Etiology of Hepatocellular Carcinoma May Influence the Pattern of Progression under Atezolizumab-Bevacizumab

Preclinical models have shown that metabolic dysfunction-associated steatotic liver disease (MASLD)-related hepatocellular carcinoma (HCC) may exhibit reduced responsiveness to immunotherapy, especially for intrahepatic lesions due to liver tumor microenvironment. Radiological pattern of progression has been validated in clinical studies as a useful tool for predicting outcomes in HCC undergoing systemic treatments.

The aim of this study was to determine whether MASLD influences the pattern of progression in patients treated with atezolizumab-bevacizumab.

This multicenter, prospective study included patients with unresectable HCC receiving atezolizumab-bevacizumab. Progression patterns were defined as previously proposed. Patients were categorized as either MASLD or controls based on a recent multisocietal Delphi consensus statement. Multivariable models analyzed the risk of specific progression patterns and their impacts on post-progression survival (PPS) and overall survival (OS). A historical cohort treated with sorafenib was also analyzed to determine whether observed patterns were specific for atezolizumab-bevacizumab.

Four-hundred twenty patients were included (MASLD: n = 88, 21.0%). Time to progression (TTP) was shorter in MASLD compared to controls, due to an increased risk of intrahepatic growth (IHG - hazard ratio [HR] 1.739, 95% confidence interval [CI] 1.206-2.507, p = 0.003]). Neither etiology nor IHG predicted a different PPS. No differences between etiologies were found in OS. Etiology did not influence the pattern of progression under sorafenib in the historical cohort.

IHG was more frequently associated with MASLD-HCC compared to controls, confirming preclinical data and suggesting biological differences between tumors, with potential implications for future research. MASLD should not be seen as a contraindication to immunotherapy.