Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
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
_version_ 1783605374449876992
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
work_keys_str_mv AT fitzpatrickamanda assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT iravanimarjan assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT millsadam assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT childslucy assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT alaguthuraithanussuyah assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT cliffordangela assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT garciamurillasisaac assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT vanlaeresteven assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT dirixluc assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT harriesmark assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT okinesalicia assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT turnernicholasc assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT haidersyed assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT tuttandrewnj assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis
AT isackeclarem assessingcsfctdnatoimprovediagnosticaccuracyandtherapeuticmonitoringinbreastcancerleptomeningealmetastasis