Cerebrospinal Fluid CTCs May Help Predict Outcomes in Leptomeningeal Disease

Quantification of circulating tumor cells (CTCs) in cerebrospinal fluid (CSF) can be used to predict survival outcomes in patients with newly diagnosed leptomeningeal disease, according to the results of a retrospective analysis presented during the Society of Neuro-Oncology’s 2020 Virtual Conference on Brain Metastases .

“CTC enumeration in CSF can be a biomarker of disease burden in the CNS compartment,” Maria Diaz, MD, of Memorial Sloan Kettering Cancer Center, said when presenting the results of the analysis.

As leptomeningeal metastases can manifest in a variety of different ways, Diaz suggested that there is often subjectivity in the interpretation of MRI images. As an alternative strategy, the use of CTCs has been considered as a novel approach to diagnose leptomeningeal disease.

The investigators used an immunomagnetic enrichment platform with the CellSearch system and EpCAM antibodies to detect and enumerate CTCs in the CSF. This platform has demonstrated the most sensitivity in the diagnosis of leptomeningeal disease, with a range from 80% to 100% across several studies. “However, the utility of CTC measurement in CSF beyond this use as a diagnostic tool for leptomeningeal metastasis has not been well established,” Diaz said.

The investigators hypothesized and sought to prove that the enumeration of CTCs in the CSF could be used to predict outcomes in patients with leptomeningeal metastasis. They thus conducted a retrospective review of all patients who underwent CTC testing of CSF.

They reviewed a total 407 patient samples that underwent CTC measurement at Memorial Sloan Kettering Cancer Center between April 2016 and June 2019. Of these, 144 patients had leptomeningeal metastases that were diagnosed 30 days before or after the time of CSF analysis, and 101 of these patients had newly diagnosed leptomeningeal disease.

From among this patient population, the primary disease site was the lung in 44%, breast in 35%, gastrointestinal in 7%, gynecologic in 3%, head and neck in 3%, bladder in 3%, and other in 6%. Diaz noted that although melanoma is one of the cancers that most often results in leptomeningeal metastases, this was not represented in this patient cohort because the CellSearch platform does not capture melanoma cells.

The median patient age was 60.8 years (range, 21.9-83.3), 70% were male, and 71% had brain metastases in addition to leptomeningeal metastases. Leptomeningeal disease was diagnosed by cytology in 30%, by neuroimaging in 28%, and by a combination of both in 43%.

The mean CSF CTC count was 127.3 CTC/3 mL in the total population (range, 0-200). The mean white blood cell count was 23.8 (range, 0-388) and the mean protein count was 123.3 (range, 19-1390). Seventy-two percent of patients had a positive or suspicious CSF cytology and 26% had a negative or atypical test.

There was a continuous relationship found between CTC count and mortality (adjusted HR, 1.004; 95% CI, 1.001-1.007; P=.02), amounting to an increase in the risk of death by 0.4% with each additional CTC, Diaz explained.

Recursive partitioning analysis found that having at least 61 CTCs per 3 mL of CSF was associated with a more than doubling of the risk of mortality (adjusted HR, 2.09; 95% CI, 1.13-3.87; P=.02).

“More importantly, cytology provides a qualitative response, dividing all patients into 2 major groups: positive or negative, whereas CTC is a quantitative measure that in our sample...was associated with outcome,” Diaz said.

Analyzing the performance of CSF cytologies demonstrated an increase in the risk of death for those with a positive or suspicious cytology test (adjusted HR, 1.79; 95% CI, 0.95-3.35; P=.07), but this did not reach statistical significance.

“Unfortunately, we only obtained CTC measurements at one point in time so we cannot comment on the relationship between dynamic changes in CTC and outcomes,” Diaz noted. “But given the continuous quantitative association between CTC count and mortality that we found in our data, it is conceivable that CTC enumeration could also be used as a biomarker of the evolution over time of leptomeningeal disease, with practical applications such as determining whether there has been a response to a certain treatment in the leptomeningeal compartment or marking disease recurrence.

“In any case, prospective studies are needed to confirm our findings and further define the utility of CTCs in CSF in the diagnosis and monitoring of patients with leptomeningeal disease,” Diaz concluded.

_Reference:

_{Diaz M, Sign P, Kotchekov I, et al. Circulating tumor cells (CTC) in cerebrospinal fluid (CSF) as a predictor of survival in CNS metastases. Presented at: 2020 SNO Conference on Brain Metastases; August 14, 2020. Abstract 57.}