Abstract Background TP53 mutations are among the most frequent alterations in biliary tract cancer (BTC), but their prognostic relevance and predictive value for immune checkpoint inhibitors (ICI) remain unclear. We assessed clinico-molecular features, prognosis, and ICI efficacy by TP53 status in advanced BTC. Methods Patients with advanced BTC from Japan and the United States who underwent tissue- or plasma-based next-generation sequencing were retrospectively analyzed. Tissue-based sequencing was used for the primary analysis, and plasma ctDNA sequencing was evaluated as an exploratory cohort. Outcomes were compared between TP53 wild-type (WT) and TP53 -mutated groups. Treatment– TP53 interactions for non-ICI versus ICI-containing regimens were assessed using multivariable Cox models. Whole-transcriptome sequencing data were analyzed using TIDE and Hallmark gene set enrichment analysis. Results Among 336 patients in the tissue-based cohort, 177 (52.7%) had TP53 -mutated tumors. SMAD4, ERBB2, PTEN and CCNE1 co-alterations were enriched in TP53 -mutated tumors, whereas IDH1, BAP1 , and FGFR2 fusions were more frequent in WT tumors. TP53 mutations were independently associated with shorter PFS, whereas OS showed a similar but nonsignificant trend (PFS: HR 1.32, P = 0.04; OS: HR 1.32, P = 0.09). TP53 mutations were associated with shorter PFS in the non-ICI cohort but numerically longer PFS in the ICI cohort, with a significant treatment– TP53 interaction for PFS ( P < 0.01). Similar trends were observed in the plasma cohort. Transcriptomic analyses ( n = 59; all MSS) showed lower TIDE scores in TP53 -mutated tumors. Conclusion TP53 mutations were associated with poor prognosis and may predict greater benefit from ICI, supporting biomarker-driven stratification.
Shibuki et al. (Mon,) studied this question.