BRAF Mutation Status in Circulating Tumor DNA from Patients with Metastatic Colorectal Cancer: Extended Mutation Analysis from the AGEO RASANC Study

Mas, Léo; Bachet, Jean‐Baptiste; Taly, Valérie; Bouché, Olivier; Taieb, Julien; Cohen, Romain; Meurisse, Aurélia; Normand, Claudine; Gornet, Jean–Marc; Artru, Pascal; Louafi, Samy; Thirot-Bidault, Anne; Baumgaertner, Isabelle; Coriat, Romain; Tougeron, David; Lecomte, Thierry; Mary, Florence; Aparicio, Thomas; Marthey, Lysiane; Blons, Hélène; Vernerey, Déwi; Laurent‐Puig, Pierre

doi:10.3390/cancers11070998

Cited by 25 publications

(15 citation statements)

References 34 publications

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“…To our knowledge, our prospective DECALIB study was the first to use ddPCR for CRC and AA detection [ 37 ]. Our study showed that ddPCR was sensitive and specific for the detection of advanced CRC, but not for in situ carcinomas or advanced adenomas.…”

Section: Discussionmentioning

confidence: 99%

Detection of Colorectal Cancer and Advanced Adenoma by Liquid Biopsy (Decalib Study): The ddPCR Challenge

Junca

Tachon

Evrard

et al. 2020

Cancers

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Background: In most countries, participation in colorectal cancer (CRC) screening programs with the immunological fecal occult blood test (iFOBT) is low. Mutations of RAS and BRAF occur early in colorectal carcinogenesis and “liquid biopsy” allows detection of mutated circulating tumor DNA (ctDNA). This prospective study aims to evaluate the performance of RAS and BRAF-mutated ctDNA in detecting CRC and advanced adenomas (AA). Methods: One hundred and thirty patients who underwent colonoscopy for suspicion of colorectal lesion were included and divided into four groups: 20 CRC, 39 AA, 31 non-advanced adenoma and/or hyperplastic polyp(s) (NAA) and 40 with no lesion. Mutated ctDNA was analyzed by droplet digital PCR. Results: ctDNA was detected in 45.0% of CRC, in 2.6% of AA and none of the NAA and “no-lesion” groups. All patients with stage II to IV mutated CRC had detectable ctDNA (n = 8/8). Among the mutated AA, only one patient had detectable ctDNA (4.3%), maybe due to limited technical sensitivity or to a low rate of ctDNA or even the absence ctDNA in plasma. Specificity and sensitivity of KRAS- and BRAF-mutated ctDNA for the detection of all CRC and AA were 100% and 16.9%, respectively. Conclusions: ctDNA had high sensitivity in detection of advanced mutated CRC but was unable to sensitively detect AA. ctDNA analysis was easy to perform and readily accepted by the population but requires combination with other circulating biomarkers before replacing iFOBT.

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Section: Discussionmentioning

confidence: 99%

Detection of Colorectal Cancer and Advanced Adenoma by Liquid Biopsy (Decalib Study): The ddPCR Challenge

Junca

Tachon

Evrard

et al. 2020

Cancers

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“…The potential for liquid biopsy in guiding treatment and monitoring the disease is compelling and may soon be translated to clinical practice. In recent years, ctDNA has been shown to be a powerful tool in (1) assessing the adequacy of surgical tumor clearance and thereby the risk of recurrence (2) in selecting the most appropriate targeted therapy and (3) in following responses to systemic treatments [73,74]. The reappearance or increase in ctDNA, along with the emergence of new mutations, is associated with recurrence, progression and resistance to therapy.…”

Section: Liquid Biopsy: Ctdna and Tumor Mutation Burdenmentioning

confidence: 99%

Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

Koncina

Haan

Rauh

et al. 2020

Cancers

167

151

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Colorectal cancer (CRC) is a leading cause of death among cancer patients. This heterogeneous disease is characterized by alterations in multiple molecular pathways throughout its development. Mutations in RAS, along with the mismatch repair gene deficiency, are currently routinely tested in clinics. Such biomarkers provide information for patient risk stratification and for the choice of the best treatment options. Nevertheless, reliable and powerful prognostic markers that can identify “high-risk” CRC patients, who might benefit from adjuvant chemotherapy, in early stages, are currently missing. To bridge this gap, genomic information has increasingly gained interest as a potential method for determining the risk of recurrence. However, due to several limitations of gene-based signatures, these have not yet been clinically implemented. In this review, we describe the different molecular markers in clinical use for CRC, highlight new markers that might become indispensable over the next years, discuss recently developed gene expression-based tests and highlight the challenges in biomarker research.

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“…Whereas a large number of studies have addressed mCRC [15][16][17][18][19][20][21][22][23] only a few have investigated the role of liquid biopsy in early, non-metastatic CRC patients at surgery, e.g. in conditions of extremely low tumor burden [24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Cross-sectional analysis of circulating tumor DNA in primary colorectal cancer at surgery and during post-surgery follow-up by liquid biopsy

Allegretti¹,

Cottone²,

Carboni³

et al. 2020

J Exp Clin Cancer Res

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Background: Liquid biopsy (LB) in early-stage, non-metastatic colorectal cancer (CRC) must be sensitive enough to detect extremely low circulating tumor DNA (ctDNA) levels. This challenge has been seldom and non-systematically investigated. Methods: Next generation sequencing (NGS) and digital PCR (dPCR) were combined to test tumor DNAs (tDNAs) and paired ctDNAs collected at surgery from 39 patients, 12 of whom were also monitored during the immediate post-surgery follow up. Patients treated for metastatic disease (n = 14) were included as controls. Results: NGS and dPCR concordantly (100% agreement) called at least one single nucleotide variant (SNV) in 34 tDNAs, estimated differences in allelic frequencies being negligible (±1.4%). However, despite dPCR testing, SNVs were only detectable in 15/34 (44.1%) ctDNAs from patients at surgery, as opposed to 14/14 (100%) metastatic patients. This was likely due to striking differences (average 10 times, up to 500) in ctDNA levels between groups. NGS revealed blood-only SNVs, suggesting spatial heterogeneity since pre-surgery disease stages, and raising the combined NGS/dPCR sensitivity to 58.8%. ctDNA levels at surgery correlated with neither tumor size, stage, grade, or nodal status, nor with variant abundance in paired tDNA. LB sensitivity reached 63.6% when ctDNA was combined with CEA. Finally, persistence and absence of ctDNA on the first conventional (month 3) post-surgery follow-up were associated with fast relapse and a disease-free status in 3 and 7 patients, respectively. Conclusions: A simple clinical NGS/dPCR/CEA combination effectively addresses the LB challenge in a fraction of non-metastatic CRC patients.

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BRAF Mutation Status in Circulating Tumor DNA from Patients with Metastatic Colorectal Cancer: Extended Mutation Analysis from the AGEO RASANC Study

Cited by 25 publications

References 34 publications

Detection of Colorectal Cancer and Advanced Adenoma by Liquid Biopsy (Decalib Study): The ddPCR Challenge

Detection of Colorectal Cancer and Advanced Adenoma by Liquid Biopsy (Decalib Study): The ddPCR Challenge

Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

Cross-sectional analysis of circulating tumor DNA in primary colorectal cancer at surgery and during post-surgery follow-up by liquid biopsy

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