scholarly journals Clinical Application of Liquid Biopsy in Targeted Therapy of Metastatic Colorectal Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-3 ◽  
Author(s):  
Jörg Trojan ◽  
Susanne Klein-Scory ◽  
Christine Koch ◽  
Wolff Schmiegel ◽  
Alexander Baraniskin
Keyword(s):  
Liquid Biopsy ◽  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Response To Treatment ◽  
Close Monitoring ◽  
Wild Type ◽  
Secondary Resistance ◽  
Mutation Status ◽  
First Case ◽  
Ras Status

Background. Colorectal cancers (CRC) shed DNA into blood circulation. There is growing evidence that the analysis of circulating tumor DNA can be effectively used for monitoring of disease, to track tumor heterogeneity and to evaluate response to treatment. Case Presentation. Here, we describe two cases of patients with advanced CRC. The first case is about a patient with no available tissue for analysis of RAS mutation status. Liquid biopsy revealed RAS-wild-type and the therapy with anti-EGFR (epidermal growth factor receptor) monoclonal antibody cetuximab could be initiated. In the second case, the mutational profile of a patient with initial wild-type RAS-status was continually tracked during the course of treatment. An acquired KRAS exon 3 mutation was detected. The number of KRAS mutated fragments decreased continuously after the discontinuation of the therapy with EGFR-specific antibodies. Conclusion. Liquid biopsy provides a rapid genotype result, which accurately reproduces the current mutation status of tumor tissue. Furthermore, liquid biopsy enables close monitoring of the onset of secondary resistance to anti-EGFR therapy.

scholarly journals Cerebrospinal Fluid Access Devices in Pediatric Diffuse Midline Glioma Patients: Literature Review and Evaluation of Institutional Practices

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Daphne Li ◽  
Wendy Stellpflug ◽  
Amanda Muhs Saratsis
Keyword(s):  
Cerebrospinal Fluid ◽  
Liquid Biopsy ◽  
Tumor Biology ◽  
Significant Proportion ◽  
Circulating Tumor Dna ◽  
Response To Treatment ◽  
Institutional Practices ◽  
Medline Search ◽  
Tumor Dna ◽  
Diffuse Midline Glioma

Abstract INTRODUCTION Diffuse midline gliomas (DMG) are the number one cause of cancer death in children. H3K27M mutations occur in 80% of DMG, with distinct tumor biology and poorer response to treatment. H3K27M is detectable in cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA), depending on CSF tumor proximity, and correlates with tumor volume and treatment response. Ventricular access devices (VAD) for serial CSF sampling (liquid biopsy) could therefore play a significant role in DMG management. Here, we set to characterize VAD placement practices in pediatric DMG. METHODS A retrospective review of patients <21 yr treated for DMG at our institution was performed (1984-2019). A MEDLINE search was conducted to identify reports of VAD placement in DMG. Full-text English reports of patients = 21 yr with VAD outcomes were analyzed. RESULTS A total of 106 DMG patients at our institution were identified. In total 49% had brainstem disease (n = 52). A total of 46.23% (n = 49) had VADs: 32.65% transient (ETV n = 5, EVD n = 11), 67.35% permanent (reservoir n = 7, shunt n = 26). A total of 17 had ETV at biopsy, 7 with concurrent reservoir placement. Of 10 ETV patients without initial reservoir, 5 ultimately underwent permanent VAD placement (reservoir n = 1, shunt n = 4). A total of 9 patients received EVDs at tumor surgery, 8 required EVD for acute hydrocephalus (HCP), with 6 converted to shunts. A total of 15 shunts were placed at tumor diagnosis: 4 required revision (27%). A total of 14 articles describing 240 DMG patients cited HCP in 22%-100%, with VAD placement in 22%-63%, and shunt-induced extraneural metastases in 7. Ventricular chemotherapy via indwelling reservoirs (481 patients) was associated with 29 infectious and 50 noninfectious complications. Standardized reservoir access procedures decreased infection rates. CONCLUSION VAD placement is clinically indicated in a significant proportion of pediatric DMG patients, with low morbidity. Ventricular CSF is superior to lumbar for ctDNA sequencing and quantification. VAD placement should therefore be considered to facilitate liquid biopsy in DMG.

The results of a study of the concordance of RAS status in liquid and invasive biopsies in patients with metastatic colorectal cancer in the Republic of Kazakhstan.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16017-e16017
Author(s):  
Kaldigul Smagulova ◽  
Dilyara Kaidarova ◽  
Yelena Ukolova ◽  
Madina Orazgalieva ◽  
Anel Kurmankulova
Keyword(s):  
Colorectal Cancer ◽  
Liquid Biopsy ◽  
Point Mutations ◽  
Diagnostic System ◽  
Circulating Tumor Dna ◽  
Diagnostic Methods ◽  
Molecular Diagnostic ◽  
Wild Type ◽  
Kras Gene ◽  
Tumor Biopsy

e16017 Background: Liquid biopsy is increasingly of interest as an alternative to invasive biopsy of solid tumors for predicting, making decisions about the treatment and monitoring of the disease. Particular preference is given to liquid biopsy in cases where it is not possible to obtain a sufficient amount of material or material of poor quality with a tumor biopsy. However, in order to find out the clinical significance of circulating tumor DNA (ctDNA), it is important to first establish the sensitivity of the method using tumor-plasma consistency studies. Methods: We selected 38 patients with a confirmed diagnosis of colorectal cancer (CRC), in whom was established the progression of the disease. All patients underwent two diagnostic methods, which we divided conditionally into 2 groups: A – invasive biopsy from available metastatic foci; to detect mutations in exons 2, 3, and 4 the KRAS gene used a reagent kit to detect 18 point mutations in codons 12,13,61,117,146 and a reagent kit to identify 10 mutations of the NRAS gene in codons 12,13,61,146 (Entrogen) on a Rotor-Gene 6000 Amplifier; B - liquid biopsy, to determine 21 mutations in the codons 12,13,59,61,117,146 of the KRAS gene, 18 mutations in the codons of 12,13,59,61,117,146 of the NRAS gene, was used Idylla automated molecular diagnostic system. Results: Of the 38 studied samples of group A: 22 (57.9%) had wild type KRAS, 16 (42.1%) were mutated, in group B: wild type had 25 (65.8%) patients, mutated - 13 (34, 2%). Thus, we see a discrepancy in the results in 3 (7.9%) of 38 cases. Conclusions: The results indicate a high degree of sensitivity (92.1%) of liquid biopsy as a diagnostic method, but confirmation of concordance with traditional tissue biopsy requires further in-depth study of this issue in a larger sample of patients.

RAS Mutations in Circulating Tumor DNA and Clinical Outcomes of Rechallenge Treatment With Anti-EGFR Antibodies in Patients With Metastatic Colorectal Cancer

2020 ◽  
pp. 898-911
Author(s):  
Yu Sunakawa ◽  
Masato Nakamura ◽  
Masahiro Ishizaki ◽  
Masato Kataoka ◽  
Hironaga Satake ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Outcomes ◽  
Circulating Tumor Dna ◽  
Wild Type ◽  
Phase Ii Trials ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Ras Status ◽  
Tumor Dna

PURPOSE Several trials have evaluated the efficacy of rechallenge treatment with anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with metastatic colorectal cancer (mCRC). A recent trial indicated that RAS status in circulating tumor DNA (ctDNA) may potentially predict patients with RAS wild-type mCRC resistant to anti-EGFR mAb who would benefit from rechallenge treatment, and the findings should be further investigated. MATERIAL AND METHODS We enrolled patients whose plasma samples were collected in prospective phase II trials, the JACCRO CC-08 (n = 36) and CC-09 (n = 25), which evaluated rechallenge chemotherapy with anti-EGFR mAb for KRAS wild-type mCRC. RAS in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC kit. RESULTS Sixteen patients were enrolled in this study, with a response rate of 0% and a disease control rate (DCR) of 62.5%. RAS mutations were found at baseline in six patients. The DCR was 33% in patients with RAS mutations in ctDNA, whereas it was 80% in patients without RAS mutation at baseline. Patients with RAS mutation at baseline had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without RAS mutation (median PFS, 2.3 v 4.7 months; hazard ratio [HR], 6.2; P = .013; median OS, 3.8 v 16.0 months; HR, 12.4; P = .0028). Six of 10 patients without RAS mutation at baseline acquired RAS mutations at progression. Postprogression survival after rechallenge treatment was numerically shorter in patients with RAS mutation at progression. CONCLUSION RAS status in ctDNA was significantly associated with clinical outcomes in patients with mCRC receiving rechallenge treatment with anti-EGFR mAb. These findings could support the clinical utility of OncoBEAM RAS CRC kits for anti-EGFR mAb rechallenge in RAS wild-type mCRC.

Trial in progress: A phase II study of second-line FOLFIRI plus panitumumab after first-line FOLFOX plus panitumumab for RAS wild-type colorectal cancer with evaluation of circulating tumor DNA.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS886-TPS886
Author(s):  
Hiromichi Maeda ◽  
Naoki Nagata ◽  
Takeshi Nagasaka ◽  
Koji Oba ◽  
Hideyuki Mishima ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Second Line ◽  
Wild Type ◽  
First Line ◽  
Mutation Status ◽  
Line Therapy ◽  
Tumor Dna

TPS886 Background: The mechanisms underlying the acquired resistance of metastatic colorectal cancer (mCRC) against panitumumab treatment is not fully understood. The efficacy and safety of FOLFIRI with panitumumab as the second-line chemotherapy after failure of FOLFOX with panitumumab treatment has yet to be determined. To address these two points, a multicenter single-arm Phase II clinical trial is being conducted with evaluation of circulating tumor DNA (ctDNA). Methods: The major inclusion criterion is that the patient has refractory measurable tumor that has progressed after the first-line therapy with FOLFOX plus panitumumab. After registration, treatment with the FOLFIRI and panitumumab will be continued in 2-week cycles until disease progression, unacceptable toxicity and/or patients’ refusal. The primary endpoint for this study is six-month progression-free survival (PFS) rate, a simple surrogate endpoint of PFS. According to a clinical trial revealing the median PFS of 4.6 months for FOLFIRI alone and 6.4 months for panitumumab plus FOLFIRI treatment in RAS wild-type patients (Peeters et al. Clin Cancer Res. 2015; 21: 5469-79), we assume the threshold and expected 6-month PFS rate as 35% and 50%, respectively. Under the settings of one-sided alpha = 0.10 and power = 80%, the required sample size is 53 patients. The target number of cases in this study is 55 patients, considering a dropout rate of 5%. The secondary endpoint includes the tumor-related gene mutation status assessed by liquid biopsy. Primary tumor and/or metastatic site tissue samples will be collected by formalin-fixed paraffin-embedded specimens at the time of registration. Blood samples will be collected at 3 time-points: (1) before second-line treatment, (2) at 6 ± 2 weeks after initiation of the treatment protocol, and (3) after confirmation of acquired resistance to this second-line therapy. The multiple evaluation of ctDNA will provide the meaningful information concerning relationship between the tumor resistance against treatment and alterations in gene mutation status. Clinical trial information: UMIN000026817.

scholarly journals Panitumumab-Induced Eruptive Seborrhoeic Keratosis in a Patient with Metastatic Colorectal Cancer

2020 ◽  
Author(s):  
Dimitra Koumaki ◽  
Sotirios Boumpoucheropoulos ◽  
Vasiliki Koumaki ◽  
Alexander Katoulis ◽  
Georgia Pappas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Wild Type ◽  
Case Presentation ◽  
First Case ◽  
Stage 4 ◽  
Seborrhoeic Keratosis ◽  
Epidermal Growth ◽  
Emerging Therapy

Objectives: Agents targeting the epidermal growth factor receptor (EGFR)-mediated signalling pathway are increasingly being used for the treatment of advanced lung, pancreatic, colorectal and head and neck cancers. Case presentation: Here, we report the first case of eruptive seborrhoeic keratosis following panitumumab treatment, an anti-EGFR monoclonal antibody, in a 73-year-old patient with stage 4 (IV) colorectal cancer with hepatic metastasis. Conclusion: While panitumumab is an emerging therapy for RAS wild-type metastatic colorectal cancer, physicians should consider panitumumab as a potential cause of eruptive seborrhoeic keratosis.

Profiling 523 cancer associated genes in circulating tumor DNA of children with CNS tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3023-3023
Author(s):  
Erin R. Bonner ◽  
Robin Harrington ◽  
Biswajit Das ◽  
Paul M. Williams ◽  
Chris Alan Karlovich ◽  
...  
Keyword(s):  
Liquid Biopsy ◽  
Molecular Subtype ◽  
Circulating Tumor Dna ◽  
Copy Number Variations ◽  
Response To Therapy ◽  
Cns Tumors ◽  
Response To Treatment ◽  
Tumor Evolution ◽  
Cns Tumor ◽  
Tumor Dna

3023 Background: Pediatric central nervous system (CNS) cancers often pose unique challenges including tumor ‘invisibility’, where surgical resection is restricted due to the sensitive tumor location and tissue biopsy is not always feasible. Detecting cancer associated mutations and copy number variations (CNV) at diagnosis is increasingly important, as the WHO classification of pediatric CNS cancers has incorporated molecular signatures with tumor grade. To achieve CNS tumor molecular ‘visibility’, we previously established a liquid biopsy platform for detecting single nucleotide variants in circulating tumor DNA (ctDNA). However, our method was limited by the restricted number of genes that can be monitored and the inability to detect genomic events including CNVs. To address this, we developed a deep sequencing liquid biopsy approach to profile alterations across selected genes. Our platform provides an opportunity for multi-gene monitoring, to assess tumor subclonal evolution and response to treatment in the absence of repeat tissue biopsies. Methods: We tested the performance of our platform using paired tissue, CSF, and plasma/serum from 10 children with diffuse midline glioma (DMG). ctDNA was analyzed using the TruSight Oncology 500 (TSO500) ctDNA targeted panel covering 523 genes. Matched tumor, CSF, and blood were assessed for concordance and sequencing results were compared to digital droplet PCR (ddPCR) detection of H3K27M mutation. Results: The median exons with ³500X coverage was 96% for 7 CSF samples with optimal input (³60ng), 0.01% for 3 CSF samples with < 5ng input, and 74.5% for plasma/serum samples. ctDNA was more readily detectable in CSF, yet concordance between paired tumor, CSF and plasma/serum was observed. DMG associated mutations in genes including H3F3A, HIST1H3B, TP53, and ACVR1 were detected in ctDNA. Of 9 H3K27M mutations identified in tumor, 8 were present in CSF and 3 in plasma/serum, for a positive percent agreement of 89% and 33%, respectively, with the tumor results. Among CSF samples, H3.3K27M was detected in 6/6 cases, and H3.1K27M in 2/3 cases, with variant allele frequencies comparable to ddPCR results. CNVs including PDGFRA/B and MDM4 amplifications were present in CSF and confirmed by analysis of paired tumor. Additional events, including PIK3CA p.E545Q, PPM1D truncation, and KRAS amplification, were detected in CSF but absent from paired tumor, indicating tissue heterogeneity. Strategies to optimize ctDNA detection, including optimization of ctDNA isolation and adjustment of library QC metrics, were identified. Conclusions: This proof-of-concept study demonstrates the feasibility of our high depth, targeted sequencing approach for detecting clinically relevant mutations in ctDNA from children with CNS tumors. This approach may aid in diagnosis of CNS tumor molecular subtype, and monitoring of tumor evolution and response to therapy in serially collected ctDNA.

Liver endothelium promotes HER3-mediated cell survival in KRAS wild-type and mutant colorectal cancer cells

2021 ◽  
Author(s):  
Moeez Rathore ◽  
Michel'le Wright ◽  
Rajat Bhattacharya ◽  
Fan Fan ◽  
Ali Vaziri-Gohar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Survival ◽  
Growth Factor Receptor ◽  
Wild Type ◽  
Mutation Status ◽  
Her Family ◽  
Epidermal Growth

Abstract We previously showed that human epidermal growth factor receptor 3 (HER3, also known as ERBB3) is a key mediator in liver endothelial cell (EC) promoting colorectal cancer (CRC) growth and chemoresistance, and suggested HER3-targeted therapy as a strategy for treating patients with metastatic CRC (mCRC) in the liver. Meanwhile, KRAS mutations occur in 40–50% of mCRC and render CRC resistant to therapies targeting the other HER family protein epidermal growth factor receptor (EGFR). It is necessary to elucidate the roles of KRAS mutation status in HER3-mediated cell survival and CRC response to HER3 inhibition. In the present study, we demonstrated that liver EC-secreted factors activated HER3 and promoted cell survival in KRAS wild-type and mutant CRC cells and tumors, and that blocking HER3 with an antibody, seribantumab, blocked EC-induced CRC survival. Our findings highlight a potential of utilizing HER3-targeted therapies for treating patients with mCRC regardless of KRAS mutation status.

scholarly journals The impact of epidermal growth factor receptor mutations on patterns of disease recurrence after chemoradiotherapy for locally advanced non–small cell lung cancer: a literature review and pooled analysis

2016 ◽  
Vol 57 (5) ◽  
pp. 449-459 ◽  
Author(s):  
Satoru Ochiai ◽  
Yoshihito Nomoto ◽  
Yui Watanabe ◽  
Yasufumi Yamashita ◽  
Yutaka Toyomasu ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Disease Recurrence ◽  
Wild Type ◽  
Mutation Status ◽  
Locally Advanced Nsclc ◽  
Significant Difference ◽  
Epidermal Growth ◽  
The Impact

Abstract The purpose of this review was to evaluate the impact of epidermal growth factor receptor (EGFR) mutation status on disease recurrence in patients treated with chemoradiotherapy (CRT) for locally advanced non–small cell lung cancer (NSCLC). A literature search was conducted and a total of three studies were analyzed. There was no significant difference in the objective response rate between the EGFR mutation group and the EGFR wild-type group (odds ratios [OR] 1.46, 95% CI, 0.79–2.70, P = 0.228), and there was no significant difference in the incidence of disease recurrence (OR 1.37, 95% CI, 0.68–2.75, P = 0.379) between the two groups. There were significant difference in the incidence of local/locoregional progression (LP) (OR 0.35, 95% CI, 0.18–0.71, P = 0.003) and distant progression (DP) (OR 2.97, 95% CI, 1.59–5.54, P &lt; 0.001). Brain metastasis (BM) was one of the main recurrence patterns of DP, and the incidence was significantly higher in the EGFR mutant group (OR 2.75, 95% CI, 1.43–5.31, P = 0.003). There were no statistically significant heterogeneities in these pooled analyses. The patterns of recurrence after CRT for locally advanced NSCLC were different according to EGFR mutation status. LP after CRT in patients with EGFR mutation was less frequent, but the high incidence of DP, especially BM, continued to be the major problem. On the other hand, LP continued to be the major problem in EGFR wild-type patients. In multimodality treatment for inoperable locally advanced NSCLC, we may need to consider different treatment strategies according to EGFR mutation status.

Nicht kleinzelliges Lungenkarzinom: Angiogenese-Hemmer als weiteres entscheidendes Element in der Behandlung

2020 ◽  
Vol 8 (6) ◽  
pp. 318-319
Author(s):  
Susanne M. Lang ◽  
Tobias Rachow
Keyword(s):  
Combination Therapy ◽  
Egfr Mutation ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Kleinzelliges Lungenkarzinom ◽  
Driver Mutations ◽  
Wild Type ◽  
Mutation Status ◽  
Type Group ◽  
Egfr Mutant

<b>Objectives:</b> Currently, combination therapy of ramucirumab (RAM) + docetaxel (DOC) must play a more important role as a second-line treatment. Epithelial growth factor receptor (EGFR) mutation accounts for around 50% of oncogenic driver mutations in patients with advanced non-small cell lung cancer (NSCLC) in Asian subsets. The number of brain metastases (BM) is relatively higher in EGFR mutation-positive patients compared to EGFR wild-type patients. The objective of this study is to evaluate the efficacy of RAM + DOC focusing on EGFR mutation and BM. <b>Methods:</b> We retrospectively reviewed consecutive advanced NSCLC patients who received combination therapy of RAM + DOC at three institutions. A total of 112 patients with NSCLC were enrolled for efficacy analyses. We evaluated the efficacy of RAM + DOC for EGFR-mutated NSCLC with endpoints including progression-free survival (PFS), time to treatment failure (TTF) and overall survival. <b>Results:</b> Median PFS was 5.7 months for the EGFR mutant group compared with 3.6 months for the EGFR wild-type group (HR 0.53, 95% CI 0.32–0.87; <i>p</i> = 0.01). Median TTF was 5.1 months for the EGFR mutant group compared with 2.8 months for the EGFR wild-type group (HR 0.53, 95% CI 0.33–0.85; <i>p</i> = 0.007). Median PFS and TTF of the EGFR mutant group was significantly longer than median PFS and TTF of the EGFR wild-type group. The multivariate analysis identified EGFR mutation status as an independent favorable factor of PFS. In subset analyses of BM, median PFS of the EGFR mutant group (2.8 months) was significantly shorter than that of the EGFR wild-type group (5.1 months) (HR 7.27, 95% CI 1.78–29.68; <i>p</i> = 0.002). <b>Conclusion:</b> This study revealed that EGFR mutation status and BM might be predictive or prognostic factors for PFS.

scholarly journals Liquid Biopsies in Solid Cancers: Implementation in a Nordic Healthcare System

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1861
Author(s):  
Oddmund Nordgård ◽  
Rakel Brendsdal Forthun ◽  
Morten Lapin ◽  
Bjørn Henning Grønberg ◽  
Karl Henning Kalland ◽  
...  
Keyword(s):  
Liquid Biopsy ◽  
Cancer Biology ◽  
Growth Factor Receptor ◽  
Relevant Information ◽  
Circulating Tumor Dna ◽  
Cancer Diagnostics ◽  
Current Evidence ◽  
Liquid Biopsies ◽  
Clinical Role

Liquid biopsies have emerged as a potential new diagnostic tool, providing detailed information relevant for characterization and treatment of solid cancers. We here present an overview of current evidence supporting the clinical relevance of liquid biopsy assessments. We also discuss the implementation of liquid biopsies in clinical studies and their current and future clinical role, with a special reference to the Nordic healthcare systems. Our considerations are restricted to the most established liquid biopsy specimens: circulating tumor DNA (ctDNA) and circulating tumor cells (CTC). Both ctDNA and CTCs have been used for prognostic stratification, treatment choices, and treatment monitoring in solid cancers. Several recent publications also support the role of ctDNA in early cancer detection. ctDNA seems to provide more robust clinically relevant information in general, whereas CTCs have the potential to answer more basic questions related to cancer biology and metastasis. Epidermal growth factor receptor-directed treatment of non-small-cell lung cancer represents a clinical setting where ctDNA already has entered the clinic. The role of liquid biopsies in treatment decisions, standardization of methods, diagnostic performance and the need for further research, as well as cost and regulatory issues were identified as factors that influence further integration in the clinic. In conclusion, substantial evidence supports the clinical utility of liquid biopsies in cancer diagnostics, but further research is still required for a more general application in clinical practice.

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