Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer

Abstract

Purpose The CellSearch® system has been used to identify circulating tumor cells (CTCs) in cerebrospinal fluid (CSF) to diagnose leptomeningeal metastasis (LM) in patients with epithelial cancers. Using this system, we prospectively explored sequential CSF CTC enumeration in patients with LM from HER2+ cancers receiving intrathecal (IT) trastuzumab to capture dynamic changes in CSF CTC enumeration. Methods CSF from patients enrolled in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was obtained on day 1 of each cycle and was evaluated by the CellSearch® platform for CTC enumeration. The results were correlated with CSF cytology from the same sample, along with clinical and radiographic response. Results Fifteen out of 34 patients with HER2+ LM were enrolled in CSF CTC analysis; 14 were women. Radiographic LM was documented in 14 (93%) patients; CSF cytology was positive in 6 (40%) and CSF CTCs were identified in 13 (87%). Median CSF CTC was 22 CTCs (range 0-200 +) per 3 ml. HER2/neu expression analysis of CTCs was performed in 8 patients; 75% had confirmed expression of HER2/neu positivity in CSF and HER2/neu expression was absent in 25%. Four of 10 patients received 7 or more cycles of IT trastuzumab; in 3 of these patients, increase in CSF CTCs enumeration from baseline was detected 2-3 months prior to changes seen on MRI, and while CSF cytology remained negative. Conclusion Our study demonstrates that enumeration of CSF CTCs may provide dynamic, quantitative assessment of tumor burden in the central nervous system compartment during treatment for LM and prior to changes on MRI or CSF cytology. Trial Registration: Clinicaltrials.gov: NCT01325207; registered March 29th, 2011.

The Underlying Biology and Therapeutic Vulnerabilities of Leptomeningeal Metastases in Adult Solid Cancers

“…Several groups have developed flow cytometry-based approaches for the detection of breast cancer LM, capturing cells positive for tumor cell specific markers from CSF [ 53 , 54 , 55 ]. Others have applied rare cell capture technologies to standard CSF cytology approaches to improve the detection sensitivity of tumor cells [ 56 , 57 , 58 , 59 ]. Approaches examining the genome, transcriptome, proteome, or miRNAs found in CSF may also hold future promise in diagnosing LM [ 37 , 60 , 61 , 62 ].…”

Advances in the diagnosis, evaluation, and management of leptomeningeal disease

“…In patients with LM secondary to breast cancer receiving intrathecal trastuzumab, a decreased number of CTCs was reported in those responding to treatment. 22 The study also reported increased CTCs in three patients approximately one month prior to clinical signs of progression. 22 These early findings suggest CTCs could provide quantitative measures of response, recurrence, and progression.…”

“… 22 The study also reported increased CTCs in three patients approximately one month prior to clinical signs of progression. 22 These early findings suggest CTCs could provide quantitative measures of response, recurrence, and progression. CSF CTCs may also have a prognostic significance: increased serum CTCs portend a worse prognosis in solid tumors 23 ; changes in the number of CSF CTCs on serial sampling may similarly predict prognosis, providing essential information for risk stratification, and treatment planning.…”

Updates on liquid biopsy: current trends and future perspectives for clinical application in solid tumors

“…It has to be noticed, that even if most of the studies on CTCs uses blood as biological sample, also other fluids may be useful. A recent study by Malani et al reports the identification of CTCs in the cerebrospinal fluid of BC patients with leptomeningeal metastases [102]. This finding will open the way to further studies to assess the clinical relevance of specific body fluids evaluation to stratify MBC patients.…”