scholarly journals THE IMPORTANCE OF CIRCULATING TUMOR DNA IN THE ASSESSMENT OF METASTATIC COLORECTAL CANCER TREATMENT EFFECTIVNE

2021 ◽  
Vol 20 (5) ◽  
pp. 149-161
Author(s):  
M. I. Sluzhev ◽  
V. V. Semiglazov ◽  
T. Yu. Semiglazova ◽  
E. V. Tkachenko ◽  
S. A. Protsenko ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Systemic Treatment ◽  
Circulating Tumor Dna ◽  
Egfr Inhibitors ◽  
Line Treatment ◽  
Ras Gene ◽  
Pilot Studies ◽  
Secondary Resistance ◽  
Tumor Dna

Challenges in cancer detection, prognosis and management are currently being solved by determining circulating tumor DNA (ctDNA). The assessment of this marker has acquired particular importance in metastatic colorectal cancer (mCRC), the systemic treatment of which depends on the RAS gene status, which has prognostic and predictive value. However, the possibilities of taking samples from the primary or metastatic lesion for pathomorphological and molecular analysis in CRC are often limited. The determination of ctDNA using liquid biopsy has an advantage over standard biopsy due to its low invasiveness and high availability of the method. Analysis of mutations using ctDNA as well as changes in the level of this marker is a criterion for the effectiveness of systemic treatment, as well as a factor that determines the risk of disease progression. Currently, the potential of using ctDNA to monitor effectiveness of first-and second-line chemotherapy, as well as to predict the development of secondary resistance to EGFR inhibitors (cetuximab and panitumumab) in the first-line treatment and assessment of RAS status for returning to therapy with EGFR inhibitors in the third-line treatment of mCRC is being studied. Several pilot studies have provided evidence of the efficacy of EGFR re-treatment. The modern literature data published in leading peer-reviewed journals in Russian and international scientific citation databases, such as Medline, Elibrary, and PubMed were analyzed. Of the 138 analyzed publications, 56 were used to write this review. 

Dynamics and characteristics of KRAS mutated circulating tumor DNA in patients with metastatic colorectal cancer during various treatments.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 665-665
Author(s):  
Yuji Takayama ◽  
Koichi Suzuki ◽  
Kosuke Ichida ◽  
Taro Fukui ◽  
Nao Kakizawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Kras Mutation ◽  
Circulating Tumor Dna ◽  
Line Treatment ◽  
Tumor Tissues ◽  
Significant Difference ◽  
Before And After ◽  
Tumor Dna

665 Background: KRAS mutated circulating tumor DNA (MctDNA) can be detected in blood of patients with metastatic colorectal cancer (mCRC) but its dynamics and characteristics during anti-EGFR and other treatments are not well known. Methods: Four hundred and fifty-one plasma samples were collected prospectively from 85 patients who underwent chemotherapy due to mCRC in 2014 - 2017. KRAS mutation in codon12/13/61 was explored in tumor tissues and plasma. Results: KRAS assessment in tumor tissues showed 29 patients with KRAS mutation (MT), 56 patients without mutation (WT). Sensitivity and specificity of MctDNA was 86.4% and 100%, respectively. In 29 patients with MT, significant difference in PFS was observed between patients with MctDNA and without during 1st line treatment (3.0 months vs.15.0 months; p = 0.005). In 56 patients with WT, 27 patients showed MctDNA during various treatments. Different characteristics in appearance were recognized during several treatments including anti-VEGF, TAS-102 and regorafenib. KRAS mutation in codon12/13 was appeared before and after disease progression. KRAS mutation in codon 61 was, however, frequently detected before disease progression. A spike like appearance of KRAS mutation in codon12/13 was likely seen in response to induction of the sequential treatment. Significant difference in PFS was observed between patients with MctDNA and without during 1st line treatment (6.0 months vs. 13.0 months; p = 0.0017), as was observed in patients with MT. Conclusions: Dynamics and characteristics of KRAS status in blood may be involved in the treatment response and outcome in mCRC patients.

Next Generation Sequencing of Circulating Tumor DNA Can Optimize Second Line Treatment in RAS Wild Type Metastatic Colorectal Cancer after Progression on Anti-EGFR Therapy: Time to Rethink Our Approach

2022 ◽  
Author(s):  
Davide Mauri ◽  
Konstantinos Kamposioras ◽  
Dimitris Matthaios ◽  
Maria Tolia ◽  
Ioanna Nixon ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Next Generation Sequencing ◽  
Metastatic Colorectal Cancer ◽  
Circulating Tumor Dna ◽  
Clinical Approach ◽  
Line Treatment ◽  
Next Generation ◽  
Wild Type ◽  
Tumor Dna ◽  
Generation Sequencing

Background Management of Raswild-type colorectal cancer (CRC) patients upon disease progression after the successful use of targeted treatment with anti-EGFR monoclonal antibodies and backbone chemotherapy remains a clinical challenge. Development of treatment resistance with prevalence of pre-existing RAS mutated clones, RAS mutation conversion, truncation of extracellular receptor domains as well as HER2 and MET amplification are molecular events that can be difficult to follow without the use of sophisticated laboratory techniques. Summary The clinical hurdle of re-biopsy and tumor heterogeneity can be overcome by the implementation Next Generation Sequencing (NGS) to analyze circulating tumor DNA (ctDNA) and identify drugable mutations or recovery of RAS-wildness. In this opinion paper we summarize with critical thinking the clinical approach to be followed after the failure of first line treatment in Ras wild-type CRC tumors with the use of NGS. Key Messages Rechallenge with anti-EGFR inhibitors, in case of persistent or recovery of Ras wildness, and targeted approach of specific mutations (BRAF inhibitors) amplifications (anti-Her2 treatment) or fusion proteins (NTRK inhibitors) can by guided by the use of NGS. The use of NGS platforms for serial analysis of ctDNA is an important step to better understand the molecular landscape of metastatic colorectal cancer and guide clinical decisions. NGS should be considered a mainstay in clinical practice for the management of CRC patients and health authorities should consider reimbursing its use in the appropriate clinical settings.

scholarly journals Small EVs-Associated DNA as Complementary Biomarker to Circulating Tumor DNA in Plasma of Metastatic Colorectal Cancer Patients

2021 ◽  
Vol 14 (2) ◽  
pp. 128
Author(s):  
Silvia Galbiati ◽  
Francesco Damin ◽  
Dario Brambilla ◽  
Lucia Ferraro ◽  
Nadia Soriani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Digital Pcr ◽  
Extracellular Vesicle ◽  
Circulating Tumor Dna ◽  
Mutation Status ◽  
Promising Practice ◽  
Colorectal Cancer Patients ◽  
Tumor Dna

It is widely accepted that assessing circular tumor DNA (ctDNA) in the plasma of cancer patients is a promising practice to evaluate somatic mutations from solid tumors noninvasively. Recently, it was reported that isolation of extracellular vesicles improves the detection of mutant DNA from plasma in metastatic patients; however, no consensus on the presence of dsDNA in exosomes has been reached yet. We analyzed small extracellular vesicle (sEV)-associated DNA of eleven metastatic colorectal cancer (mCRC) patients and compared the results obtained by microarray and droplet digital PCR (ddPCR) to those reported on the ctDNA fraction. We detected the same mutations found in tissue biopsies and ctDNA in all samples but, unexpectedly, in one sample, we found a KRAS mutation that was not identified either in ctDNA or tissue biopsy. Furthermore, to assess the exact location of sEV-associated DNA (outside or inside the vesicle), we treated with DNase I sEVs isolated with three different methodologies. We found that the DNA inside the vesicles is only a small fraction of that surrounding the vesicles. Its amount seems to correlate with the total amount of circulating tumor DNA. The results obtained in our experimental setting suggest that integrating ctDNA and sEV-associated DNA in mCRC patient management could provide a complete real-time assessment of the cancer mutation status.

scholarly journals Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer

2015 ◽  
Vol 26 (8) ◽  
pp. 1715-1722 ◽  
Author(s):  
J. Tie ◽  
I. Kinde ◽  
Y. Wang ◽  
H.L. Wong ◽  
J. Roebert ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Therapeutic Response ◽  
Circulating Tumor Dna ◽  
Early Marker ◽  
Tumor Dna

scholarly journals Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer

2018 ◽  
Vol 8 (1) ◽  
pp. 408-417 ◽  
Author(s):  
Hiroki Osumi ◽  
Eiji Shinozaki ◽  
Yoshinori Takeda ◽  
Takeru Wakatsuki ◽  
Takashi Ichimura ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Deep Sequencing ◽  
Clinical Relevance ◽  
Circulating Tumor Dna ◽  
Tumor Dna

scholarly journals Change in circulating tumor DNA after hepatic resection for metastatic colorectal cancer

HPB ◽  
2018 ◽  
Vol 20 ◽  
pp. S25
Author(s):  
R.R. Narayan ◽  
M.L. Babicky ◽  
D.A. Goldman ◽  
M. Gonen ◽  
P.J. Allen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hepatic Resection ◽  
Metastatic Colorectal Cancer ◽  
Circulating Tumor Dna ◽  
Tumor Dna

scholarly journals Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses

JAMA Oncology ◽  
2018 ◽  
Vol 4 (4) ◽  
pp. e175245 ◽  
Author(s):  
Clara Montagut ◽  
Guillem Argilés ◽  
Fortunato Ciardiello ◽  
Thomas T. Poulsen ◽  
Rodrigo Dienstmann ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Dna Analyses ◽  
Tumor Dna

Phase II study of anti-EGFR rechallenge therapy with panitumumab driven by circulating tumor DNA molecular selection in metastatic colorectal cancer: The CHRONOS trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3506-3506
Author(s):  
Andrea Sartore-Bianchi ◽  
Filippo Pietrantonio ◽  
Sara Lonardi ◽  
Benedetta Mussolin ◽  
Francesco Rua ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Liquid Biopsy ◽  
Objective Response ◽  
Circulating Tumor Dna ◽  
Type I ◽  
Tumor Dna

3506 Background: Despite advances in molecular segmentation of metastatic colorectal cancer (mCRC), beyond RAS status therapeutic actionability remains confined to the limited subgroups of ERBB2 amplified, BRAF mutated and MSI-H patients. Optimization of available treatments is therefore warranted. Rechallenge with anti-EGFR monoclonal antibodies is often empirically used with some benefit as late-line therapy. We previously found that mutant RAS and EGFR ectodomain clones, which emerge in blood during EGFR blockade, decline upon antibody withdrawal leading to regain drug sensitivity. Based on this rationale, we designed CHRONOS, a multicenter phase II trial of anti-EGFR therapy rechallenge guided by monitoring of the mutational status of RAS, BRAF and EGFR in circulating tumor DNA (ctDNA). To our knowledge, this is the first interventional clinical trial of liquid biopsy for driving anti-EGFR rechallenge therapy in mCRC. Methods: Eligible patients were PS ECOG 0-2 RAS/BRAF WT mCRC having first achieved an objective response and then progression in any treatment line with an anti-EGFR antibody containing regimen, displaying RAS, BRAF and EGFR ectodomain WT status in ctDNA at molecular screening after progression to the last anti-EGFR-free regimen. Clonal evolution in ctDNA was analyzed by ddPCR and next generation sequencing. Panitumumab 6 mg/kg was administered IV every two weeks until progression. The primary endpoint was objective response rate (ORR) by RECIST version 1.1 with independent central review. 27 total patients and 6 responses were required to declare the study positive (power = 85%, type I error = 0.05). Results: Between Aug 19, 2019 and Nov 6, 2020 52 patients were screened by liquid biopsy and 36 (69%) were negative in ctDNA for RAS/BRAF/EGFR mutations. Of these, 27 patients were enrolled in 4 centers. Median age was 64 years (range: 42-80). PS ECOG was 0/50%, 1/46%, 2/4%. Previous anti-EGFR was administered in 1st line in 63%, 2nd in 15% and > 2nd in 22%. Median number of previous treatments was 3. The primary endpoint was met, with 8/27 partial responses (PR) observed (2 unconfirmed) (ORR = 30%, 95% CI: 12-47%). Stable disease (SD) was obtained in 11/27 (40%, 95% CI: 24-59%), lasting > 4 months in 8/11. Disease control rate (PR plus SD > 4 months) was therefore obtained in 16/27 (59%, 95% CI: 41-78%). Median progression-free survival was 16 weeks. Median duration of response was 17 weeks (1 ongoing). Maximal grade toxicity was G3, limited to dermatological and occurring in 19% of patients. ctDNA dynamics were studied in all patients. Conclusions: Liquid biopsy-driven rechallenge with anti-EGFR antibodies leads to further objective responses in one third of patients. Genotyping tumor DNA in the blood to direct therapy can be effectively incorporated in the management of advanced CRCs. Clinical trial information: 2016-002597-12.

Sign in / Sign up

Export Citation Format

Share Document