Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma

Abstract

Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow‐up in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell‐free DNA from plasma samples of 58 treatment‐naive mPDAC patients was isolated and sequenced using a custom‐made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8%) samples. Cross‐check with droplet digital PCR showed good agreement in Bland–Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p < 0.001). Tumor volume (3D reconstructions from imaging) and ctDNA variant allele frequency (VAF) were correlated (Spearman's ρ = 0.544, p < 0.001). Median overall survival (OS) was 3.2 (95% confidence interval [CI] 1.6–4.9) versus 8.4 (95% CI 1.6–15.1) months in patients with detectable versus undetectable ctDNA (p = 0.005). Both ctDNA VAF and tumor volume independently predicted OS after adjustment for carbohydrate antigen 19.9 and treatment regimen (hazard ratio [HR] 1.05, 95% CI 1.01–1.09, p = 0.005; HR 1.00, 95% CI 1.01–1.05, p = 0.003). In conclusion, our study showed that ctDNA detection rates are higher in patients with larger tumor volume and liver metastases. Nevertheless, measurements may diverge and, thus, can provide complementary information. Both ctDNA VAF and tumor volume were strong predictors of OS.

Prognostic value of circulating tumor DNA in pancreatic cancer: a systematic review and meta-analysis

“…All of the included studies had OS outcomes, while 5 of them had PFS prognostic data [ 21 , 28 , 32 , 35 , 36 ]. Seven studies included patients with PC of all stages (stage: I - IV) [ 23 – 26 , 29 , 32 , 33 ], 8 studies included patients with resectable PC (stage: I - II) [ 21 , 22 , 27 , 31 , 35 , 37 , 38 , 42 ], and 12 studies included patients with advanced PC (stage: III - IV) [ 18 – 20 , 22 , 28 , 30 , 31 , 34 , 36 , 39 – 41 ]. All of the included studies sampled at baseline, and 4 of them had postoperative data [ 21 , 31 , 35 , 38 ].…”

“…According to the results of this meta-analysis, we considered that the detection of the K-ras G12D mutation is a significant prognostic factor in PC (HR = 1.77; 95% CI, 1.22-2.58, I 2 = 55.6%), although more studies are needed to further confirm this finding. On the other hand, 4 studies focused on the concentration level of ctDNA [ 28 , 30 , 40 , 41 ]. Although only 4 studies were included in this subgroup analysis, the heterogeneity among these studies was significantly high.…”

Molecular profiling of ctDNA in pancreatic cancer: Opportunities and challenges for clinical application

“…The prognostic relevance of ctDNA detection in patients with PDAC has been demonstrated across several recent studies [ 59 , 61 , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] ]. Hadano et al.…”

Prognostic and predictive factors in pancreatic cancer

“…The prognostic role of ctDNA has been mostly investigated in retrospective studies of patients undergoing surgery; in this subset of subjects, the presence of ctDNA, in particular KRAS mutant ctDNA, in plasma has been associated with worse OS and disease free survival (DFS) [67,68]. Similarly the detection of ctDNA and the ctDNA variant allelic fraction in patients affected by mPDAC have been reported to be a prognostic factor [69], these findings have, recently, be confirmed by a meta-analysis [70].…”