4232 Background: Phosphorous 32 microparticle ( 32 P) brachytherapy delivered by echoendoscopy (EUS) represents an innovative therapy in pancreatic cancer (PC). The device to implant it is approved in unresectable locally advanced PC in combination with gemcitabine-based chemotherapy. Our aim is to present the preliminary efficacy and safety results of a series that brings together the experience of thirteen centres in Spain. Methods: After being assessed by a multidisciplinary committee, patients signed consent to receive intratumoural 32 P by EUS. Complications associated with intratumoural 32P injection via EUS, associated adverse events (AEs) and preliminary efficacy results (progression-free survival [PFS], distant and locoregional, and overall survival [OS]) were analysed. Results: Fifty one patients (32 females and 19 males; age 65.5 years [range 48, 84]; 36 ECOG 1 and 14 ECOG 0) with unresectable locally advanced PC (30 in head, 5 in uncinate, 5 in neck and 11 in body; tumour size 30.8 mm [range 12, 60]) were included. The median time from tumour diagnosis to procedure was 5.9 months [0, 28.9]. Twenty-four patients (47 %) had received at least one previous line of treatment; four had received two prior lines. Fifty patients (98%) received gemcitabine-based chemotherapy concomitant with intratumoural 32P (42 gemcitabine plus nabpaclitaxel; 8 gemcitabine monotherapy. There were two AEs related to 32P injection by EUS: G1 epigastric pain (1 patient) and G2 asthenia (1 patient). A total of 30 patients (58.8%) had chemotherapy-related AEs, with 8 cases of G3 neutropenia (1 febrile neutropenia) and/or G3 thrombopenia; 22 had G1-2 toxicities: neurotoxicity (5), asthenia (4), neutropenia (3), thrombopenia (2), anaemia (4), nausea (2), diarrhoea (2), anorexia (1), onycholysis (1), mucositis (1), and constipation (1). Seven patients (13,7%) underwent surgery after intratumoural treatment (5 R0 and 2 R1). With a median follow-up of 8.7 months after injection (range: 1.02 months to 40.77 months), 25 patients (49.2 %) have progressed, 19 of them distantly, and nine also locoregionally. The median PFS since 32P injection is 8.5 months (95% CI 5.3, 17). 33 patients are alive at the end of follow-up (64.7%) with a median OS since 32P injection of 15.6 months 95% CI [10.2, 26.9]. Conclusions: Our experience suggests that intratumoural 32P associated with gemcitabine-based chemotherapy is safe. Patients after 32P injection achieve long overall survival. Surgical rescue was achieved in a high percentages of initially unresectable cases.

To develop and internally validate the PANTHEIA-SIRI prognostic model, which integrates log-transformed systemic inflammation response index (SIRI) with clinical predictors, to estimate overall survival (OS) in metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with first-line chemotherapy. We used data from the multicenter PANTHEIA-SEOM registry. OS was defined from chemotherapy start. The model was fitted as a Weibull accelerated failure time model in the survival-analysis population with multiple imputation. Predictors were log-transformed baseline SIRI, modeled with restricted cubic splines, ECOG, tumor burden, chemotherapy regimen, and anorexia-cachexia syndrome. Internal validation used a separate, non-overlapping cohort from the same registry; the centers contributing to each cohort are listed in a supplementary annex. TRIPOD was followed. Discrimination was assessed with Harrell´s C-index and calibration with IPCW Brier scores and IPA. The derivation cohort comprised 672 patients with SIRI data (593 analyzed for survival) across 22 Spanish hospitals (2015–2025); 80.1 https://pantheia-siri.shinyapps.io/calc/ ) may support prognostic communication, treatment-intensity selection, and supportive-care planning. Routine clinical implementation will require further validation in larger, fully independent cohorts.

BACKGROUND:Systemic inflammation is a key driver of progression in pancreatic ductal adenocarcinoma (PDAC). We aimed to externally validate the Systemic Inflammation Response Index (SIRI) and define its non-linear prognostic value in a large multicenter cohort. METHODS:We analyzed 672 patients with metastatic PDAC receiving first-line chemotherapy across 30 centers. SIRI was assessed using a validated cut-off (>2.3) and as a log-transformed continuous variable in multivariable Weibull accelerated failure-time models with restricted cubic splines. RESULTS:Patients with low SIRI (≤2.3) had longer median OS (14.0 vs 9.2 months; p < 0.001) and PFS (5.9 vs 3.9 months; p < 0.001) than those with high SIRI. High SIRI was associated with a lower objective response rate (25% vs 37%; p < 0.001). In multivariable analyses, higher SIRI independently predicted inferior OS and PFS (75th vs 25th percentile: HR 1.14 [95% CI 1.05-1.25], HR 1.11 [95% CI 1.03-1.21]) and poorer tumor response (OR 0.78; 95% CI 0.62-1.00). Higher SIRI correlated with greater hepatic tumor burden and cachexia. CONCLUSIONS:SIRI is a robust, independent prognostic marker in metastatic PDAC. Higher values identify a phenotype with inferior survival and poorer tumor response. An open-access web calculator is provided to illustrate and explore the nonlinear, continuous prognostic gradient of SIRI and its impact on outcome.

Abstract Background: VCN-01 (zabilugene almadenorepvec) is an oncolytic adenovirus expressing hyaluronidase to degrade tumor stroma, facilitate chemotherapy penetration and stimulate tumor immunity, which is being developed for different cancer indications. The randomized, open-label, Phase 2b VIRAGE trial tested the efficacy and safety of 2 intravenous (IV) doses of VCN-01 combined with standard of care (SoC) gemcitabine/nab-paclitaxel (GA) in mPDAC. Methods: Chemonaïve mPDAC patients were randomized 1:1 to receive SoC doses of GA on days 1, 8 and 15 of repeated 28-day cycles (Arm I) or 2 separate IV doses of VCN-01 (1x1013 vp/dose) 1 week prior to cycles 1 and 4 of GA (Arm II). Primary endpoints were overall survival (OS) and safety. Secondary objectives included progression free survival (PFS), objective response rates (ORR), duration of response (DoR) and Ca19.9 changes. VCN-01 genomes in blood and serum levels of neutralizing anti-adenovirus antibodies (anti-Ad-NAb’s) were also analyzed. Results: 96 patients in the trial received at least 1 dose of GA or VCN-01+GA (48 patients in each arm). Median OS was 10.8 vs. 8.6 months for Arm II and Arm I, respectively (HR 0.57, 95% CI 0.34-0.96; P=0.055) and PFS was 7.0 vs. 4.6 months (HR 0.55, 95% CI 0.34-0.88; P=0.011). OS benefits with VCN-01+GA vs. GA alone were consistent across different subgroups, including patients aged over 70 years, presence of hepatic metastases, or patients with >2 metastatic sites. Compared to patients in Arm I who started cycle 4 of GA, patients in Arm II who received 2 VCN-01 doses and started cycle 4 of GA showed greater improvement in OS (14.8 vs 11.6 months; HR 0.44; 95% CI 0.21-0.92; P=0.046) and PFS (11.2 vs 7.4 months; HR 0.48; 95% CI 0.25-0.91; P=0.017). ORR was 39.6% vs. 31.3% (P=0.314), and more patients had target tumor shrinkage with VCN-01 + GA than GA (84.1% vs. 69.8%; P=0.13). DoR was longer for VCN-01+GA (11.2 vs 5.4 months; HR 0.22; 95% CI 0.08 - 0.62; P=0.004) and 8 of 19 patients in this group achieved late objective responses after the second VCN-01 dose (>4 months after randomization). Ca19.9 levels declined more markedly in Arm II, with a median reduction of -61.0% versus -64.9% in Arm I vs. Arm II by cycle 3, and a further decrease to -16.7% vs -86.3% by cycle 9, following the second VCN-01 dose. No correlation between baseline levels of anti-Ad-NAbs and OS or PFS were observed. The peak of viral genome levels in blood was similar between the first and the second dose of VCN-01. Conclusions: Compared to patients in Arm I (GA), mPDAC patients in Arm II (VCN-01+GA) showed improved OS and PFS and later and more durable responses. Patients that received a second VCN-01 dose+GA showed a further delayed disease progression and extended patient survival compared to patients that received equivalent cycles of GA. Citation Format: Rocio Garcia-Carbonero, Roberto Pazo, Teresa Macarulla, Berta Laquente, Alana Nguyen, Carmen Guillén-Ponce, Andres J. Muñoz, Edward J. Kim, Mireya Cazorla, Tara Seery, Miriam Lobo de Mena, Chris Nevala-Plagemann, Vivek R. Sharma, Eva Martinez de Castro, Charles Le, Ana Mato-Berciano, Luis A. Rojas, Carmen Blasco, Manel Cascallo, Manuel Hidalgo. Analysis of tumor and biomarker responses in the VIRAGE Trial, a randomized Phase IIb, open-label, study of nab-paclitaxel and gemcitabine with/without intravenous VCN-01 in patients with metastatic pancreatic cancer (mPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT162.

Supplementary Table 2. Representativeness of Study Participants

Supplementary Table 3. Genetic variant detected in the custom gene panel through whole exome sequencing.

e16455 Background: Phosphorous 32 microparticle ( 32 P) brachytherapy delivered by echoendoscopy (EUS) represents an innovative therapy in pancreatic cancer (PC). Our aim is to evaluate efficacy and safety outcomes for Spanish patients in real clinical practice. Methods: After being assessed by a multidisciplinary committee and meeting eligibility criteria (Table 1), patients signed consent to receive intratumoural 32 P by EUS within the international observational registry OSPREY (March 2022-January 2025). Complications associated with intratumoural 32P injection via EUS, associated adverse events (AEs) and preliminary efficacy results (progression-free survival [PFS] and overall survival [OS]) were analysed. Results: Twenty-five patients (16 females and 9 males; age 67 years [range 48, 80]; 20 ECOG 1 and 5 ECOG 0) with unresectable locally advanced PC (16 in head, 4 in uncinate and 5 in body; tumour size 31.5 mm [range 12, 60]) were included. Seven patients (28%) had received a previous treatment. 23 patients (92%) received gemcitabine-based chemotherapy concomitant with intratumoural 32P (17 gemcitabine plus nabpaclitaxel; 6 gemcitabine monotherapy), 1 patient FOLFIRINOX and 1 patient did not receive concomitant chemotherapy. Two patients had AEs related to 32P injection by EUS: G2 asthenia and G1 abdominal pain, respectively. Seventeen patients (68%) had chemotherapy-related AEs, with 3 cases of G3 neutropenia and 1 of G3 thombopenia; 14 had G1-2 toxicities: neutropenia (3), thrombopenia (4), neurotoxicity (4), anaemia (2), asthenia (3), hyporexia (1), nausea (1), diarrhea (1) and constipation (1) . Four (16%) patients underwent surgery after intratumoural treatment. With a median follow-up of 17.2 months after injection, 14 patients (56%) have progressed, 13 distantly and 7 also locoregionally; 1 patient progressed only locally. The median PFS since 32P injection is 8.4 months (95% CI 4.3, 17.0). 12 patients are alive at the end of follow-up (48%) with a median OS since 32P injection of 13.8 months (95% CI 9.4, 26,9]. Conclusions: The experience of Spanish centres suggests that intratumoural 32P associated with gemcitabine-based chemotherapy is safe and achieve long survival. Our ongoing prospective registry will allow evaluation of the oncological outcomes of this therapy at longer follow-up times. Eligibility criteria. Inclusion criteria Exclusion criteria - Patients eligible for and undergo 32P implantation at an eligible treatment facility according to the approved instructions for use, as part of their clinical care. - Patients participating in an interventional clinical study. - Patients who have completed and signed the patient informed consent form (PICF) for the OSPREY Patient Registry. - Patients using an investigational agent at the time of enrolment.

e13618 Background: Access to genetic testing for detecting hereditary cancer is limited, and conventional methods for selecting candidates are often imprecise. As a result, only a small proportion of those tested are found to carry pathogenic mutations, highlighting suboptimal selection criteria. Variability in guidelines, subjective interpretations, and incomplete family histories further complicate candidate identification. This study aims to address these limitations by developing an artificial intelligence (AI) tool to enhance the selection process for germline genetic testing. Methods: The dataset comprises over 10,000 pedigrees from the Familial Cancer Unit of Hospital Universitario Ramón y Cajal. Each record includes structured data on familial relationships and demographic attributes, as well as semi-structured clinical annotations. A robust preprocessing pipeline was developed to address heterogeneity in family structures, standardize free-text clinical annotations, and impute missing values using statistical and categorical imputation methods. Three machine learning models, Gradient-Boosted Trees (XGBoost), Random Forests, and Neural Networks, were evaluated for predictive performance using an 80/20 training-testing split. The final model was selected based on its ability to predict pathogenic or likely pathogenic genetic variants with high sensitivity and specificity. An interactive user interface was developed to enable real-time predictions and seamless integration into clinical workflows. Results: The XGBoost model achieves an area under the curve (AUC) of 0.72, outperforming conventional statistical models in both accuracy and generalization across diverse cancer syndromes. Traditional models often lack specificity for hereditary cancers and are limited in their applicability to multiple cancer types. Conclusions: This AI-powered tool offers a significant advancement over existing methods by leveraging family and clinical data to improve the identification of hereditary cancer risk. With its robust generalization across cancer types, the tool enables more accurate and equitable access to genetic testing. Its integration into family cancer clinics promises to enhance resource allocation and increase detection rates of pathogenic variants, ultimately improving patient outcomes.

In patients with metastatic colorectal cancer, analysis of the number of basal circulating tumour cells (bCTCs) has been shown to be a strong prognostic indicator. In this study, we aim to explore the potential associations between whole blood mRNA and microRNA expression profiles and bCTC counts, tumour mutations and prognosis in untreated metastatic colorectal cancer patients. A total of 151 patients previously screened for inclusion in two clinical trials (VISNÚ1 and VISNÚ2) were enrolled in this study. Real-time quantitative PCR (qPCR) analyses were performed to determine the whole blood expression of selected RNAs (mRNAs and microRNAs) involved in the metastatic process. The CellSearch system was used to enumerate circulating tumour cells. The primary objective was to correlate RNA expression with the number of bCTCs, while the secondary objectives were to investigate the relationship between the levels of circulating RNA biomarkers in whole blood and the clinical, pathological, and molecular characteristics and prognosis of patients with metastatic colorectal cancer. bCTC count was significantly associated with AGR2 mRNA in the entire cohort of 151 patients. AGR2, ADAR1 and LGR5 were associated with the number of bCTC, both in the subgroup with bCTC ≥ 3 and in the subgroup with native RAS/BRAF/PIK3 CA tumours. In patients with RAS/BRAF/PIK3 CA mutations no correlations with bCTC were detected, but an upregulation of miR-224-5p and the stemness marker LGR5 and a downregulation of immune regulatory CD274 were found. Lower levels of miR-106a-5p/miR-26a-5p were associated with shorter overall survival, with independent statistical significance in the multivariate analysis. A correlation was identified between the levels of a subset of whole blood RNAs, including AGR2, ADAR1, and LGR5, and the number of bCTC and RAS/BRAF/PIK3 CA mutational status. Furthermore, another set of whole blood RNAs, specifically miR-106a-5p and miR-26a-5p, was found to be associated with poor prognosis. This may be helpful for risk stratification. Clinical Trials Gov. NCT01640405 and NCT01640444. Registered on 13 June 2012. https://clinicaltrials.gov/ .

Supplementary Table 4. Preclinical model recommendation

PURPOSE:Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options. We compared the efficacy of comprehensive precision medicine against that of the conventional treatment in PDAC. PATIENTS AND METHODS:We report a phase III trial of advanced PDAC in which patients were randomized (1:2) to a conventional treatment treated at physician's discretion (arm A) or to precision medicine (arm B). Subjects randomized to arm B underwent a tumor biopsy for whole-exome sequencing and to generate avatar mouse models and patient-derived organoids for phenotypic drug screening, with final treatment recommended by the molecular tumor board. The primary objective was median overall survival (OS). RESULTS:A total of 137 patients were enrolled with 125 randomized, 44 to arm A and 81 to arm B. Whole-exome sequencing was performed in 80.3% (65/81) patients of arm B, with potentially actionable mutations detected in 21.5% (14/65). Experimental models were generated in 16/81 patients (19.8%). Second-line treatment was administered to 39 patients in the experimental arm, but only four (10.2%) received personalized treatment, whereas 35 could not receive matched therapy because of rapid clinical deterioration, delays in obtaining study results, or the absence of actionable targets. The median OS was 8.7 and 8.6 months (P = 0.849) and the median progression-free survival was 3.8 and 4.3 months (P = 0.563) for the conventional and experimental arms, respectively. Notably, the four patients who received personalized treatment had a median OS of 19.3 months. CONCLUSIONS:Personalized medicine was challenging to implement in most patients with PDAC, limiting the interpretation of intention-to-treat analysis. Survival was improved in the subset of patients who did receive matched therapy.

Supplementary Table 5. Complete Efficacy Data

Supplementary Table 1. Custom virtual gene panel included in the whole exome sequencing analysis