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Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis
PURPOSE: Cerebrospinal fluid (CSF) cytology is the gold standard diagnostic test for breast cancer leptomeningeal metastasis (BCLM), but has impaired sensitivity, often necessitating repeated lumbar puncture to confirm or refute diagnosis. Further, there is no quantitative response tool to assess re...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612501/ https://www.ncbi.nlm.nih.gov/pubmed/34921020 http://dx.doi.org/10.1158/1078-0432.CCR-21-3017 |
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author | Fitzpatrick, Amanda Iravani, Marjan Mills, Adam Childs, Lucy Alaguthurai, Thanussuyah Clifford, Angela Garcia-Murillas, Isaac Van Laere, Steven Dirix, Luc Harries, Mark Okines, Alicia Turner, Nicholas C. Haider, Syed Tutt, Andrew N.J. Isacke, Clare M. |
author_facet | Fitzpatrick, Amanda Iravani, Marjan Mills, Adam Childs, Lucy Alaguthurai, Thanussuyah Clifford, Angela Garcia-Murillas, Isaac Van Laere, Steven Dirix, Luc Harries, Mark Okines, Alicia Turner, Nicholas C. Haider, Syed Tutt, Andrew N.J. Isacke, Clare M. |
author_sort | Fitzpatrick, Amanda |
collection | PubMed |
description | PURPOSE: Cerebrospinal fluid (CSF) cytology is the gold standard diagnostic test for breast cancer leptomeningeal metastasis (BCLM), but has impaired sensitivity, often necessitating repeated lumbar puncture to confirm or refute diagnosis. Further, there is no quantitative response tool to assess response or progression during BCLM treatment. EXPERIMENTAL DESIGN: Facing the challenge of working with small-volume samples and the lack of common recurrent mutations in breast cancers, cell-free DNA was extracted from the CSF and plasma of patients undergoing investigation for BCLM (n = 30). ctDNA fraction was assessed by ultra-low-pass whole genome sequencing (ulpWGS), which does not require prior tumor sequencing. RESULTS: In this proof-of-concept study, ctDNA was detected (fraction ≥0.10) in the CSF of all 24 patients with BCLM+ (median ctDNA fraction, 0.57), regardless of negative cytology or borderline MRI imaging, whereas CSF ctDNA was not detected in the six patients with BCLM− (median ctDNA fraction 0.03, P < 0.0001). Plasma ctDNA was only detected in patients with extracranial disease progression or who had previously received whole brain radiotherapy. ctDNA fraction was highly concordant with mutant allele fraction measured by tumor mutation-specific ddPCR assays (r = 0.852; P < 0.0001). During intrathecal treatment, serial monitoring (n = 12 patients) showed that suppression of CSF ctDNA fraction was associated with longer BCLM survival (P = 0.034), and rising ctDNA fraction was detectable up to 12 weeks before clinical progression. CONCLUSIONS: Measuring ctDNA fraction by ulpWGS is a quantitative marker demonstrating potential for timely and accurate BCLM diagnosis and therapy response monitoring, with the ultimate aim to improve management of this poor-prognosis patient group. |
format | Online Article Text |
id | pubmed-7612501 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-76125012022-03-15 Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis Fitzpatrick, Amanda Iravani, Marjan Mills, Adam Childs, Lucy Alaguthurai, Thanussuyah Clifford, Angela Garcia-Murillas, Isaac Van Laere, Steven Dirix, Luc Harries, Mark Okines, Alicia Turner, Nicholas C. Haider, Syed Tutt, Andrew N.J. Isacke, Clare M. Clin Cancer Res Precision Medicine and Imaging PURPOSE: Cerebrospinal fluid (CSF) cytology is the gold standard diagnostic test for breast cancer leptomeningeal metastasis (BCLM), but has impaired sensitivity, often necessitating repeated lumbar puncture to confirm or refute diagnosis. Further, there is no quantitative response tool to assess response or progression during BCLM treatment. EXPERIMENTAL DESIGN: Facing the challenge of working with small-volume samples and the lack of common recurrent mutations in breast cancers, cell-free DNA was extracted from the CSF and plasma of patients undergoing investigation for BCLM (n = 30). ctDNA fraction was assessed by ultra-low-pass whole genome sequencing (ulpWGS), which does not require prior tumor sequencing. RESULTS: In this proof-of-concept study, ctDNA was detected (fraction ≥0.10) in the CSF of all 24 patients with BCLM+ (median ctDNA fraction, 0.57), regardless of negative cytology or borderline MRI imaging, whereas CSF ctDNA was not detected in the six patients with BCLM− (median ctDNA fraction 0.03, P < 0.0001). Plasma ctDNA was only detected in patients with extracranial disease progression or who had previously received whole brain radiotherapy. ctDNA fraction was highly concordant with mutant allele fraction measured by tumor mutation-specific ddPCR assays (r = 0.852; P < 0.0001). During intrathecal treatment, serial monitoring (n = 12 patients) showed that suppression of CSF ctDNA fraction was associated with longer BCLM survival (P = 0.034), and rising ctDNA fraction was detectable up to 12 weeks before clinical progression. CONCLUSIONS: Measuring ctDNA fraction by ulpWGS is a quantitative marker demonstrating potential for timely and accurate BCLM diagnosis and therapy response monitoring, with the ultimate aim to improve management of this poor-prognosis patient group. American Association for Cancer Research 2022-03-15 2022-03-14 /pmc/articles/PMC7612501/ /pubmed/34921020 http://dx.doi.org/10.1158/1078-0432.CCR-21-3017 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Precision Medicine and Imaging Fitzpatrick, Amanda Iravani, Marjan Mills, Adam Childs, Lucy Alaguthurai, Thanussuyah Clifford, Angela Garcia-Murillas, Isaac Van Laere, Steven Dirix, Luc Harries, Mark Okines, Alicia Turner, Nicholas C. Haider, Syed Tutt, Andrew N.J. Isacke, Clare M. Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis |
title | Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis |
title_full | Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis |
title_fullStr | Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis |
title_full_unstemmed | Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis |
title_short | Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis |
title_sort | assessing csf ctdna to improve diagnostic accuracy and therapeutic monitoring in breast cancer leptomeningeal metastasis |
topic | Precision Medicine and Imaging |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612501/ https://www.ncbi.nlm.nih.gov/pubmed/34921020 http://dx.doi.org/10.1158/1078-0432.CCR-21-3017 |
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