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Gastroenterology. 2019 Jan;156(1):108-118.e4. doi: 10.1053/j.gastro.2018.09.022. Epub 2018 Sep 19.

Circulating Nucleic Acids Are Associated With Outcomes of Patients With Pancreatic Cancer.

Author information

1
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas.
2
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.
3
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: Haalvarez@mdanderson.org.

Abstract

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:

Biomarkers; Extracellular Vesicles; PDAC; Tumor Monitoring

PMID:
30240661
PMCID:
PMC6434712
DOI:
10.1053/j.gastro.2018.09.022
[Indexed for MEDLINE]
Free PMC Article

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