Fragment size and level of cell-free DNA provide prognostic information in patients with advanced pancreatic cancer

Morten Lapin,Tove Buhl,Rune Smaaland,Milind Javle,Oddmund Nordgård,Herish Garresori,Satu Oltedal,Kjersti Tjensvoll,Nils Idar Glenjen,Bente Kristin Abelseth,Bjørnar Gilje

doi:10.1186/s12967-018-1677-2

Abstract

BackgroundIt was recently demonstrated that the size of cell-free DNA (cfDNA) fragments that originates from tumor cells are shorter than cfDNA fragments that originates from non-malignant cells. We investigated whether cfDNA fragment size and cfDNA levels might have prognostic value in patients with advanced pancreatic cancer.MethodsBlood samples were obtained from patients with advanced pancreatic cancer, before (n = 61) initiation of chemotherapy and after the first cycle of chemotherapy (n = 39). Samples were separated with density centrifugation and plasma DNA was isolated. Mode cfDNA fragment size and cfDNA levels were then determined using a 2100 Bioanalyzer. A cohort of partially age-matched healthy volunteers (n = 28) constituted the control group.ResultsBoth a pre-treatment cfDNA fragment size of ≤ 167 bp (mode) and high pre-treatment cfDNA levels were associated with shorter progression-free survival (PFS) (p = 0.002 and p < 0.001, respectively) and overall survival (OS) (p = 0.001 and p = 0.001, respectively). Furthermore, multivariable Cox regression analyses demonstrated that pre-treatment cfDNA levels could independently predict prognosis for both PFS (HR = 3.049, p = 0.005) and OS (HR = 2.236, p = 0.028).ConclusionThis study demonstrates that cfDNA fragment size and cfDNA levels can be used to predict disease outcome in patients with advanced pancreatic cancer. The described approach, using a rapid, economic and simple test to reveal prognostic information, has potential for future treatment stratification and monitoring.

Highlights

It was recently demonstrated that the size of cell-free DNA fragments that originates from tumor cells are shorter than cfDNA fragments that originates from non-malignant cells
We demonstrated that the determination of cfDNA fragment size and cfDNA levels is a non-invasive, simple method for predicting clinical outcome in patients with advanced pancreatic cancer
Future investigations are needed to elaborate these findings with regard to clinical relevance, and to establish whether the determination of cfDNA fragment size and cfDNA level might have prognostic value for patients with localized pancreatic cancer

Summary

Introduction

It was recently demonstrated that the size of cell-free DNA (cfDNA) fragments that originates from tumor cells are shorter than cfDNA fragments that originates from non-malignant cells. High levels of cfDNA have been associated with poor survival in several cancers, including pancreatic cancer [2,3,4] Using surrogate markers, such as point mutations [5,6,7,8,9,10], copy-number aberrations [11, 12], microsatellite alterations [13] and methylations [12], it has been possible to detect the fraction of cfDNA that originates from tumor cells. We employed simple laboratory techniques to determine the fragment size and total levels of cfDNA isolated from patients with locally advanced or metastatic pancreatic cancer

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Discussion

Conclusion