Unraveling the potential clinical utility of circulating tumor DNA detection in colorectal cancer - evaluation in a nationwide Danish cohort.

Colorectal cancer cell-free DNA circulating tumor DNA minimal residual disease recurrence surveillance

Journal

Annals of oncology : official journal of the European Society for Medical Oncology
ISSN: 1569-8041
Titre abrégé: Ann Oncol
Pays: England
ID NLM: 9007735

Informations de publication

Date de publication:
20 Nov 2023
Historique:
received: 19 06 2023
revised: 29 09 2023
accepted: 13 11 2023
medline: 23 11 2023
pubmed: 23 11 2023
entrez: 22 11 2023
Statut: aheadofprint

Résumé

Increasingly, circulating tumor DNA (ctDNA) is proposed as a tool for minimal residual disease (MRD) assessment. Digital PCR (dPCR) offers low analysis costs and turnaround times of less than a day, making it ripe for clinical implementation. Here, we used tumor-informed dPCR for ctDNA detection in a large CRC cohort to evaluate the potential for postoperative risk assessment and serial monitoring, and how the metastatic site may impact ctDNA detection. Additionally, we assessed how altering the ctDNA calling algorithm could customize performance for different clinical settings. Stage II-III CRC patients (N=851) treated with curative intent were recruited. Based on whole exome sequencing on matched tumor and germline DNA, a mutational target was selected for dPCR analysis. Plasma samples (8mL) were collected within 60 days post operation and - for a patient subset (n=246) - every 3-4 months for up to 36 months. Single-target dPCR was used for ctDNA detection. Both postoperative and serial ctDNA detection was prognostic of recurrence (HR=11.3, 95%CI 7.8-16.4, P<0.001; HR=30.7, 95%CI 20.2-46.7, P<0.001), with a cumulative ctDNA detection rate of 87% at the end of sample collection in recurrence patients. The ctDNA growth rate was prognostic of survival (HR=2.6, 95%CI 1.5-4.4, P=0.001). In recurrence patients, postoperative ctDNA detection was challenging for lung metastases (4/21 detected) and peritoneal metastases (2/10 detected). By modifying the cutoff for calling a sample ctDNA positive, we were able to adjust the sensitivity and specificity of our test for different clinical contexts. The presented results from 851 stage II-III CRC patients demonstrate that our personalized dPCR approach effectively detects MRD post operation and shows promise for serial ctDNA detection for recurrence surveillance. The ability to adjust sensitivity and specificity shows exciting potential to customize the ctDNA caller for specific clinical settings.

Sections du résumé

BACKGROUND BACKGROUND
Increasingly, circulating tumor DNA (ctDNA) is proposed as a tool for minimal residual disease (MRD) assessment. Digital PCR (dPCR) offers low analysis costs and turnaround times of less than a day, making it ripe for clinical implementation. Here, we used tumor-informed dPCR for ctDNA detection in a large CRC cohort to evaluate the potential for postoperative risk assessment and serial monitoring, and how the metastatic site may impact ctDNA detection. Additionally, we assessed how altering the ctDNA calling algorithm could customize performance for different clinical settings.
PATIENTS AND METHODS METHODS
Stage II-III CRC patients (N=851) treated with curative intent were recruited. Based on whole exome sequencing on matched tumor and germline DNA, a mutational target was selected for dPCR analysis. Plasma samples (8mL) were collected within 60 days post operation and - for a patient subset (n=246) - every 3-4 months for up to 36 months. Single-target dPCR was used for ctDNA detection.
RESULTS RESULTS
Both postoperative and serial ctDNA detection was prognostic of recurrence (HR=11.3, 95%CI 7.8-16.4, P<0.001; HR=30.7, 95%CI 20.2-46.7, P<0.001), with a cumulative ctDNA detection rate of 87% at the end of sample collection in recurrence patients. The ctDNA growth rate was prognostic of survival (HR=2.6, 95%CI 1.5-4.4, P=0.001). In recurrence patients, postoperative ctDNA detection was challenging for lung metastases (4/21 detected) and peritoneal metastases (2/10 detected). By modifying the cutoff for calling a sample ctDNA positive, we were able to adjust the sensitivity and specificity of our test for different clinical contexts.
CONCLUSIONS CONCLUSIONS
The presented results from 851 stage II-III CRC patients demonstrate that our personalized dPCR approach effectively detects MRD post operation and shows promise for serial ctDNA detection for recurrence surveillance. The ability to adjust sensitivity and specificity shows exciting potential to customize the ctDNA caller for specific clinical settings.

Identifiants

DOI: 10.1016/j.annonc.2023.11.009 PMID: 37992872
pubmed: 37992872
pii: S0923-7534(23)05073-1
doi: 10.1016/j.annonc.2023.11.009
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Auteurs

T V Henriksen (TV)

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

C Demuth (C)

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

A Frydendahl (A)

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

J Nors (J)

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

M Nesic (M)

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

M H Rasmussen (MH)

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

T Reinert (T)

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

O H Larsen (OH)

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

C Jaensch (C)

Department of Surgery, Regional Hospital Gødstrup, Herning, Denmark.

U S Løve (US)

Department of Surgery, Regional Hospital Viborg, Viborg, Denmark.

P V Andersen (PV)

Department of Surgery, Odense University Hospital, Odense, Denmark.

T Kolbro (T)

Department of Surgery, Odense University Hospital, Svendborg, Denmark.

O Thorlacius-Ussing (O)

Clinical Cancer Research Center, Aalborg University, Aalborg, Denmark.

A Monti (A)

Department of Surgery, North Denmark Regional Hospital Hjørring, Hjørring, Denmark.

M Gögenur (M)

Center for Surgical Sciences, Zealand University Hospital, Køge, Denmark.

J Kildsig (J)

Department of Surgery, Copenhagen University Hospital, Herlev, Denmark.

P Bondeven (P)

Department of Surgery, Regional Hospital Randers, Randers, Denmark.

N H Schlesinger (NH)

Department of Surgery, Copenhagen University Hospital, Bispebjerg, Denmark.

L H Iversen (LH)

Department of Surgery, Aarhus University Hospital, Aarhus, Denmark.

K A Gotschalck (KA)

Department of Surgery, Regional Hospital Horsens, Horsens, Denmark.

C L Andersen (CL)

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: cla@clin.au.dk.

Classifications MeSH