Clearance of TP53 Mutations in ctDNA Reflects Therapeutic Response in Advanced Pancreatic Cancer Patients

Background/Aim: TP53 is one of the most frequently altered genes in pancreatic ductal adenocarcinoma (PDAC), yet its clinical significance as a predictive biomarker for treatment response remains unclear. The aim of study was to evaluate the feasibility of repeated ctDNA analysis and explore its potential relevance in predicting treatment outcomes by profiling the molecular evolution of PDAC patients during the 1st course of palliative chemotherapy.

Materials and Methods: We investigated the association between TP53 alterations and treatment outcomes in 19 patients with advanced PDAC who received either FOLFIRINOX or gemcitabine plus nab-paclitaxel. TP53 mutation status was assessed using next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) obtained before and after treatment.

Results: Among 21 chemotherapy-naive patients with advanced PDAC, 19 were evaluable for treatment response, with an objective response rate of 52.6%. Baseline ctDNA analysis detected Tier 1/2 mutations in 100% of samples, with TP53 (52%) and KRAS (27%) as frequent alterations. KRAS mutations were significantly more common in responders than non-responders (67% vs. 11%, p=0.040). Post-chemotherapy ctDNA analysis revealed that 42% of TP53-mutated patients showed complete clearance of these mutations, correlating with partial radiologic responses. Novel mutations such as BRCA2 and PBRM2 emerged after treatment. CA 19-9 levels decreased significantly in responders but not in non-responders. Gene Ontology analysis highlighted a post-treatment shift toward hypoxia response, chromatin remodeling, and Wnt pathway activation, suggesting clonal adaptation and potential drug resistance.

Conclusion: Dynamic changes in ctDNA, particularly the disappearance of TP53 mutations, serve as a sensitive biomarker for chemotherapy response in advanced PDAC, even when traditional markers like CA 19-9 are unreliable. Longitudinal ctDNA profiling offers a promising approach to guide early treatment evaluation and may inform therapeutic strategies targeting resistant subclones.