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Serum osteopontin predicts the response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma

  • Original Article―Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Combination therapy with anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for un-resectable hepatocellular carcinoma (uHCC). We aimed to identify predictive circulating biomarkers for the outcome/response of the combination therapy in uHCC patients.

Methods

This prospective multicenter study enrolled 70 patients with uHCC who received atezolizumab and bevacizumab (Atez/Bev). We evaluated 47 circulating proteins in sera before and after 1 and 6 weeks of Atez/Bev therapy by multiplex bead-based immunoassay and ELISA. As controls, we analyzed the sera from 62 uHCC patients before treatment of lenvatinib (LEN) and healthy volunteers (HVs).

Results

The disease control rate was 77.1%. Median progression-free survival (PFS) was 5.7 months (95% confidence interval [CI] = 3.8–9.5). The pretreatment levels of osteopontin (OPN), angiopoietin-2, VEGF, S100–calcium-binding protein A8/S100–calcium-binding protein A9, soluble programmed cell death-1, soluble CD163, and 14 cytokines/chemokines were higher in patients with uHCC than in HVs. Among these, pretreatment OPN levels were higher in PD group than in non-PD group for Atez/Bev. The PD rate was higher in high OPN group than in low OPN group. Multivariate analysis identified high pretreatment OPN and high α‐fetoprotein levels as independent predictors of PD. In the sub-analysis of Child–Pugh class A patients, PFS was also shorter in the high OPN group than in the low OPN group. Pretreatment OPN level was not associated with treatment response for LEN.

Conclusion

High serum OPN levels were associated with poor response to Atez/Bev in patients with uHCC.

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Abbreviations

AE:

Adverse event

AFP:

Alpha-fetoprotein

ANG2:

Angiopoietin-2

Atez/Bev:

Atezolizumab/bevacizumab

BCLC:

Barcelona clinic liver cancer

CI:

Confidence interval

CR:

Complete response

DCR:

Disease control rate

HCC:

Hepatocellular carcinoma

HVs:

Healthy volunteers

LEN:

Lenvatinib

MTA:

Multi-molecular target agent

OPN:

Osteopontin

OS:

Overall survival

PD:

Progressive disease

PD-L1:

Programmed death-ligand 1

PFS:

Progression-free survival

PR:

Partial response

RECIST:

Response evaluation criteria in solid tumors

ROC:

Receiver operating characteristic

sCD163:

Soluble CD163

SD:

Stable disease

sPD-1:

Soluble programmed cell death-1

S100A8/A9:

S100–Calcium-binding protein A8/S100–calcium-binding protein A9

TAM:

Tumor-associated macrophage

uHCC:

Unresectable HCC

VEGF:

Vascular endothelial growth factor

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Acknowledgements

We thank the patients for their participation in this study. We also thank Hiromi Tanikawa, Hiroko Nagai, and Chizu Tokoro for technical assistance. We also thank Joe Barber Jr., PhD, from Edanz (www.edanz.com/ac) for editing a draft of this manuscript.

Funding

This research was supported by AMED (grant numbers 22fk0210110 and 22fk0210094) and Grants-in-Aid for Scientific Research (grant numbers 21K08020).

Author information

Author notes

  1. Reika Yamauchi and Takanori Ito have contributed equally to this work.

Authors and Affiliations

  1. Department of Liver Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1, Kohnodai, Ichikawa, 272-8516, Japan

    Reika Yamauchi, Sachiyo Yoshio, Taiji Yamazoe, Taizo Mori, Eiji Kakazu & Tatsuya Kanto

  2. Division of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Takanori Ito, Takafumi Yamamoto, Kazuyuki Mizuno, Masatoshi Ishigami & Hiroki Kawashima

  3. Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan

    Satoshi Yasuda & Hidenori Toyoda

  4. Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan

    Shigeo Shimose, Hideki Iwamoto & Takumi Kawaguchi

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  1. Reika Yamauchi
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Contributions

Conceptualization, SY, TI; methodology, SY; re-sources, TI, HT, SS, HI, TK; writing—original draft preparation, RY, SY, TI; writing—review and editing, HT; supervision, MM, ST, TY, TM, EK, HT, TK; project administration, SY, TI; funding acquisition, SY. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Sachiyo Yoshio.

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Conflict of interest

Takanori Ito received speaker’s fees from Chugai Pharmaceutical Co., Ltd. Masatoshi Ishigami received grants from Chugai Pharmaceutical Co., Ltd. Hidenori Toyoda received speaker’s fees from AbbVie, Bayer, Gilead, Terumo, and Eisai. Takumi Kawaguchi received speaker’s fees from Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Taisho Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and EA Pharma Co., Ltd., Tatsuya Kanto received speaker’s fees from AbbVie and Gilead Sciences. All other authors have no conflict to disclose.

Ethical approval

The study protocol was approved by the ethics committees of the National Center for Global Health and Medicine (NCGM-G-003440–00, NCGM-G-004124–00), Nagoya University (2020–0373), and Kurume University (18246, 19055).

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Informed consent was obtained from the subjects.

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Yamauchi, R., Ito, T., Yoshio, S. et al. Serum osteopontin predicts the response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma. J Gastroenterol 58, 565–574 (2023). https://doi.org/10.1007/s00535-023-01985-w

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  • DOI: https://doi.org/10.1007/s00535-023-01985-w

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