Postoperative circulating tumor DNA as markers of recurrence risk in stages II to III colorectal cancer

Abstract

Background Precise methods for postoperative risk stratification to guide the administration of adjuvant chemotherapy (ACT) in localized colorectal cancer (CRC) are still lacking. Here, we conducted a prospective, observational, and multicenter study to investigate the utility of circulating tumor DNA (ctDNA) in predicting the recurrence risk. Methods From September 2017 to March 2020, 276 patients with stage II/III CRC were prospectively recruited in this study and 240 evaluable patients were retained for analysis, of which 1290 serial plasma samples were collected. Somatic variants in both the primary tumor and plasma were detected via a targeted sequencing panel of 425 cancer-related genes. Patients were treated and followed up per standard of care. Results Preoperatively, ctDNA was detectable in 154 of 240 patients (64.2%). At day 3–7 postoperation, ctDNA positivity was associated with remarkably high recurrence risk (hazard ratio [HR], 10.98; 95%CI, 5.31–22.72; P < 0.001). ctDNA clearance and recurrence-free status was achieved in 5 out of 17 ctDNA-positive patients who were subjected to ACT. Likewise, at the first sampling point after ACT, ctDNA-positive patients were 12 times more likely to experience recurrence (HR, 12.76; 95%CI, 5.39–30.19; P < 0.001). During surveillance after definitive therapy, ctDNA positivity was also associated with extremely high recurrence risk (HR, 32.02; 95%CI, 10.79–95.08; P < 0.001). In all multivariate analyses, ctDNA positivity remained the most significant and independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors. Serial ctDNA analyses identified recurrence with an overall accuracy of 92.0% and could detect disease recurrence ahead of radiological imaging with a mean lead time of 5.01 months. Conclusions Postoperative serial ctDNA detection predicted high relapse risk and identified disease recurrence ahead of radiological imaging in patients with stage II/III CRC. ctDNA may be used to guide the decision-making in postsurgical management.

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

“…Other groups have similarly corroborated a low recurrence risk in ctDNA-negative patients for resected stage II–III CRC (2-year RFS rate of 89.4%) based on blood draws as early as 3–7 days postoperatively [ 26 ], whereas postoperative ctDNA-positivity has been associated with increased recurrence risk using tumor-informed assays in localized, resected CRC [ 23 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

“…Although it has been well described that ctDNA analysis in plasma samples minimizes the dilution of tumor-derived DNA and optimizes the sensitivity of ctDNA analysis over serum, a question remains as to the optimal timing of the blood collection for ctDNA assessment [ 152 , 153 ]. It has been shown that preoperative ctDNA positivity is predictive of recurrence risk compared to preoperative ctDNA negativity in CRC patients with both localized and metastatic disease [ 26 , 154 , 155 ]. However, most localized CRC cases are preoperative ctDNA positive (up to 90%) [ 27 ], and the constellation of evidence supports that postoperative ctDNA in resected, stage I–III CRC is most predictive of RFS ( Table 1 ).…”

Genomic temporal heterogeneity of circulating tumour DNA in unresectable metastatic colorectal cancer under first-line treatment

“…18 Several groups have also provided evidence supporting that ctDNA could reflect the existence of minimal residual disease postoperatively. [19][20][21] Moreover, the serial ctDNA testing may help monitor treatment efficacy, with the early change in ctDNA serving as a marker of clinical response. 22 23 And ctDNA could track RAS clones to monitor drug resistance or the potential to receive anti-EGFR rechallenge.…”

Integrating Molecular Biomarker Inputs Into Development and Use of Clinical Cancer Therapeutics

“…ctDNA is tumor-released single- or double-stranded DNA that enters the bloodstream and can be detected for diagnosis, guidance of treatment, and monitoring of disease progression. Recently, ctDNA has been used to guide clinical decision-making in several tumor types including CRC ( Chen et al, 2021 ), NSCLC ( Song et al, 2020 ), and metastatic breast cancer (MBC) ( Darrigues et al, 2021 ). In CRC, postoperative serial ctDNA detection identified recurrence before radiological imaging and was predictive of high relapse risk ( Chen et al, 2021 ).…”

“…Recently, ctDNA has been used to guide clinical decision-making in several tumor types including CRC ( Chen et al, 2021 ), NSCLC ( Song et al, 2020 ), and metastatic breast cancer (MBC) ( Darrigues et al, 2021 ). In CRC, postoperative serial ctDNA detection identified recurrence before radiological imaging and was predictive of high relapse risk ( Chen et al, 2021 ). ctDNA has suggested a novel therapeutic rechallenge strategy for CRC based on evidence that resistance mechanisms to anti-EGFR therapy extinguish over time off of that therapy ( Misale et al, 2014 ; Parseghian et al, 2019 ; Sartore-Bianchi et al, 2021 ).…”