{ "abstract": "Background/Objectives: First-line treatment selection for advanced (locally advanced or metastatic) pancreatic ductal adenocarcinoma (PDAC) is currently based on clinical characteristics rather than predictive biomarkers. While homologous recombination deficiency (HRD) is associated with increased sensitivity to platinum-based chemotherapy, established predictive biomarkers, such as pathogenic alterations in BRCA1, BRCA2, and PALB2, identify only a small subset of patients who are likely to benefit from platinum-based first-line treatment. The Genomic Instability Score (GIS) may capture broader HRD-associated genomic scarring beyond single-gene testing and support biomarker-guided platinum selection. However, the clinical utility of the GIS in PDAC remains uncertain, and no PDAC-specific GIS cutoff has yet been established. Methods: In this retrospective multicenter cohort, 127 patients with advanced PDAC underwent TruSight Oncology 500 HRD testing between 2022 and 2025. GIS was evaluable in 99 patients; 80 received first-line therapy. The primary endpoint was time to failure of the first-line strategy (TFS). An exploratory candidate GIS cutoff for platinum sensitivity was identified using maximally selected log-rank statistics, and survival was analyzed using Kaplan–Meier estimates and Cox regression. Results: In the first-line platinum cohort, an exploratory GIS threshold of 39 showed the greatest discrimination for treatment failure-free survival (TFS) within this cohort. Patients with GIS ≥ 39 had significantly longer TFS than those with GIS < 39 (9.9 vs. 5.9 months; HR 0.33, 95% CI 0.13–0.80; p = 0.015), and this association remained significant after multivariable adjustment. Among individual genes, BRCA2-mutated tumors exhibited significantly higher GIS than BRCA2-wild-type tumors (median 54 vs. 19; FDR-adjusted p = 0.002), although 30% of GIS-high tumors lacked BRCA1/2 mutations. Combined stratification by GIS and first-line treatment demonstrated a stepwise improvement in overall survival, with median OS of 8.2 months in non-platinum/GIS < 39 patients, 15.1 months in platinum/GIS < 39 patients, and 30.7 months in platinum/GIS ≥ 39 patients (p = 0.002). Conclusions: GIS may identify patients with advanced PDAC who experience favorable outcomes during first-line platinum-based chemotherapy. The observed association between higher GIS and improved treatment outcomes supports further investigation of GIS as a biomarker for treatment stratification in advanced PDAC and warrants prospective validation.", "abstract_shown": true, "affiliations": [ "Department of Internal Medicine I for Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, 4010 Linz, Austria", "Faculty of Medicine, Johannes Kepler University Linz, 4020 Linz, Austria", "Department of Internal Medicine III, Hematology and Oncology, LMU University Hospital, 81377 Munich, Germany", "Laboratory for Molecular Genetic Diagnostics, Ordensklinikum Linz, 4010 Linz, Austria", "Department of Internal Medicine IV for Hematology and Medical Oncology, Hospital Wels-Grieskirchen, 4600 Wels, Austria", "Department of Internal Medicine II for Medical Oncology, State Hospital Pyhrn-Eisenwurzen, 4400 Steyr, Austria", "Department of Internal Medicine I for Hematology and Medical Oncology, Sisters of Charity Hospital Ried, 4910 Ried im Innkreis, Austria", "Department of Internal Medicine, State Hospital Rohrbach, 4150 Rohrbach, Austria", "Department of Surgery, Ordensklinikum Linz, 4010 Linz, Austria" ], "article_type": "research article", "arxiv": null, "author_total": 17, "authors": [ { "affs": [ 0, 1, 2 ], "name": "Justus Leinhos", "orcid": "0009-0006-0445-1986" }, { "affs": [ 3 ], "name": "Theodora Malli", "orcid": "0000-0003-4244-7954" }, { "affs": [ 0 ], "name": "Anna Gabler" }, { "affs": [ 0 ], "name": "Daniel Nothdurfter", "orcid": "0009-0007-9690-2293" }, { "affs": [ 0, 1 ], "name": "Andreas Reichinger", "orcid": "0000-0002-1319-9798" }, { "affs": [ 1, 3 ], "name": "Jonathan Burghofer", "orcid": "0000-0001-6720-4671" }, { "affs": [ 3 ], "name": "Stefan Schwarz" }, { "affs": [ 4 ], "name": "Johann Mandl" }, { "affs": [ 5 ], "name": "Georg Schreil" }, { "affs": [ 6 ], "name": "Alexander Andorfer" }, { "affs": [ 0 ], "name": "Hannes Windhager" }, { "affs": [ 7 ], "name": "Karl J. Aichberger" }, { "affs": [ 1, 8 ], "name": "Patrick Kirchweger", "orcid": "0000-0003-2806-4594" }, { "affs": [ 8 ], "name": "Florian Primavesi" }, { "affs": [ 1, 3 ], "name": "Gerald Webersinke", "orcid": "0000-0001-5654-6190" }, { "affs": [ 0 ], "name": "Holger Rumpold", "orcid": "0000-0002-4118-0111" }, { "affs": [ 0, 1 ], "name": "Bernhard Doleschal", "orcid": "0009-0004-4813-4435" } ], "bibtex": "https://research.draconitic.com/paper/ca4myvz1xvbsg.bib", "cited_by": 0, "doi": "10.3390/jcm15197632", "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13666186/?tool=EBI", "id": "ca4myvz1xvbsg", "issns": [ "2077-0383" ], "landing_url": "https://europepmc.org/article/PMC/PMC13666186", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2730|Pancreatic and Hepatic Oncology Research" ] ], "openalex": "W7215871542", "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13666186/pdf/?tool=EBI", "pmcid": "PMC13666186", "pmid": null, "published": "2026-10-01", "publisher": "MDPI AG", "ris": "https://research.draconitic.com/paper/ca4myvz1xvbsg.ris", "sources": [ { "first_seen": "2026-10-30T12:17:31Z", "native_id": "PMC:PMC13666186", "source": "europepmc", "url": "https://europepmc.org/article/PMC/PMC13666186" }, { "first_seen": "2026-10-30T12:20:00Z", "native_id": "10.3390/jcm15197632", "source": "crossref", "url": "https://www.mdpi.com/2077-0383/15/19/7632" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2730|Pancreatic and Hepatic Oncology Research", "subfield": "oncology" } ], "title": "Understanding Genomic Instability Score in Platinum-Treated Advanced Pancreatic Ductal Adenocarcinoma", "title_text": "Understanding Genomic Instability Score in Platinum-Treated Advanced Pancreatic Ductal Adenocarcinoma", "type": "peer-reviewed", "updated_at": "2026-10-30T12:20:00Z", "url": "https://research.draconitic.com/paper/ca4myvz1xvbsg", "venue": "Journal of clinical medicine", "versions": [] }