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

Vincent Bernard, Dong U. Kim, F. Anthony San Lucas, Jonathan Aaron Castillo Arias, Kelvin Allenson, Feven C. Mulu, Bret M. Stephens, Jonathan Huang, Alexander Semaan, Paola Andrea Guerrero, Nabiollah Kamyabi, Jun Zhao, Mark W. Hurd, Eugene Jon Koay, Cullen Taniguchi, Joseph M Herman, Milind Javle, Robert A Wolff, Matthew Harold Katz, Gauri R Varadhachary & 2 others Anirban Maitra, Hector A Alvarez

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)108-118.e4
JournalGastroenterology
Volume156
Issue number1
DOIs
StatePublished - Jan 1 2019

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Pancreatic Neoplasms
Nucleic Acids
Exosomes
Circulating Neoplastic Cells
DNA
Biopsy
Disease-Free Survival
Survival
Multivariate Analysis
Alleles
Neoadjuvant Therapy
Mutation Rate

Keywords

  • Biomarkers
  • Extracellular Vesicles
  • PDAC
  • Tumor Monitoring

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Circulating Nucleic Acids Are Associated With Outcomes of Patients With Pancreatic Cancer. / Bernard, Vincent; Kim, Dong U.; San Lucas, F. Anthony; Castillo Arias, Jonathan Aaron; Allenson, Kelvin; Mulu, Feven C.; Stephens, Bret M.; Huang, Jonathan; Semaan, Alexander; Guerrero, Paola Andrea; Kamyabi, Nabiollah; Zhao, Jun; Hurd, Mark W.; Koay, Eugene Jon; Taniguchi, Cullen; Herman, Joseph M; Javle, Milind; Wolff, Robert A; Katz, Matthew Harold; Varadhachary, Gauri R; Maitra, Anirban; Alvarez, Hector A.

In: Gastroenterology, Vol. 156, No. 1, 01.01.2019, p. 108-118.e4.

Research output: Contribution to journalArticle

Bernard, Vincent ; Kim, Dong U. ; San Lucas, F. Anthony ; Castillo Arias, Jonathan Aaron ; Allenson, Kelvin ; Mulu, Feven C. ; Stephens, Bret M. ; Huang, Jonathan ; Semaan, Alexander ; Guerrero, Paola Andrea ; Kamyabi, Nabiollah ; Zhao, Jun ; Hurd, Mark W. ; Koay, Eugene Jon ; Taniguchi, Cullen ; Herman, Joseph M ; Javle, Milind ; Wolff, Robert A ; Katz, Matthew Harold ; Varadhachary, Gauri R ; Maitra, Anirban ; Alvarez, Hector A. / Circulating Nucleic Acids Are Associated With Outcomes of Patients With Pancreatic Cancer. In: Gastroenterology. 2019 ; Vol. 156, No. 1. pp. 108-118.e4.
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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.",
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author = "Vincent Bernard and Kim, {Dong U.} and {San Lucas}, {F. Anthony} and {Castillo Arias}, {Jonathan Aaron} and Kelvin Allenson and Mulu, {Feven C.} and Stephens, {Bret M.} and Jonathan Huang and Alexander Semaan and Guerrero, {Paola Andrea} and Nabiollah Kamyabi and Jun Zhao and Hurd, {Mark W.} and Koay, {Eugene Jon} and Cullen Taniguchi and Herman, {Joseph M} and Milind Javle and Wolff, {Robert A} and Katz, {Matthew Harold} and Varadhachary, {Gauri R} and Anirban Maitra and Alvarez, {Hector A}",
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TY - JOUR

T1 - Circulating Nucleic Acids Are Associated With Outcomes of Patients With Pancreatic Cancer

AU - Bernard, Vincent

AU - Kim, Dong U.

AU - San Lucas, F. Anthony

AU - Castillo Arias, Jonathan Aaron

AU - Allenson, Kelvin

AU - Mulu, Feven C.

AU - Stephens, Bret M.

AU - Huang, Jonathan

AU - Semaan, Alexander

AU - Guerrero, Paola Andrea

AU - Kamyabi, Nabiollah

AU - Zhao, Jun

AU - Hurd, Mark W.

AU - Koay, Eugene Jon

AU - Taniguchi, Cullen

AU - Herman, Joseph M

AU - Javle, Milind

AU - Wolff, Robert A

AU - Katz, Matthew Harold

AU - Varadhachary, Gauri R

AU - Maitra, Anirban

AU - Alvarez, Hector A

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Biomarkers

KW - Extracellular Vesicles

KW - PDAC

KW - Tumor Monitoring

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U2 - 10.1053/j.gastro.2018.09.022

DO - 10.1053/j.gastro.2018.09.022

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JO - Gastroenterology

JF - Gastroenterology

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