Postoperative circulating tumour DNA is associated with pathologic response and recurrence-free survival after resection of colorectal cancer liver metastases.

Karen Bolhuis,Cornelis J.A Punt,Clinton Mijnals,Iris Van 'T Erve,Gerrit A Meijer,Joost Huiskens,Marta Lopez-Yurda,Daan Van Den Broek,Rutger-Jan Swijnenburg,Remond J.A Fijneman,Pien M Delis – Van Diemen,Aysun Komurcu

doi:10.1016/j.ebiom.2021.103498

Abstract

BackgroundRecurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Postoperative circulating tumour DNA (ctDNA) is a promising prognostic biomarker. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS).MethodsTwenty-three patients were selected from an ongoing phase-3 trial who underwent resection of RAS-mutant CRLM after induction systemic treatment. CtDNA analysis was performed by droplet digital PCR using blood samples collected at baseline, before and after resection. Pathologic response of CRLM was determined via the Tumour Regression Grading system.FindingsWith a median follow-up of 19.6 months, the median RFS for patients with detectable (N = 6, [26%]) and undetectable (N = 17, [74%]) postoperative ctDNA was 4.8 versus 12.1 months, respectively. Among 21 patients with available tumour tissue, pathologic response in patients with detectable compared to undetectable postoperative ctDNA was found in one of six (17%) and 15 of 15 (100%) patients, respectively (p < 0.001). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1–9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4–15, p = 0.01) were associated with poorer RFS and were strongly correlated (r = 0.88, p < 0.001). After adjusting for clinical characteristics in pairwise multivariable analyses, postoperative ctDNA status remained associated with RFS.InterpretationThe detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response.

Highlights

The liver is the primary metastatic site of colorectal cancer (CRC)
This study analysed the association between postoperative circulating tumour DNA (ctDNA) and both pathologic response and recurrence-free survival (RFS) in patients with initially unresectable cancer liver metastases (CRLM) after radical resection of both CRLM and primary tumour
The results indicate that postoperative ctDNA analysis within a high-risk cohort may potentially identify patients with a higher risk of disease recurrence after secondary resection

Summary

Introduction

The liver is the primary metastatic site of colorectal cancer (CRC). In patients with metastatic CRC, 70 to 80% have liver metastases [1].Research in contextEvidence before this studyRecurrence rates after resection of colorectal liver metastases (CRLM) are high and caused by micro-metastases left in situ after resection. Studies in patients with stage I-III colorectal cancer demonstrated that postoperative circulating tumour DNA (ctDNA) is a strong independent prognostic biomarker for MRD and recurrence-free survival. Recurrence rates after resection of colorectal cancer liver metastases (CRLM) are high and correlate with worse survival. Focusing on patients with resected CRLM, this study aimed to evaluate the association between the detection of postoperative ctDNA, pathologic response and recurrence-free survival (RFS). In univariable Cox regression analyses both postoperative detectable ctDNA (HR = 3.3, 95%CI = 1.1À9.6, p = 0.03) and pathologic non-response (HR = 4.6, 95%CI = 1.4À15, p = 0.01) were associated with poorer RFS and were strongly correlated (r = 0.88, p < 0.001). Interpretation: The detection of postoperative ctDNA after secondary resection of CRLM is a promising prognostic factor for RFS and appeared to be highly correlated with pathologic response.

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