Quantitative analysis of the  BRAF  V595E mutation in plasma cell-free DNA from dogs with urothelial carcinoma

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Abstract

Circulating tumor DNA (ctDNA), which carries tumor-specific mutations, is an emerging candidate biomarker for malignancies and for monitoring disease status in various human tumors. Recently, BRAF V595E mutation has been reported in 80% of dogs with urothelial carcinoma. This study investigates the BRAF V595E allele concentration in circulating cell-free DNA (cfDNA) and assesses the clinical significance of BRAF-mutated ctDNA levels in canines with urothelial carcinoma. A total of 15 dogs with urothelial carcinoma were included. cfDNA concentration was measured using a real-time polymerase chain reaction (PCR) of the LINE-1 gene. To measure the concentration of the mutated BRAF gene in cfDNA, allele-specific real-time PCR with a locked nucleic acid probe was performed. BRAF mutations were detected in 11 (73%) of the 15 tested tumor samples. BRAF-mutated ctDNA concentrations were significantly higher in dogs with the BRAF mutation (14.05 ± 13.51 ng/ml) than in wild-type dogs (0.21 ± 0.41 ng/ml) ( p = 0.031). The amount of BRAF-mutated ctDNA in plasma increased with disease progression and responded to treatment. Our results show that BRAF-mutated ctDNA can be detected using allele-specific real-time PCR in plasma samples of canines with urothelial carcinoma with the BRAF V595E mutation. This ctDNA analysis may be a potentially useful tool for monitoring the progression of urothelial carcinoma and its response to treatment.

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Most cited references 23

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Response evaluation criteria for solid tumours in dogs (v1.0): a Veterinary Cooperative Oncology Group (VCOG) consensus document.

S Nguyen, D H Thamm, D. M. Vail … (2015)

In veterinary medical oncology, there is currently no standardized protocol for assessing response to therapy in solid tumours. The lack of such a formalized guideline makes it challenging to critically compare outcome measures across various treatment protocols. The Veterinary Cooperative Oncology Group (VCOG) membership consensus document presented here is based on the recommendations of a subcommittee of American College of Veterinary Internal Medicine (ACVIM) board-certified veterinary oncologists. This consensus paper has used the human response evaluation criteria in solid tumours (RECIST v1.1) as a framework to establish standard procedures for response assessment in canine solid tumours that is meant to be easy to use, repeatable and applicable across a variety of clinical trial structures in veterinary oncology. It is hoped that this new canine RECIST (cRECIST v1.0) will be adopted within the veterinary oncology community and thereby facilitate the comparison of current and future treatment protocols used for companion animals with cancer.

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Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer

B. Lee, L. Lipton, J. Cohen … (2019)

In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N = 42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4 months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P = 0.002)] and OS (HR 4.1; P = 0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P < 0.0001) and OS (HR 4.0; P = 0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

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Quantitative assessment of BRAF V600 mutant circulating cell-free tumor DNA as a tool for therapeutic monitoring in metastatic melanoma patients treated with BRAF/MEK inhibitors

Max Schreuer, Geert Meersseman, Sari Van Den Herrewegen … (2016)

Background BRAF V600 mutant circulating cell-free tumor DNA (BRAF V600mut ctDNA) could serve as a specific biomarker in patients with BRAF V600 mutant melanoma. We analyzed the value of BRAF V600mut ctDNA from plasma as a monitoring tool for advanced melanoma patients treated with BRAF/MEK inhibitors. Methods Allele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations was performed on DNA extracted from plasma of patients with known BRAF V600 mutant melanoma who were treated with dabrafenib and trametinib. Results 245 plasma samples from 36 patients were analyzed. In 16 patients the first plasma sample was obtained before the first dosing of dabrafenib/trametinib. At baseline, BRAF V600mut ctDNA was detected in 75 % of patients (n = 12/16). BRAF V600mut ctDNA decreased rapidly upon initiation of targeted therapy (p < 0.001) and became undetectable in 60 % of patients (n = 7/12) after 6 weeks of treatment. During treatment, disease progression (PD) was diagnosed in 27 of 36 patients. An increase of the BRAF V600mut ctDNA copy number and fraction, identified PD with a sensitivity of 70 % (n = 19/27) and a specificity of 100 %. An increase in the BRAF V600mut ctDNA fraction was detected prior to clinical PD in 44 % of cases (n = 12/27) and simultaneously with PD in 26 % of patients (n = 7/27). Conclusions Quantitative analysis of BRAF V600mut ctDNA in plasma has unique features as a monitoring tool during treatment with BRAF/MEK inhibitors. Its potential as an early predictor of acquired resistance deserves further evaluation.

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Author and article information

Contributors

Michihito Tagawa:

ORCID: http://orcid.org/0000-0003-1645-4413

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draftRole: Writing – review & editing

Naomi Tambo: Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing – original draft

Masaki Maezawa: Role: MethodologyRole: Writing – review & editing

Mizuki Tomihari: Role: Writing – review & editing

Ken-ichi Watanabe: Role: MethodologyRole: Writing – review & editing

Hisashi Inokuma: Role: ResourcesRole: SupervisionRole: Writing – review & editing

Kazuro Miyahara: Role: SupervisionRole: Writing – review & editing

Douglas H. Thamm: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 24 April 2020

Publication date Collection: 2020

Volume: 15

Issue: 4

Electronic Location Identifier: e0232365

Affiliations

[1 ] Veterinary Medical Center, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan

[2 ] Division of Clinical Veterinary Medicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan

[3 ] Research Center for Global Agromedicine, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, Japan

Colorado State University, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: mtagawa@ 123456obihiro.ac.jp

Author information

Michihito Tagawa http://orcid.org/0000-0003-1645-4413

Article

Publisher ID: PONE-D-20-00894

DOI: 10.1371/journal.pone.0232365

PMC ID: 7182225

PubMed ID: 32330187

SO-VID: 791a0459-6f1a-4d40-a468-4efb8e138b86

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 10 January 2020

Date accepted : 13 April 2020

Page count

Figures: 7, Tables: 2, Pages: 13

Funding

The author(s) received no specific funding for this work.

Custom metadata

Data Availability All relevant data are within the paper and its Supporting Information files.

Quantitative analysis of the BRAF V595E mutation in plasma cell-free DNA from dogs with urothelial carcinoma

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