Case Report:

The E-cadherin 1 (CDH-1) gene mutation is present in 30% to 60% of Invasive lobular carcinoma (ILC) of the breast. It results in loss of the E-cadherin–mediated adhesion, promoting subtle and atypical metastatic patterns.

This case illustrates the critical role of cerebrospinal fluid (CSF) cell-free DNA analysis in diagnosing an elusive leptomeningeal metastasis.

A 39-year-old woman with stage I, CDH1-mutant ILC on Tamoxifen presented with isolated, incomplete third cranial nerve palsy. Initial brain MRI showed enhancement of the right third nerve, but multiple CSF analyses were negative for malignancy. Mildly elevated GAD-65 antibodies led to a treatment for chronic inflammatory demyelinating polyneuropathy with steroids and intravenous immunoglobulin without improvement.

Three years later she had completed third nerve palsy. Repeat MR revealed worsening thickening of the oculomotor nerve and possible nodular enhancement along the cervical area and cauda equina suggestive of leptomeningeal metastases. Lumbar puncture detected 8 circulating tumor cells (CTCs), but cytology remained negative. A subsequent cisternal puncture revealed 28 CTCs, and crucially, cell free DNA testing using the CSF IMPACT assay confirmed a CDH1 mutation identical to the primary breast tumor—confirming the diagnosis of leptomeningeal metastasis.

Following this molecular confirmation, the patient underwent focal proton radiation to the oculomotor nerve, along with ovarian suppression with letrozole. Cyclin-dependent kinase inhibitor, Abemaciclib, was added after completing radiation.

This case highlights the importance of maintaining a high index of suspicion for metastatic disease in patients harboring CDH1 mutation and emphasizes the relevance of CSF cell-free DNA in uncovering, indolent metastatic patterns of leptomeningeal disease. The molecular profiling of CSF can decisively guide management and improve outcomes in patients with central nervous system involvement.