Abstract
Introduction
Atezolizumab plus bevacizumab is a standard first-line therapy for unresectable hepatocellular carcinoma (HCC); however, a proportion of patients develop early progressive disease (PD). Reliable pretreatment predictive biomarkers remain an unmet need. This study investigated the association between baseline serum microRNA-122 (miR-122) levels and early PD.
Methods
We retrospectively analyzed 64 consecutive patients with unresectable HCC and Child-Pugh class A treated with atezolizumab plus bevacizumab between October 2020 and January 2026 with available baseline serum samples. Early PD was defined as radiological progression within 6 weeks according to modified RECIST. Clinical, laboratory, and tumor characteristics were compared between patients with and without early PD. Receiver operating characteristic analysis determined optimal cutoff values, and logistic regression identified factors associated with early PD.
Results
Early PD at the radiological assessment within 6 weeks of treatment initiation was observed in 16 patients (25.0%). Baseline serum aspartate aminotransferase, alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA-II), miR-122 levels, and the presence of macrovascular invasion were significantly different between early PD and non-early PD. Multivariate logistic regression analysis identified higher levels of miR-122 levels (≥0.101 fold changes) and AFP (≥332.35 μg/L) as independent predictors of early PD. Even when limited to cases without prior treatment with molecularly targeted therapy, the same results were obtained.
Conclusion
Baseline serum miR-122 levels were independently associated with early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab. Serum miR-122 may serve as a predictive biomarker to identify patients at high risk of early treatment failure.
Keywords: Hepatocellular carcinoma, Bevacizumab, Atezolizumab, Serum microRNA-122
Introduction
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Although surveillance and locoregional therapies have improved outcomes in early-stage disease, many patients are diagnosed at an advanced stage and require systemic therapy. The combination of atezolizumab, an anti-programmed death-ligand 1 antibody, and bevacizumab, an anti-vascular endothelial growth factor antibody, has demonstrated superior overall survival (OS) and progression-free survival compared with sorafenib [1] and has become one of the standard first-line treatments for unresectable HCC.
Exploratory analysis of IMbrave150 on OS stratified by the treatment response revealed that the median OS of patients with the best response to progressive disease (PD) treated with atezolizumab plus bevacizumab was much shorter (6.8 months) than that of the responders [1]. A considerable proportion of patients experience early PD, often within the first radiological evaluation, which may lead to rapid clinical deterioration and loss of subsequent treatment opportunities. Therefore, identifying reliable biomarkers that can predict treatment response prior to therapy initiation is a critical unmet need in the management of unresectable HCC.
Several clinical and biological factors, including liver function, tumor burden, inflammatory markers, and serum alpha-fetoprotein (AFP) levels, have been reported to be associated with outcomes of immune checkpoint inhibitor-based therapy [2–6]. However, no validated biomarker has been established for routine clinical use, and currently available markers have limited predictive accuracy when used alone.
MicroRNA-122 (miR-122) is a liver-specific microRNA that accounts for a large proportion of total hepatic microRNA expression and plays a key role in hepatocyte differentiation, lipid metabolism, and liver homeostasis. Altered expression of miR-122 has been implicated in hepatocarcinogenesis, tumor progression, and prognosis in HCC [7, 8]. However, the clinical relevance of baseline serum miR-122 levels as a predictive biomarker for atezolizumab plus bevacizumab therapy has not been fully elucidated.
In this study, we aimed to investigate the association between baseline serum miR-122 levels and treatment outcomes in patients with unresectable HCC treated with atezolizumab plus bevacizumab. Specifically, we evaluated whether miR-122 could serve as a predictive factor for early PD, with the goal of identifying a clinically useful biomarker to optimize treatment strategies in this patient population.
Methods
Patients and Study Design
We retrospectively analyzed 64 consecutive patients with unresectable HCC and Child-Pugh class A (5 or 6 points) who received atezolizumab and bevacizumab combination therapy between October 2020 and January 2026 for whom baseline serum samples for biomarker were available. The Human Ethics Review Committee in Toranomon Hospital approved this study protocol (#1438, #1547, #1843). At the start of atezolizumab and bevacizumab combination therapy, we received signed informed consents from all of patients. The study followed the 2013 Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice (E6).
Treatment Protocols
Patients with unresectable HCC were treated with atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) every 3 weeks. Their treatment response was evaluated 3–6 weeks after treatment initiation. Treatment was discontinued if unacceptable adverse events or PD were observed [9].
Evaluation of Treatment Response
Tumor response was assessed using contrast-enhanced cycle threshold or MRI according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Early PD was defined as radiological progression within 6 weeks after treatment initiation according to mRECIST, based on the timing of early radiological evaluation used in previous studies of atezolizumab plus bevacizumab therapy, including the IMbrave150 trial [1].
Candidate Predictive Factors
The baseline of clinical, laboratory, and tumor-related characteristics were compared between patients with and without early PD, as shown in Table 1. These variables included age, sex, etiology, history of other systemic chemotherapy, ECOG performance status, Barcelona Clinic Liver Cancer (BCLC) stage, aspartate aminotransferase, alanine aminotransferase, albumin, total bilirubin, prothrombin activity, modified albumin-bilirubin grade, AFP, protein induced by vitamin K absence or antagonist II (PIVKA-II), C-reactive protein, neutrophil-to-lymphocyte ratio, and serum miR-122 level. In addition, tumor-related factors such as maximum tumor diameter, tumor number, macrovascular invasion, and extrahepatic metastasis have also been included to better characterize the baseline patient profile.
Table 1.
A comparison of clinical profiles and laboratory data between patients with and without early PD in HCC who received combination therapy with atezolizumab and bevacizumab
| Variables | Total (n = 64) | Patients without early PD (n = 48) | Patients with early PD (n = 16) | p valuea |
|---|---|---|---|---|
| Clinical findings | ||||
| Female/male ratio | 15/49 | 10/38 | 5/11 | 0.498 |
| Age, years | 75 (41–97) | 75 (48–97) | 73 (41–88) | 0.393 |
| Etiology (viral/nonviral) | 37/27 | 28/20 | 9/7 | 1.000 |
| Prior treatment with molecularly targeted therapy (Absence/Presence) | 46/18 | 35/13 | 11/5 | 0.756 |
| ECOG performance status (0/1) | 59/5 | 44/4 | 15/1 | 1.000 |
| BCLC stage (B/C) | 26/38 | 22/26 | 4/12 | 0.239 |
| Laboratory findings | ||||
| Aspartate aminotransferase, U/L | 40.00 (15–262) | 36.00 (11–262) | 52.50 (17–128) | 0.038 |
| Alanine aminotransferase, U/L | 26.00 (6–186) | 26.00 (6–186) | 25.00 (11–143) | 0.686 |
| Albumin, g/dL | 3.60 (2.8–4.6) | 3.60 (2.8–4.6) | 3.55 (3.0–4.2) | 0.469 |
| Total bilirubin, mg/L | 0.85 (0.3–2.8) | 0.90 (0.3–2.8) | 0.70 (0.4–1.7) | 0.100 |
| Prothrombin activity, % | 83.90 (51.6–115.3) | 82.15 (51.6–115.3) | 84.3 (59.9–101.2) | 0.871 |
| modified ALBI grade (1/2a/2b) | 14/14/36 | 11/11/26 | 3/3/10 | 0.859 |
| AFP, μg/L | 178.95 (2–613,099) | 75.15 (2–30,353) | 1,612.85 (4–613,099) | 0.008 |
| PIVKA-II, AU/L | 502.50 (8–390,634) | 111.50 (8–390,634) | 1,843.50 (17–361,610) | 0.038 |
| CRP, mg/dL | 0.24 (0.01–17.64) | 0.23 (0.02–17.64) | 0.38 (0.01–11.37) | 0.480 |
| Neutrophil-to-lymphocyte ratio | 3.13 (0.78–18.17) | 3.07 (0.78–18.17) | 3.63 (1.23–10.93) | 0.461 |
| Serum miR-122 (fold changes) | 0.083 (0.002–1.610) | 0.058 (0.002–1.610) | 0.181 (0.006–0.719) | 0.062 |
| Imaging findings | ||||
| Size of the largest lesion (≤30/>30 mm) | 30/33 | 24/23b | 6/10 | 0.397 |
| Number of tumors (<4/≥4) | 25/39 | 20/28 | 5/11 | 0.561 |
| Macrovascular invasion (absence/presence) | 44/20 | 37/11 | 7/9 | 0.027 |
| Extrahepatic metastasis (absence/presence) | 46/18 | 32/16 | 14/2 | 0.197 |
Data are presented as number or median (range).
PD, progressive disease; BCLC, Barcelona Clinic Liver Cancer; ALBI, albumin-bilirubin; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist II.
aPatients with early PD are compared to those without early PD.
bOne case without PD could not be detected viable HCC in the liver.
Measurement of Serum miR-122
The serum sample was frozen at −80°C within 4 h of collection and thawed just before analysis. Circulating microRNA was extracted from 200 μL of serum samples using the QIAGEN miRNeasy Serum/Plasma Kit according to the manufacturer’s instructions (QIAGEN K.K., Tokyo, Japan). RNA was reverse transcribed using TaqMan MicroRNA Reverse Transcription Kit (Life Technologies Japan, Tokyo, Japan). Caenorhabditis elegans miR-39 (cel-miR-39) was spiked in each sample as the control for extraction and amplification steps. The protocol used for measurement of serum miR-122 was based on the method provided by the manufacturer (TaqMan Small RNA Assays; Applied Biosystems). Serum miR-122 was amplified using primers and probes provided by Applied Biosystems in the TaqMan microRNA assay according to the instructions provided by the manufacturer. The relative expression of serum miR-122 was calculated using the comparative cycle threshold method (2−ΔΔCT) [10, 11], with spiked cel-miR-39 as normalized internal control. The microRNA expression levels were reported relative to the levels of serum miR-122 measured in 286 clinical samples [12]. In the reproducibility of the serum miR-122 measurement, triplicate assay was performed and their mean values were adopted. Samples that indicated wide variations were re-examined [13].
Statistical Analysis
Receiver operating characteristic (ROC) curve analysis was performed for continuous variables that showed significant difference (p < 0.05) or trend differences (p < 0.10) in the baseline comparison between the patients with and without early PD, as shown in Table 1. The optimal cutoff values were determined by maximizing the Youden index, as shown in online supplementary material.
The association between baseline variables and early PD was first assessed using univariate logistic regression analysis. Variables with p values <0.05 in the univariate analysis were subsequently included in the multivariate logistic regression model. Statistical significance was set as p values <0.05. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were also calculated. All statistical analyses were performed using SPSS Statistics (version 22.0; IBM, Armonk, NY, USA).
Results
Patient Characteristics
As shown in Table 1, baseline clinical, laboratory, and tumor-related characteristics were compared between patients with and without early PD. The median age of the entire population was 75 years, and 49 patients (76.6%) were male. BCLC stages were B in 26 patients (40.6%) and C in 38 patients (59.4%). Forty-six patients (71.9%) had no history of molecularly targeted therapy.
Treatment Response and Early PD
Early PD was observed in 16 patients (25.0%). Among these variables, AST, AFP, PIVKA-II, serum miR-122 levels, and the number of patients with macrovascular invasion were significantly different between early PD and non-early PD. ROC curve analysis was performed to determine the optimal cutoff values for AST, AFP, PIVKA-II, and serum miR-122 levels for predicting early PD, as shown in Table 2.
Table 2.
Predictive performance of baseline biomarkers for early PD after atezolizumab plus bevacizumab therapy
| Factors | Cutoff | AUROC | 95% CI | Sensitivity, % | Specificity, % |
|---|---|---|---|---|---|
| Aspartate aminotransferase, U/L | 48.50 | 0.68 | 0.513–0.836 | 62.5 | 75.0 |
| AFP, μg/L | 332.35 | 0.72 | 0.577–0.870 | 75.0 | 66.7 |
| PIVKA-II, AU/L | 128.00 | 0.67 | 0.532–0.817 | 87.5 | 54.2 |
| Serum miR-122 (fold changes) | 0.101 | 0.66 | 0.504–0.810 | 75.0 | 66.7 |
PD, progressive disease; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist II.
Univariate and Multivariate Analyses for Early PD
Univariate logistic regression analysis identified several factors associated with early PD. These factors included baseline AST, AFP, PIVKA-II, serum miR-122 levels, and the number of patients with macrovascular invasion which were then incorporated into a multivariate logistic regression model. In the multivariate analysis, higher levels of serum miR-122 (≥0.101 fold changes; ORs: 4.810; 95% CI: 1.170–19.768; p = 0.029) and AFP (≥332.35 μg/L; ORs: 5.915; 95% CI: 1.447–24.174; p = 0.013) were identified as independent predictors of early PD (Table 3). Furthermore, even when the same analysis was performed on the 46 patients who had not received prior treatment with molecular targeted therapy, multivariate analysis showed that higher levels of serum miR-122 (≥0.101 fold changes; ORs: 11.313; 95% CI: 1.625–78.789; p = 0.014) and AFP (≥332.35 μg/L; ORs: 19.511; 95% CI: 2.500–152.269; p = 0.005) were identified as independent predictors of early PD (Table 4). Patients were stratified according to the optimal cutoff value (0.101 fold changes) of serum miR-122 determined by ROC curve analysis, and baseline characteristics were compared between the two groups (Table 5). As a result, AST and PIVKA-II levels were significantly higher in patients with higher serum miR-122 levels (≥0.101 fold changes) than those with lower serum miR-122 levels (<0.101 fold changes).
Table 3.
Pretreatment noninvasive predictors associated with early PD after the start of atezolizumab plus bevacizumab in all of 64 patients
| Factors | Category | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|---|
| odds ratios | 95% confidence interval | p valuea | odds ratios | 95% confidence interval | p valuea | ||
| Laboratory findings | |||||||
| Aspartate aminotransferase, U/L | <48.50 | 1 | | | | | |
| ≥48.5 | 5.000 | 1.499–16.678 | 0.009 | | | | |
| AFP, μg/L | <332.35 | 1 | | | 1 | | |
| ≥332.35 | 5.812 | 1.612–20.955 | 0.007 | 5.915 | 1.447–24.174 | 0.013 | |
| PIVKA-II, AU/L | <128.00 | 1 | | | | | |
| ≥128.00 | 7.955 | 1.625–38.949 | 0.011 | | | | |
| Serum microRNA-122 (fold changes) | <0.101 | 1 | | | 1 | | |
| ≥0.101 | 6.000 | 1.667–21.599 | 0.006 | 4.810 | 1.170–19.768 | 0.029 | |
| Imaging findings | |||||||
| Macrovascular invasion | Absence | 1 | | | 1 | | |
| Presence | 4.325 | 1.309–14.291 | 0.016 | 3.305 | 0.814–13.411 | 0.094 | |
PD, progressive disease; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist II.
aUni- and multivariate logistic regression analyses were applied to identify pretreatment noninvasive predictors associated with progressive disease within 6 weeks after the start of treatment. Variables that achieved statistical significance (p < 0.05) on univariate analysis were entered into multiple logistic regression analysis to identify significant independent factors.
Table 4.
Pretreatment noninvasive predictors associated with early PD after the start of atezolizumab plus bevacizumab in 46 patients without prior treatment with molecularly targeted therapy
| Factors | Category | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|---|
| odds ratios | 95% confidence interval | p valuea | odds ratios | 95% confidence interval | p valuea | ||
| Laboratory findings | |||||||
| Aspartate aminotransferase, U/L | <48.50 | 1 | | | | | |
| ≥48.5 | 4.375 | 1.046–18.295 | 0.043 | | | | |
| AFP, μg/L | <332.35 | 1 | | | 1 | | |
| ≥332.35 | 9.409 | 1.732–51.109 | 0.009 | 19.511 | 2.500–152.269 | 0.005 | |
| PIVKA-II, AU/L | <128.00 | 1 | | | | | |
| ≥128.00 | 5.700 | 1.068–30.433 | 0.042 | | | | |
| Serum microRNA-122 (fold changes) | <0.101 | 1 | | | 1 | | |
| ≥0.101 | 5.111 | 1.141–22.890 | 0.033 | 11.313 | 1.625–78.789 | 0.014 | |
| Imaging findings | |||||||
| Macrovascular invasion | Absence | 1 | | | | | |
| Presence | 5.906 | 1.372–25.432 | 0.017 | | | | |
PD, progressive disease; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist II.
aUni- and multivariate logistic regression analyses were applied to identify pretreatment noninvasive predictors associated with progressive disease within 6 weeks after the start of treatment. Variables that achieved statistical significance (p < 0.05) on univariate analysis were entered into multiple logistic regression analysis to identify significant independent factors.
Table 5.
A comparison of clinical profiles and laboratory data between higher and lower serum miR-122 levels in patients with HCC who received combination therapy with atezolizumab and bevacizumab
| Variables | Serum microRNA-122 (fold changes) | p valuea | |
|---|---|---|---|
| <0.101 (n = 36) | ≥0.101 (n = 28) | ||
| Clinical findings | |||
| Female/male ratio | 10/26 | 5/23 | 0.390 |
| Age, years | 77 (52–94) | 72 (41–97) | 0.073 |
| Etiology (viral/nonviral) | 20/16 | 17/11 | 0.800 |
| Prior treatment with molecularly targeted therapy (absence/presence) | 26/10 | 20/8 | 1.000 |
| ECOG performance status (0/1) | 32/4 | 27/1 | 0.375 |
| BCLC stage (B/C) | 18/18 | 8/20 | 0.124 |
| Laboratory findings | |||
| Aspartate aminotransferase, U/L | 34.50 (11–128) | 47.00 (13–262) | 0.041 |
| Alanine aminotransferase, U/L | 26.00 (6–175) | 26.00 (11–186) | 0.416 |
| Albumin, g/dL | 3.55 (2.8–4.6) | 3.60 (2.8–4.3) | 0.854 |
| Total bilirubin, mg/L | 0.90 (0.4–2.4) | 0.75 (0.3–2.8) | 0.285 |
| Prothrombin activity, % | 82.05 (55.9–115.3) | 84.30 (51.6–109.2) | 0.288 |
| Modified ALBI grade (1/2a/2b) | 8/8/20 | 6/6/16 | 1.000 |
| AFP, μg/L | 137.40 (2–30,353) | 257.30 (3–613,099) | 0.409 |
| PIVKA-II, AU/L | 91.50 (8–116,157) | 1,646.50 (16–390,634) | 0.011 |
| CRP, mg/dL | 0.27 (0.01–17.64) | 0.18 (1.23–15.71) | 0.285 |
| Neutrophil-to-lymphocyte ratio | 3.10 (0.78–18.17) | 0.18 (0.02–11.37) | 0.396 |
| Imaging findings | |||
| Size of the largest lesion (≤30/>30 mm) | 19/16b | 11/17 | 0.312 |
| Number of tumors (<4/≥4) | 15/21 | 10/18 | 0.797 |
| Macrovascular invasion (absence/presence) | 28/8 | 16/12 | 0.105 |
| Extrahepatic metastasis (absence/presence) | 26/10 | 20/8 | 1.000 |
Data are presented as number or median (range).
BCLC, Barcelona Clinic Liver Cancer, ALBI, albumin-bilirubin; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence or antagonist II.
aPatients with microRNA-122 <0.101 are compared to those with miR-122 ≥0.101.
bOne case with serum microRNA-122 <0.101 could not be detected viable HCC in the liver.
Discussion
This study demonstrated that baseline serum miR-122 levels were significantly associated with treatment outcomes in patients with unresectable HCC treated with atezolizumab and bevacizumab. Patients with higher baseline serum miR-122 levels (≥0.101 fold changes) were more likely to develop PD within 6 weeks of treatment initiation. Importantly, baseline miR-122 levels remained an independent predictor of early disease progression.
The biological mechanisms underlying the association between miR-122 and treatment response to atezolizumab plus bevacizumab combination therapy have not yet been fully elucidated. MiR-122 is a liver-specific microRNA that plays a critical role in maintaining hepatic homeostasis. Previous studies have demonstrated that miR-122 exerts tumor-suppressive effects in HCC, including inhibition of cell proliferation, invasion, and metastasis [14]. However, these findings were primarily derived from mouse models and tissue-based analyses, and their direct applicability to circulating miR-122 levels in human serum remains uncertain.
Serum miR-122 is known to be released into the circulation in response to hepatocellular injury, inflammation, and liver dysfunction, and its levels may reflect not only the biological characteristics of the tumor but also the status of the surrounding non-tumorous liver tissue. In the present study, high baseline serum miR-122 levels may suggest active hepatocellular injury or an inflammatory response, which may attenuate the efficacy of immune checkpoint inhibitors and antiangiogenic therapy and contribute to the increased incidence of early PD observed in patients with high serum miR-122 levels. On the other hand, previous studies have reported that miR-122 is a liver-specific microRNA that is released into the circulation in response to hepatocyte damage and has also been associated with tumor burden and tumor aggressiveness in HCC [15, 16]. As shown in Table 5, patients with higher serum miR-122 levels showed significantly higher AST and PIVKA-II levels compared with those with lower miR-122 levels. These findings suggest that circulating miR-122 may reflect not only hepatocellular injury but also tumor-related biological characteristics in patients with HCC. Therefore, elevated serum miR-122 levels may represent a composite biomarker reflecting both liver functional status and tumor biology.
From a clinical perspective, assessing baseline serum miR-122 levels may help refine treatment strategies for unresectable HCC. Patients with elevated serum miR-122 levels may require closer monitoring during the early stages of treatment or consideration of alternative treatments. Furthermore, integrating serum miR-122 levels with established clinical parameters, such as liver function indexes and tumor burden, may facilitate the development of more comprehensive predictive models for immunotherapy-based outcomes. Especially, in the present study, miR-122 and AFP were independent predictive factors, and it is expected that combining it with previous reported factors including AFP [6] will allow for more accurate prediction of early PD.
This study has several limitations. First, the retrospective, single-center study design may have introduced selection bias. Furthermore, the cutoff value for serum miR-122 was determined within the same cohort used for analysis, and external validation was not performed. Therefore, the clinical applicability of this cutoff requires confirmation in the other independent cohorts. Second, the relatively small sample size and low number of early PD events may have posed a risk of model overfitting in multivariate analysis. Therefore, the results should be interpreted cautiously, and validation in a larger cohort is needed. Furthermore, immune checkpoint inhibitor-based therapy may occasionally show discrepancies between the initial radiological assessment and the best overall response, which should be considered when interpreting early radiological progression. Third, mechanistic insights into how serum miR-122 affects response to immune checkpoint inhibitors and antiangiogenic therapy have not been directly explored. Despite these limitations, this study provides new clinical evidence supporting the potential role of baseline serum miR-122 as a predictive biomarker for atezolizumab and bevacizumab combination therapy in patients with unresectable HCC. Future prospective studies with larger cohorts and integrative translational analyses are needed to validate these findings and clarify the biological mechanisms underlying the observed associations.
Acknowledgments
The authors thank Kenichi Tadokoro and Rie Mineta for their research assistance.
Statement of Ethics
The Human Ethics Review Committee in Toranomon Hospital approved this study protocol (#1438, #1547, #1843). At the start of atezolizumab and bevacizumab combination therapy, we received signed informed consents from all of patients. The study followed the 2013 Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice (E6).
Conflict of Interest Statement
Tetsuya Hosaka has received honoraria from Gilead Sciences and Eisai Co., Ltd. Hiromitsu Kumada has received honoraria from Gilead Sciences, AbbVie Inc., and Chugai Pharmaceutical Co., Ltd. Fumitaka Suzuki has received honoraria from Gilead Sciences. All other authors declare no conflicts of interest.
Funding Sources
This study was supported in part by Grants-in-Aid from the Japan Agency for Medical Research and Development (JP24fk0210113, JP24fk0210129, JP25fk0210129, JP24fk0210149, JP25fk0210149, JP25fk0210174, JP25fk0210129, JP26fk0210174, JP26fk0210149), Ministry of Health, Labour and Welfare (23HC2002, 24HC0101), and a grant from the Japanese Society of Gastroenterology (JSGE).
Author Contributions
Shigeki Yamamoto, Norio Akuta, Tetsuya Hosaka, Yasuka Eriksson, Shunya Goto, Yasue Takeuchi, Hitomi Sezaki, Satoshi Saitoh, Mariko Kobayashi, Hiromitsu Kumada, and Fumitaka Suzuki contributed to this work. Shigeki Yamamoto and Norio Akuta analyzed the data. Shigeki Yamamoto and Norio Akuta wrote the manuscript.
Funding Statement
This study was supported in part by Grants-in-Aid from the Japan Agency for Medical Research and Development (JP24fk0210113, JP24fk0210129, JP25fk0210129, JP24fk0210149, JP25fk0210149, JP25fk0210174, JP25fk0210129, JP26fk0210174, JP26fk0210149), Ministry of Health, Labour and Welfare (23HC2002, 24HC0101), and a grant from the Japanese Society of Gastroenterology (JSGE).
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
Supplementary Material.
References
- 1. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–905. [DOI] [PubMed] [Google Scholar]
- 2. Scheiner B, Pomej K, Kirstein MM, Hucke F, Finkelmeier F, Waidmann O, et al. Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score. J Hepatol. 2022;76(2):353–63. [DOI] [PubMed] [Google Scholar]
- 3. Ohama H, Hiraoka A, Tada T, Hirooka M, Kariyama K, Hatanaka T, et al. Clinical usefulness of newly developed prognostic predictive score for atezolizumab plus bevacizumab for hepatocellular carcinoma. Cancer Rep Hob. 2024;7(4):e2042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Spahn S, Roessler D, Pompilia R, Gabernet G, Gladstone BP, Horger M, et al. Clinical and genetic tumor characteristics of responding and non-responding patients to PD-1 inhibition in hepatocellular carcinoma. Cancers. 2020;12(12):3830. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Muhammed A, Fulgenzi CAM, Dharmapuri S, Pinter M, Balcar L, Scheiner B, et al. The systemic inflammatory response identifies patients with adverse clinical outcome from immunotherapy in hepatocellular carcinoma. Cancers. 2021;14(1):186. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Ono A, Hayes CN, Miura R, Kawaoka T, Tsuge M, Oka S. Noninvasive prediction of the clinical benefit of immunotherapy in hepatocellular carcinoma. J Gastroenterol. 2025;60(9):1053–69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS. Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene. 2009;28(40):3526–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Wu J, Wu Y, Luo Y, Li X, Lin N, Yang X, et al. Circulating miRNA-199a and miR-122 levels as potential diagnostic and prognostic biomarkers for hepatocellular carcinoma. Ann Clin Lab Sci. 2020;50(2):219–27. [PubMed] [Google Scholar]
- 9. Sho T, Suda G, Ogawa K, Kimura M, Kubo A, Tokuchi Y, et al. Early response and safety of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in patients who do not meet IMbrave150 eligibility criteria. Hepatol Res. 2021;51(9):979–89. [DOI] [PubMed] [Google Scholar]
- 10. Kroh EM, Parkin RK, Mitchell PS, Tewari M. Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods. 2010;50(4):298–301. Erratum. In: Methods 2010; 52:268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Yu S, Liu Y, Wang J, Guo Z, Zhang Q, Yu F, et al. Circulating microRNA profiles as potential biomarkers for diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2012;97(6):2084–92. [DOI] [PubMed] [Google Scholar]
- 12. Akuta N, Kawamura Y, Suzuki F, Saitoh S, Arase Y, Kunimoto H, et al. Impact of circulating miR-122 for histological features and hepatocellular carcinoma of nonalcoholic fatty liver disease in Japan. Hepatol Int. 2016;10(4):647–56. [DOI] [PubMed] [Google Scholar]
- 13. Gong Y, Xu W, Chen Y, Liu Y, Yang Y, Wang B, et al. miR-20a-5p regulates pulmonary surfactant gene expression in alveolar type II cells. J Cell Mol Med. 2019;23(11):7664–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Hsu SH, Wang B, Kota J, Yu J, Costinean S, Kutay H, et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Investig. 2012;122(8):2871–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Pelizzaro F, Cardin R, Sartori A, Imondi A, Penzo B, Aliberti C, et al. Circulating MicroRNA-21 and MicroRNA-122 as prognostic biomarkers in hepatocellular carcinoma patients treated with transarterial chemoembolization. Biomedicines. 2021;9(8):890. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Parizadeh SM, Jafarzadeh-Esfehani R, Ghandehari M, Goldani F, Parizadeh SMR, Hassanian SM, et al. MicroRNAs as potential diagnostic and prognostic biomarkers in hepatocellular carcinoma. Curr Drug Targets. 2019;20(11):1129–40. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
