Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study

Nadia Øgaard; Thomas Reinert; Tenna V. Henriksen; Amanda Frydendahl; Emilie Aagaard; Mai Britt W. Ørntoft; Marie Larsen; Anders R. Knudsen; Frank V. Mortensen; Claus L. Andersen

doi:10.1016/j.ejca.2021.12.026

Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study

Nadia Øgaard, Thomas Reinert, Tenna V. Henriksen, Amanda Frydendahl, Emilie Aagaard, Mai Britt W. Ørntoft, Marie Larsen, Anders R. Knudsen, Frank V. Mortensen, Claus L. Andersen^*

^*Corresponding author for this work

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Abstract

Purpose: Nearly 50% of patients recur within two years after curatively intended resection of colorectal cancer liver metastasis (CRLM). The optimal surveillance strategy is unknown due to the lack of evidence. Here, we explored the potential for improving postoperative CRLM surveillance by performing serial circulating tumour DNA (ctDNA) assessments parallel to standard-of-care surveillance. Experimental design: 499 prospectively collected serial plasma samples from 96 patients undergoing CRLM resection were analysed using the tumour-agnostic methylation multiplex droplet-digital PCR test ‘TriMeth’. Results: Patients with ctDNA postoperatively or post adjuvant chemotherapy experienced a significant lower recurrence-free survival than patients without ctDNA (hazard ratio (HR) 4.5; P < 0.0001 and HR 8.4, P < 0.0001). ctDNA status was a stronger predictor of recurrence than standard clinical risk factors and carcinoembryonic antigen. Serial TriMeth analysis detected ctDNA before radiological recurrence in 55.6% of ctDNA-positive patients, with up to 10.6 months lead-time (median 3.1 months). During surveillance, 24% of patients had inconclusive CT scans, which was associated with a significant delay in recurrence diagnosis (median 3.5 months versus 1.0 month, P < 0.0001). Uniquely, ctDNA status at the time of inconclusive CT scans predicted recurrence with positive and negative predictive values of 100%, and 75% (P = 0.0003). Serial TriMeth analysis allowed ctDNA growth rate assessment and revealed that fast ctDNA growth was associated with poor overall survival (HR: 1.6, P = 0.0052). Conclusions: Serial postoperative ctDNA analysis has a strong prognostic value and is more sensitive for recurrence detection than standard-of-care CRLM surveillance tools. Altogether, TriMeth provides several opportunities for improving postoperative surveillance of CRLM patients.

Original language	English
Journal	European Journal of Cancer
Volume	163
Pages (from-to)	163-176
Number of pages	14
ISSN	0959-8049
DOIs	https://doi.org/10.1016/j.ejca.2021.12.026
Publication status	Published - Mar 2022

Keywords

Cancer biomarker
Circulating tumour DNA
Colorectal cancer
DNA methylation
Metastasis
Recurrence
Surveillance
Prognosis
Prospective Studies
Circulating Tumor DNA/genetics
Humans
Liver Neoplasms/genetics
Neoplasm Recurrence, Local/pathology
Biomarkers, Tumor/genetics
Colorectal Neoplasms/diagnosis
Cell-Free Nucleic Acids

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10.1016/j.ejca.2021.12.026Licence: CC BY

1-s2.0-S0959804921013071-mainFinal published version, 1.18 MBLicence: CC BY

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Øgaard, N., Reinert, T., Henriksen, T. V., Frydendahl, A., Aagaard, E., Ørntoft, M. B. W., Larsen, M., Knudsen, A. R., Mortensen, F. V., & Andersen, C. L. (2022). Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study. European Journal of Cancer, 163, 163-176. https://doi.org/10.1016/j.ejca.2021.12.026

@article{15047ea7b96d474dbe1efd61f91796cd,

title = "Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study",

abstract = "Purpose: Nearly 50% of patients recur within two years after curatively intended resection of colorectal cancer liver metastasis (CRLM). The optimal surveillance strategy is unknown due to the lack of evidence. Here, we explored the potential for improving postoperative CRLM surveillance by performing serial circulating tumour DNA (ctDNA) assessments parallel to standard-of-care surveillance. Experimental design: 499 prospectively collected serial plasma samples from 96 patients undergoing CRLM resection were analysed using the tumour-agnostic methylation multiplex droplet-digital PCR test {\textquoteleft}TriMeth{\textquoteright}. Results: Patients with ctDNA postoperatively or post adjuvant chemotherapy experienced a significant lower recurrence-free survival than patients without ctDNA (hazard ratio (HR) 4.5; P < 0.0001 and HR 8.4, P < 0.0001). ctDNA status was a stronger predictor of recurrence than standard clinical risk factors and carcinoembryonic antigen. Serial TriMeth analysis detected ctDNA before radiological recurrence in 55.6% of ctDNA-positive patients, with up to 10.6 months lead-time (median 3.1 months). During surveillance, 24% of patients had inconclusive CT scans, which was associated with a significant delay in recurrence diagnosis (median 3.5 months versus 1.0 month, P < 0.0001). Uniquely, ctDNA status at the time of inconclusive CT scans predicted recurrence with positive and negative predictive values of 100%, and 75% (P = 0.0003). Serial TriMeth analysis allowed ctDNA growth rate assessment and revealed that fast ctDNA growth was associated with poor overall survival (HR: 1.6, P = 0.0052). Conclusions: Serial postoperative ctDNA analysis has a strong prognostic value and is more sensitive for recurrence detection than standard-of-care CRLM surveillance tools. Altogether, TriMeth provides several opportunities for improving postoperative surveillance of CRLM patients.",

keywords = "Cancer biomarker, Circulating tumour DNA, Colorectal cancer, DNA methylation, Metastasis, Recurrence, Surveillance, Prognosis, Prospective Studies, Circulating Tumor DNA/genetics, Humans, Liver Neoplasms/genetics, Neoplasm Recurrence, Local/pathology, Biomarkers, Tumor/genetics, Colorectal Neoplasms/diagnosis, Cell-Free Nucleic Acids",

author = "Nadia {\O}gaard and Thomas Reinert and Henriksen, {Tenna V.} and Amanda Frydendahl and Emilie Aagaard and {\O}rntoft, {Mai Britt W.} and Marie Larsen and Knudsen, {Anders R.} and Mortensen, {Frank V.} and Andersen, {Claus L.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = mar,

doi = "10.1016/j.ejca.2021.12.026",

language = "English",

volume = "163",

pages = "163--176",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Ltd",

}

Øgaard, N , Reinert, T , Henriksen, TV , Frydendahl, A, Aagaard, E, Ørntoft, MBW, Larsen, M, Knudsen, AR , Mortensen, FV & Andersen, CL 2022, 'Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study', European Journal of Cancer, vol. 163, pp. 163-176. https://doi.org/10.1016/j.ejca.2021.12.026

Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study. / Øgaard, Nadia ; Reinert, Thomas ; Henriksen, Tenna V. et al.
In: European Journal of Cancer, Vol. 163, 03.2022, p. 163-176.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases

T2 - A prospective cohort study

AU - Øgaard, Nadia

AU - Reinert, Thomas

AU - Henriksen, Tenna V.

AU - Frydendahl, Amanda

AU - Aagaard, Emilie

AU - Ørntoft, Mai Britt W.

AU - Larsen, Marie

AU - Knudsen, Anders R.

AU - Mortensen, Frank V.

AU - Andersen, Claus L.

PY - 2022/3

Y1 - 2022/3

N2 - Purpose: Nearly 50% of patients recur within two years after curatively intended resection of colorectal cancer liver metastasis (CRLM). The optimal surveillance strategy is unknown due to the lack of evidence. Here, we explored the potential for improving postoperative CRLM surveillance by performing serial circulating tumour DNA (ctDNA) assessments parallel to standard-of-care surveillance. Experimental design: 499 prospectively collected serial plasma samples from 96 patients undergoing CRLM resection were analysed using the tumour-agnostic methylation multiplex droplet-digital PCR test ‘TriMeth’. Results: Patients with ctDNA postoperatively or post adjuvant chemotherapy experienced a significant lower recurrence-free survival than patients without ctDNA (hazard ratio (HR) 4.5; P < 0.0001 and HR 8.4, P < 0.0001). ctDNA status was a stronger predictor of recurrence than standard clinical risk factors and carcinoembryonic antigen. Serial TriMeth analysis detected ctDNA before radiological recurrence in 55.6% of ctDNA-positive patients, with up to 10.6 months lead-time (median 3.1 months). During surveillance, 24% of patients had inconclusive CT scans, which was associated with a significant delay in recurrence diagnosis (median 3.5 months versus 1.0 month, P < 0.0001). Uniquely, ctDNA status at the time of inconclusive CT scans predicted recurrence with positive and negative predictive values of 100%, and 75% (P = 0.0003). Serial TriMeth analysis allowed ctDNA growth rate assessment and revealed that fast ctDNA growth was associated with poor overall survival (HR: 1.6, P = 0.0052). Conclusions: Serial postoperative ctDNA analysis has a strong prognostic value and is more sensitive for recurrence detection than standard-of-care CRLM surveillance tools. Altogether, TriMeth provides several opportunities for improving postoperative surveillance of CRLM patients.

AB - Purpose: Nearly 50% of patients recur within two years after curatively intended resection of colorectal cancer liver metastasis (CRLM). The optimal surveillance strategy is unknown due to the lack of evidence. Here, we explored the potential for improving postoperative CRLM surveillance by performing serial circulating tumour DNA (ctDNA) assessments parallel to standard-of-care surveillance. Experimental design: 499 prospectively collected serial plasma samples from 96 patients undergoing CRLM resection were analysed using the tumour-agnostic methylation multiplex droplet-digital PCR test ‘TriMeth’. Results: Patients with ctDNA postoperatively or post adjuvant chemotherapy experienced a significant lower recurrence-free survival than patients without ctDNA (hazard ratio (HR) 4.5; P < 0.0001 and HR 8.4, P < 0.0001). ctDNA status was a stronger predictor of recurrence than standard clinical risk factors and carcinoembryonic antigen. Serial TriMeth analysis detected ctDNA before radiological recurrence in 55.6% of ctDNA-positive patients, with up to 10.6 months lead-time (median 3.1 months). During surveillance, 24% of patients had inconclusive CT scans, which was associated with a significant delay in recurrence diagnosis (median 3.5 months versus 1.0 month, P < 0.0001). Uniquely, ctDNA status at the time of inconclusive CT scans predicted recurrence with positive and negative predictive values of 100%, and 75% (P = 0.0003). Serial TriMeth analysis allowed ctDNA growth rate assessment and revealed that fast ctDNA growth was associated with poor overall survival (HR: 1.6, P = 0.0052). Conclusions: Serial postoperative ctDNA analysis has a strong prognostic value and is more sensitive for recurrence detection than standard-of-care CRLM surveillance tools. Altogether, TriMeth provides several opportunities for improving postoperative surveillance of CRLM patients.

KW - Cancer biomarker

KW - Circulating tumour DNA

KW - Colorectal cancer

KW - DNA methylation

KW - Metastasis

KW - Recurrence

KW - Surveillance

KW - Prognosis

KW - Prospective Studies

KW - Circulating Tumor DNA/genetics

KW - Humans

KW - Liver Neoplasms/genetics

KW - Neoplasm Recurrence, Local/pathology

KW - Biomarkers, Tumor/genetics

KW - Colorectal Neoplasms/diagnosis

KW - Cell-Free Nucleic Acids

UR - http://www.scopus.com/inward/record.url?scp=85123185942&partnerID=8YFLogxK

U2 - 10.1016/j.ejca.2021.12.026

DO - 10.1016/j.ejca.2021.12.026

M3 - Journal article

C2 - 35074652

AN - SCOPUS:85123185942

SN - 0959-8049

VL - 163

SP - 163

EP - 176

JO - European Journal of Cancer

JF - European Journal of Cancer

ER -

Tumour-agnostic circulating tumour DNA analysis for improved recurrence surveillance after resection of colorectal liver metastases: A prospective cohort study

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