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Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy
BACKGROUND: Circulating tumour DNA (ctDNA) analysis promises to improve the clinical care of people with cancer, address health inequities and guide translational research. This observational cohort study used ctDNA to follow 29 patients with advanced-stage cutaneous melanoma through multiple cycles...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10131510/ https://www.ncbi.nlm.nih.gov/pubmed/37099071 http://dx.doi.org/10.1007/s40291-023-00651-4 |
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author | Fitzgerald, Sandra Blenkiron, Cherie Stephens, Rosalie Mathy, Jon A. Somers-Edgar, Tiffany Rolfe, Gill Martin, Richard Jackson, Christopher Eccles, Michael Robb, Tamsin Rodger, Euan Lawrence, Ben Guilford, Parry Lasham, Annette Print, Cristin G. |
author_facet | Fitzgerald, Sandra Blenkiron, Cherie Stephens, Rosalie Mathy, Jon A. Somers-Edgar, Tiffany Rolfe, Gill Martin, Richard Jackson, Christopher Eccles, Michael Robb, Tamsin Rodger, Euan Lawrence, Ben Guilford, Parry Lasham, Annette Print, Cristin G. |
author_sort | Fitzgerald, Sandra |
collection | PubMed |
description | BACKGROUND: Circulating tumour DNA (ctDNA) analysis promises to improve the clinical care of people with cancer, address health inequities and guide translational research. This observational cohort study used ctDNA to follow 29 patients with advanced-stage cutaneous melanoma through multiple cycles of immunotherapy. METHOD: A melanoma-specific ctDNA next-generation sequencing (NGS) panel, droplet digital polymerase chain reaction (ddPCR) and mass spectrometry analysis were used to identify ctDNA mutations in longitudinal blood plasma samples from Aotearoa New Zealand (NZ) patients receiving immunotherapy for melanoma. These technologies were used in conjunction to identify the breadth and complexity of tumour genomic information that ctDNA analysis can reliably report. RESULTS: During the course of immunotherapy treatment, a high level of dynamic mutational complexity was identified in blood plasma, including multiple BRAF mutations in the same patient, clinically relevant BRAF mutations emerging through therapy and co-occurring sub-clonal BRAF and NRAS mutations. The technical validity of this ctDNA analysis was supported by high sample analysis–reanalysis concordance, as well as concordance between different ctDNA measurement technologies. In addition, we observed > 90% concordance in the detection of ctDNA when using cell-stabilising collection tubes followed by 7-day delayed processing, compared with standard EDTA blood collection protocols with rapid processing. We also found that the undetectability of ctDNA at a proportion of treatment cycles was associated with durable clinical benefit (DCB). CONCLUSION: We found that multiple ctDNA processing and analysis methods consistently identified complex longitudinal patterns of clinically relevant mutations, adding support for expanded clinical trials of this technology in a variety of oncology settings. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40291-023-00651-4. |
format | Online Article Text |
id | pubmed-10131510 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-101315102023-04-27 Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy Fitzgerald, Sandra Blenkiron, Cherie Stephens, Rosalie Mathy, Jon A. Somers-Edgar, Tiffany Rolfe, Gill Martin, Richard Jackson, Christopher Eccles, Michael Robb, Tamsin Rodger, Euan Lawrence, Ben Guilford, Parry Lasham, Annette Print, Cristin G. Mol Diagn Ther Original Research Article BACKGROUND: Circulating tumour DNA (ctDNA) analysis promises to improve the clinical care of people with cancer, address health inequities and guide translational research. This observational cohort study used ctDNA to follow 29 patients with advanced-stage cutaneous melanoma through multiple cycles of immunotherapy. METHOD: A melanoma-specific ctDNA next-generation sequencing (NGS) panel, droplet digital polymerase chain reaction (ddPCR) and mass spectrometry analysis were used to identify ctDNA mutations in longitudinal blood plasma samples from Aotearoa New Zealand (NZ) patients receiving immunotherapy for melanoma. These technologies were used in conjunction to identify the breadth and complexity of tumour genomic information that ctDNA analysis can reliably report. RESULTS: During the course of immunotherapy treatment, a high level of dynamic mutational complexity was identified in blood plasma, including multiple BRAF mutations in the same patient, clinically relevant BRAF mutations emerging through therapy and co-occurring sub-clonal BRAF and NRAS mutations. The technical validity of this ctDNA analysis was supported by high sample analysis–reanalysis concordance, as well as concordance between different ctDNA measurement technologies. In addition, we observed > 90% concordance in the detection of ctDNA when using cell-stabilising collection tubes followed by 7-day delayed processing, compared with standard EDTA blood collection protocols with rapid processing. We also found that the undetectability of ctDNA at a proportion of treatment cycles was associated with durable clinical benefit (DCB). CONCLUSION: We found that multiple ctDNA processing and analysis methods consistently identified complex longitudinal patterns of clinically relevant mutations, adding support for expanded clinical trials of this technology in a variety of oncology settings. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40291-023-00651-4. Springer International Publishing 2023-04-26 2023 /pmc/articles/PMC10131510/ /pubmed/37099071 http://dx.doi.org/10.1007/s40291-023-00651-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Original Research Article Fitzgerald, Sandra Blenkiron, Cherie Stephens, Rosalie Mathy, Jon A. Somers-Edgar, Tiffany Rolfe, Gill Martin, Richard Jackson, Christopher Eccles, Michael Robb, Tamsin Rodger, Euan Lawrence, Ben Guilford, Parry Lasham, Annette Print, Cristin G. Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy |
title | Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy |
title_full | Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy |
title_fullStr | Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy |
title_full_unstemmed | Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy |
title_short | Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy |
title_sort | dynamic ctdna mutational complexity in patients with melanoma receiving immunotherapy |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10131510/ https://www.ncbi.nlm.nih.gov/pubmed/37099071 http://dx.doi.org/10.1007/s40291-023-00651-4 |
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