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

mutations are frequent genetic alterations in cancers and also prevalent in biliary tract cancer (BTC). In non-small cell lung cancer, mutations have been reported to enhance immune checkpoint inhibitor (ICI) efficacy and improve outcomes. However, their impact on BTC remains unclear. This study investigated the clinico-molecular characteristics, prognosis, and ICI efficacy in -mutated BTC. Patient data were collected from the SCRUM-Japan GOZILA and MONSTAR-SCREEN-1/2 databases (Japan) and the Duke university and Mayo clinic databases (U.S.), which included patients receiving first-line ICI therapy. Comparisons between wild-type (WT) and mutation groups were performed in the Japanese cohort. Subsequently, analyses were expanded to include U.S. patients, focusing on comparisons between non-ICI and ICI groups. Tumor Immune Dysfunction and Exclusion (TIDE) scores were calculated using MONSTAR-SCREEN-2 whole transcriptome sequencing (WTS) data to evaluate ICI responsiveness, and gene set enrichment analysis (GSEA) explored pathways associated with mutations. In the Japanese cohort (n=594), mutations were identified in 311 patients (52.4%). , , , and alterations were more frequent in the mutation group, while , and fusions were more common in the WT group. Multivariable analysis showed mutations were independent prognostic factors for poor outcomes (progression-free survival [PFS]: HR 1.37, 95% CI: 1.11–1.69, P=0.003; overall survival [OS]: HR 1.36, 95% CI: 1.06–1.75, P=0.017). Incorporating the U.S. cohort (n=625; non-ICI: 548; ICI: 77), no significant differences in overall response rate (ORR) or disease control rate (DCR) were observed in the non-ICI group between the groups. However, in the ICI group, mutations tended to show higher ORR (21.1% vs. 38.5%, P=0.16) and DCR (47.4% vs. 66.7%, P=0.14). In the non-ICI group, mutations were associated with worse PFS (HR 1.46, median PFS: 7.4 vs. 5.3 months, P<0.001), whereas, in the ICI group, no significant difference was observed; however, a trend toward better PFS was seen in the mutation group (median PFS: 5.0 vs. 6.4 months, P=0.163). TIDE scores were significantly lower in the mutation group, indicating higher ICI responsiveness. GSEA revealed enrichment of oxidative phosphorylation and hypoxia pathways. mutations are independent prognostic factors for poor outcomes in BTC. However, patients with mutations may derive greater benefits from ICIs, underscoring the importance of tailored therapeutic strategies in mutated BTC.

Duke Scholars

Author John Strickler Medicine, Medical Oncology