Introduction: The analysis of cell-free DNA (cfDNA) for genetic abnormalities is a promising new approach for the diagnosis and prognosis of pancreatic cancer patients. Insights into the molecular characteristics of pancreatic cancer may provide valuable information, leading to its earlier detection and the development of targeted therapies. Material and Methods: We conducted a systematic review and a meta-analysis of studies that reported cfDNA in pancreatic ductal adenocarcinoma (PDAC). The studies were considered eligible if they included patients with PDAC, if they had blood tests for cfDNA/ctDNA, and if they analyzed the prognostic value of cfDNA/ctDNA for patients’ survival. The studies published before 22 October 2020 were identified through the PubMED, EMBASE, Web of Science and Cochrane Library databases. The assessed outcomes were the overall (OS) and progression-free survival (PFS), expressed as the log hazard ratio (HR) and standard error (SE). The summary of the HR effect size was estimated by pooling the individual trial results using the Review Manager, version 5.3, Cochrane Collaboration. The heterogeneity was assessed using the Cochran Q test and I² statistic. Results: In total, 48 studies were included in the qualitative review, while 44 were assessed in the quantitative synthesis, with the total number of patients included being 3524. Overall negative impacts of cfDNA and KRAS mutations on OS and PFS in PDAC (HR = 2.42, 95% CI: 1.95–2.99 and HR = 2.46, 95% CI: 2.01–3.00, respectively) were found. The subgroup analysis of the locally advanced and metastatic disease presented similar results (HR = 2.51, 95% CI: 1.90–3.31). In the studies assessing the pre-treatment presence of KRAS, there was a moderate to high degree of heterogeneity (I² = 87% and I² = 48%, for OS and PFS, respectively), which was remarkably decreased in the analysis of the studies measuring post-treatment KRAS (I² = 24% and I² = 0%, for OS and PFS, respectively). The patients who were KRAS positive before but KRAS negative after treatment had a better prognosis than the persistently KRAS-positive patients (HR = 5.30, 95% CI: 1.02–27.63). Conclusion: The assessment of KRAS mutation by liquid biopsy can be considered as an additional tool for the estimation of the disease course and outcome in PDAC patients.

Recent research suggests a link between KRAS mutations and the effectiveness of ICIs, as KRAS-driven tumors may possess unique immunogenic features that influence the tumor microenvironment. These mutations can increase tumor mutation burden (TMB) and neoantigen load, potentially leading to improved responses to ICIs. This meta-analysis aims to consolidate existing evidence on the impact of KRAS mutations as a predictive factor for survival and treatment outcomes in patients with advanced NSCLC treated with ICIs. A comprehensive search strategy was designed by a biostatistician and pulmonologist, targeting PubMed, Web of Science, and Scopus databases up to May 2022. The outcomes assessed included overall survival (OS) and progression-free survival (PFS), reported as log hazard ratios (HRs) with corresponding standard errors (SEs). A pooled estimate of the HR effect size was calculated using Review Manager (RevMan, Cochrane Collaboration, London, UK). Heterogeneity among studies was evaluated using the Cochran Q test and the I² statistic. Ultimately, 10 articles were deemed suitable for inclusion in the systematic review from a total of 8722 screened titles and abstracts. The presence of KRAS+ mutations had a significant prognostic factor for better OS in NSCLC patients treated with checkpoint inhibitors (HR = 0.89, 95% CI: 0.79–0.99) and for better PFS in NSCLC patients treated with checkpoint inhibitors (HR = 0.72, 95% CI: 0.59–0.87). In conclusion, our study indicates that KRAS mutations may serve as a potential positive predictive biomarker in patients with advanced non-small-cell lung cancer treated with immune checkpoint inhibitor monotherapy.