Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma

Marin Strijker, Eline C. Soer, Matteo de Pastena, Aafke Creemers, Alberto Balduzzi, Jamie J. Beagan, Olivier R. Busch, Otto M. van Delden, Hans Halfwerk, Jeanin E. van Hooft, Krijn P. van Lienden, Giovanni Marchegiani, Sybren L. Meijer, Carel J. van Noesel, Roy J. Reinten, Eva Roos, Sandor Schokker, Joanne Verheij, Marc J. van de Vijver, Cynthia Waasdorp & 6 others Johanna W. Wilmink, Bauke Ylstra, Marc G. Besselink, Maarten F. Bijlsma, Frederike Dijk, Hanneke W. van Laarhoven

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow-up in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell-free DNA from plasma samples of 58 treatment-naive mPDAC patients was isolated and sequenced using a custom-made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8%) samples. Cross-check with droplet digital PCR showed good agreement in Bland–Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p < 0.001). Tumor volume (3D reconstructions from imaging) and ctDNA variant allele frequency (VAF) were correlated (Spearman's ρ = 0.544, p < 0.001). Median overall survival (OS) was 3.2 (95% confidence interval [CI] 1.6–4.9) versus 8.4 (95% CI 1.6–15.1) months in patients with detectable versus undetectable ctDNA (p = 0.005). Both ctDNA VAF and tumor volume independently predicted OS after adjustment for carbohydrate antigen 19.9 and treatment regimen (hazard ratio [HR] 1.05, 95% CI 1.01–1.09, p = 0.005; HR 1.00, 95% CI 1.01–1.05, p = 0.003). In conclusion, our study showed that ctDNA detection rates are higher in patients with larger tumor volume and liver metastases. Nevertheless, measurements may diverge and, thus, can provide complementary information. Both ctDNA VAF and tumor volume were strong predictors of OS.
Original languageEnglish
JournalInternational Journal of Cancer
DOIs
Publication statusPublished - 2019

Cite this

Strijker, Marin ; Soer, Eline C. ; de Pastena, Matteo ; Creemers, Aafke ; Balduzzi, Alberto ; Beagan, Jamie J. ; Busch, Olivier R. ; van Delden, Otto M. ; Halfwerk, Hans ; van Hooft, Jeanin E. ; van Lienden, Krijn P. ; Marchegiani, Giovanni ; Meijer, Sybren L. ; van Noesel, Carel J. ; Reinten, Roy J. ; Roos, Eva ; Schokker, Sandor ; Verheij, Joanne ; van de Vijver, Marc J. ; Waasdorp, Cynthia ; Wilmink, Johanna W. ; Ylstra, Bauke ; Besselink, Marc G. ; Bijlsma, Maarten F. ; Dijk, Frederike ; van Laarhoven, Hanneke W. / Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma. In: International Journal of Cancer. 2019.
@article{fdccdf635079425399d441e57d1fffa4,
title = "Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma",
abstract = "Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow-up in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell-free DNA from plasma samples of 58 treatment-naive mPDAC patients was isolated and sequenced using a custom-made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8{\%}) samples. Cross-check with droplet digital PCR showed good agreement in Bland–Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p < 0.001). Tumor volume (3D reconstructions from imaging) and ctDNA variant allele frequency (VAF) were correlated (Spearman's ρ = 0.544, p < 0.001). Median overall survival (OS) was 3.2 (95{\%} confidence interval [CI] 1.6–4.9) versus 8.4 (95{\%} CI 1.6–15.1) months in patients with detectable versus undetectable ctDNA (p = 0.005). Both ctDNA VAF and tumor volume independently predicted OS after adjustment for carbohydrate antigen 19.9 and treatment regimen (hazard ratio [HR] 1.05, 95{\%} CI 1.01–1.09, p = 0.005; HR 1.00, 95{\%} CI 1.01–1.05, p = 0.003). In conclusion, our study showed that ctDNA detection rates are higher in patients with larger tumor volume and liver metastases. Nevertheless, measurements may diverge and, thus, can provide complementary information. Both ctDNA VAF and tumor volume were strong predictors of OS.",
author = "Marin Strijker and Soer, {Eline C.} and {de Pastena}, Matteo and Aafke Creemers and Alberto Balduzzi and Beagan, {Jamie J.} and Busch, {Olivier R.} and {van Delden}, {Otto M.} and Hans Halfwerk and {van Hooft}, {Jeanin E.} and {van Lienden}, {Krijn P.} and Giovanni Marchegiani and Meijer, {Sybren L.} and {van Noesel}, {Carel J.} and Reinten, {Roy J.} and Eva Roos and Sandor Schokker and Joanne Verheij and {van de Vijver}, {Marc J.} and Cynthia Waasdorp and Wilmink, {Johanna W.} and Bauke Ylstra and Besselink, {Marc G.} and Bijlsma, {Maarten F.} and Frederike Dijk and {van Laarhoven}, {Hanneke W.}",
year = "2019",
doi = "10.1002/ijc.32586",
language = "English",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",

}

Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma. / Strijker, Marin; Soer, Eline C.; de Pastena, Matteo; Creemers, Aafke; Balduzzi, Alberto; Beagan, Jamie J.; Busch, Olivier R.; van Delden, Otto M.; Halfwerk, Hans; van Hooft, Jeanin E.; van Lienden, Krijn P.; Marchegiani, Giovanni; Meijer, Sybren L.; van Noesel, Carel J.; Reinten, Roy J.; Roos, Eva; Schokker, Sandor; Verheij, Joanne; van de Vijver, Marc J.; Waasdorp, Cynthia; Wilmink, Johanna W.; Ylstra, Bauke; Besselink, Marc G.; Bijlsma, Maarten F.; Dijk, Frederike; van Laarhoven, Hanneke W.

In: International Journal of Cancer, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma

AU - Strijker, Marin

AU - Soer, Eline C.

AU - de Pastena, Matteo

AU - Creemers, Aafke

AU - Balduzzi, Alberto

AU - Beagan, Jamie J.

AU - Busch, Olivier R.

AU - van Delden, Otto M.

AU - Halfwerk, Hans

AU - van Hooft, Jeanin E.

AU - van Lienden, Krijn P.

AU - Marchegiani, Giovanni

AU - Meijer, Sybren L.

AU - van Noesel, Carel J.

AU - Reinten, Roy J.

AU - Roos, Eva

AU - Schokker, Sandor

AU - Verheij, Joanne

AU - van de Vijver, Marc J.

AU - Waasdorp, Cynthia

AU - Wilmink, Johanna W.

AU - Ylstra, Bauke

AU - Besselink, Marc G.

AU - Bijlsma, Maarten F.

AU - Dijk, Frederike

AU - van Laarhoven, Hanneke W.

PY - 2019

Y1 - 2019

N2 - Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow-up in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell-free DNA from plasma samples of 58 treatment-naive mPDAC patients was isolated and sequenced using a custom-made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8%) samples. Cross-check with droplet digital PCR showed good agreement in Bland–Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p < 0.001). Tumor volume (3D reconstructions from imaging) and ctDNA variant allele frequency (VAF) were correlated (Spearman's ρ = 0.544, p < 0.001). Median overall survival (OS) was 3.2 (95% confidence interval [CI] 1.6–4.9) versus 8.4 (95% CI 1.6–15.1) months in patients with detectable versus undetectable ctDNA (p = 0.005). Both ctDNA VAF and tumor volume independently predicted OS after adjustment for carbohydrate antigen 19.9 and treatment regimen (hazard ratio [HR] 1.05, 95% CI 1.01–1.09, p = 0.005; HR 1.00, 95% CI 1.01–1.05, p = 0.003). In conclusion, our study showed that ctDNA detection rates are higher in patients with larger tumor volume and liver metastases. Nevertheless, measurements may diverge and, thus, can provide complementary information. Both ctDNA VAF and tumor volume were strong predictors of OS.

AB - Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow-up in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell-free DNA from plasma samples of 58 treatment-naive mPDAC patients was isolated and sequenced using a custom-made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8%) samples. Cross-check with droplet digital PCR showed good agreement in Bland–Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p < 0.001). Tumor volume (3D reconstructions from imaging) and ctDNA variant allele frequency (VAF) were correlated (Spearman's ρ = 0.544, p < 0.001). Median overall survival (OS) was 3.2 (95% confidence interval [CI] 1.6–4.9) versus 8.4 (95% CI 1.6–15.1) months in patients with detectable versus undetectable ctDNA (p = 0.005). Both ctDNA VAF and tumor volume independently predicted OS after adjustment for carbohydrate antigen 19.9 and treatment regimen (hazard ratio [HR] 1.05, 95% CI 1.01–1.09, p = 0.005; HR 1.00, 95% CI 1.01–1.05, p = 0.003). In conclusion, our study showed that ctDNA detection rates are higher in patients with larger tumor volume and liver metastases. Nevertheless, measurements may diverge and, thus, can provide complementary information. Both ctDNA VAF and tumor volume were strong predictors of OS.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85071182861&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31340061

U2 - 10.1002/ijc.32586

DO - 10.1002/ijc.32586

M3 - Article

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

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