TP53 Mutations in BTC: A Prognostic Marker and a Potential Target for Immune Checkpoint Inhibitors

Biliary tract cancer (BTC) is a rare and aggressive malignancy with poor outcomes, and its molecular landscape is highly heterogeneous. Among its genetic alterations, mutations in TP53 are common but poorly understood in terms of their clinical and therapeutic implications. Although TP53 mutations have been associated with enhanced immune checkpoint inhibitor (ICI) efficacy in other cancer types, such as non–small cell lung cancer, their impact in BTC remains unclear. A recent study sought to address this gap by analyzing the clinical and molecular characteristics, prognosis, and responsiveness to ICIs in TP53-mutated BTC using data from both Japanese and US cohorts.

The study included patient data from the SCRUM-Japan GOZILA and MONSTAR-SCREEN-1/2 databases (Japan), along with cohorts from Duke University and the Mayo Clinic (United States). Comparisons between the TP53 wild-type (WT) and mutation groups were performed in the Japanese cohort. Subsequently, analyses were expanded to include US patients, focusing on comparisons between groups utilizing and not utilizing ICIs. In total, 653 patients were analyzed for clinical and molecular characteristics. TP53 mutations were identified in 343 patients and 310 were identified as WT.

In the Japanese cohort, TP53 mutations were associated with worse outcomes, establishing them as independent prognostic factors for poor outcomes. Multivariable analysis showed that TP53 mutations were linked to shorter median progression-free survival (PFS; 16.0 months vs 21.2 months) and median overall survival (5.5 months vs 6.9 months) compared with WT.

When analyzing treatment outcomes, this study found that TP53-mutated BTC responded differently to ICIs compared with non-ICI therapies. In the non-ICI group, patients with TP53 mutations had worse PFS compared with WT patients (median, 5.3 months vs 7.4 months; hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.21-1.75). In the ICI group, patients with TP53 had a numerically better PFS (median, 6.4 months vs 5.0 months; HR, 0.70; 95% CI, 0.42-1.16), although the difference was not significant. In the ICI-treated group, TP53-mutated patients had higher overall response rates (ORRs; 38.5% vs 21.1%) and disease control rates (DCRs; 66.7% vs 47.4%) compared with TP53 WT patients. In the non-ICI groups, TP53-mutated patients had lower ORRs (16.8% vs 23.1%) and DCRs (64.4% vs 71.4%) compared with TP53 WT patients.

Researchers also analyzed Tumor Immune Dysfunction and Exclusion (TIDE) scores using whole-transcriptome sequencing data. TP53-mutated tumors had significantly lower TIDE scores, indicating a higher likelihood of ICI responsiveness compared with WT.

In conclusion, TP53 mutations in BTC are associated with worse prognosis but may predict enhanced responsiveness to ICIs. This duality highlights the need for tailored treatment strategies in TP53-mutated BTC, potentially prioritizing ICIs in this subgroup. These findings underscore the importance of molecular profiling in BTC and pave the way for further research into leveraging TP53 mutations as both a prognostic marker and a therapeutic target.

Source:

Shibuki T, Hoyek C, Ramaker R, et al. Clinico-molecular characteristics and enhanced efficacy of immune checkpoint inhibitors in TP53-mutated advanced biliary tract cancer. Presented at: 2025 ASCO Annual Meeting. May 30-June 3, 2025; Chicago, IL. Poster 409.