Serial Circulating Tumor DNA Mutational Status in Patients with KRAS-Mutant Metastatic Colorectal Cancer from the Phase 3 AIO KRK0207 Trial (original) (raw)
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Clinical cancer research : an official journal of the American Association for Cancer Research, 2017
Purpose. Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy. <p>Experimental design. This prospective study enrolled consecutive mCRC patients receiving a first- or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C0), second (C1) and/or third (C2) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hypermethylation (WIF1, NPY). Computed tomography scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity and treatment line.</p> <p>Results. Eighty-two mCRC patients treated in first (82.9%) or second (17.1%) line chemotherapy were included. Patients with a high (>10...
Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017
We investigated if detection of circulating tumor DNA (ctDNA) after resection of colorectal cancer (CRC) identifies the patients with the highest risk of relapse, and furthermore, whether longitudinal ctDNA analysis allows early detection of relapse and informs about response to intervention.<br /><br />Experimental Design: In this longitudinal cohort study we used massively parallel sequencing to identify somatic mutations and used these as ctDNA markers to detect minimal residual disease and to monitor changes in tumor burden during a three year follow-up period.<br /><br />Results: A total of 45 patients and 371 plasma samples were included. Longitudinal samples from 27 patients revealed ctDNA post-operatively in all relapsing patients (n=14), but not in any of the non-relapsing patients. ctDNA detected relapse with an average lead-time of 9.4 months compared to CT imaging. Of 21 patients treated for localized disease, six had ctDNA detected within 3 month...
Canadian journal of gastroenterology & hepatology, 2018
Since circulating tumor DNA (ctDNA) offers clear advantages as a minimally invasive method for tumor monitoring compared with tumor tissue, we aimed to evaluate genotyping ctDNA using a next-generation sequencing- (NGS-) based panel to identify the prognostic value of mutation status in metastatic colorectal cancer (mCRC) patients with primary tumor resected and with subsequent lines of treatment in this study. 76 mCRC patients treated in Beijing Chao-Yang Hospital from 2011 to 2017 were enrolled. Genotyping of RAS/BRAF in tumor tissue and ctDNA was determined by ARMS PCR and with a 40-gene panel using NGS, respectively. Patient clinicopathologic features and RAS/BRAF gene mutation status were evaluated by survival analysis for disease-free survival (DFS) and progression-free survival (PFS). Among 76 patients, KRAS distributions were not significantly correlated with any clinicopathologic features. The concordance between tumor tissue and ctDNA KRAS mutation was 81.25%. Mutations of...
Oncotarget, 2018
Predictive biomarkers are eagerly awaited in advanced colorectal cancer (aCRC). Targeted sequencing performed on tumor and baseline plasma samples in 20 patients with aCRC treated with regorafenib identified 89 tumor-specific mutations of which ≥50% are also present in baseline plasma. Droplet digital PCR (ddPCR) assays were optimized to monitor circulating tumor DNA (ctDNA) levels in plasmatic samples collected throughout the treatment course and showed the importance of using the absolute value for ctDNA rather than the mutant/wild type ratio in monitoring the therapy outcome. High baseline cell free DNA (cfDNA) levels are associated with shorter overall survival (OS) (HR 7.38, P=0.001). An early increase (D14) in mutated copies/mL is associated with a significantly worse PFS (HR 6.12, P=0.008) and OS (HR 8.02, P=0.004). These data suggest a high prognostic value for early ctDNA level changes and support the use of blood-born genomic markers as a tool for treatment.
Cancers, 2021
Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highlight landmark studies that have formed the basis for ongoing studies on the clinically applicability of plasma ctDNA assays in resected, stage I–III CRC and metastatic CRC. We discuss clinical settings by which ctDNA may have the most immediate impact in routine clinical practice. These include the potential for ctDNA to (1) guide surveillance and intensification or de-intensification strategies of adjuvant therapy in resected, stage I–III CRC, (2) predict treatment response to neoadjuvant th...
Circulating Tumor DNA in Colorectal Cancer—From Concept to Clinic
Oncology & Hematology Review (US)
A dvances in the ability to detect molecular alterations in cancer have led to the development of personalized oncology treatments in colorectal cancer. Tumor biopsies are currently the standard of care for both diagnosis and molecular testing, but have limitations in frequency of sampling, turnaround time and underrepresentation of tumor molecular heterogeneity. The advent of liquid biopsies, in the form of circulating tumor DNA (ctDNA), has many potential clinical applications including non-invasive methods of tumor genotyping, prognostication, monitoring treatment response and resistance, and detection of minimal residual disease. Prospective ctDNA-guided randomized adjuvant clinical trials are currently underway, taking us one step closer towards clinical implementation of ctDNA-guided personalized oncology in colorectal cancer.
Scientific Reports
Preoperative ctDNA status in relation to recurrence in cases of CRC remains unclear. We examined preoperative ctDNA detection by targeting KRAS gene mutations as a predictive marker for recurrence after CRC surgery. We measured the preoperative KRAS mutated ctDNA status and analyzed the correlation with clinicopathologic features of 180 patients that underwent surgery for CRC. We studied the association between preoperative KRAS mutated ctDNA and postoperative recurrence in patients (n = 150) that underwent radical surgery. KRAS mutated ctDNA was detected in 59 patients (32.8%). Median mutant allele frequency of KRAS in ctDNA was 0.20%. KRAS status in ctDNA and lymph node metastasis and distant metastasis were not significantly different. Among patients that underwent radical resection, recurrence occurred in 21 (14.0%, median follow-up 24 months). In Kaplan–Meier analysis, preoperative detection of KRAS mutated ctDNA was associated with inferior recurrence-free interval (RFI) (p = ...
British Journal of Cancer, 2021
BACKGROUND: Within the OMITERC prospective study (OMIcs application from solid to liquid biopsy for a personalised ThERapy of Cancer), we explored the prognostic role of liquid biopsy encompassing cell-free DNA (cfDNA) and circulating tumour cells (CTCs) in KRAS mutated metastatic colorectal cancer (mCRC). METHODS: We defined a workflow including pre-analytical and analytical procedures collecting blood before therapy and every 3 months until disease progression (PD). CTCs were counted by CellSearch® and isolated by DEPArray™. NGS sequencing of CTCs and cfDNA was performed using a panel of cancer/CRC related genes respectively. RESULTS: KRAS mutational status was mostly concordant between tumour tissues and liquid biopsy. The percentage of cfDNA samples with mutations in CRC driver genes was in line with literature. In longitudinal monitoring circulating biomarkers anticipated or overlapped conventional diagnostic tools in predicting PD. The presence of CTCs at baseline was confirmed a negative prognostic marker. CONCLUSIONS: Cell-free DNA and CTCs are readily available candidates for clinical application in mCRC. While CTCs demonstrated a prognostic significance at baseline, cfDNA was confirmed an easily accessible material for monitoring the mutational status of the tumour over time. Moreover, in the longitudinal study, the two markers emerged as complementary in assessing disease progression.
Circulating Tumor DNA in Precision Oncology and Its Applications in Colorectal Cancer
International Journal of Molecular Sciences
Circulating tumor DNA (ctDNA) is a component of cell-free DNA (cfDNA) that is shed by malignant tumors into the bloodstream and other bodily fluids. ctDNA can comprise up to 10% of a patient’s cfDNA depending on their tumor type and burden. The short half-life of ctDNA ensures that its detection captures tumor burden in real-time and offers a non-invasive method of repeatedly evaluating the genomic profile of a patient’s tumor. A challenge in ctDNA detection includes clonal hematopoiesis of indeterminate potential (CHIP), which can be distinguished from tumor variants using a paired whole-blood control. Most assays for ctDNA quantification rely on measurements of somatic variant allele frequency (VAF), which is a mutation-dependent method. Patients with certain types of solid tumors, including colorectal cancer (CRC), can have levels of cfDNA 50 times higher than healthy patients. ctDNA undergoes a precipitous drop shortly after tumor resection and therapy, and rising levels can for...