Soluble Urokinase Plasminogen Activator Receptor Predicts Survival and Hepatic Decompensation in Advanced Hepatocellular Carcinoma

Abstract

Background and aims: The introduction of immune checkpoint inhibitor (ICI) based therapies has significantly improved the prognosis of patients with unresectable hepatocellular carcinoma (HCC). However, the variable treatment response and the uncertain benefit in patients with advanced liver cirrhosis emphasise the urgent need for prognostic and predictive biomarkers guiding patient selection. The soluble urokinase plasminogen activator receptor (suPAR) is strongly associated with inflammation, liver cirrhosis and various types of cancer. In this study, we investigated suPAR as a potential novel biomarker in patients with unresectable HCC.

Methods: This multicenter retrospective study, conducted at three German tertiary care centers, included 90 patients with unresectable HCC and suPAR measurements prior to and during atezolizumab/bevacizumab therapy. Patients with liver cirrhosis without HCC (n = 235) and non-cirrhotic patients with other gastrointestinal tumours (n = 155) were selected as control cohorts.

Results: Median suPAR levels were significantly higher in patients with liver cirrhosis compared to non-cirrhotic cancer patients. A strong association with parameters of liver function, but not with HCC characteristics, was observed. In patients with HCC receiving atezolizumab/bevacizumab, suPAR was the most accurate independent predictor of hepatic decompensation and overall survival (OS). In addition, suPAR was able to stratify the risk of hepatic decompensation within the different Child-Pugh classes.

Conclusions: SuPAR represents a promising novel biomarker in patients with HCC treated with ICI-based therapies and bears the potential to guide the selection of antitumoral systemic therapies in patients with advanced liver cirrhosis.

Keywords: atezolizumab; bevacizumab; biomarker; hepatocellular carcinoma (HCC); soluble urokinase plasminogen activator receptor (suPAR); survival.

FIGURE 1

Baseline suPAR concentrations. (A) suPAR concentrations are significantly higher in cirrhotic patients with (n = 90) and without HCC (n = 235) compared to patients with neuroendocrine tumour (n = 132) or neuroendocrine carcinoma (n = 25). (B) suPAR levels show a significant stepwise increase according to Child‐Pugh class independent of the presence of HCC. Data are expressed as medians with IQR. p‐values are from a non‐parametric signed‐rank test accounting for between and within group differences. Ns, non‐significant; ***p < 0.001.

FIGURE 2

Changes in Child‐Pugh score and MELD score according to suPAR risk groups in cirrhotic patients with HCC. Depicted are absolute changes of Child‐Pugh score (A) and MELD score (B) after 6 months of therapy, risk‐stratified by quartiles of pre‐treatment suPAR levels (Q1, Q2 + 3, Q4). Data are expressed as medians with IQR. p‐values are from a non‐parametric signed‐rank test accounting for between‐ and within‐group differences. *p < 0.05, **p < 0.01, ***p < 0.001. MELD, model for end‐stage liver disease; suPAR, soluble urokinase plasminogen activator receptor.

FIGURE 3

Kaplan–Meier analysis of time without hepatic decompensation in cirrhotic patients with HCC. Depicted are Kaplan–Meier estimates of time without hepatic decompensation, risk‐stratified by quartiles (Q1, Q2 + 3, Q4) of pre‐treatment suPAR levels (A), Child‐Pugh score (B), MELD score (C) and ALBI score (D) in cirrhotic patients with HCC receiving atezolizumab/bevacizumab. Tick marks indicate censored data. p‐values from log‐rank test are given. ALBI score, albumin‐bilirubin score; MELD, model for end‐stage liver disease; suPAR, soluble urokinase plasminogen activator receptor.

FIGURE 4

Prognostic performance for 6‐ and 12‐month mortality. Depicted are ROCs and AUCs with 95% confidence intervals (95% CI) for the prediction of 6‐ (A) and 12‐month mortality (B) in cirrhotic patients with HCC. The combination of suPAR levels and relative lymphocyte counts was performed by logistic regression. ALBI score, albumin‐bilirubin score; AUC, area under the receiver operating characteristic curve; CRP, C‐reactive protein; ROC, receiver‐operating characteristic curve; suPAR, soluble urokinase plasminogen activator receptor.

FIGURE 5

Hepatic decompensation and suPAR levels predict overall survival. Depicted are Kaplan–Meier estimates of overall survival according to HCC progression plus hepatic decompensation (A) and HCC progression plus suPAR quartiles (B). Tick marks indicate censored data. p‐values from log‐rank test are given. SuPAR, soluble urokinase plasminogen activator receptor.

FIGURE 6

SuPAR identifies patients with poor outcomes within the Child‐Pugh classes in cirrhotic patients with HCC. (A–D) Depicted are Kaplan–Meier estimates of overall survival and time without hepatic decompensation in patients with Child‐Pugh class A cirrhosis (A, C) and patients with Child‐Pugh class B cirrhosis (B, D). Patients were stratified for low versus high baseline suPAR concentrations (< 12 ng/mL vs. ≥ 12 ng/mL), with 12 ng/mL corresponding to the upper quartile within the Child‐Pugh A group. (E, F) Number of deaths (E) and hepatic decompensations (F) after 6 and 12 months stratified by Child‐Pugh class and low versus high baseline suPAR levels.