Cerebrospinal fluid and plasma circulating tumor DNA dynamics as a biomarker of response during trastuzumab deruxtecan treatment in patients with breast cancer with leptomeningeal disease

PURPOSE: Leptomeningeal disease (LMD) from breast cancer remains associated with poor outcomes and there are limited tools for quantitative response assessment. We evaluated cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) as a biomarker of treatment response in patients with LMD treated with trastuzumab deruxtecan (T‑DXd) in a prospective clinical trial cohort. EXPERIMENTAL DESIGN: Serial CSF and plasma samples were collected from seven patients with cytology-confirmed LMD enrolled in cohort 5 of the phase II DEBBRAH trial. ctDNA tumour fraction (TF) was quantified using ultra-low-pass whole-genome sequencing, and targeted unique molecular identifiers (UMI)-based sequencing was performed for mutational profiling. RESULTS: ctDNA was detected by ulpWGS in all baseline CSF samples but in only two of six baseline plasma samples. Early reductions in CSF ctDNA TF were observed within 1-2 cycles of T‑DXd and were associated with prolonged radiological control of LMD. In contrast, plasma ctDNA primarily reflected extracranial disease status. Genomic profiling revealed marked compartmentalization between CSF and plasma, including copy number alterations and subclonal variants which may correlate with treatment response and resistance. CONCLUSIONS: CSF ctDNA represents a potential sensitive and dynamic biomarker of LMD burden and treatment response, supporting its integration into clinical trials for precision monitoring of LMD disease.