Tumor-informed or tumor-agnostic circulating tumor DNA as a biomarker for risk of recurrence in resected colorectal cancer patients

Abstract

IntroductionCirculating tumor DNA (ctDNA) has been increasingly recognized as a promising minimally-invasive biomarker that could identify patients with minimal residual disease and a high risk of recurrence after definitive treatment. In this study, we’ve compared the clinical utility and sensitivity of 2 different approaches to ctDNA analyses: tumor-informed and tumor-agnostic in the management of colorectal (CRC) patients. The clinical benefits of a single timepoint ctDNA analysis compared to serial ctDNA monitoring after definitive treatment were also evaluated to uncover the ideal surveillance protocol.MethodsPatient-paired resected tumor tissues, peripheral blood cells, and a total of 127 pre-operative and serial plasma cell-free DNA (cfDNA) samples after definitive treatment from 38 CRC patients that had undergone curative intent surgery were analyzed using a commercial NGS cfDNA panel.ResultsUp to 84% (32/38) of the recruited patients were detected with at least 1 genomic alteration from the tumor tissues that could be monitored using the tumor-informed ctDNA approach and none of the detected alterations were clonal hematopoiesis (CH) related. In contrast, 37% (14/38) of patients were detected with at least 1 monitoring alteration after exclusion of CH mutations using the tumor-agnostic approach. Serial plasma samples after definitive therapy were available for 31 patients. In the landmark ctDNA analysis, 24% (7/29) of patients had detectable ctDNA and were more likely to relapse than ctDNA-negative patients (p < 0.05). The landmark analysis sensitivity and specificity for recurrence were 67% and 87%, respectively. The incorporation of longitudinal ctDNA analysis at 6-months intervals improved the sensitivity to 100%. The median variant allele frequency (VAF) of the ctDNA mutations detected during surveillance was 0.028% (range: 0.018-0.783), where up to 80% (8/10) of the mutations were detected at VAF lower than the tumor-agnostic detection limit of 0.1%. Utilizing the tumor-agnostic approach reduced the recurrence detection sensitivity to 67% (4/6). Serial ctDNA analyses predicted disease recurrence at a median of 5 months ahead of radiological imaging.ConclusionLongitudinal monitoring using tumor-informed ctDNA testing shows high analytical sensitivity, low probability of false-positive results due to CH mutations, and improved sensitivity in detecting recurrence which may modify the clinical management of CRC.

Circulating Tumor DNA Profiling in Liver Transplant for Hepatocellular Carcinoma, Cholangiocarcinoma, and Colorectal Liver Metastases: A Programmatic Proof of Concept

“…To address this concern, tumor-informed genetic testing may be considered due to its ability to differentiate ctDNA from germline-derived variants, clonal hematopoiesis of indeterminate potential, and dd-cfDNA. Such tumor-informed tools have been developed and are actively being explored in clinical studies and trials [ 32 ]. However, these methods do have limitations in patients who have received extensive pre-LT locoregional and systemic therapy, as adequate viable tumor is necessary for tissue-informed testing.…”

Prognostic value of preoperative combined with postoperative systemic immune-inflammation index for disease-free survival after radical rectal cancer surgery: a retrospective cohort study

“…However, most studies have focused only on the relationship between preoperative SII and the prognosis of CRC. Even if patients undergo curative surgery, they may still experience recurrence or metastasis ( 25 ). Therefore, postoperative monitoring of the patient’s condition is necessary.…”

Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

“…As technology continues to evolve and our understanding of ctDNA deepens, liquid biopsies hold the promise of transforming the way colorectal cancer is diagnosed, monitored, and treated, ultimately enhancing the precision of patient care. 199,200 6.2. Targeted Delivery Systems.…”

“…However, challenges remain, including the need for further standardization and validation of liquid biopsy techniques. As technology continues to evolve and our understanding of ctDNA deepens, liquid biopsies hold the promise of transforming the way colorectal cancer is diagnosed, monitored, and treated, ultimately enhancing the precision of patient care. , …”