87MO - Assessing tumour fraction of CSF cfDNA improves diagnostic accuracy and therapeutic monitoring in breast cancer leptomeningeal metastasis (BCLM)

Background

CSF cytology is the gold standard diagnostic test for leptomeningeal metastasis, but has a low sensitivity often requiring multiple repeats. Ultra low pass whole genome sequencing (ulpWGS) allows estimation of the tumour-derived fraction in cell-free DNA (cfDNA) without prior sequencing of primary tumour, and could improve BCLM diagnosis when CSF cytology is equivocal.

Methods

cfDNA was extracted from CSF collected at the time of diagnostic lumbar puncture in patients with breast cancer undergoing investigation for BCLM (n = 25). ulpWGS (0.1X) and estimation of tumour-derived cfDNA fraction (CSF TF) was performed. Serial CSF TF were also measured from patients subsequently undergoing intrathecal therapy for confirmed BCLM.

Results

In 32% (8/25) multiple CSF sampling was performed due to initial negative or equivocal cytology. 20/25 cases had confirmed BCLM: positive MRI and CSF cytology (14/25, 56%); MRI only (3/25, 12%), or cytology only (3/25, 12%). The remaining 5/25 had suspected but non-confirmed BCLM, with negative CSF cytology (5/25) and normal (4/25) or borderline (1/25) MRI findings. At median 20 months follow up, these patients had no evidence of BCLM. CSF TF in confirmed cases was significantly higher (median 61.2%) than non-confirmed BCLM (median 5.0%) (p <0.0001). In those with confirmed BCLM, CSF TF was similar regardless of variable final cytology status (Table). Serial sampling showed that CSF TF changed in response to intrathecal therapy, while CSF cytology and MRI were often unchanged or equivocal. Relapse of BCLM during intrathecal chemotherapy was detected up to 4 weeks before clinical deterioration. Table: 87MO

Conclusions

Measuring CSF TF by ulpWGS appears to better identify confirmed vs non-confirmed BCLM than CSF cytology, and could remove the need for repeat lumbar punctures. Serial CSF TF measurement during intrathecal chemotherapy also provides a quantitative response biomarker to help guide clinical management.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Medical Research Council.

Disclosure

All authors have declared no conflicts of interest.