Clinical utility of circulating DNA analysis for rapid detection of actionable mutations to select metastatic colorectal patients for anti-EGFR treatment

Thierry, Alain R.; Messaoudi, Safia El; Mollévi, Caroline; Raoul, Jean‐Luc; Guimbaud, Rosine; Pezet, Denis; Artru, Pascal; Assenat, Éric; Borg, Christophe; Mathonnet, Muriel; Fouchardière, Christelle De La; Bouché, Olivier; Gavoille, Céline; Fiess, Catherine; Auzemery, B.; Meddeb, Romain; Lopez-Crapez, Evelyne; Sanchez, Colline; Pastor, Brice; Ychou, Marc

doi:10.1093/annonc/mdx330

Cited by 95 publications

(102 citation statements)

References 47 publications

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“…However, the application of plasma RAS testing remains an important challenge to develop clinically meaningful thresholds for the RAS MAF in ctDNA for appropriately selecting patients who may benefit from anti‐EGFR therapy. When a low sensitivity threshold of MAF is applied, ctDNA analysis can identify patients with a very low number of RAS mutant cells who could benefit from anti‐EGFR therapy . Indeed, a prospective‐retrospective study showed that a RAS mutation with a MAF detected by ctDNA ≥0.1 was significantly associated with short PFS after anti‐EGFR therapy, whereas the PFS of patients with a RAS mutation with a MAF detected by ctDNA <0.1 was similar to that of the RAS wild‐type .…”

Section: Identification Of Biomarkers Related To Resistance To Epidermentioning

confidence: 99%

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Nakamura

Yoshino

2018

The Oncologist

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Multiple genomic changes caused by clonal evolution induced by therapeutic pressure and corresponding intratumoral heterogeneity have posed great challenges for personalized therapy against metastatic colorectal cancer (mCRC) in the past decade. Liquid biopsy has emerged as an excellent molecular diagnostic tool for assessing predominant spatial and temporal intratumoral heterogeneity with minimal invasiveness.Previous studies have revealed that genomic alterations in ,, , and, as well as other cancer-related genes associated with resistance to anti-epidermal growth factor receptor (EGFR) therapy, can be analyzed with high diagnostic accuracy by circulating tumor DNA (ctDNA) analysis. Furthermore, by longitudinally monitoring ctDNAs during anti-EGFR therapy, the emergence of genomic alterations can be detected as acquired resistance mechanisms in specific genes, mainly those associated with the mitogen-activated protein kinase signaling pathway. Analysis of ctDNA can also identify predictive biomarkers to immune checkpoint inhibitors, such as mutations in mismatch repair genes, microsatellite instability-high phenotype, and tumor mutation burden. Some prospective clinical trials evaluating targeted agents for genomic alterations in ctDNA or exploring resistance biomarkers by monitoring of ctDNA are ongoing.To determine the value of ctDNA analysis for decision-making by more accurate molecular marker-based selection of patients and identification of resistance mechanisms to targeted therapies or sensitive biomarkers for immune checkpoint inhibitors, clinical trials must be refined to evaluate the efficacy of study treatment in patients with targetable genomic alterations confirmed by ctDNA analysis, and resistance biomarkers should be explored by monitoring ctDNA in large-scale clinical trials. In the near future, ctDNA analysis will play an important role in precision medicine for mCRC. IMPLICATIONS FOR PRACTICE: Treatment strategies for metastatic colorectal cancer (mCRC) are determined according to the molecular profile, which is confirmed by analyzing tumor tissue. Analysis of circulating tumor DNA (ctDNA) may overcome the limitations of tissue-based analysis by capturing spatial and temporal intratumoral heterogeneity of mCRC. Clinical trials must be refined to test the value of ctDNA analysis in patient selection and identification of biomarkers. This review describes ctDNA analysis, which will have an important role in precision medicine for mCRC.

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Section: Identification Of Biomarkers Related To Resistance To Epidermentioning

confidence: 99%

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Nakamura

Yoshino

2018

The Oncologist

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“…Other studies of ctDNA profiling in gastrointestinal cancers have focused on colon cancer, and most have been limited in size, and in some cases restricted to hotspot alterations in a limited set of genes (21, 28, 34). Strickler and colleagues recently reported cell-free DNA genomic profiling results for over 1,000 colorectal carcinoma patients, but analysis was largely focused on short variant alterations, and no comparison with paired tissue samples was available (22).…”

Section: Discussionmentioning

confidence: 99%

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

Schrock

Pavlick

Klempner

et al. 2018

Clinical Cancer Research

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Purpose: Genomic profiling of tumor biopsies from advanced gastrointestinal and anal cancers is increasingly used to inform treatment. In some cases, tissue biopsy can be prohibitive, and we sought to investigate whether analysis of blood-derived circulating tumor DNA (ctDNA) may provide a minimally invasive alternative. Experimental Design: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 417 patients with gastrointestinal carcinomas to assess the presence of genomic alterations (GA) and compare with matched tissue samples. Results: Evidence of ctDNA was detected in 344of417 samples (82%), and of these, ≥1 reportable GA was detected in 89% (306/344) of samples. Frequently altered genes were TP53 (72%), KRAS (35%), PIK3CA (14%), BRAF (8%), and EGFR (7%). In temporally matched ctDNA and tissue samples available from 25 patients, 86% of alterations detected in tissue were also detected in ctDNA, including 95% of short variants, but only 50% of amplifications. Conversely, 63% of alterations detected in ctDNA were also detected in matched tissue. Examples demonstrating clinical utility are presented. Conclusions: Genomic profiling of ctDNA detected potentially clinically relevant GAs in a significant subset of patients with gastrointestinal carcinomas. In these tumor types, most alterations detected in matched tissue were also detected in ctDNA, and with the exception of amplifications, ctDNA sequencing routinely detected additional alterations not found in matched tissue, consistent with tumor heterogeneity. These results suggest feasibility and utility of ctDNA testing in advanced gastrointestinal cancers as a complementary approach to tissue testing, and further investigation is warranted.

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“…ctDNA detected in plasma has been described as representative of tumor heterogeneity and several studies showed a good concordance with tissue samples. In the study conducted by Thierry et al, samples from 140 patients with mCRC have been analyzed and a concordance of 72% was showed between KRAS exon 2 status found in plasma and FFPE tissue [8,9]. In the RASANC prospective study, RAS status was determined using next-generation sequencing (NGS) on 412 paired plasma and tumor samples.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of KRAS, NRAS and BRAF mutations detection in plasma using an automated system for patients with metastatic colorectal cancer

Franczak¹,

Witz²,

Geoffroy³

et al. 2020

PLoS ONE

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BackgroundCell-free DNA detection is becoming a surrogate assay for tumor genotyping. Biological fluids often content a very low amount of cell-free tumor DNA and assays able to detect very low allele frequency mutant with a few quantities of DNA are required. We evaluated the ability of the fully-automated molecular diagnostics platform Idylla for the detection of KRAS, NRAS and BRAF hotspot mutations in plasma from patients with metastatic colorectal cancer (mCRC). Materials and methodsFirst, we evaluated the limit of detection of the system using two set of laboratory made samples that mimic mCRC patient plasma, then plasma samples from patients with mCRC were assessed using Idylla system and BEAMing digital PCR technology. ResultsLimits of detection of 0.1%, 0.4% and 0.01% for KRAS, NRAS and BRAF respectively have been reached. With our laboratory made samples, sensitivity up to 0.008% has been reached. Among 15 patients' samples tested for KRAS mutation, 2 discrepant results were found between Idylla and BEAMing dPCR. A 100% concordance between the two assays has been found for the detection of NRAS and BRAF mutations in plasma samples.

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Clinical utility of circulating DNA analysis for rapid detection of actionable mutations to select metastatic colorectal patients for anti-EGFR treatment

Abstract: Our study showed that ctDNA could replace tumor-tissue analysis, and also clinical utility of ctDNA analysis by considerably reducing data turnaround time.

Cited by 95 publications

References 47 publications

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer

Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus

Evaluation of KRAS, NRAS and BRAF mutations detection in plasma using an automated system for patients with metastatic colorectal cancer

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