Clinico-molecular characteristics and enhanced efficacy of immune checkpoint inhibitors in TP53-mutated advanced biliary tract cancer.

Publication Title

Journal of gastroenterology

Authors

• Taro Shibuki
• Celine Hoyek
• Ryne Ramaker
• Madhuri Gottam
• Makoto Ueno
• Yasuyuki Kawamoto
• Shinji Itoh
• Kanae Inoue
• Tadayoshi Hashimoto
• Takao Fujisawa
• Mitsuho Imai
• Yoshiaki Nakamura
• Hideaki Bando
• Angelo Pirozzi
• Binbin Zheng-Lin, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA.Follow
• Oluseyi Abidoye
• Cody R Eslinger
• Mohamad Bassam Sonbol
• Hani Babiker
• Nguyen Tran
• Chigusa Morizane
• John H Strickler
• Takayuki Yoshino
• Tanios Bekaii-Saab
• Masafumi Ikeda

Document Type

Article

Publication Date

5-25-2026

Keywords

TP53; Advanced biliary tract cancer; Immune checkpoint inhibitor; Prognosis; Systemic therapy.; oregon; chiles

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.

Area of Special Interest

Cancer

Area of Special Interest

Digestive Health

DOI

10.1007/s00535-026-02439-9