Toward precision chemotherapy in pancreatic ductal adenocarcinoma: molecular, transcriptomic and clinical determinants

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with chemotherapy remaining the backbone of systemic treatment across disease stages. Although multi-agent regimens such as modified FOLFIRINOX and gemcitabine plus nab-paclitaxel-based combinations, with or without cisplatin and capecitabine (AG or PAXG), have improved outcomes in selected patients, therapeutic benefit remains highly heterogeneous and frequently limited by toxicity. This review summarizes evidence supporting shift from empirical chemotherapy selection toward a more personalized approach integrating tumour biology, molecular biomarkers, and patient-related factors, including pharmacogenetics, comorbidities, and toxicity profiles. We discuss established standards of care and highlight the strengths and limitations of available randomized data. The molecular landscape of PDAC, including homologous recombination repair deficiency, mismatch repair deficiency, and rare actionable oncogenic fusions, currently enables precision strategies in a minority of patients. The rapid development of KRAS-targeted therapies may extend molecularly guided treatment to a broader population. Beyond genomics, emerging biomarkers such as transcriptomic signatures, liquid biopsies, proteomic and metabolomic markers, and tumour microenvironment features may refine treatment selection and guide de-escalation or intensification strategies. Finally, we review biomarker-driven clinical trials and outline future directions for adaptive, biology-informed chemotherapy. Integrating molecular and clinical data into routine care may enable a more rational use of chemotherapy and improve outcomes in PDAC.