journal contribution
posted on 2023-03-31, 23:40 authored by Amanda Fitzpatrick, Marjan Iravani, Adam Mills, Lucy Childs, Thanussuyah Alaguthurai, Angela Clifford, Isaac Garcia-Murillas, Steven Van Laere, Luc Dirix, Mark Harries, Alicia Okines, Nicholas C. Turner, Syed Haider, Andrew N.J. Tutt, Clare M. Isacke Supplementary Figure from Assessing CSF ctDNA to Improve Diagnostic Accuracy and Therapeutic Monitoring in Breast Cancer Leptomeningeal Metastasis
Funding
Medical Research Council Clinical Research Training Fellowship
NIHR Biomedical Research Centre
Royal Marsden
ICR postdoctoral support funding
Breast Cancer Now Toby Robins Research Centre
Breast Cancer Now Research Unit
Cancer Research UK
History
ARTICLE ABSTRACT
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.
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.
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.
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.
