Circulating tumour DNA as biomarker for rectal cancer: A systematic review and meta-analyses

Abstract

BackgroundCirculating tumour DNA (ctDNA) has been established as a promising (prognostic) biomarker with the potential to personalise treatment in cancer patients. The objective of this systematic review is to provide an overview of the current literature and the future perspectives of ctDNA in non-metastatic rectal cancer.MethodsA comprehensive search for studies published prior to the 4th of October 2022 was conducted in Embase, Medline, Cochrane, Google scholar, and Web of Science. Only peer-reviewed original articles and ongoing clinical trials investigating the association between ctDNA and oncological outcomes in non-metastatic rectal cancer patients were included. Meta-analyses were performed to pool hazard ratios (HR) for recurrence-free survival (RFS).ResultsA total of 291 unique records were screened, of which 261 were original publications and 30 ongoing trials. Nineteen original publications were reviewed and discussed, of which seven provided sufficient data for meta-analyses on the association between the presence of post-treatment ctDNA and RFS. Results of the meta-analyses demonstrated that ctDNA analysis can be used to stratify patients into very high and low risk groups for recurrence, especially when detected after neoadjuvant treatment (HR for RFS: 9.3 [4.6 – 18.8]) and after surgery (HR for RFS: 15.5 [8.2 – 29.3]). Studies investigated different types of assays and used various techniques for the detection and quantification of ctDNA.ConclusionsThis literature overview and meta-analyses provide evidence for the strong association between ctDNA and recurrent disease. Future research should focus on the feasibility of ctDNA-guided treatment and follow-up strategies in rectal cancer. A blueprint for agreed-upon timing, preprocessing, and assay techniques is needed to empower adaptation of ctDNA into daily practice.

Circulating Tumour DNA as Biomarker for Colorectal Liver Metastases: A Systematic Review and Meta-Analysis

“…The current study found a hazard ratio for ctDNA presence after surgery in CRLM patients of 3.12 (95% CI 2.27-4.28) for recurrence and of 5.04 (95% CI 2.53-10.04) for overall survival. Faulkner et al reported similar hazard ratios for the overall survival in the primary colorectal cancer setting, in which more extensive ctDNA research has been conducted [30]. On the other hand, the hazard ratio for recurrence seems to be lower for colorectal cancer patients.…”

“…23-29.34), marking its importance in the primary setting [31]. Another recently published systematic review showed a progression-free survival with a hazard ratio of 7.93 (95% CI 4.27-14.75) in a subgroup meta-analysis of postoperative ctDNA following surgery for primary colorectal cancer, in favour of a postoperatively negative ctDNA status [30]. In the metastasised setting, this difference was still significant but to a lesser extent (HR 4.58, 95% CI 2.26-9.28).…”

Evaluation of Changes in Circulating Cell-Free DNA as an Early Predictor of Response to Chemoradiation in Rectal Cancer—A Pilot Study

“…Patients with recurrent disease displayed a median level of 13,000 copies/mL, in contrast to the 5200 copies/mL observed in non-recurrent patients (p = 0.08). This investigation also established a correlation between the total cell-free DNA levels and both the pathological stage and nodal involvement [22].…”

Point/Counterpoint #2

“…In the ctDNA-guided arm, only 28% of patients were ctDNA-positive 4-7 weeks after TME, resulting in fewer patients treated with adjuvant chemotherapy compared with patients randomized to standard management. 79 In rectal cancer, a meta-analysis demonstrated that ctDNA analysis can be used to risk stratify patients for recurrence, specifically when detected after neoadjuvant therapy. 80 A prospective biomarker study of 154 rectal cancer patients reports detectable ctDNA in 77% prior to chemoradiation, 8.3% after chemoradiation, and 12% after surgery.…”