Analysis of Cell-Free DNA to Assess Risk of Tumoremia Following Endoscopic Ultrasound Fine-Needle Aspiration of Pancreatic Adenocarcinomas

Michael J. Levy, Benjamin R. Kipp, Dragana Milosevic, Amber R. Schneider, Jesse S. Voss, Rajeswari Avula, Sarah E. Kerr, Michael R. Henry, W Edward Jr. Highsmith, Minetta C Liu, Ferga C. Gleeson

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Abstract

Background & Aims: Cellular and nuclear material from tumors disseminates into the bloodstream (tumoremia), but it is not clear whether medical procedures cause release of this material or contribute to formation of metastases. We performed a prospective study of blood samples from patients with pancreatic adenocarcinoma (PDAC) to determine whether endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) associates with markers of tumoremia. Methods: We obtained peripheral blood from 104 patients (35 with PDAC) before and after EUS-FNA of primary tumors; blood samples from 69 healthy individuals were used as controls. Plasma concentrations of cell-free DNA (cfDNA) were measured, and cfDNA and primary tumor samples were analyzed to detect activating mutations in KRAS. Potential development of tumoremia was defined by an increase in cfDNA of 2-fold or more, and/or detection of mutant KRAS in samples collected after FNA from patients whose blood samples did not contain detectable mutant KRAS before FNA. Results: Peripheral blood concentrations of cfDNA were 1200 ng/ml (500–3300 ng/ml) before FNA vs 1400 ng/ml (900–4000 ng/ml) after FNA (P =.391). Tumoremia was detected in 10/35 patients (28.6%): 7 patients had a ≥2-fold increase in cfDNA concentration (20.6%) and 3 patients had circulating tumor DNA with KRAS mutations after FNA that were not detected before FNA (8.8%). New distant metastases were detected in 1.3 ± 0.82 patients with tumoremia vs 0.64 ± 0.81 without (P =.0375). Overall mortality did not differ significantly between patients with tumoremia (10/10 deaths, 100%) vs those without (19/25 deaths, 76%) nor did survival times of deceased patients (13.3 months for patients with tumoremia; range, 5.8–14.9 months vs 11.1 months for patients without tumoremia; range, 5.5–14.5 months). However, 6 patients without tumoremia were alive at a mean 23.9 months after EUS-FNA (range, 19.9–25 months after EUS-FNA) vs none of the patients with tumoremia. Conclusion: In patients with PDAC, EUS-FNA associates with increased plasma concentration of cfDNA and increased detection of mutant KRAS after the procedure (markers of tumoremia and possible new distant metastasis). Although levels of cfDNA and activating mutations in KRAS are logical markers of tumoremia, they may not serve as the ideal biomarkers of this process. These findings are preliminary and do not indicate a need to modify current practice, yet further studies are needed.

Original languageEnglish (US)
JournalClinical Gastroenterology and Hepatology
DOIs
StateAccepted/In press - Jan 1 2018

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Fine Needle Biopsy
Adenocarcinoma
DNA
Endoscopic Ultrasound-Guided Fine Needle Aspiration
Neoplasm Metastasis
Plasma Cells
Mutation
Neoplasms
Blood Cells
Biomarkers

Keywords

  • Cancer Detection
  • Diagnostic
  • Molecular Cytogenetic Biomarker
  • Pathology

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Analysis of Cell-Free DNA to Assess Risk of Tumoremia Following Endoscopic Ultrasound Fine-Needle Aspiration of Pancreatic Adenocarcinomas. / Levy, Michael J.; Kipp, Benjamin R.; Milosevic, Dragana; Schneider, Amber R.; Voss, Jesse S.; Avula, Rajeswari; Kerr, Sarah E.; Henry, Michael R.; Highsmith, W Edward Jr.; Liu, Minetta C; Gleeson, Ferga C.

In: Clinical Gastroenterology and Hepatology, 01.01.2018.

Research output: Contribution to journalArticle

Levy, Michael J. ; Kipp, Benjamin R. ; Milosevic, Dragana ; Schneider, Amber R. ; Voss, Jesse S. ; Avula, Rajeswari ; Kerr, Sarah E. ; Henry, Michael R. ; Highsmith, W Edward Jr. ; Liu, Minetta C ; Gleeson, Ferga C. / Analysis of Cell-Free DNA to Assess Risk of Tumoremia Following Endoscopic Ultrasound Fine-Needle Aspiration of Pancreatic Adenocarcinomas. In: Clinical Gastroenterology and Hepatology. 2018.
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title = "Analysis of Cell-Free DNA to Assess Risk of Tumoremia Following Endoscopic Ultrasound Fine-Needle Aspiration of Pancreatic Adenocarcinomas",
abstract = "Background & Aims: Cellular and nuclear material from tumors disseminates into the bloodstream (tumoremia), but it is not clear whether medical procedures cause release of this material or contribute to formation of metastases. We performed a prospective study of blood samples from patients with pancreatic adenocarcinoma (PDAC) to determine whether endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) associates with markers of tumoremia. Methods: We obtained peripheral blood from 104 patients (35 with PDAC) before and after EUS-FNA of primary tumors; blood samples from 69 healthy individuals were used as controls. Plasma concentrations of cell-free DNA (cfDNA) were measured, and cfDNA and primary tumor samples were analyzed to detect activating mutations in KRAS. Potential development of tumoremia was defined by an increase in cfDNA of 2-fold or more, and/or detection of mutant KRAS in samples collected after FNA from patients whose blood samples did not contain detectable mutant KRAS before FNA. Results: Peripheral blood concentrations of cfDNA were 1200 ng/ml (500–3300 ng/ml) before FNA vs 1400 ng/ml (900–4000 ng/ml) after FNA (P =.391). Tumoremia was detected in 10/35 patients (28.6{\%}): 7 patients had a ≥2-fold increase in cfDNA concentration (20.6{\%}) and 3 patients had circulating tumor DNA with KRAS mutations after FNA that were not detected before FNA (8.8{\%}). New distant metastases were detected in 1.3 ± 0.82 patients with tumoremia vs 0.64 ± 0.81 without (P =.0375). Overall mortality did not differ significantly between patients with tumoremia (10/10 deaths, 100{\%}) vs those without (19/25 deaths, 76{\%}) nor did survival times of deceased patients (13.3 months for patients with tumoremia; range, 5.8–14.9 months vs 11.1 months for patients without tumoremia; range, 5.5–14.5 months). However, 6 patients without tumoremia were alive at a mean 23.9 months after EUS-FNA (range, 19.9–25 months after EUS-FNA) vs none of the patients with tumoremia. Conclusion: In patients with PDAC, EUS-FNA associates with increased plasma concentration of cfDNA and increased detection of mutant KRAS after the procedure (markers of tumoremia and possible new distant metastasis). Although levels of cfDNA and activating mutations in KRAS are logical markers of tumoremia, they may not serve as the ideal biomarkers of this process. These findings are preliminary and do not indicate a need to modify current practice, yet further studies are needed.",
keywords = "Cancer Detection, Diagnostic, Molecular Cytogenetic Biomarker, Pathology",
author = "Levy, {Michael J.} and Kipp, {Benjamin R.} and Dragana Milosevic and Schneider, {Amber R.} and Voss, {Jesse S.} and Rajeswari Avula and Kerr, {Sarah E.} and Henry, {Michael R.} and Highsmith, {W Edward Jr.} and Liu, {Minetta C} and Gleeson, {Ferga C.}",
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language = "English (US)",
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T1 - Analysis of Cell-Free DNA to Assess Risk of Tumoremia Following Endoscopic Ultrasound Fine-Needle Aspiration of Pancreatic Adenocarcinomas

AU - Levy, Michael J.

AU - Kipp, Benjamin R.

AU - Milosevic, Dragana

AU - Schneider, Amber R.

AU - Voss, Jesse S.

AU - Avula, Rajeswari

AU - Kerr, Sarah E.

AU - Henry, Michael R.

AU - Highsmith, W Edward Jr.

AU - Liu, Minetta C

AU - Gleeson, Ferga C.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background & Aims: Cellular and nuclear material from tumors disseminates into the bloodstream (tumoremia), but it is not clear whether medical procedures cause release of this material or contribute to formation of metastases. We performed a prospective study of blood samples from patients with pancreatic adenocarcinoma (PDAC) to determine whether endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) associates with markers of tumoremia. Methods: We obtained peripheral blood from 104 patients (35 with PDAC) before and after EUS-FNA of primary tumors; blood samples from 69 healthy individuals were used as controls. Plasma concentrations of cell-free DNA (cfDNA) were measured, and cfDNA and primary tumor samples were analyzed to detect activating mutations in KRAS. Potential development of tumoremia was defined by an increase in cfDNA of 2-fold or more, and/or detection of mutant KRAS in samples collected after FNA from patients whose blood samples did not contain detectable mutant KRAS before FNA. Results: Peripheral blood concentrations of cfDNA were 1200 ng/ml (500–3300 ng/ml) before FNA vs 1400 ng/ml (900–4000 ng/ml) after FNA (P =.391). Tumoremia was detected in 10/35 patients (28.6%): 7 patients had a ≥2-fold increase in cfDNA concentration (20.6%) and 3 patients had circulating tumor DNA with KRAS mutations after FNA that were not detected before FNA (8.8%). New distant metastases were detected in 1.3 ± 0.82 patients with tumoremia vs 0.64 ± 0.81 without (P =.0375). Overall mortality did not differ significantly between patients with tumoremia (10/10 deaths, 100%) vs those without (19/25 deaths, 76%) nor did survival times of deceased patients (13.3 months for patients with tumoremia; range, 5.8–14.9 months vs 11.1 months for patients without tumoremia; range, 5.5–14.5 months). However, 6 patients without tumoremia were alive at a mean 23.9 months after EUS-FNA (range, 19.9–25 months after EUS-FNA) vs none of the patients with tumoremia. Conclusion: In patients with PDAC, EUS-FNA associates with increased plasma concentration of cfDNA and increased detection of mutant KRAS after the procedure (markers of tumoremia and possible new distant metastasis). Although levels of cfDNA and activating mutations in KRAS are logical markers of tumoremia, they may not serve as the ideal biomarkers of this process. These findings are preliminary and do not indicate a need to modify current practice, yet further studies are needed.

AB - Background & Aims: Cellular and nuclear material from tumors disseminates into the bloodstream (tumoremia), but it is not clear whether medical procedures cause release of this material or contribute to formation of metastases. We performed a prospective study of blood samples from patients with pancreatic adenocarcinoma (PDAC) to determine whether endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) associates with markers of tumoremia. Methods: We obtained peripheral blood from 104 patients (35 with PDAC) before and after EUS-FNA of primary tumors; blood samples from 69 healthy individuals were used as controls. Plasma concentrations of cell-free DNA (cfDNA) were measured, and cfDNA and primary tumor samples were analyzed to detect activating mutations in KRAS. Potential development of tumoremia was defined by an increase in cfDNA of 2-fold or more, and/or detection of mutant KRAS in samples collected after FNA from patients whose blood samples did not contain detectable mutant KRAS before FNA. Results: Peripheral blood concentrations of cfDNA were 1200 ng/ml (500–3300 ng/ml) before FNA vs 1400 ng/ml (900–4000 ng/ml) after FNA (P =.391). Tumoremia was detected in 10/35 patients (28.6%): 7 patients had a ≥2-fold increase in cfDNA concentration (20.6%) and 3 patients had circulating tumor DNA with KRAS mutations after FNA that were not detected before FNA (8.8%). New distant metastases were detected in 1.3 ± 0.82 patients with tumoremia vs 0.64 ± 0.81 without (P =.0375). Overall mortality did not differ significantly between patients with tumoremia (10/10 deaths, 100%) vs those without (19/25 deaths, 76%) nor did survival times of deceased patients (13.3 months for patients with tumoremia; range, 5.8–14.9 months vs 11.1 months for patients without tumoremia; range, 5.5–14.5 months). However, 6 patients without tumoremia were alive at a mean 23.9 months after EUS-FNA (range, 19.9–25 months after EUS-FNA) vs none of the patients with tumoremia. Conclusion: In patients with PDAC, EUS-FNA associates with increased plasma concentration of cfDNA and increased detection of mutant KRAS after the procedure (markers of tumoremia and possible new distant metastasis). Although levels of cfDNA and activating mutations in KRAS are logical markers of tumoremia, they may not serve as the ideal biomarkers of this process. These findings are preliminary and do not indicate a need to modify current practice, yet further studies are needed.

KW - Cancer Detection

KW - Diagnostic

KW - Molecular Cytogenetic Biomarker

KW - Pathology

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U2 - 10.1016/j.cgh.2018.02.048

DO - 10.1016/j.cgh.2018.02.048

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C2 - 29526691

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JO - Clinical Gastroenterology and Hepatology

JF - Clinical Gastroenterology and Hepatology

SN - 1542-3565

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