Circulating Tumor DNA as a Preoperative Marker of Recurrence in Patients with Peritoneal Metastases of Colorectal Cancer: A Clinical Feasibility Study.

Jamie J Beagan,Jurriaan B Tuynman,Nicole C T Van Grieken,Paul P Eijk,Nina R Sluiter,Sander Bach,Miranda Kusters,Geert Kazemier,Daniëlle A M Heideman,Bauke Ylstra,Stijn L Vlek,D Michiel Pegtel

doi:10.3390/jcm9061738

Abstract

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC) may be curative for colorectal cancer patients with peritoneal metastases (PMs) but it has a high rate of morbidity. Accurate preoperative patient selection is therefore imperative, but is constrained by the limitations of current imaging techniques. In this pilot study, we explored the feasibility of circulating tumor (ct) DNA analysis to select patients for CRS-HIPEC. Thirty patients eligible for CRS-HIPEC provided blood samples preoperatively and during follow-up if the procedure was completed. Targeted Next-Generation Sequencing (NGS) of DNA from PMs was used to identify bespoke mutations that were subsequently tested in corresponding plasma cell-free (cf) DNA samples using droplet digital (dd) PCR. CtDNA was detected preoperatively in cfDNA samples from 33% of patients and was associated with a reduced disease-free survival (DFS) after CRS-HIPEC (median 6.0 months vs median not reached, p = 0.016). This association could indicate the presence of undiagnosed systemic metastases or an increased metastatic potential of the tumors. We demonstrate the feasibility of ctDNA to serve as a preoperative marker of recurrence in patients with PMs of colorectal cancer using a highly sensitive technique. A more appropriate treatment for patients with preoperative ctDNA detection may be systemic chemotherapy in addition to, or instead of, CRS-HIPEC.

Highlights

Metastatic colorectal cancer (CRC) remains the second most common cause of cancer-related death, despite improvements in treatment over recent decades [1]
Patients were preoperatively excluded from the study if: the estimated extent of Peritoneal metastases (PMs) was deemed to be irresectable by subsequent (PET-) CT or diagnostic laparoscopy (DLS); systemic metastases were detected [35]; or PMs removed during a previous procedure were found by histological assessment to be non-colorectal in origin or were not adenocarcinoma
The outcome of the CRS was determined according to the maximal size of residual tumor tissue and was classified as: R1) when no macroscopically visible tumor remained in situ, R2a) when the residual tumor was smaller than 2.5 mm or R2b) when it was larger than 2.5 mm [36]

Summary

Introduction

Metastatic colorectal cancer (CRC) remains the second most common cause of cancer-related death, despite improvements in treatment over recent decades [1]. If restricted to the peritoneum, referred to as isolated PMs, treatment with systemic chemotherapy confers a median overall survival (OS) of 12–18 months [5,6,7,8]. Patients with the least extensive peritoneal spread have the potential to experience the greatest benefit from CRS-HIPEC, reflected in a median OS of 56 months [13]. The addition of HIPEC following CRS did not show significant survival benefit in the recent large randomized-controlled PRODIGE-7 trial [14]. CRS performed in high-volume expert centers resulted in an OS of 41 months [14].

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