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Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma

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Abstract

Background

The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC).

Method

We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay.

Results

More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 pg/ml) and LAG-3 (cut-off value: 3736.3 pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251–0.677) (p = 0.0005) for PFS and 0.252 (0.125–0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249–0.705) (p = 0.0011) for PFS and 0.294 (0.140–0.617) (p = 0.0012) for OS) were independent positive predictive factors.

Conclusion

Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

HCC:

Hepatocellular carcinoma

u-HCC:

Unresectable HCC

anti-PD-L1:

Anti-programmed death-ligand-1

ICI:

Immune-checkpoint inhibitor

RECIST:

Response evaluation criteria in solid tumors

ATZ:

Atezolizumab

BV:

Bevacizumab

MTA:

Molecular targeted agent

OR:

Objective response

PR:

Partial response

SD:

Stable disease

PD:

Progressive disease

AFP:

α-Fetoprotein

BCLC:

Barcelona clinic liver cancer

OS:

Overall survival

PFS:

Progression-free survival

CXCL9:

Chemokine (C-X-C motif) ligand 9

LAG-3:

Lymphocyte-activation gene 3 (LAG-3)

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Acknowledgements

The authors would like to thank all the patients and their families, as well as the investigators and staff at the participating institutions. Additional investigators are as follows: Ichiro Kawana, Satoshi Hishiki (Saiseikai Yokohamashi-Nanbu Hospital), Katsuaki Ogushi, Akihiro Funaoka (Yokohama City University Medical Center) and Katsuaki Tanaka (Hadano Red Cross Hospital).

Funding

This study was supported in part by a grant from JSPS KAKENHI (grant no. 21K07899).

Author information

Author notes

  1. Makoto Chuma, Makoto Sugimori, Takashi Kumada are contributed equally to this work.

Authors and Affiliations

  1. Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan

    Makoto Chuma, Kazushi Numata, Makoto Sugimori & Akito Nozaki

  2. Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan

    Haruki Uojima, Shuichiro Iwasaki, Hisashi Hidaka & Chika Kusano

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

    Hidenori Toyoda, Satoshi Yasuda, Yuichi Koshiyama & Takashi Kumada

  4. Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan

    Atsushi Hiraoka

  5. Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan

    Yoshitake Arase, Yusuke Mishima, Kota Tsuruya & Tatehiro Kagawa

  6. Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Hospital, Tokyo, Japan

    Masanori Atsukawa & Norio Itokawa

  7. Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan

    Tomomi Okubo

  8. Department of Gastroenterology, Himeji Red Cross Hospital, Himeji, Japan

    Toshifumi Tada

  9. Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center Hospital, Yokohama, Japan

    Manabu Morimoto

  10. Division of Gastroenterology, Saiseikai Yokohamashi-Nanbu Hospital, Yokohama, Japan

    Chikako Tokoro

  11. Gastroenterology Division, Hadano Red Cross Hospital, Hadano, Japan

    Yuki Miura

  12. Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan

    Takashi Kumada

  13. Department of Gastroenterology, Yokohama City University Hospital, Yokohama, Japan

    Shin Maeda

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  1. Makoto Chuma
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Correspondence to Makoto Chuma.

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Conflict of interest

Makoto Chuma has received lecture fees from Chugai Pharmaceutical. Hidenori Toyoda has received lecture fees from Gilead Sciences Inc., AbbVie, Eisai Co., Ltd., Fujifilm WAKO, Terumo, Kowa and Takeda Pharmaceuticals. Atsushi Hiraoka has received lecture fees from Chugai Pharmaceutical, Eli Lilly Japan and Astra Zeneca Plc. Toshifumi Tada has received lecture fees from Chugai Pharmaceutical, AbbVie and Eisai Co., Ltd. Tatehiro Kagawa has received scholarship donations from Chugai Pharmaceutical and lecture fees from Chugai Pharmaceutical. The other authors have no conflicts of interest.

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12072_2024_10680_MOESM1_ESM.jpg

Supplementary file1 Flow chart of the study. ctDNA, circulating tumor DNA; HCC, hepatocellular carcinoma; ATZ+BV, atezolizumab plus bevacizumab; OR, objective response; PD, progressive disease (JPG 105 KB)

12072_2024_10680_MOESM2_ESM.jpg

Supplementary file2 Representative liver HCC lesions in arterial phase computed tomography images. Computed tomography (CT) image of a patient after atezolizumab + bevacizumab treatment for HCC at baseline (A), 8 weeks (B) and 32 weeks (C). Changes in the tumor markers α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) between baseline and after ATZ+BV treatment (A-C). (JPG 144 KB)

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Supplementary file5 (DOCX 30 KB)

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Chuma, M., Uojima, H., Toyoda, H. et al. Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma. Hepatol Int (2024). https://doi.org/10.1007/s12072-024-10680-8

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