Unexpected Long-Term Survival in Resected Pancreatic Ductal Adenocarcinoma Harboring KRAS G12R with an Ultra-Low-VAF SMAD4 Mutation: A Case Report and Mini-Review.

Background and Clinical Significance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, even in resectable disease. Molecular alterations in the four major driver genes (KRAS, SMAD4, CDKN2A, and TP53) have been associated with disease progression and patient outcomes. However, reliable prognostic biomarkers remain limited, particularly in resected PDAC, where recurrence rates remain high; Case presentation: We report the case of a 71-year-old woman incidentally diagnosed with PDAC carrying KRAS G12R with an ultra-low-variant allele frequency (VAF) SMAD4 mutation, with low baseline neutrophil-to-lymphocyte ratio (NLR) and circulating cell-free DNA (ccfDNA) levels. The patient underwent distal pancreatectomy with splenectomy and portal vein resection with multiple postoperative complications requiring re-intervention. The patient demonstrated excellent tolerance to the therapy, experiencing no significant adverse events and reaching an overall survival of 53 months. Conclusions: This case highlights the potential value of integrating molecular alterations with inflammatory and liquid biopsy biomarkers, including NLR and ccfDNA levels for improving risk stratification in PDAC. A focused review of the literature further supports the need for multimodal prognostic assessment in resected disease.