Circulating tumor DNA as a clinical test in resected pancreatic cancer

Vincent P. Groot, Stacy Mosier, Ammar A. Javed, Jonathan A. Teinor, Georgios Gemenetzis, Ding Ding, Lisa M. Haley, Jun Yu, Richard A. Burkhart, Alina Hasanain, Marija Debeljak, Hirohiko Kamiyama, Amol Narang, Daniel A. Laheru, Lei Zheng, Ming Tseh Lin, Christopher D. Gocke, Elliot K. Fishman, Ralph H. Hruban, Michael G. GogginsI. Quintus Molenaar, John L. Cameron, Matthew J. Weiss, Victor E. Velculescu, Jin He, Christopher L. Wolfgang, James R. Eshleman

Research output: Contribution to journalArticle

Abstract

Purpose: In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology–certified clinical laboratory. Experimental Design: Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed. Results: ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-na€ve patients (21% vs. 69%; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%–98%), specificity 88% (95% CI, 62%–98%)] with a median lead time of 84 days (interquartile range, 25–146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P ¼ 0.011). Conclusions: Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.

Original languageEnglish (US)
Pages (from-to)4973-4984
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number16
DOIs
StatePublished - Aug 15 2019

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Pancreatic Neoplasms
DNA
Neoplasms
Adenocarcinoma
Recurrence
Survival
Confidence Intervals
Tumor Biomarkers
Postoperative Period
Research Design
Biopsy
Drug Therapy
Polymerase Chain Reaction
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Groot, V. P., Mosier, S., Javed, A. A., Teinor, J. A., Gemenetzis, G., Ding, D., ... Eshleman, J. R. (2019). Circulating tumor DNA as a clinical test in resected pancreatic cancer. Clinical Cancer Research, 25(16), 4973-4984. https://doi.org/10.1158/1078-0432.CCR-19-0197

Circulating tumor DNA as a clinical test in resected pancreatic cancer. / Groot, Vincent P.; Mosier, Stacy; Javed, Ammar A.; Teinor, Jonathan A.; Gemenetzis, Georgios; Ding, Ding; Haley, Lisa M.; Yu, Jun; Burkhart, Richard A.; Hasanain, Alina; Debeljak, Marija; Kamiyama, Hirohiko; Narang, Amol; Laheru, Daniel A.; Zheng, Lei; Lin, Ming Tseh; Gocke, Christopher D.; Fishman, Elliot K.; Hruban, Ralph H.; Goggins, Michael G.; Quintus Molenaar, I.; Cameron, John L.; Weiss, Matthew J.; Velculescu, Victor E.; He, Jin; Wolfgang, Christopher L.; Eshleman, James R.

In: Clinical Cancer Research, Vol. 25, No. 16, 15.08.2019, p. 4973-4984.

Research output: Contribution to journalArticle

Groot VP, Mosier S, Javed AA, Teinor JA, Gemenetzis G, Ding D et al. Circulating tumor DNA as a clinical test in resected pancreatic cancer. Clinical Cancer Research. 2019 Aug 15;25(16):4973-4984. https://doi.org/10.1158/1078-0432.CCR-19-0197
Groot, Vincent P. ; Mosier, Stacy ; Javed, Ammar A. ; Teinor, Jonathan A. ; Gemenetzis, Georgios ; Ding, Ding ; Haley, Lisa M. ; Yu, Jun ; Burkhart, Richard A. ; Hasanain, Alina ; Debeljak, Marija ; Kamiyama, Hirohiko ; Narang, Amol ; Laheru, Daniel A. ; Zheng, Lei ; Lin, Ming Tseh ; Gocke, Christopher D. ; Fishman, Elliot K. ; Hruban, Ralph H. ; Goggins, Michael G. ; Quintus Molenaar, I. ; Cameron, John L. ; Weiss, Matthew J. ; Velculescu, Victor E. ; He, Jin ; Wolfgang, Christopher L. ; Eshleman, James R. / Circulating tumor DNA as a clinical test in resected pancreatic cancer. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 16. pp. 4973-4984.
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title = "Circulating tumor DNA as a clinical test in resected pancreatic cancer",
abstract = "Purpose: In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology–certified clinical laboratory. Experimental Design: Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed. Results: ctDNA was detected preoperatively in 29 (49{\%}) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-na€ve patients (21{\%} vs. 69{\%}; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90{\%} (95{\%} confidence interval (CI), 74{\%}–98{\%}), specificity 88{\%} (95{\%} CI, 62{\%}–98{\%})] with a median lead time of 84 days (interquartile range, 25–146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P ¼ 0.011). Conclusions: Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.",
author = "Groot, {Vincent P.} and Stacy Mosier and Javed, {Ammar A.} and Teinor, {Jonathan A.} and Georgios Gemenetzis and Ding Ding and Haley, {Lisa M.} and Jun Yu and Burkhart, {Richard A.} and Alina Hasanain and Marija Debeljak and Hirohiko Kamiyama and Amol Narang and Laheru, {Daniel A.} and Lei Zheng and Lin, {Ming Tseh} and Gocke, {Christopher D.} and Fishman, {Elliot K.} and Hruban, {Ralph H.} and Goggins, {Michael G.} and {Quintus Molenaar}, I. and Cameron, {John L.} and Weiss, {Matthew J.} and Velculescu, {Victor E.} and Jin He and Wolfgang, {Christopher L.} and Eshleman, {James R.}",
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TY - JOUR

T1 - Circulating tumor DNA as a clinical test in resected pancreatic cancer

AU - Groot, Vincent P.

AU - Mosier, Stacy

AU - Javed, Ammar A.

AU - Teinor, Jonathan A.

AU - Gemenetzis, Georgios

AU - Ding, Ding

AU - Haley, Lisa M.

AU - Yu, Jun

AU - Burkhart, Richard A.

AU - Hasanain, Alina

AU - Debeljak, Marija

AU - Kamiyama, Hirohiko

AU - Narang, Amol

AU - Laheru, Daniel A.

AU - Zheng, Lei

AU - Lin, Ming Tseh

AU - Gocke, Christopher D.

AU - Fishman, Elliot K.

AU - Hruban, Ralph H.

AU - Goggins, Michael G.

AU - Quintus Molenaar, I.

AU - Cameron, John L.

AU - Weiss, Matthew J.

AU - Velculescu, Victor E.

AU - He, Jin

AU - Wolfgang, Christopher L.

AU - Eshleman, James R.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - Purpose: In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology–certified clinical laboratory. Experimental Design: Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed. Results: ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-na€ve patients (21% vs. 69%; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%–98%), specificity 88% (95% CI, 62%–98%)] with a median lead time of 84 days (interquartile range, 25–146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P ¼ 0.011). Conclusions: Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.

AB - Purpose: In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology–certified clinical laboratory. Experimental Design: Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed. Results: ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-na€ve patients (21% vs. 69%; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%–98%), specificity 88% (95% CI, 62%–98%)] with a median lead time of 84 days (interquartile range, 25–146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P ¼ 0.011). Conclusions: Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.

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