Many real-world patients with advanced biliary tract cancer (BTC) are excluded by TOPAZ-1 criteria; this study assessed cisplatin and gemcitabine plus durvalumab (CGD) efficacy and safety in these patients. Data from 1358 patients with advanced BTC treated with first-line CGD across 55 international centers were retrospectively analyzed. Patients were classified as TOPAZ-1-in (meeting all inclusion criteria) or TOPAZ-1-out (meeting ≥ 1 exclusion criterion). Primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Furthermore, OS and PFS of the TOPAZ-1-out cohort were compared with reconstructed survival data from the phase III trial. 912 (67.1%) patients were classified as TOPAZ-1-in, and 446 (32.9%) as TOPAZ-1-out. After a median follow-up of 14.5 months (95% CI: 13.7-36.5), OS was 16.1 months in TOPAZ-1-in and 12.5 months in TOPAZ-1-out (HR 0.69, 95% CI: 14.6-16.5, p = 0.0001); PFS was 8.2 versus 6.5 months (HR 0.73, 95% CI: 7.1-8.1, p < 0.0001). Median OS in the TOPAZ-1-out cohort (12.5 months) was nearly identical to the phase III trial experimental arm (12.9 months; HR 1.15, p = 0.13); for PFS the HR was 1.12 (95% CI 0.93-1.42; p = 0.09). Among TOPAZ-1-out patients, active infection, elevated bilirubin, and ECOG PS > 1 were linked to poorer OS, while no detrimental impact emerged for ALT/AST abnormalities, corticosteroid use, renal or hematologic parameters, or prior surgery within 6 months, suggesting treatment effectiveness was broadly maintained across clinical subgroups. Furthermore, TOPAZ-1-out patients experienced no significant increase in adverse events compared with the TOPAZ-1-in group. Real-world data suggest CGD may be effective in TOPAZ-1-out patients, with no evident increase in toxicity, supporting the potential expanded use of the regimen in clinical practice.

The potential for using therapeutic antisense oligonucleotides (ASOs) has been hampered by a lack of understanding of how they enter cells and subsequently access their targets. Endocytosis contributes to ASO uptake, but the machinery mediating subsequent ASO trafficking to permit suppression of their target mRNAs has not been described. Here, we show that direct ASO engagement with a scavenger receptor (CD44) activates the ERK-RSK axis to promote serine phosphorylation of a receptor tyrosine kinase (EPHA2). Serine phosphorylation of EPHA2 permits endocytosis, trafficking, and accumulation of ASOs in nuclear-captured endosomes. These endosomes are then subject to lipid peroxidation and become leaky, allowing ASOs to escape and effectively suppress target mRNA expression. Inhibition of stress granule-mediated repair of these leaky endosomes further enhances ASO effectiveness. These data identify an endocytic route to the nucleus which may be exploited to maximize the effectiveness of ASO-mediated therapies.

BACKGROUND AND AIMS:Cholangiocarcinoma (CCA) is an aggressive cancer with rising incidence and mortality worldwide. Chronic liver disease (CLD) is a well-recognized risk factor, but its influence on tumor presentation and clinical outcomes remains unclear. We aimed to compare the clinical course of CCA in patients with and without CLD. METHODS:We retrospectively analyzed 3,743 patients diagnosed with CCA between 2010 and 2024 across international centers. CLD was defined by documented primary sclerosing cholangitis, cirrhosis, viral hepatitis, or other chronic liver disorders; remaining patients were classified as non-CLD. Demographic, clinical, biochemical, treatment, and survival features were compared. RESULTS:Among the CCA cohort, 993 patients had CLD. Compared with non-CLD patients (n=2,750), those with CLD were more frequently male (67% vs. 53%) and younger (median age 63 vs. 66 years). CLD-CCA patients more often presented with intrahepatic tumors (64% vs. 42%), better performance status (ECOG 0: 53% vs. 35%), lower CA19.9 levels (56 vs. 135 U/mL), and earlier-stage disease (localized: 57% vs. 43%; metastatic: 23% vs. 31%). In propensity score-matched analyses, patients with prior CLD were diagnosed at earlier CCA stages than non-CLD controls. Consequently, curative-intent tumor surgery was performed more frequently in CLD patients (60% vs. 48%), resulting into longer median overall survival (mOS 12.2 vs. 11.1 months; HR 0.88, 95%CI 0.80-0.98) and higher 5-year survival (OR 1.70, 95%CI 1.37-2.11), particularly in intrahepatic CCA (mOS: 14.2 vs. 11.1 months; HR 0.77, 95%CI 0.68-0.87; 5-year survival OR 2.19, 95%CI 1.60-3.01). Treatment responses across modalities were comparable between groups. CONCLUSION:Pre-existing CLD is associated with earlier-stage CCA diagnosis and improved survival, supporting the implementation of structured surveillance strategies in high-risk CLD populations. IMPACT AND IMPLICATIONS:This international multicenter study show that pre-existing CLD is associated with earlier-stage CCA diagnosis, likely due to closer clinical surveillance, greater eligibility for curative-intent surgery, and improved survival. Treatment responses were similar regardless of CLD status. These findings support established surveillance in high-risk groups and highlight the need to optimize strategies for selected moderate-to-high risk CLD populations, alongside prospective evaluation of their clinical utility, cost-effectiveness, and potential refinement through more accurate non-invasive biomarkers.

Pathology is central to many biologically driven cancer clinical trials. Biomarker-led and translational studies depend on robust tissue pathways, cellular and molecular assays, pathology-derived endpoints, and clinically meaningful interpretation of discovery science. Where trials depend on tumour material, biomarker-defined eligibility or mechanism-focused endpoints, pathology expertise should be embedded early, before protocols, budgets, and assays are fixed. Early pathology input strengthens feasibility, specimen governance, assay selection, quality assurance, and the long-term value of collected samples. In the UK, the Clinical Trials Pathology Advisory Group, now within the new Pathological Society of Great Britain and Ireland Clinical Trials Pathology subcommittee, provides a practical route for pre-submission specialist review. This Perspective argues that pathology is core infrastructure for biologically rich trials, linking discovery science to clinical translation.

Surgery after response to first-line chemoimmunotherapy may offer a potential curative option for patients with locally advanced biliary tract cancer (BTC) initially considered unresectable. However, robust real-world evidence in this setting remains limited. We retrospectively analyzed patients with locally advanced BTC treated with first-line cisplatin, gemcitabine, and durvalumab (CGD) across 55 centers in 12 countries. Endpoints included overall survival (OS), progression-free survival (PFS), disease-free survival (DFS) among resected patients, objective response rate (ORR), and the prognostic impact of surgery. A multivariable logistic regression model was developed to predict surgical conversion using baseline clinical and laboratory variables. Among 1358 screened patients, 219 had locally advanced disease and were included in the analysis. Median follow-up was 14.5 months. ORR was 34.6%, with median PFS and OS of 10.0 and 20.7 months, respectively. Twenty-four patients (10.9%) underwent surgical resection after systemic therapy. Median OS was 22.5 months in resected patients versus 19.9 months in those who did not undergo surgery. Median DFS after resection was 15.8 months. Pathological lymph node involvement was independently associated with shorter DFS. Larger baseline tumor size correlated with higher odds of radiological response but not with OS. An exploratory elastic-net model retained four baseline variables and showed moderate discriminative ability for surgical conversion, with an apparent AUC of 0.72 and an optimism-corrected AUC of 0.65. First-line CGD enabled secondary resection in approximately 11% of patients with locally advanced BTC. A simple baseline model may support patient selection for conversion surgery, although prospective validation is needed.

Importance:Gastrointestinal stromal tumors (GISTs) harboring KIT exon 9 mutations represent a biologically distinct subgroup with reduced sensitivity to standard-dose imatinib in the advanced setting. The benefit of adjuvant imatinib in this population remains uncertain. Objective:To evaluate the association between adjuvant imatinib and recurrence-free survival (RFS) and overall survival (OS) in patients with resected GISTs with KIT exon 9 mutations. Design, Setting, and Participants:This international, multicenter cohort study included patients with localized, molecularly confirmed GISTs with KIT exon 9 mutations who underwent curative-intent surgery between January 1990 and July 2022 at 35 referral centers in Europe, the US, and Japan, or were registered in the Life Raft Group database. The analysis took place between January 2025 and November 2025. Exposures:Adjuvant imatinib initiated after curative surgery, modeled as a time-dependent covariate to account for immortal time bias. Main Outcomes and Measures:The primary end points were RFS (time from surgery to recurrence or death) and OS (time from surgery to death) in the full cohort and in the high-risk subgroup defined by modified National Institutes of Health (mNIH) criteria. Multivariable Cox regression models included established prognostic covariates and cluster-robust standard errors. Overlap weighting (OW) based on propensity scores was used as a causal inference model. Secondary analyses evaluated 400 mg/d vs 800 mg/d dosing in the mNIH high-risk subgroup. Results:A total of 367 patients were included, 187 (51.0%) male and 180 (49%) female, with a mean (SD) age of 56 (13) years. Among these, 91 (24.8%) were observed and 276 (75.2%) received adjuvant imatinib (median [IQR] duration, 27.3 [13.5-36.0] months; 116 [42.0%] treated ≥3 years). Consistent with a cytostatic activity, adjuvant imatinib in the full cohort was associated with a reduced early hazard of recurrence or death (HR, 0.19; 95% CI, 0.10-0.36), with attenuation over time (time-interaction hazard ratio [HR], 1.85 per log-year). Treatment was also associated with improved OS (HR, 0.37; 95% CI, 0.17-0.83). Similar results were obtained when limiting the analysis to patients with mNIH high-risk disease. OW models and sensitivity analyses confirmed similar associations with RFS and OS. Among 257 patients with mNIH high-risk disease receiving imatinib, no significant difference was observed between 400 mg/d and 800 mg/d dosing. Conclusion and relevance:In this large international cohort study of resected GISTs with KIT exon 9 mutations, adjuvant imatinib was independently associated with delayed recurrence and improved survival. These findings support the use of adjuvant imatinib in mNIH high-risk GISTs with KIT exon 9 mutations and underscore the need for prospective studies to define optimal dosing and treatment duration.

Background: Biliary tract cancers (BTCs) are aggressive malignancies with limited treatment options. The addition of durvalumab or pembrolizumab to cisplatin–gemcitabine improves overall survival (OS), but validated biomarkers of benefit remain limited. Immune-mediated adverse events (imAEs) have been proposed as treatment-emergent clinical correlates of immune activation. Methods: We retrospectively analyzed an international cohort of patients with locally advanced or metastatic BTC treated with first-line cisplatin–gemcitabine plus durvalumab. Primary endpoints were OS and progression-free survival (PFS). The principal exposure was the occurrence of any imAE. A post hoc complete-case Cox model was adjusted for age, sex, primary tumor site, prior surgery, ECOG performance status, disease stage, albumin, bilirubin, and neutrophil-to-lymphocyte ratio (NLR); analyses of individual AEs were exploratory. Exact AE onset dates were not consistently available, precluding a reliable formal time-dependent exposure analysis. Results: A total of 1358 patients were included; all received durvalumab, and 276 (20.3%) developed at least one imAE. In the fully baseline-adjusted model, any imAE remained associated with a lower risk of death (adjusted HR 0.72, 95% CI 0.57–0.92; p = 0.008) and progression or death (adjusted HR 0.63, 95% CI 0.52–0.77; p < 0.001). In exploratory baseline-adjusted analyses of individual imAEs, other imAEs remained associated with OS (HR 0.39, 95% CI 0.24–0.62; p < 0.001) and PFS (HR 0.56, 95% CI 0.40–0.77; p < 0.001), while hypothyroidism remained associated with PFS only (HR 0.65, 95% CI 0.43–0.97; p = 0.034); rash and hyperthyroidism were not independently associated after full baseline adjustment. In AE-focused exploratory models, decreased appetite and hyponatremia were associated with worse outcomes, neutropenia with better outcomes, and ALT elevation with worse PFS. Baseline corticosteroid use was uncommon (n = 21), and all steroid analyses are vulnerable to confounding by indication and exposure-timing bias. Conclusions: Treatment-emergent imAEs may represent potential prognostic markers or clinical correlates of benefit, but they are not validated surrogate endpoints. Prospective studies with precise AE-onset capture are required.

BACKGROUND:Currently, data concerning the prognostic impact of metastatic sites in biliary tract cancers (BTC) are limited. OBJECTIVE:The aim of the present study is to evaluate the prognostic impact of metastatic sites in patients with BTC treated with cisplatin-gemcitabine-durvalumab (CGD). PATIENTS AND METHODS:The study population comprised a large worldwide cohort of patients treated with CGD. The primary objectives were overall survival (OS) and progression-free survival (PFS) based on the location and number of metastatic sites. RESULTS:A total of 666 patients with locally advanced (111) or metastatic (555) BTC treated with CGD were included in the study. None of the metastatic sites were shown to have a prognostic impact on OS at multivariate analysis. Patients with one to two metastatic sites had longer OS (hazard ratio [HR] 0.59; p = 0.005) and PFS (HR 0.73; p = 0.03) compared with those with three to five metastatic sites in the univariate analysis but not in the multivariate analysis. No statistically significant differences were observed in OS or PFS across different metastatic sites limited to a single organ. Patients with progressive disease (PD) on first-line CGD with a change in metastatic sites from baseline showed no statistically significant differences in OS2 (defined as the time from PD on first-line therapy to death for any cause) compared with those without a change in metastatic sites (HR 0.88; p = 0.60). CONCLUSIONS:Our study did not show statistically significant differences in outcomes associated with location and number of metastatic sites in a large population of patients with BTC treated with CGD.

Cholangiocarcinomas (CCAs) are cancers that arise in the peripheral or central bile ducts. They have substantial heterogeneity in their etiologies and histopathologic phenotypes, ranging from cholangiolar carcinomas arising from the smallest bile ducts or from dedifferentiating hepatocytes through cellular plasticity, to ductular cancers in medium and large-sized bile ducts. The surgical delineation of intrahepatic, perihilar, and distal CCAs does not match the biological classification, as intrahepatic CCAs include both small duct cholangiolar carcinoma and intermediate duct ductular or mucinous CCAs, which have different genomic and genetic characteristics. Despite their overall poor prognosis, CCAs have proven to include the most actionable target-rich types of cancer, with intrahepatic CCAs including relatively high percentages of fibroblast growth factor receptor 2 fusions and isocitrate dehydrogenase 1 or 2 mutations, as well as other currently or potentially targetable aberrations. We discuss the etiologies and risk factors for CCAs, review the pathophysiologic basis for tumor molecular heterogeneity in CCA, and discuss the known links with mutational signatures in subgroups of CCA, such as oxidative stress, aging, and exogenous exposures. The potential roles of differences in cell type-specific replication timing and immunoselective and metabolic pressures are discussed, as are the implications of synergistic or antagonistic oncogenic effects, leading to unique patterns of co-occurrence vs mutual exclusivity of alterations. In addition, we review the impacts of common genetic variants and known pathogenic germline or somatic variants that predispose carriers to CCA. Finally, we discuss the role of epigenetics and variations in DNA methylation in heterogeneity of CCA within the context of evolving treatment options and remaining key gaps in knowledge.

BACKGROUND & AIMS:Targeted therapies for biliary tract cancers (BTC) are approved in the second-line setting. We investigated response to first-line platinum-based palliative systemic anti-cancer treatment in patients with the most common druggable alterations to determine the optimal positioning of targeted therapies in the treatment algorithm. METHODS:Patients treated at the Beatson West of Scotland centralized BTC clinic who underwent genomic profiling were retrospectively selected; those with the most common actionable alterations who received platinum-based treatment were included in clinical analyses. Observations were supported by tracking IDH1 mutations with digital droplet PCR on longitudinal cell-free DNA samples. RESULTS:Druggable alterations were identified in 39.7% of patients; HER2 overexpression/amplification and IDH1 R132 mutations were the most commonly identified alterations. Compared to patients with HER2-positive tumors (n = 11), patients with IDH1 R132 mutations (n = 6) had longer median time to best response (5.99 vs. 2.5 months; hazard ratio [HR] 0.28; 95% CI 0.09-0.91; p = 0.0033), and median time to progression (17.2 vs. 5.6 months; HR 0.266; 95% CI 0.0955-0.741; p = 0.0075). Compared to a cohort of patients without either alteration, those with IDH1-mutated BTC had longer median overall survival (HR 0.30; 95% CI 0.14-0.67; p = 0.0229); those with HER2-positive BTC showed a worse median time to progression (HR 1.97; 95% CI 0.85-4.58; p = 0.0408) and a trend towards worse median overall survival (HR 1.38; 95% CI 0.61-3.13; p = 0.3884). IDH1 variant allele frequency decreased during first-line treatment, regardless of response; prolonged benefit from ivosidenib in the second line was observed when variant allele frequency was <1 at the start of targeted treatment. CONCLUSIONS:These preliminary data suggest that targeted therapies may need to be introduced earlier, including in the first-line setting, with strategies tailored to specific molecular alterations. Access to platinum-based palliative systemic anti-cancer treatment remains particularly important for patients with IDH1-mutated BTC. IMPACT AND IMPLICATIONS:We conducted an analysis to determine whether patients with biliary tract cancer harboring the most common actionable alterations (i.e. IDH1 R132 mutations and HER2 overexpression or amplification) had different patterns of response to first-line platinum-based chemo(immuno)therapy. The goal was to determine whether the introduction of targeted therapies in the first-line setting should be tailored based on the alteration detected. In our cohort, patients with IDH1 R132 mutations experienced durable benefit from platinum-based chemotherapy, while those with HER2-positive tumors only experienced a short-lived benefit from it. Although these findings are exploratory and limited by small sample size, they may inform future strategies for earlier integration of targeted therapies and support the design of prospective clinical trials.

The development of Next-Generation Sequencing (NGS) techniques for extended genomic profiling has led to the identification of actionable molecular alterations in approximately half of the patients with biliary tract cancer (BTC), with the highest incidences among those with intrahepatic cholangiocarcinoma. Targeted drugs have demonstrated the ability to confer clinical benefit while maintaining a manageable safety profile. As a result, despite the lack of a head-to-head comparison with standard second-line chemotherapy, they are now recommended for patients with advanced disease who are still fit after progression to first-line palliative systemic anti-cancer treatment. In this review, we will contextualize the results observed with targeted drugs in clinical trials within the framework of clinical practice. We will provide an overview of available single-gene analyses that should be considered in case of lack of access to NGS, defining testing priorities, differences in yields, and therapeutic implications. Lastly, we will discuss future perspectives in the field of precision medicine for BTC, focusing on new strategies to overcome treatment resistance, on the optimal collocation of targeted drugs in the treatment algorithm, and on newly identified actionable alterations for which compounds are currently under investigation.

Background: Durvalumab (anti-PD-L1) in combination with gemcitabine and cisplatin has become the first-line treatment for patients with locally advanced, surgically unresectable, or metastatic biliary tract cancer, following the survival benefit demonstrated in the TOPAZ-1 phase III trial. This study presents real-world data from UK centres in patients who received early access to the regimen via AstraZeneca's scheme. The aim was to assess the safety and efficacy of this treatment approach in routine clinical practice and compare it to outcomes reported in the TOPAZ-1 trial. Method: This retrospective study included patients with locally advanced, surgically unresectable, or metastatic biliary tract adenocarcinoma who received durvalumab in combination with gemcitabine and cisplatin. Data were collected across ten UK centres. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), overall response rate (ORR), and safety outcomes, encompassing both chemotherapy and immunotherapy-related adverse events (AEs). Results: A total of 134 patients treated between April 2022 and December 2023 were included. The median follow-up was 12.8 months (95% CI: 11-16.8). The median PFS was 8.83 months (95% CI: 5.73-11.7), closely aligning with the 7.2 months reported in TOPAZ-1 (95% CI: 6.7-7.4). The median OS was 12 months (95% CI: 10.7-13.9), slightly below the 12.8 months observed in TOPAZ-1 (95% CI: 11.1-14.0). The ORR was 29.1% (TOPAZ-1: 26.7%), and the disease control rate was 61.2%. In terms of safety, 64 patients (52.3%) experienced any-grade AEs, and 9 patients (6.8%) had grade 3-4 AEs, representing a lower toxicity profile than TOPAZ-1. Immunotherapy-related AEs occurred in 25 patients (18.7%), with grade 3-4 events in 3%. Conclusions: These real-world findings from UK cancer centres support the outcomes of the TOPAZ-1 trial, demonstrating comparable efficacy and a favourable safety profile for durvalumab combined with gemcitabine-cisplatin as first-line treatment for advanced biliary tract cancer.

In recent years, treatment options for patients with advanced biliary tract cancer (BTC) have increased significantly due to the positive results from phase 2/3 clinical trials of immune checkpoint inhibitors, combined with chemotherapy, and molecularly targeted agents. These advances have led to the need for molecular testing to identify actionable alterations and patients amenable to targeted therapies. However, these improvements have brought with them many questions and challenges, including the identification of resistance mechanisms and therapeutic sequences. In this Series paper we aim to provide an overview of the current systemic treatment options for patients with BTC, highlighting disparities in access to innovative treatments and molecular testing across European countries, which lead to inequalities in the possibilities of treating patients with advanced BTC. We also discuss how ongoing European collaborative projects, such as the COST Action Precision-BTC-Network CA22125, supported by COST (European Cooperation in Science and Technology), linked to the European Network for the Study of Cholangiocarcinoma (ENSCCA), can help overcome these disparities and improve the current scenario.

BACKGROUND & AIMS:Patients with cholangiocarcinoma (CCA) have poor prognosis. Current cisplatin-based first-line chemotherapy offers limited survival benefit. Cisplatin induces single-strand DNA breaks, activating DNA repair mechanisms that diminish its effectiveness. Here, we present the design, chemical synthesis, and therapeutic evaluation of a new generation of chemotherapeutic agents (Aurkines) with unique polyelectrophilic properties. These agents cause a high frequency of double-strand DNA breaks, bypassing DNA repair, and promoting cancer cell death. METHODS:Two novel compounds, Aurkine 16 and Aurkine 18, were designed and evaluated for their antitumor effects in both naïve and cisplatin-resistant CCA cells, cancer-associated fibroblasts, healthy cholangiocytes, and in vivo models. RESULTS:Aurkines effectively induced double-strand DNA breaks, leading to increased DNA damage and elevated levels of reactive oxygen species, resulting in greater cytotoxicity than cisplatin in CCA cells. Phosphoproteomic and molecular analysis revealed that cisplatin activates DNA repair pathways, while Aurkines primarily induce apoptosis. Importantly, Aurkines also triggered apoptosis in cisplatin-resistant CCA cells and cancer-associated fibroblasts without harming healthy cholangiocytes. Additionally, Aurkines demonstrated cytotoxicity in other cisplatin-resistant cancers, such as breast and ovarian cancer. This tumor selectivity results from reduced uptake, increased efflux, and compact chromatin structure in normal cells, limiting Aurkine-DNA interactions. In vivo, Aurkines inhibited the growth of subcutaneous naïve and cisplatin-resistant CCA tumors, as well as orthotopic tumors in immunocompetent mice, promoting antitumor immune cell recruitment without any adverse events. Transport studies revealed that Aurkines were selectively taken up by OCT1, OCT3, CTR1, and OATP1A2, whereas only CTR1 transported cisplatin. CONCLUSIONS:Aurkines represent promising therapeutic drugs for both naïve and cisplatin-resistant cancers due to their unique polyelectrophilic properties and selective targeting of malignant cells. IMPACT AND IMPLICATIONS:This study introduces a novel therapeutic strategy designed to induce frequent double-strand DNA breaks selectively in both naïve and cisplatin-resistant cancer cells, without evident toxic side effects at therapeutic doses. This approach may form the basis for new strategies to overcome the critical challenge of drug resistance in cancer treatment and has the potential to be a breakthrough not only for the treatment of biliary tumors but also for other cancers.

Pathogens are major drivers of cancer globally and the processes of infection and carcinogenesis unfold over decades making them difficult to observe in human or natural populations. We investigate these hidden dynamics for the foodborne trematode Opisthorchis viverrini, which is a primary cause of biliary cancer (cholangiocarcinoma) and infects 12 million people in Southeast Asia. In tumors from patients exposed to O. viverrini, we find that the earliest chromosomal amplifications carrying driver genes occurred at 30 y old on average, two to four decades before cancer diagnosis, and disproportionately contain TP53, PTEN and FGFR2 genes. We then fitted transmission models to parasitological data from Thailand spanning 27 y (n = 11,517) finding that, for people born between 1960 and 1989, first exposure occurred at two years old and by 30 y individuals had been cumulatively infected with a median of 72 worms. Trematodes are long-lived and our analysis quantifies the average lifespan of O. viverrini as 13 y (90% credible interval [CrI] 7 to 26 y) within human hosts. The lifetime probability of diagnosis with cholangiocarcinoma is 4.9% (90% CrI 4.7 to 5.0%) given prior exposure to O. viverrini, which is fourteen-fold higher than in populations nonendemic for the parasite. We find strong evidence for a dramatic decline in parasite transmission from 1990 onward in Thailand, suggesting that the incidence of cholangiocarcinoma will decline over the coming decades. Our study demonstrates how pathogen exposure drives patterns of cancer within a population and provides evidence for public health and therapeutic interventions.

Standard of care first-line systemic treatment for advanced biliary tract cancer includes chemo-immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo-immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo-immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty-eight patients were included in this study. Two hundred twenty-seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first-line chemo-immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil-to-lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.