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Abstract

Background: Despite the significant progress in prevention and therapy, hepatocellular carcinoma (HCC) is still one of the most prevalent and lethal human cancers worldwide.

Purpose: Recently, the combination of atezolizumab (an immune checkpoint inhibitor, anti-programmed death ligand 1 antibody) and bevacizumab (an antiangiogenic agent, anti-vascular endothelial growth factor antibody) has emerged as a new and effective first-line systemic therapy in the treatment of patients with unresectable HCC. However, the development of prognostic biomarkers for the early identification and timely intervention of HCC patients with poor prognosis after atezolizumab plus bevacizumab combination therapy remains a key goal to achieve better patient survival.

Research Design: This review provides a comprehensive summary of the evidence in the literature validating a single or a combination of biomarker(s) in various sampling sources at diverse time points with prognostic value in predicting the outcomes of HCC patients receiving atezolizumab plus bevacizumab combination therapy. A plethora of promising prognostic biomarkers is identified here, and further studies to implement these biomarkers in clinical practices are urgently needed.

Keywords

hepatocellular carcinoma first-line systemic therapy atezolizumab plus bevacizumab combination therapy prognostic biomarkers single or combination biomarkers

Introduction

Hepatocellular carcinoma (HCC) is the most dominant type of primary liver cancer, accounting for up to 90% of primary liver malignancies; it represents the sixth most prevalent and the third most fatal human cancer worldwide, contributing over 800 000 new cases and 700 000 new deaths annually.^1,2 Various therapeutic strategies have been developed for the treatment of HCC patients, including surgical therapy (such as liver resection and transplantation),³ locoregional therapy (such as radiation, ablation, and embolization),⁴ systemic therapy (such as chemotherapy and molecular targeted therapy),⁵ and immunotherapy (such as chimeric antigen receptor T cell therapy and immune checkpoint blockade).⁶ However, the survival benefits of these therapeutic options for HCC patients still need to be improved. Therefore, the identification of valuable prognostic biomarkers for the outcomes of HCC patients is vital for the early detection and timely management of patients with poor prognosis to aid in their survival.

As a combination of immunotherapeutic agents and molecular targeted agents, atezolizumab (an anti-programmed death ligand 1 (PD-L1) antibody) plus bevacizumab (an anti-vascular endothelial growth factor (VEGF) antibody) have been approved by the United States Food and Drug Administration (FDA) as a new first-line systemic therapy for the treatment of patients with unresectable HCC in 2020.^7,8 Compared with sorafenib, the first systemic therapy to be approved for unresectable HCC in the first-line setting, the results of a phase 3 IMbrave150 trial demonstrated that atezolizumab plus bevacizumab combination therapy had improved the median overall survival (OS: 19.2 months vs 13.4 months) and progression-free survival (RFS: 6.9 months vs 4.3 months) as well as showing a better objective response rate (ORR: 29.8% vs 11.3%) and complete response rate (7.7% vs 0.6%).^9,10 The superior efficacy of atezolizumab plus bevacizumab combination therapy is attributed to the direct effect of bevacizumab, which enables efficient priming and activation of T cell responses, normalizes tumor vasculature to increase T cell recruitment, and reprograms the tumor microenvironment from being immune suppressive to immune permissive, in addition to its synergistic effect with atezolizumab, which restores T cell-mediated tumor cell killing.^11,12 However, there remains an urgent need for biomarkers to predict the prognosis of HCC patients receiving atezolizumab plus bevacizumab combination therapy.

Considering that atezolizumab plus bevacizumab has replaced sorafenib as a more powerful first-line systemic therapy for unresectable HCC, this review comprehensively summarizes the evidence in the literature validating the prognostic significance of a single or a combination of biomarker(s) in tissue, whole blood, serum, plasma, or urine specimens of HCC patients at pre-treatment or in-treatment time points of atezolizumab plus bevacizumab combination therapy.

Single Prognostic Biomarkers for HCC Patients Treated with Atezolizumab plus Bevacizumab Combination Therapy

Multiple lines of studies have validated the prognostic significance of many single biomarkers in HCC patients receiving atezolizumab plus bevacizumab combination therapy (Table 1). The prognostic value of various blood proteins has been evaluated in several studies. Four studies have been conducted to evaluate the prognostic value of α-fetoprotein (AFP). Kuzuya et al. performed enzyme-linked immunosorbent assay (ELISA) to analyze the in-treatment change in serum AFP levels in 50 retrospectively enrolled patients with unresectable advanced HCC, at 3 weeks after treatment initiation, and showed that a high AFP ratio (≥1.4) was associated with a shorter progression-free survival (PFS).¹³ Tamaki et al. carried out ELISA to detect the in-treatment change in serum AFP levels in 91 prospectively enrolled patients with unresectable HCC, at 6 weeks after treatment initiation, and identified that an AFP decrease (≥50%) predicted a longer PFS.¹⁴ Zhu et al. conducted ELISA to measure the in-treatment change in serum AFP levels in 150 prospectively enrolled patients with unresectable HCC, at 6 weeks after treatment initiation, and indicated that an AFP decrease (≥75%) and an AFP increase (≤10%) were correlated with longer overall survival (OS) and PFS.¹⁵ Lu et al. performed ELISA to analyze the in-treatment change in serum AFP levels in 264 prospectively enrolled patients with unresectable HCC, after treatment initiation, and showed that a sharp-falling AFP trajectory was associated with a longer OS and PFS.¹⁶ The study conducted by Kaneko et al. performed ELISA to analyze the pre-treatment serum C-reactive protein (CRP) levels in 213 retrospectively enrolled patients with unresectable HCC and confirmed that a high CRP level (≥1 mg/dL) was associated with a shorter OS and PFS.¹⁷ Using ELISA-based analysis of the pre-treatment serum des‐gamma‐carboxy prothrombin (DCP) levels, Chon et al. revealed that a high DCP level (≥200 mAU/mL) predicted a shorter OS and PFS in 121 retrospectively enrolled patients with unresectable HCC.¹⁸ By conducting ELISA to detect the pre-treatment serum osteopontin (OPN) levels, Yamauchi et al. demonstrated that a high OPN level (≥61.375 ng/mL) was correlated with a shorter PFS in 70 prospectively enrolled patients with unresectable advanced HCC.¹⁹ Moreover, the prognostic value of various cytokines and immune-related proteins has been evaluated in several studies. Four studies were conducted to evaluate the prognostic value of interleukin (IL)-6. Myojin et al. performed multiplex immunoassays to measure the pre-treatment plasma IL-6 levels in 64 prospectively enrolled patients with unresectable advanced HCC and verified that a high IL-6 level (>4.77 pg/mL) was associated with a shorter OS and PFS.²⁰ Yang et al. carried out flow cytometric bead array to assay the pre-treatment serum IL-6 levels in 263 prospectively enrolled patients with unresectable HCC and showed that a high IL-6 level (≥18.49 pg/mL) predicted a shorter OS and PFS.²¹ Miura et al. conducted multiplex immunoassays to analyze the pre-treatment serum IL-6 levels in 90 retrospectively enrolled patients with unresectable HCC and found that a high IL-6 level (≥9.2 pg/mL) was correlated with a shorter OS and PFS.²² Suzuki et al. performed chemiluminescence enzyme immunoassays (CLEIAs) to detect the in-treatment serum IL-6 levels in 94 retrospectively enrolled patients with unresectable HCC at 3 weeks after treatment initiation and ascertained that a high IL-6 level (≥7.4 pg/mL) was associated with a shorter OS and PFS.²³ The study conducted by Lee et al. carried out multiplex immunoassays to measure the in-treatment change in serum IL-10 and tumor necrosis factor-α (TNF-α) levels in 32 prospectively enrolled patients with unresectable advanced HCC, at 3 weeks after treatment initiation, and validated that a high IL-10 ratio (≥2.15) and high TNF-α ratio (≥2.95) individually predicted a longer OS.²⁴ In 134 prospectively enrolled patients with unresectable HCC, Chuma et al. conducted ELISA to analyze the pre-treatment serum C-X-C motif chemokine ligand (CXCL) 9 and lymphocyte-activation gene 3 (LAG-3) levels and determined that a high CXCL9 level (≥419.1 pg/mL) and low LAG-3 level (≤3763.3 pg/mL) were individually correlated with a longer OS and PFS.²⁵ Based on ELISA analysis of the in-treatment serum CXCL10 levels at 3 weeks after treatment initiation, Suzuki et al. showed that a high CXCL10 level (≥690 pg/mL) was associated with a longer OS and PFS in 56 retrospectively enrolled patients with unresectable advanced HCC.²⁶ The study conducted by Kaseb et al. carried out ELISA to detect the pre-treatment serum insulin-like growth factor-1 (IGF-1) levels in 256 prospectively enrolled patients with unresectable advanced HCC and identified that a low IGF-1 level (<26 ng/mL) predicted a longer OS and PFS.²⁷ By performing ELISA to measure the pre-treatment plasma growth hormone levels, Mohamed et al. indicated that a high growth hormone level (>0.9 μg/L for men and > 3.7 μg/L for women) was correlated with a shorter OS in 37 prospectively enrolled patients with unresectable advanced HCC.²⁸ In 63 prospectively enrolled patients with unresectable advanced HCC, Sasaki et al performed ELISA to analyze the pre-treatment serum anti-programmed death 1 (PD-1) autoantibody levels and confirmed that a high anti-PD-1 autoantibody level (≥0.57) was associated with a shorter OS. In addition, the prognostic value of various nonprotein-based biomarkers and pathological features has been evaluated in several studies.²⁹ The study conducted by Matsumae et al. carried out next-generation sequencing (NGS) to analyze the pre-treatment serum circulating tumor DNA (ctDNA) mutation profiles in 85 prospectively enrolled patients with unresectable HCC and revealed that presence of the telomerase reverse transcriptase (TERT) promoter mutated ctDNA predicted a shorter OS.³⁰ By conducting nanoparticle tracking analysis (NTA) to detect the in-treatment serum extracellular vesicle (EV) size and change in EV size at 3 weeks after treatment initiation, Egerer et al. demonstrated that a small EV size was correlated with a longer OS, and the EV size decrease was associated with a longer PFS in 53 retrospectively enrolled patients with unresectable advanced HCC.³¹ Five studies were conducted to evaluate the prognostic value of immune cells. Giovannini et al. performed flow cytometry to measure the pre-treatment PD-1⁺ granulocyte levels in blood of 34 prospectively enrolled patients with unresectable HCC and verified that a low PD1⁺ granulocyte level predicted a longer time to progression (TTP).³² Based on flow cytometry assay of the pre-treatment neutrophil-to-lymphocyte ratio (NLR) in the blood of 281 prospectively enrolled patients with unresectable HCC, Wu et al. determined that a high NLR (≥5) was correlated with a shorter OS.³³ The study conducted by Chon et al. carried out flow cytometry to analyze the pre-treatment NLR in the blood of 121 retrospectively enrolled patients with unresectable HCC and showed that a high NLR (≥2.5) was associated with a shorter OS and PFS.¹⁸ Using flow cytometry-based detection of the pre-treatment T cell subpopulation levels in the blood of 29 retrospectively enrolled patients with unresectable advanced HCC, Lee et al. found that a high CD8⁺PD-1⁺Ki-67⁺ T cell level (>9.975%) and a low CD4⁺forkhead box protein 3 (Foxp3)⁺PD-1⁺LAG-3⁺ T cell level (<9.08%) individually predicted a shorter OS.³⁴ The study conducted by Shirane et al. performed flow cytometry to measure the pre-treatment CD8⁺ central memory T cell levels and in-treatment change in CD8⁺ central memory T cell levels in the blood of 83 retrospectively enrolled patients with unresectable advanced HCC, at 3 weeks after treatment initiation, and ascertained that a high CD8⁺ central memory T cell level (≥5.72%) was correlated with a longer PFS, and a CD8⁺ central memory T cell increase was associated with a longer OS and PFS.³⁵ Two studies were conducted to evaluate the prognostic value of circulating tumor cells (CTCs). Nosaka et al. performed flow cytometry to detect the in-treatment change in CD90⁺ or epithelial cell adhesion molecule (EpCAM)⁺ CTC numbers in the blood of 20 retrospectively enrolled patients with unresectable HCC after treatment initiation and determined that an increase in the CD90⁺ or EpCAM⁺ CTC number was associated with a shorter OS.³⁶ Murata et al. conducted NGS to detect the in-treatment change in CTC molecular expression patterns in the blood of 10 prospectively enrolled patients with unresectable HCC, after treatment initiation, and found that an increase in the transforming growth factor-β (TGF-β) signaling molecule expression level in CTCs predicted a shorter OS and PFS.³⁷ In 74 retrospectively enrolled patients with unresectable advanced HCC, Ishihara et al. conducted magnetic resonance imaging (MRI) to assay the pre-treatment tumor nodule numbers and validated that a high tumor nodule number (>1) predicted a longer TTP.³⁸ The study conducted by Kuwano et al. performed MRI to analyze the pre-treatment rim arterial phase hyperenhancement (APHE) in 51 prospectively enrolled patients with unresectable HCC and determined that the presence of rim APHE was correlated with a longer PFS.³⁹ Two studies were conducted to evaluate the prognostic value of the prognostic nutritional index (PNI). Tada et al. carried out ELISA and flow cytometry to detect the pre-treatment PNI in 342 prospectively enrolled patients with unresectable advanced HCC and showed that a high PNI (≥47) was associated with a longer OS and PFS.⁴⁰ Suzuki et al. conducted ELISA and flow cytometry to measure the in-treatment PNI in 125 retrospectively enrolled patients with unresectable advanced HCC, at 3 weeks after treatment initiation, and identified that a high PNI (≥40.4) predicted a longer OS and PFS.⁴¹ Two studies were conducted to evaluate the prognostic value of treatment-related adverse events. By performing ELISA to assay the in-treatment proteinuria, Yang et al. indicated that the presence of proteinuria (grade ≥ 2) was correlated with a longer OS in 75 retrospectively enrolled patients with unresectable HCC.⁴² The study conducted by Tada et al. analyzed the in-treatment hypertension and fatigue in 263 retrospectively enrolled patients with unresectable HCC and confirmed that the presence of hypertension was associated with a longer PFS, and the presence of fatigue predicted a shorter OS.⁴³

Table 1.

Prognostic Biomarkers for HCC Patients Treated With Atezolizumab Plus Bevacizumab Combination Therapy.

Biomarkers	Sampling time	Sampling source	Detection method	Study design	Patients analyzed	Prognostic significance^a	Year	References
Single biomarkers
AFP	In-treatment	Serum	ELISA	Retrospective	50 patients with unresectable advanced HCC	A high AFP ratio (≥1.4) predicted a shorter PFS^b	2022	Kuzuya et al.¹³
	In-treatment	Serum	ELISA	Prospective	91 patients with unresectable HCC	An AFP decrease (≥50%) predicted a longer PFS^c	2022	Tamaki et al.¹⁴
	In-treatment	Serum	ELISA	Prospective	150 patients with unresectable HCC	An AFP decrease (≥75%) and an AFP increase (≤10%) predicted a longer OS and PFS^d	2022	Zhu et al.¹⁵
	In-treatment	Serum	ELISA	Prospective	264 patients with unresectable HCC	A sharp-falling AFP trajectory predicted a longer OS and PFS^e	2023	Lu et al.¹⁶
CRP	Pre-treatment	Serum	ELISA	Retrospective	213 patients with unresectable HCC	A high CRP level (≥1 mg/dL) predicted a shorter OS and PFS	2024	Kaneko et al.¹⁷
DCP	Pre-treatment	Serum	ELISA	Retrospective	121 patients with unresectable HCC	A high DCP level (≥200 mAU/mL) predicted a shorter OS and PFS	2023	Chon et al.¹⁸
OPN	Pre-treatment	Serum	ELISA	Prospective	70 patients with unresectable advanced HCC	A high OPN level (≥61.375 ng/mL) predicted a shorter PFS	2023	Yamauchi et al.¹⁹
IL-6	Pre-treatment	Plasma	Multiplex immunoassay	Prospective	64 patients with unresectable advanced HCC	A high IL-6 level (>4.77 pg/mL) predicted a shorter OS and PFS	2022	Myojin et al.²⁰
	Pre-treatment	Serum	Flow cytometric bead array	Prospective	263 patients with unresectable HCC	A high IL-6 level (≥18.49 pg/mL) predicted a shorter OS and PFS	2023	Yang et al.²¹
	Pre-treatment	Serum	Multiplex immunoassay	Retrospective	90 patients with unresectable HCC	A high IL-6 level (≥9.2 pg/mL) predicted a shorter OS and PFS	2024	Miura et al.²²
	In-treatment	Serum	CLEIA	Retrospective	94 patients with unresectable advanced HCC	A high IL-6 level (≥7.4 pg/mL) predicted a shorter OS and PFS^f	2024	Suzuki et al.²³
IL-10	In-treatment	Serum	Multiplex immunoassay	Prospective	32 patients with unresectable advanced HCC	A high IL-10 ratio (≥2.15) predicted a longer OS^g	2024	Lee et al.²⁴
TNF-α	In-treatment	Serum	Multiplex immunoassay	Prospective	32 patients with unresectable advanced HCC	A high TNF-α ratio (≥2.95) predicted a longer OS^g	2024	Lee et al.²⁴
CXCL9	Pre-treatment	Serum	ELISA	Prospective	134 patients with unresectable HCC	A high CXCL9 level (≥419.1 pg/mL) predicted a longer OS and PFS	2024	Chuma et al.²⁵
CXCL10	In-treatment	Serum	ELISA	Retrospective	56 patients with unresectable advanced HCC	A high CXCL10 level (≥690 pg/mL) predicted a longer OS and PFS^h	2024	Suzuki et al.²⁶
IGF-1	Pre-treatment	Serum	ELISA	Prospective	256 patients with unresectable advanced HCC	A low IGF-1 level (<26 ng/mL) predicted a longer OS and PFS	2022	Kaseb et al.²⁷
Growth hormone	Pre-treatment	Plasma	ELISA	Prospective	37 patients with unresectable advanced HCC	A high growth hormone level (>0.9 μg/L for men; > 3.7 μg/L for women) predicted a shorter OS	2022	Mohamed et al.²⁸
LAG-3	Pre-treatment	Serum	ELISA	Prospective	134 patients with unresectable HCC	A low LAG-3 level (≤3763.3 pg/mL) predicted a longer OS and PFS	2024	Chuma et al.²⁵
Anti-PD-1 autoantibody	Pre-treatment	Serum	ELISA	Prospective	63 patients with unresectable advanced HCC	A high anti-PD-1 autoantibody level (≥0.57) predicted a shorter OSⁱ	2024	Sasaki et al.²⁹
TERT promoter mutation in ctDNA	Pre-treatment	Serum	NGS	Prospective	85 patients with unresectable HCC	Presence of the TERT promoter mutated ctDNA predicted a shorter OS	2022	Matsumae et al.³⁰
EV size	In-treatment	Serum	NTA	Retrospective	53 patients with unresectable advanced HCC	A small EV size predicted a longer OS; the EV size decrease predicted a longer PFS^j	2024	Egerer et al.³¹
PD-1⁺ granulocyte	Pre-treatment	Blood	Flow cytometry	Prospective	34 patients with unresectable HCC	A low PD1⁺ granulocyte level predicted a longer TTP^k	2023	Giovannini et al.³²
NLR	Pre-treatment	Blood	Flow cytometry	Prospective	281 patients with unresectable HCC	A high NLR (≥5) predicted a shorter OS^l	2022	Wu et al.³³
NLR	Pre-treatment	Blood	Flow cytometry	Retrospective	121 patients with unresectable HCC	A high NLR (≥2.5) predicted a shorter OS and PFS^l	2023	Chon et al.¹⁸
CD8⁺PD-1⁺Ki-67⁺ T cell	Pre-treatment	Blood	Flow cytometry	Retrospective	29 patients with unresectable advanced HCC	A high CD8⁺PD-1⁺Ki-67⁺ T cell level (>9.975%) predicted a shorter OS^m	2024	Lee et al.³⁴
CD4⁺Foxp3⁺PD-1⁺LAG-3⁺ T cell	Pre-treatment	Blood	Flow cytometry	Retrospective	29 patients with unresectable advanced HCC	A low CD4⁺Foxp3⁺PD-1⁺LAG-3⁺ T cell level (<9.08%) predicted a shorter OS^m	2024	Lee et al.³⁴
CD8⁺ central memory T cell	Pre-treatment/ In-treatment	Blood	Flow cytometry	Retrospective	83 patients with unresectable advanced HCC	A high CD8⁺ central memory T cell level (≥5.72%) predicted a longer PFS; the CD8⁺ central memory T cell increase predicted a longer OS and PFSⁿ	2024	Shirane et al.³⁵
CTC	In-treatment	Blood	Flow cytometry	Retrospective	20 patients with unresectable HCC	Increase in the CD90⁺ or EpCAM⁺ CTC number predicted a shorter OS	2024	Nosaka et al.³⁶
CTC	In-treatment	Blood	NGS	Prospective	10 patients with unresectable HCC	Increase in the TGF-β signaling molecule expression level in CTCs predicted a shorter OS and PFS	2024	Murata et al.³⁷
Tumor nodule number	Pre-treatment	NA	MRI	Retrospective	74 patients with unresectable advanced HCC	A high tumor nodule number (>1) predicted a longer TTP	2024	Ishihara et al.³⁸
Rim APHE	Pre-treatment	NA	MRI	Prospective	51 patients with unresectable HCC	Presence of the rim APHE predicted a longer PFS	2023	Kuwano et al.³⁹
PNI	Pre-treatment	Blood	ELISA/Flow cytometry	Prospective	342 patients with unresectable advanced HCC	A high PNI (≥47) predicted a longer OS and PFS^o	2023	Tada et al.⁴⁰
PNI	In-treatment	Blood	ELISA/Flow cytometry	Retrospective	125 patients with unresectable advanced HCC	A high PNI (≥40.4) predicted a longer OS and PFS^p	2024	Suzuki et al.⁴¹
Proteinuria	In-treatment	Urine	ELISA	Retrospective	75 patients with unresectable HCC	Presence of the proteinuria (grade ≥ 2) predicted a longer OS^q	2024	Yang et al.⁴²
Hypertension and fatigue	In-treatment	NA	NA	Retrospective	263 patients with unresectable HCC	Presence of the hypertension predicted a longer PFS; presence of the fatigue predicted shorter OS	2023	Tada et al.⁴³
Combination biomarkers
AFP decrease combined with ALBI grade	In-treatment/ Pre-treatment/	Serum	ELISA	Retrospective	70 patients with unresectable HCC	An AFP decrease (≤20%) combined with a high ALBI grade (grade 2) predicted the shortest OS and PFS^r	2023	Campani et al.⁴⁴
AFP level combined with mALBI grade	Pre-treatment	Serum	ELISA	Retrospective	426 patients with unresectable HCC	A high AFP level (≥100 ng/mL) combined with a high mALBI grade (grade 2b/3) predicted the shortest OS and PFS^s	2023	Hatanaka et al.⁴⁵
AFP, mALBI grade, BCLC staging, and DCP score	Pre-treatment	Serum	ELISA	Retrospective	719 patients with unresectable HCC	The highest AFP, mALBI grade, BCLC staging, and DCP score (5 points) predicted the shortest OS and PFS^t	2024	Ohama et al.⁴⁶
AFP level combined with CRP level	Pre-treatment	Serum	ELISA	Retrospective	297 patients with unresectable HCC	A high AFP level (≥100 ng/mL) combined with a high CRP level (≥1 mg/dL) predicted the shortest OS and PFS	2022	Hatanaka et al.⁴⁷
AFP, CRP, and NLR score	Pre-treatment	Blood	ELISA/Flow cytometry	Retrospective	119 patients with unresectable HCC	A high AFP, CRP, and NLR score (≥0) predicted a longer OS and PFS^u	2023	Ueno et al.⁴⁸
CRP level combined with ALBI grade	Pre-treatment	Serum	ELISA	Retrospective	421 patients with unresectable advanced HCC	A high CRP level (>1 mg/dL) combined with a high ALBI grade (grade 2/3) predicted the shortest OS and PFS	2023	Tada et al.⁴⁹
IGF-1, albumin, bilirubin, and prothrombin prolongation time score	Pre-treatment	Serum	ELISA	Prospective	256 patients with unresectable advanced HCC	The lowest IGF-1, albumin, bilirubin, and prothrombin prolongation time score (4-5 points) predicted the longest OS and PFS^v	2022	Kaseb et al.²⁷
PD-1^-CD45RA⁺CD8⁺ effector memory T cell combined with PD-L1⁺CXCL10⁺ macrophage	Pre-treatment	Tumor tissue	scRNAseq	Prospective	253 patients with unresectable advanced HCC	A high PD-1^-CD45RA⁺CD8⁺ effector memory T cell level combined with a high PD-L1⁺CXCL10⁺ macrophage level predicted the longest OS and PFS^w	2023	Cappuyns et al.⁵⁰
PD-L1⁺ tumor cell and PD-L1⁺ tumor-infiltrating cell score	Pre-treatment	Tumor tissue	IHC staining	Retrospective	72 patients with unresectable HCC	A high PD-L1⁺ tumor cell and PD-L1⁺ tumor-infiltrating cell score (≥10) predicted a longer OS and PFS^x	2024	Lee et al.⁵¹

^aOS was defined as the time from treatment initiation to death due to any cause. PFS was defined as the time from treatment initiation to radiological progression or death due to any cause. TTP was defined as the time from treatment initiation to radiological progression (but not death) due to any cause.

^bAFP ratio was calculated by dividing the level of AFP at 3 weeks after treatment initiation by pre-treatment level.

^cAFP decrease was defined as reduction in serum AFP levels at 6 weeks after treatment initiation relative to pre-treatment levels.

^dAFP decrease and increase were defined as reduction and elevation in serum AFP levels at 6 weeks after treatment initiation relative to pre-treatment levels, respectively.

^eChange in AFP level was stratified into three distinct trajectories. In the sharp-falling group, pre-treatment AFP level declined from ≥ 100 ng/mL toward the range (0-20 ng/mL) within 4 months after treatment initiation. In the high-rising group, AFP increased from an elevated pre-treatment level (>100 ng/mL) toward a higher level. In the low-stable group, pre-treatment AFP level < 100 ng/mL decreased and remained below 20 ng/mL.

^fIL-6 level was detected at 3 weeks after treatment initiation.

^gThe ratio of IL-10 and TNF-α was calculated by dividing their level at 3 weeks after treatment initiation by pre-treatment level.

^hCXCL10 level was detected at 3 weeks after treatment initiation.

ⁱAnti-PD-1 autoantibody level was defined as the ratio relative to the lowest level of anti-PD-1 autoantibodies in 63 healthy volunteers.

^jEV size was detected at 3 weeks after treatment initiation. Change in EV size was detected at 9 weeks after treatment initiation and relative to pre-treatment size.

^kThe level of PD1⁺ granulocytes was defined as their percentage in total white blood cells and was categorized as high or low level based on their mean percentage as a cut off.

^lNLR was calculated by dividing blood neutrophil count by blood lymphocyte count.

^mThe level of CD8⁺PD-1⁺Ki-67⁺ T cells and CD4⁺Foxp3⁺PD-1⁺LAG3⁺ T cells was defined as their percentage in total peripheral blood mononuclear cells.

ⁿThe level of CD8⁺ central memory T cells was defined as their percentage in total peripheral blood mononuclear cells. Change in CD8⁺ central memory T cell level was detected at 3 weeks after treatment initiation and relative to pre-treatment size.

^oPNI was defined as serum albumin level (g/dL) multiplied by 10 plus peripheral lymphocyte count per μL multiplied by 0.005.

^pPNI was detected at 3 weeks after treatment initiation.

^qGrade ≥ 2 proteinuria was defined as a urine protein–creatinine ratio of ≥ 2.0 g/g creatinine.

^rAFP decrease was defined as reduction in serum AFP levels at 3 weeks after treatment initiation relative to pre-treatment levels. ALBI grade was defined as log10 serum bilirubin level (mg/dL) multiplied by 0.66 plus serum albumin level (g/dL) multiplied by −0.085 and was stratified as grade 1 (≤−2.60), 2 (>−2.60 to ≤ −1.39), or 3 (>−1.39). No patients were ALBI grade 3 in the analysis.

^smALBI grade was calculated by the same formula as ALBI grade and stratified as grade 1 (≤−2.60), grade 2a (>−2.60 to ≤ −2.27), grade 2b (>−2.27 to ≤ −1.39), or grade 3 (>−1.39).

^tAFP, mALBI grade, BCLC staging, and DCP score was calculated as the summation of points from AFP (<100 and ≥ 100 ng/mL as points 0 and 1, respectively), mALBI (1, 2a, and 2b/3 as points 0, 1, and 2), BCLC (0/A/B and C/D as points 0 and 1, respectively), and DCP (<100 and ≥ 100 mAU/mL as points 0 and 1, respectively) and was categorized as 0 point, 1 point, 2 points, 3 points, 4 points, or 5 points.

^uAFP, CRP, and NLR score was defined as 1.62 minus 0.38 multiplied by log10 serum AFP level (mg/mL) minus 0.61 multiplied by serum CRP level (mg/dL) minus 0.37 multiplied by NLR.

^vIGF-1, albumin, bilirubin, and prothrombin prolongation time score was calculated as the summation of points from IGF-1 (>50, 26-50, and < 26 ng/mL as points 1, 2, and 3, respectively), albumin (>3.5, 2.8-3.5, and < 2.8 g/dL as points 1, 2, and 3, respectively), bilirubin (<2, 2-3, and > 3 mg/dL as points 1, 2, and 3, respectively), and prothrombin prolongation time (<4, 4-6, and > 6 seconds as points 1, 2, and 3, respectively) and was categorized as 4-5 points, 6-7 points, or > 7 points.

^wThe level of PD1^-CD45RA⁺CD8⁺ effector memory T cells and PD-L1⁺CXCL10⁺ macrophages was defined as their density in tumor tissues and was categorized as high or low level based on their respective median densities as a cut off.

^xPD-L1⁺ tumor cell and PD-L1⁺ tumor-infiltrating cell score was calculated by summing the number of PD-L1⁺ tumor cells and the number of PD-L1⁺ tumor-infiltrating cells and then dividing that total by the overall number of tumor cells, with a maximum score of 100.

Abbreviations: HCC, hepatocellular carcinoma; AFP, α-fetoprotein; ELISA, enzyme-linked immunosorbent assay; PFS, progression-free survival; OS, overall survival; CRP, C-reactive protein; DCP, des‐gamma‐carboxy prothrombin; OPN, osteopontin; IL, interleukin; CLEIA, chemiluminescence enzyme immunoassay; TNF-α, tumor necrosis factor-α; CXCL, C-X-C motif chemokine ligand; IGF-1, insulin-like growth factor-1; LAG-3, lymphocyte-activation gene 3; PD-1, programmed death 1; TERT, telomerase reverse transcriptase; ctDNA, circulating tumor DNA; NGS, next-generation sequencing; EV, extracellular vesicle; NTA, nanoparticle tracking analysis; TTP, time to progression; NLR, neutrophil-to-lymphocyte ratio; Foxp3, forkhead box protein 3; CTC, circulating tumor cell; EpCAM, epithelial cell adhesion molecule; TGF-β, transforming growth factor-β; NA, not applicable; MRI, magnetic resonance imaging; APHE, arterial phase hyperenhancement; PNI, prognostic nutritional index; ALBI, albumin–bilirubin; mALBI, modified ALBI; BCLC, Barcelona Clinic Liver Cancer; PD-L1, programmed death ligand 1; scRNAseq, single-cell RNA sequencing; IHC, immunohistochemistry.

Combination Prognostic Biomarkers for HCC Patients Treated with Atezolizumab plus Bevacizumab Combination Therapy

In addition to single biomarkers, the prognostic significance of several combination biomarkers in HCC patients receiving atezolizumab plus bevacizumab combination therapy has been validated in multiple lines of studies (Table 1). The study conducted by Campani et al. carried out ELISA to detect the pre-treatment albumin–bilirubin (ALBI) grade and the in-treatment decrease in the serum AFP levels at 3 weeks after treatment initiation, as combination biomarkers, to stratify 70 retrospectively enrolled patients with unresectable HCC and revealed that patients with an AFP decrease (≤20%) combined with a high ALBI grade (grade 2) had the shortest OS and PFS.⁴⁴ By conducting ELISA to measure the pre-treatment serum AFP levels and modified ALBI (mALBI) grade as combination biomarkers, Hatanaka et al. stratified 426 retrospectively enrolled patients with unresectable HCC and demonstrated that patients with a high AFP level (≥100 ng/mL) combined with a high mALBI grade (grade 2b/3) had the shortest OS and PFS.⁴⁵ The study conducted by Ohama et al. performed ELISA and combined the pre-treatment serum levels of AFP (<100 and ≥ 100 ng/mL scored with points 0 and 1, respectively) and DCP (<100 and ≥100 mAU/mL scored with points 0 and 1, respectively), mALBI grade (1, 2a, and 2b/3 scored with points 0, 1, and 2), and BCLC staging (0/A/B and C/D scored with points 0 and 1, respectively) in a scoring system to stratify 719 retrospectively enrolled patients with unresectable HCC and verified that patients with the highest summation score (5 points) had the shortest OS and PFS.⁴⁶ Based on ELISA analysis of the pre-treatment serum levels of AFP and CRP as combination biomarkers, Hatanaka et al. stratified 297 retrospectively enrolled patients with unresectable HCC and determined that patients with a high AFP level (≥100 ng/mL) combined with a high CRP level (≥1 mg/dL) had the shortest OS and PFS.⁴⁷ The study conducted by Ueno et al. used ELISA and flow cytometry to detect and combine the pre-treatment serum levels of AFP, CRP, and NLR in a scoring system to stratify 119 retrospectively enrolled patients with unresectable HCC and found that patients with high AFP, CRP, and NLR scores (≥0) had longer OS and PFS.⁴⁸ Using ELISA-based measurement of the pre-treatment serum CRP levels and ALBI grade as combination biomarkers, Tada et al. stratified 421 retrospectively enrolled patients with unresectable advanced HCC and ascertained that patients with a high CRP level (>1 mg/dL) combined with a high ALBI grade (grade 2/3) had the shortest OS and PFS.⁴⁹ The study conducted by Kaseb et al. carried out ELISA and combined the pre-treatment serum levels of IGF-1 (>50, 26-50, and < 26 ng/mL scored with points 1, 2, and 3, respectively), albumin (>3.5, 2.8-3.5, and < 2.8 g/dL scored with points 1, 2, and 3, respectively), bilirubin (<2, 2-3, and > 3 mg/dL scored with points 1, 2, and 3, respectively), and the prothrombin prolongation time (<4, 4-6, and > 6 seconds scored with points 1, 2, and 3, respectively) in a scoring system to stratify 256 prospectively enrolled patients with unresectable advanced HCC and validated that patients with the lowest summation score (4-5 points) had the longest OS and PFS.²⁷ The study conducted by Cappuyns et al. conducted single-cell RNA sequencing (scRNAseq) to analyze the pre-treatment levels of PD-1^-CD45RA⁺CD8⁺ effector memory T cells and PD-L1⁺CXCL10⁺ macrophages in tumor tissues as combination biomarkers to stratify 253 prospectively enrolled patients with unresectable advanced HCC and determined that patients with a high PD-1^-CD45RA⁺CD8⁺ effector memory T cell level combined with a high PD-L1⁺CXCL10⁺ macrophage level had the longest OS and PFS.⁵⁰ Lee et al. performed immunohistochemistry (IHC) staining to detect and combine the pre-treatment levels of PD-L1⁺ tumor cells and PD-L1⁺ tumor-infiltrating cells in tumor tissues in a scoring system to stratify 72 retrospectively enrolled patients with unresectable HCC and showed that patients with a high PD-L1⁺ tumor cell and PD-L1⁺ tumor-infiltrating cell score (≥10) predicted a longer OS and PFS.⁵¹

Conclusions

This review provided a comprehensive summary of the evidence in the literature validating the prognostic significance of a variety of a single or a combination biomarker(s) in different sampling sources at different sampling time points in HCC patients receiving atezolizumab plus bevacizumab combination therapy. These prognostic biomarkers hold great potential in identifying the HCC patients with poor outcomes after atezolizumab plus bevacizumab combination therapy for earlier diagnosis and better treatment to improve their survival. When a patient is stratified as the high-risk population based on the prognostic threshold of specific biomarkers detected in the indicated specimens at the pre-treatment or the indicated in-treatment time points, the medical follow-ups after therapy can be arranged more frequently for the patient to monitor the health status and disease progression and ensure the patient to receive timely healthcare and treatment management. Most of the current biomarkers for atezolizumab plus bevacizumab combination therapy in HCC patients, including protein-based, nonprotein-based, and immune cell biomarkers, are derived from liquid biopsies such as whole blood, serum, plasma, and urine, highlighting the convenience and safety of using noninvasive sampling sources in clinical application. In addition, some biomarkers are derived from the MRI imaging of tumor nodule numbers and pathological features, as well as treatment-related adverse events, in a noninvasive manner with no need for sampling. Other biomarkers are derived from the profiling of tumor cells and immune cell subpopulations in tumor tissues. Moreover, many biomarkers are based on cytokines, immune-related proteins, or immune cells, suggesting the clinical implication of the tumor immune microenvironment in the treatment efficacy of atezolizumab plus bevacizumab combination therapy in HCC patients. In clinical practice, ELISA is considered a cost-, time-, and labor-effective method applied in biomarker detection compared with NGS, scRNAseq, NTA, flow cytometry, and IHC staining. Compared with tumor tissues which represent only one part of the whole tumor, liquid biopsies contain more homogeneous molecules from the blood circulation to minimize bias in the detection of biomarkers. In contrast to an in-treatment time point, the detection of biomarkers at a pre-treatment time point may allow more time for therapeutic decision making to improve patient outcomes. In addition, the accuracy and reproducibility of the findings of current biomarkers should be taken into consideration in terms of the sample size, patient heterogeneity, methodological difference, and study design. The prognostic value of some biomarkers (such as AFP, IL-6, NLR, CTC, and PNI) in HCC patients receiving atezolizumab plus bevacizumab combination therapy has been evaluated in different lines of studies. The association of these biomarkers with patient outcomes is consistent among different studies, supporting their potential in clinical use. However, the threshold of the same biomarker, even detected using the same method at the same time point, varied among different studies. Aside from these biomarkers, the prognostic significance of many other single or combination of biomarker(s) remains only validated in one study each. Therefore, more studies are still needed to reach a consensus on the outcome correlation and prognostic threshold for the current biomarkers to facilitate their translation into clinical application. Moreover, a prospective multicenter large cohort study with a stratified analysis of patient characteristics is required to provide more robust and unbiased evidence. The establishment of standardized methodological and technical protocols for biomarker measurement in different types of specimens is necessary to improve the consistency and reliability of the biomarkers. Future investigation is worthwhile to develop biomarker panels that are tailored for specific characteristics of patients through the facilitation of artificial intelligence-based approaches in combination with current bioinformatics software. In addition to atezolizumab plus bevacizumab combination therapy, durvalumab (an anti-PD-L1 antibody) in combination with tremelimumab (an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody) is the other preferred FDA-approved first-line systemic therapy for the treatment of patients with unresectable HCC.^52,53 However, current studies regarding the prognostic biomarkers for HCC patients treated with durvalumab plus tremelimumab combination therapy remain very limited, raising an urgent need for discovering biomarkers for this therapy. This is also the reason why the present review focuses on the biomarkers for atezolizumab plus bevacizumab combination therapy. Furthermore, the therapeutic efficacy of three-drug combinations using an atezolizumab plus bevacizumab framework for unresectable HCC in the first-line setting is being evaluated in several clinical trials, including a phase II trial for atezolizumab plus bevacizumab plus SRF388 (an anti-interleukin 27 antibody),⁵⁴ a phase II/III trial for atezolizumab plus bevacizumab plus ipilimumab (an anti-CTLA-4 antibody),⁵⁵ and a phase III trial for atezolizumab plus bevacizumab plus tiragolumab (an anti-T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) antibody).⁵⁶ Compared with atezolizumab plus bevacizumab, the triplet combination of atezolizumab, bevacizumab, and tiragolumab has shown a longer median OS (28.9 months vs 15.1 months) and RFS (12.3 months vs 4.2 months), as well as a higher ORR (43% vs 11%) in a phase Ib/II trial for unresectable HCC.⁵⁷ The current biomarkers for atezolizumab plus bevacizumab combination therapy may have promising potential to guide the development of biomarkers for tiragolumab in combination with atezolizumab plus bevacizumab in patients with unresectable HCC in the future.

Footnotes

Acknowledgements

This work was supported by grants from the China Medical University Hospital, Taichung, Taiwan (DMR-113-027).

ORCID iD

Chiao-Fang Teng

Author Contributions

Conceptualization, Long-Bin Jeng, Horng-Ren Yang, and Chiao-Fang Teng; Funding acquisition, Chiao-Fang Teng; Visualization, Long-Bin Jeng, Horng-Ren Yang, and Chiao-Fang Teng; Writing—original draft, Chiao-Fang Teng; Writing—review and editing, Chiao-Fang Teng.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the China Medical University Hospital, Taichung, Taiwan (DMR-113-027).

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Appendix

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Prognostic Biomarkers for Hepatocellular Carcinoma Patients Treated With Atezolizumab plus Bevacizumab Combination Therapy

Abstract

Keywords

Introduction

Single Prognostic Biomarkers for HCC Patients Treated with Atezolizumab plus Bevacizumab Combination Therapy

Combination Prognostic Biomarkers for HCC Patients Treated with Atezolizumab plus Bevacizumab Combination Therapy

Conclusions

Footnotes

Acknowledgements

ORCID iD

Author Contributions

Funding

Declaration of Conflicting Interests

Appendix

References