Tumor steatosis and glutamine synthetase expression in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy

Yutaka Kurebayashi; Hanako Tsujikawa; Katsutoshi Sugimoto; Daisuke Yunaiyama; Yoichi Araki; Kazuhiro Saito; Hiroshi Takahashi; Tatsuya Kakegawa; Takuya Wada; Yusuke Tomita; Masakazu Abe; Yu Yoshimasu; Hirohito Takeuchi; Taiki Hirata; Kentaro Sakamaki; Kazuhiro Kakimi; Toshitaka Nagao; Takao Itoi; Michiie Sakamoto

doi:10.1111/hepr.13933

Tumor steatosis and glutamine synthetase expression in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy

Hepatol Res. 2023 Oct;53(10):1008-1020. doi: 10.1111/hepr.13933. Epub 2023 Jun 23.

Authors

Yutaka Kurebayashi¹, Hanako Tsujikawa^{1

2}, Katsutoshi Sugimoto³, Daisuke Yunaiyama⁴, Yoichi Araki⁴, Kazuhiro Saito⁴, Hiroshi Takahashi³, Tatsuya Kakegawa³, Takuya Wada³, Yusuke Tomita³, Masakazu Abe³, Yu Yoshimasu³, Hirohito Takeuchi³, Taiki Hirata³, Kentaro Sakamaki⁵, Kazuhiro Kakimi⁶, Toshitaka Nagao⁷, Takao Itoi³, Michiie Sakamoto¹

Affiliations

¹ Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
² Department of Diagnostic Pathology, Keio University Hospital, Tokyo, Japan.
³ Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan.
⁴ Department of Radiology, Tokyo Medical University, Tokyo, Japan.
⁵ Center for Data Science, Yokohama City University, Yokohama, Japan.
⁶ Department of Immuno-therapeutics, The University of Tokyo Hospital, Tokyo, Japan.
⁷ Department of Anatomical Pathology, Tokyo Medical University, Tokyo, Japan.

PMID: 37300323
DOI: 10.1111/hepr.13933

Abstract

Aim: The anti-programmed death-ligand 1 antibody atezolizumab and vascular endothelial growth factor-neutralizing antibody bevacizumab in combination (Atezo + Bev) have become the first-line therapy in advanced hepatocellular carcinoma (HCC). Distinct types of tumor immune microenvironment (TIME) and their associations with specific molecular subclasses and driver gene mutations have been identified in HCC; however, these insights are mainly based on surgically resected early-stage tumors. The current study aimed to reveal the biology and TIME of advanced HCC and their significance in predicting clinical outcomes of Atezo + Bev therapy.

Methods: Thirty-three patients with advanced HCC who were scheduled for treatment with Atezo + Bev therapy were included in this study. Pretreatment tumor biopsy, pre- and posttreatment diffusion-weighted magnetic resonance imaging (MRI) with nine b values (0-1500 s/mm² ), and other clinicopathologic factors were analyzed.

Results: Compared with resectable HCC, advanced HCC was characterized by higher proliferative activity, a higher frequency of Wnt/β-catenin-activated HCC, and lower lymphocytic infiltration. Prognostically, two metabolism-related factors, histopathologically determined tumor steatosis and/or glutamine synthetase (GS) expression, and MRI-determined tumor steatosis, were the most significant prognostic indicators for progression-free survival (PFS) and overall survival after Atezo + Bev therapy. Furthermore, changes in the pre- and posttreatment true diffusion coefficients on MRI, which might reflect changes in TIME after treatment, were significantly associated with better PFS.

Conclusions: The biology and TIME of HCC were strikingly different in advanced HCC compared with those of surgically resected HCC. Two metabolism-related factors, pathologically determined tumor steatosis and/or GS expression, and MRI-determined tumor steatosis, were found to be the most significant prognostic indicators for Atezo + Bev therapy in advanced HCC.

Keywords: hepatocellular carcinoma; immune microenvironment; immunotherapy; intravoxel incoherent motion; magnetic resonance imaging.