B cell receptor-associated protein 31 levels in serum-derived extracellular vesicles are associated with therapeutic response and prognosis in patients with advanced hepatocellular carcinoma receiving atezolizumab plus bevacizumab: a multicenter study.

BACKGROUND: There remains an unmet need for reliable biomarkers associated with therapeutic response to immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC). We retrospectively examined protein levels in serum-derived extracellular vesicles (EVs) as candidate biomarkers associated with treatment response in patients with advanced HCC. METHODS: A total of 122 patients with advanced HCC treated with atezolizumab plus bevacizumab (ATZ/BEV) were retrospectively selected. The discovery group comprised 12 patients, whose serum-derived EV samples underwent comprehensive proteomic profiling by quantitative data-independent acquisition mass spectrometry. The remaining 110 patients comprised the validation group, in whom selected EV proteins were quantified by parallel reaction monitoring analysis. RESULTS: B cell receptor-associated protein 31 (BAP31) was identified as an exploratory biomarker associated with early treatment response. Receiver operating characteristic analysis of pretreatment log2 BAP31 levels for distinguishing non-progressive disease from progressive disease at the initial response in the validation group yielded an area under the curve of 0.719 and an optimal cut-off of -14.582. This threshold stratified overall survival (OS) in the entire cohort (44.8 vs 25.3 months for low- vs high-level groups, P = 0.039). Multivariable analysis showed that EV BAP31 levels were independently associated with OS (HR 1.78, P = 0.044); however, this association was attenuated and was no longer statistically significant after propensity score adjustment. No significant association with progression-free survival was observed. CONCLUSIONS: Pretreatment BAP31 levels in serum-derived EVs may represent an exploratory biomarker potentially associated with early treatment response and prognosis in patients with advanced HCC receiving ATZ/BEV. Further validation is warranted.