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Background CSF cytology is the gold standard diagnostic test for BCLM, but is hampered by a low sensitivity, often necessitating repeated lumbar puncture to confirm or refute the diagnosis. Furthermore, during the treatment of BCLM, there is no robust quantitative response tool to guide treatment decisions. Material and Methods cfDNA was obtained from CSF and plasma in patients with breast cancer undergoing investigation for BCLM (n = 28) and during subsequent intrathecal treatment (n = 13). Ultra low pass whole genome sequencing (ulpWGS) and estimation of the ctDNA fraction was performed. Results were validated by mutation-specific digital droplet PCR (ddPCR). Results 22/28 cases had confirmed BCLM by positive MRI and/or CSF cytology. The remaining 6/28 had suspected but non-confirmed BCLM, and at median 20 months follow up, these patients were BCLM-free. CSF ctDNA fraction was significantly elevated (median 57.5, IQR 38.3 - 84.9%) in confirmed BCLM compared to 6 non-confirmed BCLM (median 5.0, IQR 0.0 - 6.7%) (p &amp;lt;0.0001). ctDNA fraction was detected in BCLM confirmed cases regardless of negative cytology or MRI. Plasma ctDNA fraction was only detected in extra-cranial disease progression. ctDNA fraction was concordant with mutant allele fraction measured by ddPCR (n = 118 samples). Serial CSF ctDNA fraction during intrathecal treatment showed dynamic changes, while CSF cytology and MRI were often unchanged or equivocal. Early reduction in CSF ctDNA fraction was associated with longer responses to intrathecal therapy. Further, rising ctDNA fraction during intrathecal chemotherapy could be detected up to 6 weeks before relapse in neurological symptoms, cytology or MRI. Conclusion Measuring CSF ctDNA fraction is a sensitive diagnostic test for BCLM and could lead to more timely and accurate diagnosis. During intrathecal chemotherapy, CSF ctDNA also provides a quantitative response biomarker to help guide clinical management in this difficult treatment scenario.

LMD-18. Detection and serial monitoring of CSF ctDNA in breast cancer leptomeningeal disease (BCLM)