Gastroenterology

Gastroenterology

Volume 156, Issue 1, January 2019, Pages 108-118.e4
Gastroenterology

Original Research
Full Report: Clinical—Pancreas
Circulating Nucleic Acids Are Associated With Outcomes of Patients With Pancreatic Cancer

https://doi.org/10.1053/j.gastro.2018.09.022Get rights and content

Background & Aims

We aimed to investigate the clinical utility of circulating tumor cell DNA (ctDNA) and exosome DNA (exoDNA) in pancreatic cancer.

Methods

We collected liquid biopsy samples from 194 patients undergoing treatment for localized or metastatic pancreatic adenocarcinoma from April 7, 2015, through October 13, 2017 (425 blood samples collected before [baseline] and during therapy). Additional liquid biopsy samples were collected from 37 disease control individuals. Droplet digital polymerase chain reaction was used to determine KRAS mutant allele fraction (MAF) from ctDNA and exoDNA purified from plasma. For the longitudinal analysis, we analyzed exoDNA and ctDNA in 123 serial blood samples from 34 patients. We performed analysis including Cox regression, Fisher exact test, and Bayesian inference to associate KRAS MAFs in exoDNA and ctDNA with prognostic and predictive outcomes.

Results

In the 34 patients with potentially resectable tumors, an increase in exoDNA level after neoadjuvant therapy was significantly associated with disease progression (P = .003), whereas ctDNA did not show correlations with outcomes. Concordance rates of KRAS mutations present in surgically resected tissue and detected in liquid biopsy samples were greater than 95%. On univariate analysis, patients with metastases and detectable ctDNA at baseline status had significantly shorter times of progression-free survival (PFS) (hazard ratio [HR] for death, 1.8; 95% CI, 1.1–3.0; P = .019), and overall survival (OS) (HR, 2.8; 95% CI, 1.4–5.7; P = .0045) compared with patients without detectable ctDNA. On multivariate analysis, MAFs ≥5% in exoDNA were a significant predictor of PFS (HR, 2.28; 95% CI, 1.18–4.40; P = .014) and OS (HR, 3.46; 95% CI, 1.40–8.50; P = .007). A multianalyte approach showed detection of both ctDNA and exoDNA MAFs ≥5% at baseline status to be a significant predictor of OS (HR, 7.73, 95% CI, 2.61–22.91, P = .00002) on multivariate analysis. In the longitudinal analysis, an MAF peak above 1% in exoDNA was significantly associated with radiologic progression (P = .0003).

Conclusions

In a prospective cohort of pancreatic cancer patients, we show how longitudinal monitoring using liquid biopsy samples through exoDNA and ctDNA provides both predictive and prognostic information relevant to therapeutic stratification.

Keywords

PDAC
Extracellular Vesicles
Biomarkers
Tumor Monitoring

Abbreviations used in this paper

CA
carbohydrate antigen
CI
confidence interval
CT
computed tomographic
ctDNA
circulating tumor DNA
ddPCR
digital droplet polymerase chain reaction
exoDNA
exosome-derived DNA
MAF
mutant allelic fraction
OR
odds ratio
OS
overall survival
PBS
phosphate-buffered saline
PDAC
pancreatic ductal adenocarcinoma
PFS
progression-free survival

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Conflicts of interest The authors disclose no conflicts.

Funding This work was supported by the MD Anderson Moonshot Program and the Khalifa Bin Zayed Al-Nahyan Foundation (no grant numbers apply); the National Institutes of Health (U01CA196403 and U01CA200468 to Anirban Maitra); the Cancer Prevention Research Institute of Texas (RP160517 to Anirban Maitra; Vincent Bernard and Nabiollah Kamyabi were funded through a fellowship from Cancer Prevention Research Institute of Texas Research Training Program RP170067; and the German Research Foundation (SE-2616/2-1 to Alexander Semaan). We are grateful the Precision Medicine Research Associates/Fox Family Foundation for partially supporting the studies described in this manuscript.

Authors share co-first authorship.

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