2026-06-15 | The interplay between bile acid metabolism and gut microbiome in biliary tract cancers.
The gut microbiota and bile acids (BAs) exist in a tightly regulated, bidirectional relationship that influences host metabolism, immune function, and disease. Primary BAs synthesized in the liver are chemically transformed by intestinal microbes into a diverse pool of secondary BAs, which exert antimicrobial effects and activate host signaling pathways including Farnesoid X Receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), and sphingosine-1-phosphate receptor 2 (S1PR2). These pathways regulate BA homeostasis, epithelial barrier integrity, inflammation, and carcinogenesis. Disruption of this BA-microbiome axis has been implicated in biliary tract cancers (BTCs), a group of aggressive malignancies with rising global incidence and limited therapeutic options. Secondary BAs and BA receptor signaling contribute to tumor initiation and progression through NF-κB activation, oxidative stress, and altered cell survival, whereas reduced FXR signaling and obstructed enterohepatic circulation further promote inflammatory dysregulation. Emerging evidence demonstrates that microbial dysbiosis and altered BA metabolism are associated with distinct BTC microbial profiles, enriched in taxa such as Fusobacterium, Salmonella, Prevotella, and Actinomyces, alongside depletion of commensals including Lactobacillus. These taxa influence inflammatory signaling, BA transformation, and epithelial injury, contributing to carcinogenesis. Microbiome-BA interactions also shape anti-tumor immunity and responses to immune checkpoint inhibitors (ICIs). Specific microbial signatures-particularly enrichment of Lachnospiraceae, Erysipelotrichaceae, Bacteroidetes, and Alistipes-correlate with enhanced immune activation and improved clinical outcomes in hepatobiliary cancers. Modulation of gut microbiota through antibiotics, probiotics, or fecal microbiota transplantation can influence BA composition, immune surveillance, and therapeutic efficacy. Collectively, these data highlight the central role of the BA-microbiome axis in BTC pathogenesis and treatment response. Microbial and BA metabolite profiling represent promising avenues for biomarker development, while targeted manipulation of BA signaling and microbial ecology offers potential therapeutic strategies to improve BTC outcomes.
Open article ↗
2026-05-28 | Zolbetuximab in CLDN18.2-positive biliary tract cancer after prior systemic therapy: A prospective observational pilot cohort study of early outcomes, safety, and patient-reported quality of life.
e16174 Background: CLDN18.2 is a validated therapeutic target in advanced gastric and gastroesophageal junction cancer; however, its role in biliary tract cancer (BTC; intrahepatic or extrahepatic cholangiocarcinoma, or gallbladder carcinoma) remains poorly defined. Immunohistochemical studies suggest that a subset of BTCs express CLDN18.2, but prospective clinical and quality-of-life (QoL) - focused data in BTC are lacking. Patients with advanced, pretreated BTC have limited treatment options after gemcitabine-based therapy. We conducted a prospective observational pilot cohort study to assess feasibility of prospective data capture, early clinical outcomes, safety, and patient-reported QoL among CLDN18.2-positive BTC patients receiving zolbetuximab in the salvage setting. Methods: This single-center, prospective, observational study included adults with unresectable or metastatic BTC treated between January 1, 2025, and December 15, 2025. Eligibility required CLDN18.2 expression in ≥50% of tumor cells (moderate/strong membranous staining) after progression on ≥1 prior systemic therapy. Patients received zolbetuximab in the salvage setting; monotherapy or combination with chemotherapy and dosing schedule (commonly every 3 weeks) were determined by the treating physician. Treatment decisions were at physician discretion; the study did not assign treatment or mandate dosing. The primary endpoint was change in EORTC QLQ-C30 global health status/QoL from baseline to week 6. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), treatment duration, and treatment-emergent adverse events (TEAEs). Results: Seven eligible patients (ECOG 0-2) were included (median age 63 years, range 52-73); all had received ≥2 prior systemic lines. High CLDN18.2 expression (≥75%) was observed in 5/7 patients. ORR was 14% (1 partial response) and DCR was 57%. Median treatment duration was 3.4 months. Mean global health status/QoL improved from 52 to 63 at week 6 (+11 points); 4/7 patients achieved a clinically meaningful ≥10-point improvement. Pain (-15 points) and appetite loss (-12 points) improved most. Any-grade TEAEs occurred in 6/7 patients; grade ≥2 TEAEs occurred in 2/7. No treatment-related deaths occurred. Conclusions: In this prospective, biomarker-selected observational pilot cohort of heavily pretreated BTC, zolbetuximab use was feasible, showed encouraging disease control, and was associated with clinically meaningful QoL improvement. These hypothesis-generating data support further investigation of CLDN18.2-directed strategies in BTC.
Open article ↗
2026-05-05 | Deciphering potential significances of biliary microbiome in cholelithiasis and cholangiocarcinoma.
This study aims to investigate the role of biliary microbiota (defined as the microbial community colonizing the biliary tract, including the gallbladder, intrahepatic and extrahepatic bile ducts) in the pathogenesis of cholelithiasis (CHOL) and cholangiocarcinoma (CCA), with a focus on the associations between microbial communities and these biliary diseases. We conducted a comprehensive bioinformatics analysis using high-throughput sequencing data obtained from the Sequence Read Archive (SRA) database to characterize the composition of microbial communities in patients with CCA and CHOL. We performed operational taxonomic unit (OTU) clustering, statistical analyses and Mendelian randomization (MR) to elucidate the causal relationships between specific bacterial strains and disease outcomes. Our findings revealed differences in the relative abundance of specific microbial taxa among research groups. The CCA + CHOL group exhibited a significant increase in the abundance of Fusobacteria, particularly Fusobacterium, compared to the Control or CCA group. This suggests a potential pathogenic role for these microorganisms in CHOL formation. Additionally, the CCA group demonstrated a higher diversity index, indicating that increased microbial diversity may contribute to the progression of the disease. MR analysis identified nominally significant statistical associations between specific bacterial strains. However, the presence of pleiotropy in some analyses necessitates caution when interpreting causal relationships. Our study highlights the complex interplay between biliary microbiota and the pathogenesis of CHOL and CCA. Modulating biliary microbiota may represent a promising therapeutic strategy for managing these diseases. Future research should focus on the functional roles of specific taxa in bile metabolism and immune modulation, ultimately improving our understanding of biliary health and disease management.
Open article ↗
2026-04-14 | Second-line Treatment Strategies in Biliary Tract Cancers
Biliary tract cancers (BTCs) are a highly heterogenous group of tumours arising from the bile ducts (cholangiocarcinoma [CCA]) and gallbladder. Of note, tumours of the ampulla of Vater typically fall under this definition but tend to be excluded from second-line treatment studies. Cholangiocarcinomas are further classified into intrahepatic (iCCA, including hilar) and extrahepatic (eCCA). Together, they account for approximately 15% of primary liver cancers and 3% of all gastrointestinal malignancies. However, iCCA and eCCA are separate entities that differ in incidence, clinical presentation, natural evolution, and molecular profile. Specifically, iCCA is less commonly associated with biliary obstructive symptoms and thus tends to be diagnosed incidentally and at a more advanced stage than eCCA. The diagnostic challenges partly stem from the localization of these tumours, deep in the hepatic and biliary systems, where it is often difficult to obtain a tissue biopsy or an adequate aspiration cytology. iCCA can be misclassified as carcinoma of unknown primary (CUP) as histologically it can be impossible to distinguish from metastatic adenocarcinoma of an extrahepatic primary tumour, and the primary tumour can be small and not well identified on imaging. The unique features of these tumours may in part explain their poor prognosis. Overall, the 5-year survival rate of CCA is estimated to be less than 25% for all stages combined, reflecting a very modest treatment effect. Chemoimmunotherapy combinations are now globally accepted as the standard first-line treatment, but uncertainties remain regarding second and later lines of treatment. This review will summarize the available treatments beyond the first line with a focus on the emerging field of molecular precision medicine.
Open article ↗
2026-01-10 | ERBB2/HER2 status in biliary tract cancer patients in the Spanish RETUD registry.
498 Background: ERBB2 gene amplification or HER2 receptor overexpression is a well-known oncogenic driver and represents a therapeutic target in biliary tract cancer (BTC). We aimed to describe the epidemiology of a cohort of BTC patients (pt) according to HER2 status, treatment patterns and efficacy outcomes. Methods: We evaluated a real-world pt cohort from the Spanish RETUD registry, diagnosed with BTC from January 1st, 2017, to May 30th, 2025. Pt populations were defined as resectable disease (RD) for pt with neoadjuvant/adjuvant systemic therapy (ST) and/or radical treatment (surgery and/or locoregional treatment); and advanced disease (AD) for RC pt who experienced tumor relapse and those initially treated with first line ST. ERBB2/HER2 status was assessed by next-generation sequencing (NGS), immunohistochemistry (IHC), and/or fluorescence/chromogenic in situ hybridization (FISH/CISH). HER2+ status was considered as amplification with FISH/CISH (if IHQ++) or NGS, or overexpression (IHQ+++). Data included demographic and clinical characteristics, molecular profile, therapeutic procedures, and efficacy outcomes (EO). Progression-free survival (PFS), overall survival (OS) and time to next therapy (TTNT) were estimated using the Kaplan-Meier method. Results: ERBB2/HER2 status was determined in 448 BTC pt from 31 centers. At diagnosis (dx), 148 pt (33.0%) presented RD and 300 pt AD (67.0%). 128 RD pt experienced tumor relapse. HER2+ was confirmed in 5.4% pt and varied by tumor location: 3.3% in extrahepatic distal and intrahepatic cholangiocarcinoma, 7.3% in extrahepatic hilar and 15.3% in gallbladder carcinoma. Median (m) age at diagnosis in HER2+ pt was 63.8 years; with 75% of women. Treatments were administered in HER2+ and HER2- groups as follows: Surgery in 37.5% vs. 33.0%; locoregional therapy in 4.2% vs 11.6%, neoadjuvant/adjuvant ST in 20.8% vs. 21.7% and ST in AD pt in 100% vs 98.8%. A total of 29 pt (6.5%) received immunotherapy. Metastatic disease occurred in 87.5% of HER2+ vs 77.8% of HER2- pt. Regarding treatments in AD HER2+ pt, most frequent schemes for first and second line were CISGEM (70.6%) and FOLFOX (41.2%) and a total of 29.2% received anti-HER2 therapy. With a m (min, max) follow-up time for the overall population of 16.5 (0.9, 81.2) months (mo), mOS in AD HER2+ pt not treated with anti-HER2 therapies was 13.1 mo (95% CI 9.3-17.0) compared to 15.0 mo (95% CI 13.5-17.3) in HER2- pt (p=0.012) and 32.7 mo (95% CI 20.7-NA) in HER2+ treated pt (p=0.003). EO in first line for HER2+ vs HER2- pt: mPFS 6.6 mo (95% CI 4.5-8.1) vs 6.6 mo (95% CI 5.9-7.7) (p=0.075); mTTNT 7.8 mo (95% CI 6.7-NA) vs 10.0 mo (95% CI 9.2-11.2) (p=0.047); ORR 36.8% vs 27.8% (p = 0.393). Conclusions: This analysis provides insights into the characterization of real-world HER2+ BTC pt showing a significant impact in mOS upon treatment with anti-HER2 therapies.
Open article ↗
