Pancreatic ductal adenocarcinoma (PDAC) remains clinically managed largely through anatomical stage and performance status, despite major inter-patient heterogeneity and dynamic pathway adaptation during progression. In this review, we propose a hypothesis-generating, stage-aware framework in which clinical stage and established molecular subtypes are considered complementary rather than competing stratification axes. Stage-resolved transcriptomic modeling identified a directional separation across up-front resectable, borderline/locally advanced, primary metastatic and liver metastatic samples, with PC1 explaining 51.1% of the variance and separating early from metastatic states, whereas PC2 explained 30.2% and captured immune/stromal remodeling. We interpret these observations cautiously as pathway-level signals that require functional and clinical validation, not as an established biological paradigm. The model suggests a transition from MAPK-enriched, proliferative and partially immune-competent tumors toward metastatic ecosystems characterized by PI3K-AKT-mTOR engagement, MYC amplification, mitochondrial metabolism, proteostasis support and immune exclusion. We further distinguish approved standards, negative clinical experiences, early clinical signals and preclinical hypotheses. The central conclusion is that PDAC therapeutic stratification should integrate stage, molecular subtype, treatment line, tissue context and evidence level before pathway-directed interventions are clinically prioritized. Accordingly, this review should be read as a translational prioritization framework rather than as a treatment algorithm: it organizes where pathway-directed hypotheses are most biologically plausible, where they are clinically supported, and where they remain insufficiently validated for routine decision-making.

BACKGROUND & AIMS:Biliary tract cancers (BTCs) are rare, heterogeneous tumors associated with a poor prognosis, even after curative-intent surgery. Adjuvant capecitabine is currently the standard of care; however, real-world data on its efficacy and tolerance are lacking. PATIENTS AND METHODS:This French, retrospective, multicentre study, nested within the ACABi-PRONOBIL observational cohort, assessed adjuvant capecitabine efficacy in patients, with resected intrahepatic, perihilar, distal cholangiocarcinoma, or gallbladder carcinoma. who had not received prior systemic therapy. Patients treated with adjuvant capecitabine after 2017 were compared with patients diagnosed before 2017 and managed with surveillance only. The primary endpoint was overall survival (OS), secondary endpoints were recurrence-free survival (RFS) and toxicity. Inverse probability of treatment weighting (IPTW) in Cox regressions was used to adjust for measured confounding, imbalanced factors between groups. RESULTS:A total of 320 patients were included (197 in the capecitabine group and 123 in the surveillance group). In IPTW analysis, adjuvant capecitabine was not significantly associated with improved RFS (IPTW HR, 0.81, CI 95%, 0.54-1.21; p = 0.304), or OS (IPTW HR, 0.94, CI 95%, 0.58-1.52; p = 0.798). The point estimate for RFS was consistent with the ITT analysis of the BILCAP trial. In the capecitabine group, 49% of patients required at least one dose reduction, and 35.7% discontinued treatment due to mainly grade 3/4 gastrointestinal (13.4%) and cutaneous (25.8%) toxicities. CONCLUSIONS:In this real-world cohort, adjuvant capecitabine was not significantly associated with improved RFS or OS in patients undergoing curative-intent resection for BTC, although a numerical trend in favor of capecitabine for RFS. These findings support the need for refined patient selection strategies and for prospective evaluation of novel adjuvant approaches. CLINICAL TRIAL REGISTRATION:NCT04935853 IMPACT AND IMPLICATIONS: This multicentre real-world study - BILCAP real study provides important complementary evidence to randomized trials by evaluating the effectiveness and tolerability of adjuvant capecitabine for resected biliary tract cancers in routine clinical practice.Although no statistically significant survival benefit was observed, the consistency of the recurrence-free survival estimate with the intention-to-treat results of the BILCAP trial and the observed toxicity profile provide clinically relevant information for physicians, patients, and multidisciplinary teams involved in postoperative treatment decisions.These findings support shared decision-making by helping clinicians balance the potential benefit of delaying recurrence against the risk of treatment-related toxicity, while emphasizing the need for careful patient selection and toxicity management in daily practice.Given the retrospective design and the possibility of residual confounding despite propensity-score adjustment, these results should be interpreted cautiously and primarily serve to inform the design of future biomarker-driven and prospective adjuvant studies rather than to change current clinical practice.

Background: Transcriptomic FOLFIRINOX-component sensitivity signatures have been clinically evaluated in resected and advanced PDAC, but their relevance and longitudinal stability in the neoadjuvant BR/LA setting are unknown. Patients and methods: We retrospectively studied 77 patients with borderline resectable or locally advanced PDAC treated with neoadjuvant FOLFIRINOX followed by resection. Pretreatment sensitivity to 5-fluorouracil, oxaliplatin and irinotecan was determined using previously developed locked transcriptomic classifiers and integrated into a regimen-level FOLFIRINOX classification. The primary molecular cohort comprised 53 patients whose pretreatment biopsies had ≥10% tumour cellularity. Cox models assessed associations with survival. Longitudinal changes were assessed in 35 paired tumours. Results: Thirty-one pretreatment tumours were classified as FOLFIRINOX-sensitive (FFX-Sens), and 22 were not classified as FOLFIRINOX-sensitive (FFX-Res). FFX-Sens status was associated with longer overall survival (OS; hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.25-0.93; p=0.029). In the complete-case model adjusted for baseline carbohydrate antigen 19-9 (CA19-9) and tumour size (n=50), the association with OS persisted (adjusted HR 0.47, 95% CI 0.23-0.96; p=0.037), whereas the adjusted association with disease-free survival was not statistically significant (adjusted HR 0.55, 95% CI 0.28-1.10; p=0.090). Among paired tumours, 15 changed from FFX-Sens to FFX-Res and four in the opposite direction (exact McNemar p=0.019). The OS association also persisted after adjustment for postoperative pathological factors (adjusted HR 0.40; p=0.015). Conclusions: Pretreatment FOLFIRINOX sensitivity was associated with OS under neoadjuvant FOLFIRINOX, while matched pretreatment and residual-tumour analyses revealed significant directional reclassification after treatment. These findings extend the clinical evaluation of validated drug-specific FOLFIRINOX sensitivity classifiers to the neoadjuvant setting and provide a longitudinal assessment of their stability during treatment. They support prospective evaluation of both pretreatment stratification and molecular reassessment of residual disease.

Pancreatic ductal adenocarcinoma shows early dissemination, stromal remodeling, and therapy resistance, but how tumor programs co-evolve with immune and stromal changes across stages remains unclear. We built a stage-resolved transcriptomic atlas using bulk RNA sequencing of FFPE samples from 443 untreated tumors spanning resectable, locally advanced, primary metastatic, and liver metastatic disease. Integrative modeling identified ten transcriptional programs with monotonic dynamics during progression. Early stages were enriched for epithelial differentiation and immune-stimulatory signals. Advanced stages showed increased cytoskeletal remodeling, vesicular trafficking, oxidative stress responses, and mitochondrial metabolism. Pathway analysis revealed enhanced PI3K-AKT-mTOR signaling and MYC target engagement in metastatic disease. Immune deconvolution showed loss of CD8+ T cells, dendritic cells, and M1 macrophages. Compact gene signatures stratified stage and survival and generalized to TCGA and ICGC cohorts. Functional assays confirmed greater invasiveness, altered redox balance, and mitochondrial dependence in advanced disease, suggesting stage-associated metabolic vulnerabilities.

Single-cell RNA sequencing is a powerful approach for characterising cellular heterogeneity and elucidating transcriptional programs that drive tumour plasticity, therapeutic resistance, and disease progression. In this study, we present a single-cell transcriptomic dataset comprising 41 patient-derived cell cultures (PDCs) established from pancreatic ductal adenocarcinoma (PDAC). The dataset was generated using Evercode™ technology, which is based on Split Pool Ligation-based Transcriptome sequencing (SPLiT-seq). This scalable method enables high-throughput profiling across multiple samples without droplet-based microfluidics, allowing efficient capture of inter-sample heterogeneity. This functionally annotated collection of experimentally derived models reveals transcriptional heterogeneity both within and across PDCs, enabling in-depth exploration of PDAC cell diversity, to support the development of computational tools for single-cell analysis, and to guide functional studies on tumour cell subpopulations. This resource constitutes a valuable reference for computational and experimental studies aiming to decipher PDAC heterogeneity and identify therapeutic vulnerabilities.

Signal-driven relocation of GalNAc-transferases (GALNTs) from the Golgi to the ER, termed GALA, promotes tumour growth, but its effects on glycosylation are unclear. Unlike N-glycosylation, which is co-translational, O-glycosylation initiates post-translationally in the Golgi. Here we show that GALA subverts this arrangement in pancreatic ductal adenocarcinomas (PDAC) and in murine pancreatic tumours, where it stimulates growth. Quantitative glycoproteomics on a cellular model reveals a substantial expansion of the O-glycoproteome, consisting in thousands of sites across hundreds of proteins, ER-resident proteins, cell-surface receptors, secreted factors, and extracellular matrix components. Profiling of murine tumours and patient-derived xenografts confirms widespread activation and cross-species conservation of glycosylation patterns. Structural analysis reveals that GALA-specific residues have solvent accessibility as low as N-glycosylation sites, and below Golgi O-glycosylation or phosphorylation sites, indicating that ER O-glycosylation occurs co-translationally. By inverting the normal temporal sequence of folding and glycosylation, cancer cells generate alternative glycoforms that foster tumour growth.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with poor prognosis and limited therapeutic options. Early biomarkers for the detection and prediction of treatment response are sorely lacking. The tumour secretome, the set of proteins released by cancer cells, represents a promising source of biomarkers and provides insights into tumour biology, as these factors may be detectable in blood and suitable for non-invasive monitoring. However, most secretome studies have relied on established cell lines or mouse models, poorly reflecting human tumour heterogeneity. To address this gap, we generated a comprehensive proteomic dataset of secretomes from 48 low-passage, treatment-naïve, patient-derived primary PDAC cultures, which retain the molecular and phenotypic features of their tumours of origin. Across samples, we identified 4,204 proteins, including 793 shared by all cultures. Annotation showed that most of these proteins matched extracellular vesicle contents and canonical secreted proteins that may reach the circulation. Consequently, this dataset provides a valuable resource for the identification of circulating biomarkers and for comparative analyses of PDAC secretomes.

Abstract Purpose This study evaluated the effectiveness, safety, and dosimetry of selective internal radiation therapy with Y90 in a real-world clinical setting. Herein, we present the final data for iCCA. Materials and methods All patients treated with yttrium-90 (Y90) glass microspheres (TheraSphere™) across 34 French institutions who agreed to data collection were included. Overall survival (OS) was assessed by Kaplan-Meier analysis. Adverse events (AEs) were assessed using CTCAE v5. Results Among 207 intrahepatic cholangiocarcinoma (iCCA) patients, key baseline and treatment characteristics were: fibrosis/cirrhosis (31.8%), solitary lesion (52.7%), treatment-naïve (52.2%), prior treatment (37.2%; systemic, n = 70; locoregional, n = 7; surgery, n = 10), concomitant treatment (33.8%; mainly gemcitabine and/or cisplatin); multicompartment dosimetry (68.1%), and selective treatment administration (58.9%). Median index lesion (IL) size was 7.0 cm according to RECIST 1.1 and central read. Mean pretreatment absorbed dose to the IL was 357.03 Gy. Median OS was 21.9 months (M). By subgroup, median OS was 23.3M without cirrhosis/fibrosis versus 19.8M with cirrhosis/fibrosis; 23.3M in treatment-naïve patients versus 11.4M in recurrent disease; 21.3M without concomitant treatment versus 21.9M with concomitant treatment; 22.6M in IL tumors ≤7cm versus 23.7M in > 7cm tumors. Patients with surgery had the greatest survival benefit (n = 27; median not reached) compared to patients with subsequent treatment excluding surgery (n = 90; 21.3M), and no subsequent treatment (n = 76; 17.4M). In total, 18 Grade ≥3 AEs and 18 serious AEs were reported. Conclusion This real-world study demonstrates an acceptable safety profile and meaningful survival including patients with cirrhosis and confirms that Y90 should be considered for iCCA patients.

BACKGROUND:Ampullary adenocarcinoma (AAC) is a rare and aggressive cancer with a 5-year overall survival (OS) rate ranging from 30% to 67% after resection due to a high recurrence rate. Yet, adjuvant therapy's role is still debated. Recent French FFCD-AC cohort study highlighted that adjuvant therapy, can benefit intermediate and high-risk patients. Chemotherapy regimens, include gemcitabine and 5-fluorouracil (5FU) but practices are highly heterogenous due to the low level of evidence. Previous studies suggest that combination chemotherapy, such as mFOLFIRINOX, could offer improved outcomes. DESIGN:PRODIGE 98 - AMPIRINOX trial (NCT06813976) is a multicenter, open-label, randomized phase 3 trial designed to compare the efficacy of adjuvant mFOLFIRINOX versus single-agent chemotherapy (capecitabine or gemcitabine) in patients with resected AAC. Primary outcome is disease free survival and secondary outcomes include overall survival (OS), safety and quality of life. Patients (ages 18-79) must have undergone macroscopically complete (R0/R1) resection of AAC, with exclusion of patients previously treated with chemotherapy, and pT1N0M0 tumors. Ancillary studies will focus on an in-depth molecular profiling of AAC to identify prognostic and predictive biomarkers. AMPIRINOX is currently recruiting and is expected to provide essential data on how to optimize treatment for AAC patients in the coming years.

Abstract Circulating tumor cells (CTCs) are the potential seeds of distant metastases; however, little is known about how they survive in the bloodstream. Using a large cohort of colorectal cancer (CRC) patients, we found that the pseudokinase receptor PTK7 is highly expressed in primary tumors and metastatic lesions. Consistent with previous reports, high PTK7 expression is associated with reduced disease-free survival and increased metastatic dissemination. Surprisingly, PTK7 is absent from most CTCs and undergoes a cell-autonomous ON tumor /OFF CTC /ON metastasis switch that can be recapitulated in a xenografted mouse model, in in vitro systems, and a fluidic platform. PTK7-negative cancer cells exhibit increased expression of YAP1-driven genes, senescence-like features, and enhanced resistance to hemodynamic stress following loss of cell-cell and cell-matrix adhesion. This adaptive phenotype depends on metalloproteases, notably ADAM17, whose cleavage activity remodels the CTCs surfaceome. Functionally, the PTK7 OFF CTC state confers enhanced metastatic potential in vivo , and can be pharmacologically suppressed using metalloprotease inhibitors. Collectively, our findings identify a reversible, cell-autonomous, protease-driven surfaceome remodeling program that enables metastatic adaptation during hematogenous dissemination. Highlights / statement of significance By investigating potential markers for circulating colorectal tumor cells with strong metastatic potential, we describe a reversible and cell-autonomous remodeling of the circulating tumor cell surfaceome in patients that confers resistance to anoikis and stress induced by entry into the bloodstream. One Sentence Summary The dynamic regulation of PTK7 serves as a surrogate marker for tumor cell plasticity, aggressiveness, survival in the bloodstream, and efficiency in forming metastases. Trial registration CTC colon Cohort: registered on https://ClinicalTrials.gov identifier NCT03256084 ; date of registration 2017-07-17 B-Org cohort: registered on https://ClinicalTrials.gov NCT05384184 ; date of registration 2019-06-06 Ethics statement for animal experiments Studies on animals were conducted in accordance with the current ethical standards of the European Community (Directive 2010/63/EU), the Ethics Committee for Animal Experimentation (CEEA#14) and the French Ministry of Higher Education and Research, which approved and authorized the entire procedure described in this paper (project number APAFIS #35294).

Pancreatic ductal adenocarcinoma shows early dissemination, stromal remodeling, and therapy resistance, but how tumor programs co-evolve with immune and stromal changes across stages remains unclear. We built a stage-resolved transcriptomic atlas using bulk RNA sequencing of FFPE samples from 443 untreated tumors spanning resectable, locally advanced, primary metastatic, and liver metastatic disease. Integrative modeling identified ten transcriptional programs with monotonic dynamics during progression. Early stages were enriched for epithelial differentiation and immune-stimulatory signals. Advanced stages showed increased cytoskeletal remodeling, vesicular trafficking, oxidative stress responses, and mitochondrial metabolism. Pathway analysis revealed enhanced PI3K-AKT-mTOR signaling and MYC target engagement in metastatic disease. Immune deconvolution showed loss of CD8+ T cells, dendritic cells, and M1 macrophages. Compact gene signatures stratified stage and survival and generalized to TCGA and ICGC cohorts. Functional assays confirmed greater invasiveness, altered redox balance, and mitochondrial dependence in advanced disease, suggesting stage-associated metabolic vulnerabilities.

Pancreatic cancer is a rising cause of cancer death. Therapeutic options are scarce and of limited efficacy. Up to 26% of patients with metastatic pancreatic cancer could benefit from targeted therapies. We report here for the first time the case of three patients with metastatic pancreatic ductal adenocarcinoma (PDAC) without KRAS alteration for whom an activating mutation in exon 19 of the epidermal growth factor receptor ( EGFR ) gene was found through mainstreaming NGS. The EGFR variant was confirmed on multiple tumor samples and by circulating tumor DNA (ctDNA) analysis in two patients. The three patients were treated with osimertinib with early molecular, biologic, and morpho-metabolic responses. At the last follow-up, one patient had an ongoing response after 17 months, and disease control had been maintained for 8 and 6 months in the other two. Known resistance mechanisms were observed on ctDNA analysis at progression. These observations demonstrate the benefit of osimertinib for treating EGFR -mutated PDAC and highlight the interest in investigating rare molecular alterations, especially in patients without KRAS alterations.

PURPOSE For elderly patients with pancreatic ductal adenocarcinoma (PDAC), FOLFIRINOX (FFX) is often contraindicated due to frequent grade III adverse events (AEs) limiting available data on this population. MATERIALS AND METHODS This retrospective single-center study identified patients older than70 years treated with FFX for PDAC (2011-2022). Tumor, G8 score calculation (score <14/17 indicates geriatric examination), geriatric, and nutritional parameters were collected. The primary end point was toxicity, defined as grade ≥3 GI AEs or unplanned hospitalization. Overall survival (OS) and toxicity associated factors were analyzed using Cox regression with stepwise selection. RESULTS We included 142 patients: 73 with metastatic PDAC (mPDAC) and 69 with non-mPDAC (nmPDAC). Median age was 74 years (71-84), with 43% age 75 years and older. 80% had Eastern Cooperative Oncology Group 0-1. G8 score ≤14 and severe malnutrition were more frequent in mPDAC (82% and 51%) than in nmPDAC (64% and 27%). Low muscle mass was present in >80% of cases. Median FFX exposure was four cycles in mPDAC and 4.5 in nmPDAC. Overall, 56% experienced toxicity, including two treatment-related deaths. Frequent grade ≥3 AEs included infections (26%), nausea/vomiting (22%), and diarrhea (18%). Early toxicity within 2 months was associated with worse OS. Factors linked to toxicity included metastatic status (hazard ratio [HR], 2.41) and psychiatric comorbidities (HR, 6.96), while cardiovascular disease (HR, 0.35) and history of cancer (HR, 0.22) were protective. In nmPDAC, multidimensional geriatric assessment (MGA) reduced toxicity in G8 ≤ 14 patients. CONCLUSION FFX is feasible in highly selected elderly patients with PDAC. Severe toxicity remains frequent and proactive supportive care—including MGA in cases of G8 ≤ 14—to avoid early severe toxicity that impact significantly survival.

BACKGROUND:Immune checkpoint inhibitors (ICIs) significantly improve survival in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI) tumors. In 2022, ICIs were approved as first-line treatment with chemotherapy for advanced biliary tract cancers (BTCs). MSI/dMMR BTC represents a rare subtype, and its response to ICIs remains poorly understood. This multicenter real-world study aimed to describe clinical characteristics and outcomes of those patients. METHODS:We retrospectively included all patients with MSI/dMMR BTC treated at 23 French centers. Primary endpoint was overall survival (mOS) from the initiation of ICIs. RESULTS:Between 2012 and 2023, 48 patients with MSI/dMMR BTC were included with a median follow-up of 25.1 months. Thirty-seven (77 %) patients received ICIs: 10 (27 %) in first-line combined with chemotherapy, 4 (11 %) as first-line monotherapy and 23 (62 %) in later lines (20 as monotherapy, 3 as double immunotherapy). From the initiation of ICIs, mOS was 40.9 months (CI95 %: 16.39-NR) and median progression-free survival (mPFS) was 11.24 months (CI95 %: 6.44-NR). Overall response rate was 36 % and disease control rate was 75 %. Grade 3-4 adverse events occurred in 15 % and 50 % of patients treated with ICIs without chemotherapy or with chemotherapy, respectively. Among patients with available molecular profiling (69 %), co-alterations were identified in 16 (48 %) patients, most frequently in TP53 (12 %), CDKN2A/B (12 %), KRAS (12 %), GNAS (9 %), FGFR2/3 (6 %), SMAD4 (6 %), and IDH1 (6 %) genes. CONCLUSION:This first real-world cohort study of patients with MSI/dMMR BTC demonstrated that ICI-based treatment offers a prolonged response and improved survival in this subgroup of BTC.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with chemotherapy as the mainstay but highly variable efficacy and toxicity. Current regimens, such as FOLFIRINOX and gemcitabine-based combinations, are selected empirically without validated biomarkers to guide choice. Several strategies have been explored to personalize therapy. Patient-derived organoids and molecular classifiers such as PurIST have improved biological understanding but have limited clinical applicability. More recently, predictive transcriptomic signatures have emerged as practical tools. GemPred identifies patients likely to benefit from adjuvant gemcitabine; GemCore, validated in both resected and metastatic tumors, is compatible with small biopsies; and Pancreas-View integrates multiple drug-specific predictors, including for all FOLFIRINOX components and gemcitabine, enhanced by AI. These approaches, retrospectively validated in large cohorts and clinical trials, consistently link predicted sensitivity with improved survival. Beyond regimen selection, signatures enable treatment de-escalation, optimize first-line choices, and identify multidrug-resistant tumors. Ongoing prospective trials will establish their feasibility, supporting transcriptomic profiling as a step toward precision chemotherapy in PDAC.