Letter: Tumour Burden Score for Predicting Extrahepatic Metastasis in Hepatocellular Carcinoma After Curative Resection. Authors' Reply

We thank Su and colleagues for their valuable letter [1] extending the application of the tumour burden score (TBS) to patients with hepatocellular carcinoma (HCC) undergoing curative hepatectomy. Their multicenter analysis of 2528 patients in the GUIDANCE database provides important external validation and broadens the clinical utility of this prognostic tool. Our study [2] demonstrated that TBS effectively stratifies the risk of extrahepatic progression (EHP) in patients treated with transarterial chemoembolization (TACE), with a cut-off of 3.66 accurately distinguishing high- from low-risk patients. Notably, Su et al. [1] identified an optimal TBS cut-off of 4.81 for their hepatectomy cohort. This difference likely reflects distinct patient populations: candidates for curative resection typically present with earlier-stage disease and better liver function than those receiving TACE, which may explain the higher threshold required to stratify risk in the surgical cohort. Importantly, despite differences in treatment modalities and cutoff values, both studies reach the same fundamental conclusion: TBS effectively predicts the risk of extrahepatic metastasis across HCC treatment settings. The 5-year cumulative risk of extrahepatic metastasis in the GUIDANCE cohort (21.3% in high-TBS vs. 9.3% in low-TBS) aligns with our observations of differential EHP rates between TBS groups. Furthermore, their confirmation that combining TBS with alpha-fetoprotein (AFP) enhances risk stratification reinforces our findings and suggests broad applicability of this combined approach. Su et al. appropriately highlights the implications for adjuvant therapy after curative resection. Given that landmark trials such as STORM [3], IMbrave050 [4] and KEYNOTE-937 [5] have not demonstrated consistent survival benefits with adjuvant therapy, precision-stratified approaches based on TBS-AFP combined scores may help identify the subset of patients most likely to benefit from postoperative treatment. In this regard, also assessment of the ITA.LI.CA cohort of patients treated with curative surgery and subdivided according to the IMbrave050 [4] criteria into high- and low-risk of recurrence, showed that patients with high-recurrence risk had significantly higher AFP levels compared to patients with lower risk [6], further emphasising the potential additional prognostic role of AFP also in this setting, as highlighted by Su et al. [1] Similarly, in the palliative setting, the combination regimens evaluated in EMERALD-1 [7], LEAP-012 [8] and TALENTACE [9] demonstrate the evolving therapeutic landscape for intermediate-stage HCC, where TBS may guide treatment sequencing between locoregional and systemic approaches. In conclusion, we agree with Su et al. that TBS is a universal tumour burden quantification tool with prognostic value beyond TACE-treated patients. Future prospective studies should validate TBS-based stratification across treatment modalities and assess its utility in guiding personalised therapeutic strategies for HCC patients. Elisa Pinto: conceptualization, data curation, formal analysis, writing – original draft. Filippo Pelizzaro: conceptualization, data curation, formal analysis, writing – original draft. Laura Bucci: data curation. Martina Gambato: data curation. Fabio Farinati: supervision. Edoardo G. Giannini: writing – review and editing, supervision. Francesco Paolo Russo: writing – review and editing, supervision. The authors have nothing to report. This article is linked to Pinto et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70534 and https://doi.org/10.1111/apt.70564. The authors have nothing to report.