Early assessment of circulating tumor DNA after curative-intent resection predicts tumor recurrence in early-stage and locally advanced non-small-cell lung cancer

Silvia Waldeck; Jan Mitschke; Sebastian Wiesemann; Michael Rassner; Geoffroy Andrieux; Max Deuter; Jurik Mutter; Anne Marie Lüchtenborg; Daniel Kottmann; Laurin Titze; Christoph Zeisel; Martina Jolic; Ulrike Philipp; Silke Lassmann; Peter Bronsert; Christine Greil; Justyna Rawluk; Heiko Becker; Lisa Isbell; Alexandra Müller; Soroush Doostkam; Bernward Passlick; Melanie Börries; Justus Duyster; Julius Wehrle; Florian Scherer; Nikolas von Bubnoff

doi:10.1002/1878-0261.13116

Early assessment of circulating tumor DNA after curative-intent resection predicts tumor recurrence in early-stage and locally advanced non-small-cell lung cancer

Silvia Waldeck, Jan Mitschke, Sebastian Wiesemann, Michael Rassner, Geoffroy Andrieux, Max Deuter, Jurik Mutter, Anne Marie Lüchtenborg, Daniel Kottmann, Laurin Titze, Christoph Zeisel, Martina Jolic, Ulrike Philipp, Silke Lassmann, Peter Bronsert, Christine Greil, Justyna Rawluk, Heiko Becker, Lisa Isbell, Alexandra MüllerSoroush Doostkam, Bernward Passlick, Melanie Börries, Justus Duyster, Julius Wehrle, Florian Scherer^*, Nikolas von Bubnoff^*

^*Corresponding author for this work

Clinic of Hematology and Oncology

77 Citations (Scopus)

Abstract

Circulating tumor DNA (ctDNA) has demonstrated great potential as a noninvasive biomarker to assess minimal residual disease (MRD) and profile tumor genotypes in patients with non-small-cell lung cancer (NSCLC). However, little is known about its dynamics during and after tumor resection, or its potential for predicting clinical outcomes. Here, we applied a targeted-capture high-throughput sequencing approach to profile ctDNA at various disease milestones and assessed its predictive value in patients with early-stage and locally advanced NSCLC. We prospectively enrolled 33 consecutive patients with stage IA to IIIB NSCLC undergoing curative-intent tumor resection (median follow-up: 26.2 months). From 21 patients, we serially collected 96 plasma samples before surgery, during surgery, 1–2 weeks postsurgery, and during follow-up. Deep next-generation sequencing using unique molecular identifiers was performed to identify and quantify tumor-specific mutations in ctDNA. Twelve patients (57%) had detectable mutations in ctDNA before tumor resection. Both ctDNA detection rates and ctDNA concentrations were significantly higher in plasma obtained during surgery compared with presurgical specimens (57% versus 19% ctDNA detection rate, and 12.47 versus 6.64 ng·mL⁻¹, respectively). Four patients (19%) remained ctDNA-positive at 1–2 weeks after surgery, with all of them (100%) experiencing disease progression at later time points. In contrast, only 4 out of 12 ctDNA-negative patients (33%) after surgery experienced relapse during follow-up. Positive ctDNA in early postoperative plasma samples was associated with shorter progression-free survival (P = 0.013) and overall survival (P = 0.004). Our findings suggest that, in early-stage and locally advanced NSCLC, intraoperative plasma sampling results in high ctDNA detection rates and that ctDNA positivity early after resection identifies patients at risk for relapse.

Original language	English
Journal	Molecular Oncology
Volume	16
Issue number	2
Pages (from-to)	527-537
Number of pages	11
ISSN	1574-7891
DOIs	https://doi.org/10.1002/1878-0261.13116
Publication status	Published - 01.2022

Funding

F.S. received research funding from Roche Sequencing Solutions. S.L. received Advisory Board and/or scientific meeting/presentation sponsorship; Agilent, AstraZeneca, Illumina, Novartis, Roche, as well as research project sponsorship Bristol–Myers–Squibb. All other authors declare no conflict of interest.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Research Area: Luebeck Integrated Oncology Network (LION)
Centers: University Cancer Center Schleswig-Holstein (UCCSH)

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10.1002/1878-0261.13116

Cite this

Waldeck, S., Mitschke, J., Wiesemann, S., Rassner, M., Andrieux, G., Deuter, M., Mutter, J., Lüchtenborg, A. M., Kottmann, D., Titze, L., Zeisel, C., Jolic, M., Philipp, U., Lassmann, S., Bronsert, P., Greil, C., Rawluk, J., Becker, H., Isbell, L., ... von Bubnoff, N. (2022). Early assessment of circulating tumor DNA after curative-intent resection predicts tumor recurrence in early-stage and locally advanced non-small-cell lung cancer. Molecular Oncology, 16(2), 527-537. https://doi.org/10.1002/1878-0261.13116

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title = "Early assessment of circulating tumor DNA after curative-intent resection predicts tumor recurrence in early-stage and locally advanced non-small-cell lung cancer",

abstract = "Circulating tumor DNA (ctDNA) has demonstrated great potential as a noninvasive biomarker to assess minimal residual disease (MRD) and profile tumor genotypes in patients with non-small-cell lung cancer (NSCLC). However, little is known about its dynamics during and after tumor resection, or its potential for predicting clinical outcomes. Here, we applied a targeted-capture high-throughput sequencing approach to profile ctDNA at various disease milestones and assessed its predictive value in patients with early-stage and locally advanced NSCLC. We prospectively enrolled 33 consecutive patients with stage IA to IIIB NSCLC undergoing curative-intent tumor resection (median follow-up: 26.2 months). From 21 patients, we serially collected 96 plasma samples before surgery, during surgery, 1–2 weeks postsurgery, and during follow-up. Deep next-generation sequencing using unique molecular identifiers was performed to identify and quantify tumor-specific mutations in ctDNA. Twelve patients (57\%) had detectable mutations in ctDNA before tumor resection. Both ctDNA detection rates and ctDNA concentrations were significantly higher in plasma obtained during surgery compared with presurgical specimens (57\% versus 19\% ctDNA detection rate, and 12.47 versus 6.64 ng·mL−1, respectively). Four patients (19\%) remained ctDNA-positive at 1–2 weeks after surgery, with all of them (100\%) experiencing disease progression at later time points. In contrast, only 4 out of 12 ctDNA-negative patients (33\%) after surgery experienced relapse during follow-up. Positive ctDNA in early postoperative plasma samples was associated with shorter progression-free survival (P = 0.013) and overall survival (P = 0.004). Our findings suggest that, in early-stage and locally advanced NSCLC, intraoperative plasma sampling results in high ctDNA detection rates and that ctDNA positivity early after resection identifies patients at risk for relapse.",

author = "Silvia Waldeck and Jan Mitschke and Sebastian Wiesemann and Michael Rassner and Geoffroy Andrieux and Max Deuter and Jurik Mutter and L{\"u}chtenborg, \{Anne Marie\} and Daniel Kottmann and Laurin Titze and Christoph Zeisel and Martina Jolic and Ulrike Philipp and Silke Lassmann and Peter Bronsert and Christine Greil and Justyna Rawluk and Heiko Becker and Lisa Isbell and Alexandra M{\"u}ller and Soroush Doostkam and Bernward Passlick and Melanie B{\"o}rries and Justus Duyster and Julius Wehrle and Florian Scherer and \{von Bubnoff\}, Nikolas",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Molecular Oncology published by John Wiley \& Sons Ltd on behalf of Federation of European Biochemical Societies",

year = "2022",

month = jan,

doi = "10.1002/1878-0261.13116",

language = "English",

volume = "16",

pages = "527--537",

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Waldeck, S, Mitschke, J, Wiesemann, S, Rassner, M, Andrieux, G, Deuter, M, Mutter, J, Lüchtenborg, AM, Kottmann, D, Titze, L, Zeisel, C, Jolic, M, Philipp, U, Lassmann, S, Bronsert, P, Greil, C, Rawluk, J, Becker, H, Isbell, L, Müller, A, Doostkam, S, Passlick, B, Börries, M, Duyster, J, Wehrle, J, Scherer, F & von Bubnoff, N 2022, 'Early assessment of circulating tumor DNA after curative-intent resection predicts tumor recurrence in early-stage and locally advanced non-small-cell lung cancer', Molecular Oncology, vol. 16, no. 2, pp. 527-537. https://doi.org/10.1002/1878-0261.13116

TY - JOUR

T1 - Early assessment of circulating tumor DNA after curative-intent resection predicts tumor recurrence in early-stage and locally advanced non-small-cell lung cancer

AU - Waldeck, Silvia

AU - Mitschke, Jan

AU - Wiesemann, Sebastian

AU - Rassner, Michael

AU - Andrieux, Geoffroy

AU - Deuter, Max

AU - Mutter, Jurik

AU - Lüchtenborg, Anne Marie

AU - Kottmann, Daniel

AU - Titze, Laurin

AU - Zeisel, Christoph

AU - Jolic, Martina

AU - Philipp, Ulrike

AU - Lassmann, Silke

AU - Bronsert, Peter

AU - Greil, Christine

AU - Rawluk, Justyna

AU - Becker, Heiko

AU - Isbell, Lisa

AU - Müller, Alexandra

AU - Doostkam, Soroush

AU - Passlick, Bernward

AU - Börries, Melanie

AU - Duyster, Justus

AU - Wehrle, Julius

AU - Scherer, Florian

AU - von Bubnoff, Nikolas

PY - 2022/1

Y1 - 2022/1

N2 - Circulating tumor DNA (ctDNA) has demonstrated great potential as a noninvasive biomarker to assess minimal residual disease (MRD) and profile tumor genotypes in patients with non-small-cell lung cancer (NSCLC). However, little is known about its dynamics during and after tumor resection, or its potential for predicting clinical outcomes. Here, we applied a targeted-capture high-throughput sequencing approach to profile ctDNA at various disease milestones and assessed its predictive value in patients with early-stage and locally advanced NSCLC. We prospectively enrolled 33 consecutive patients with stage IA to IIIB NSCLC undergoing curative-intent tumor resection (median follow-up: 26.2 months). From 21 patients, we serially collected 96 plasma samples before surgery, during surgery, 1–2 weeks postsurgery, and during follow-up. Deep next-generation sequencing using unique molecular identifiers was performed to identify and quantify tumor-specific mutations in ctDNA. Twelve patients (57%) had detectable mutations in ctDNA before tumor resection. Both ctDNA detection rates and ctDNA concentrations were significantly higher in plasma obtained during surgery compared with presurgical specimens (57% versus 19% ctDNA detection rate, and 12.47 versus 6.64 ng·mL−1, respectively). Four patients (19%) remained ctDNA-positive at 1–2 weeks after surgery, with all of them (100%) experiencing disease progression at later time points. In contrast, only 4 out of 12 ctDNA-negative patients (33%) after surgery experienced relapse during follow-up. Positive ctDNA in early postoperative plasma samples was associated with shorter progression-free survival (P = 0.013) and overall survival (P = 0.004). Our findings suggest that, in early-stage and locally advanced NSCLC, intraoperative plasma sampling results in high ctDNA detection rates and that ctDNA positivity early after resection identifies patients at risk for relapse.

AB - Circulating tumor DNA (ctDNA) has demonstrated great potential as a noninvasive biomarker to assess minimal residual disease (MRD) and profile tumor genotypes in patients with non-small-cell lung cancer (NSCLC). However, little is known about its dynamics during and after tumor resection, or its potential for predicting clinical outcomes. Here, we applied a targeted-capture high-throughput sequencing approach to profile ctDNA at various disease milestones and assessed its predictive value in patients with early-stage and locally advanced NSCLC. We prospectively enrolled 33 consecutive patients with stage IA to IIIB NSCLC undergoing curative-intent tumor resection (median follow-up: 26.2 months). From 21 patients, we serially collected 96 plasma samples before surgery, during surgery, 1–2 weeks postsurgery, and during follow-up. Deep next-generation sequencing using unique molecular identifiers was performed to identify and quantify tumor-specific mutations in ctDNA. Twelve patients (57%) had detectable mutations in ctDNA before tumor resection. Both ctDNA detection rates and ctDNA concentrations were significantly higher in plasma obtained during surgery compared with presurgical specimens (57% versus 19% ctDNA detection rate, and 12.47 versus 6.64 ng·mL−1, respectively). Four patients (19%) remained ctDNA-positive at 1–2 weeks after surgery, with all of them (100%) experiencing disease progression at later time points. In contrast, only 4 out of 12 ctDNA-negative patients (33%) after surgery experienced relapse during follow-up. Positive ctDNA in early postoperative plasma samples was associated with shorter progression-free survival (P = 0.013) and overall survival (P = 0.004). Our findings suggest that, in early-stage and locally advanced NSCLC, intraoperative plasma sampling results in high ctDNA detection rates and that ctDNA positivity early after resection identifies patients at risk for relapse.

UR - https://www.scopus.com/pages/publications/85118251877

U2 - 10.1002/1878-0261.13116

DO - 10.1002/1878-0261.13116

M3 - Journal articles

C2 - 34653314

AN - SCOPUS:85118251877

SN - 1574-7891

VL - 16

SP - 527

EP - 537

JO - Molecular Oncology

JF - Molecular Oncology

IS - 2

ER -

Early assessment of circulating tumor DNA after curative-intent resection predicts tumor recurrence in early-stage and locally advanced non-small-cell lung cancer

Abstract

Funding

UN SDGs

Research Areas and Centers

Access to Document

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