ctDNA and Adjuvant Therapy for Colorectal Cancer: Time to Re-Invent Our Treatment Paradigm

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While there have been significant developments in the treatments for patients with metastatic CRC in recent years, improving outcomes in the adjuvant setting has been more challenging. Recent technological advances in circulating tumour DNA (ctDNA) assay with the ability to detect minimal residual disease (MRD) after curative intent surgery will fundamentally change how we assess recurrence risk and conduct adjuvant trials. Studies in non-metastatic CRC have now demonstrated the prognostic impact of ctDNA analysis after curative intent surgery over and above current standard of care clinicopathological criteria. This ability of ctDNA analysis to stratify patients into low- and very-high-risk groups provides a window of opportunity to personalise adjuvant treatment where escalation/de-escalation of adjuvant systemic therapy could potentially increase cure rates and also reduce treatment-related physical and financial toxicity. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. This real-time assessment of treatment benefit could be used as a surrogate endpoint for adjuvant novel drug development. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer.

Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases

“…Additionally, previous studies have shown ctDNA clearance to be a proxy of treatment efficacy, especially in the adjuvant setting where postoperative ctDNA negativity shows better outcomes compared with ctDNA-positive patients. 39 We acknowledge the limitation of our small data set to establish this evidence. However, we do see a clear pattern, wherein 100% of the patients who remain positive or turn positive at the second time point progress as compared with the ctDNA-negative patients.…”

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

“…In mCRC patients on systemic therapy, it should be noted that ctDNA dynamics can be rapid with rapid decreases in MAFs as early as the first 48 h of FOLFOX infusion with potential correlation between ctDNA MAFs that remain low and tumor response (stable disease or partial response) [ 133 ]. ctDNA shedding and therefore detection in plasma has also been shown to be affected by site of metastases in mCRC, with the liver being among the sites of highest ctDNA shedding, while higher ctDNA content increases with CRC tumor stage [ 18 , 159 ]. These are clinical variables that would need to be considered in our interpretation of ctDNA results during this period of rapid clinical development.…”

“…The purpose of this review is to highlight where the field is moving in the clinical applications of ctDNA in CRC. We do not to cover the technical considerations in isolation, sample analysis, performance, validation, standardization, or bioinformatics analysis of ctDNA assays herein as these have been extensively reviewed elsewhere [ 16 , 17 , 18 ]. Specifically, we focus on the applications of ctDNA that have the most immediate potential for impact and implementation into routine clinical practice.…”

Postoperative Circulating Tumor DNA Can Predict High Risk Patients with Colorectal Cancer Based on Next-Generation Sequencing

“…Serial ctDNA levels in CRC-resected patients can be used to detect disease recurrence earlier than conventional postoperative surveillance [19]. There are several ongoing randomized trials worldwide to determine the clinical utility of ctDNA in colorectal cancer [20].…”