本。我们使用全基因组表达数据 (n = 83)、突变分析 (n = 72) 和具有客观反应终点的组织学评估进行了分子分析和免疫反卷积。

结果

在 83 名具有转录组学数据的患者中，28 名在一线接受治疗，而 55 名患者在酪氨酸激酶抑制剂 (TKI) 后接受二线或三线治疗。在前线接受治疗的应答者表现出上调的干扰素-γ 信号和主要组织相容性复合物 II 相关抗原呈递。我们生成了一个 11 基因特征(IFNAP )，捕捉这些分子特征，预测一线接受抗 PD1 治疗的患者的反应和存活率。该特征在 aHCC 和 >240 名其他实体癌类型患者的单独队列中得到验证，在这些患者中它还可以预测反应和存活率。值得注意的是，相同的特征无法预测接受一线 TKI 治疗的患者的档案组织中的反应，这突出表明在免疫治疗之前需要进行新鲜活检。