Advancing precision medicine in pancreatic cancer through bioinformatics-assisted genomic profiling and clinical stratification

<p dir="ltr">Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies, characterized by late diagnosis, pronounced molecular heterogeneity, and limited responsiveness to current treatments. 0The unifying theme is the integration of molecular, clinical, and epidemiological insights to better understand PDAC's pathogenesis and to guide more effective, individualized approaches for prevention, early intervention, and treatment.</p><p dir="ltr">In studies I and IV, tumor and matched control samples from 14 and 39 PDAC patients, respectively, were processed under SWEDAC-certified workflows at the Department of Clinical Pathology and Cytology, Karolinska University Hospital. Blocks were reviewed by the pathologist with blocks containing >20% tumor cells used for DNA extraction. Sequencing was preformed; data was subsequently processed using a clinical decision support systems (CDSS). Reports predicting drug efficacy, resistance, and toxicity, oncogenic relevance using the OncoScore algorithm, and assesses variant impact with an evidence-weighted functional impact scoring system. Pharmacogenomic toxicity predictions were cross- validated against the PharmGKB database and FDA adverse event reporting system. In study I, no therapeutic recommendations were made, and the study was a retrospective study to assess the feasibility of implementing personalized cancer medicine in routine clinical practice. However, study IV produced off-label recommendations which were recommended as second-line therapy.</p><p dir="ltr">Study II investigated predictors of malignant transformation in intraductal papillary mucinous neoplasms (IPMNs), a recognized PDAC precursor. In a retrospective cohort of surgically resected IPMNs (152 patients between 2008- 2015), main pancreatic duct dilation 26 mm, jaundice, and elevated CA19-9 were independently associated with high-grade dysplasia (HGD) or invasive cancer. These findings identify preoperative clinical features that may aid earlier intervention in high-risk patients.</p><p dir="ltr">Study III examined the association between new-onset diabetes mellitus (NODM), anti-diabetic medications, and pancreatic cancer risk in a nested case-control design within the UK Health Improvement Network (1996-2010). New-onset T2DM and rising glycated hemoglobin (HbA1c) levels were independent risk factors for pancreatic cancer. Risk varied by medication, with the highest observed among insulin users, followed by sulphonylureas, and a weaker association seen with metformin use.</p><p dir="ltr">All four studies are linked by their shared focus on improving the early detection, risk stratification, and personalized management of pancreatic ductal adenocarcinoma (PDAC). Precision oncology approaches, using next-generation sequencing offer potential to identify actionable alterations, predict treatment efficacy and toxicity, and demonstrated potential for integration into routine care within a 2-week timeframe. Specific preoperative features can identify IPMN patients at high risk for advanced dysplasia, and metabolic factors such as NODM and worsening glycemic control are independent pancreatic cancer risk factors. Together, these findings inform strategies for PDAC risk assessment, early intervention, and potential integration of precision oncology into clinical care, while emphasizing the need for critical evaluation of emerging molecular tools.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Malgerud L,</b> Lindberg J, Wirta V, Gustafsson-Liljefors M, Karimi M, Moro CF, Stecker K, Picker A, Huelsewig C, Stein M, Bohnert R, Del Chiaro M, Haas SL, Heuchel RL, Permert J, Maeurer MJ, Brock S, Verbeke CS, Engstrand L, Jackson DB, Grönberg H, Löhr JM. Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer. Mol Oncol. 2017;11(10):1413-29. <a href="https://doi.org/10.1002/1878-0261.12108" rel="noreferrer" target="_blank">https://doi.org/10.1002/1878-0261.12108</a></p><p dir="ltr">II. Ateeb Z, Valente R, Pozzi-Mucelli RM, <b>Malgerud L,</b> Schlieper Y, Rangelova E, Fernandez-Moro C, Löhr JM, Arnelo U, Del Chiaro M. Main pancreatic duct dilation greater than 6 mm and elevated preoperative CA19-9 levels are associated with an increased risk of high-grade dysplasia and cancer in IPMN patients. Langenbecks Arch Surg. 2019;404(1):31-37. <a href="https://doi.org/10.1007/s00423-018-1740-8" rel="noreferrer" target="_blank">https://doi.org/10.1007/s00423-018-1740-8</a></p><p dir="ltr">III. Lu Y, García-Rodríguez LA, <b>Malgerud L,</b> González-Pérez A, Martín- Pérez M, Lagergren J, Bexelius TS. New-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer. Br J Cancer. 2015 Nov 17;113(11):1607-1614. <a href="https://doi.org/10.1038/bjc.2015.353" rel="noreferrer" target="_blank">https://doi.org/10.1038/bjc.2015.353</a></p><p dir="ltr">IV. <b>Malgerud L*</b>, Kordes M*, Frödin J-E, Yachnin J, Fernandez Moro C, Ghazi S, Pozzi Mucelli R, Kartalis N, Ghorbani P, Del Chiaro M, Wirta V, Björnstedt M, Liljefors MG, Lohr J-M. Consistency of a clinical decision support system with molecular tumour board recommendations for tumour sequencing-guided treatment of pancreatic cancer: a prospective observational study. ESMO Gastrointestinal Oncology. 2024;1(1):100070. <a href="https://doi.org/10.1016/j.esmogo.2024.100070" rel="noreferrer noopener" target="_blank">https://doi.org/10.1016/j.esmogo.2024.100070</a> *Equal contributions as first authors</p>