Meta-Analysis of Circulating Cell-Free DNA's Role in the Prognosis of Pancreatic Cancer

Abstract

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.

Keywords: cell-free DNA; meta-analysis; pancreatic ductal adenocarcinoma; survival.

Figure 1

Flow chart of the study selection.

Figure 2

Geographical overview of the patient cases included in the meta-analyses. Data from multicenter and multicountry studies were excluded.

Figure 3

Forest plot presenting the relationship between the presence of KRAS mutations before treatment in PDAC patients and OS.

Figure 4

Forest plot presenting the relationship between the presence of KRAS mutations before treatment in PDAC patients and PFS.

Figure 5

Forest plot presenting the relationship between the presence of KRAS mutations after treatment in PDAC patients and OS.

Figure 6

Forest plot presenting the relationship between the presence of KRAS mutations after treatment in PDAC patients and PFS.

Figure 7

Forest plot presenting the relationship between the presence of KRAS mutations before treatment in locally-advanced and metastatic PDAC patients and OS.

Figure 8

Forest plot presenting the relationship between the presence of KRAS mutations before treatment in locally-advanced and metastatic PDAC patients and PFS.