Abstract
PurposeThe 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.MethodsCSF 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.ResultsFifteen 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.ConclusionOur 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.
Highlights
Diagnosis, prognosis, and treatment of leptomeningeal metastasis (LM) carries a significant implication for oncologists and patients [1,2,3]
This multi-institutional phase I/II dose escalation trial of IT trastuzumab for LM [17] was conducted in six medical centers from August 2012 to July 2016, and included cerebrospinal fluid (CSF) circulating tumor cells (CTCs) enumeration as an optional exploratory arm to define whether CSF CTCs were present in the CNS compartment at trial entry and whether there was a quantitative change in CTCs during treatment
We demonstrate the value of CSF CTC enumeration in patients with LM enrolled on a phase I/II dose escalation trial of intrathecal trastuzumab
Summary
Prognosis, and treatment of leptomeningeal metastasis (LM) carries a significant implication for oncologists and patients [1,2,3]. Once the diagnosis is established, MRI and CSF cytology are insensitive to determine treatment response [1, 4] To overcome these limitations, a variety of techniques including circulating tumor cell (CTC) [5,6,7,8] technologies have been developed, adapted to CSF, and validated. A variety of techniques including circulating tumor cell (CTC) [5,6,7,8] technologies have been developed, adapted to CSF, and validated This includes CSF CTC methodology by the CellSearch® system (Menarini Silicon Biosystems), which is a highly-sensitive method to diagnose LM with better diagnostic performance compared to CSF cytology and MRI [9,10,11,12]. The value of CSF CTCs as a prognostic biomarker, and as a biomarker of therapeutic response, has not yet been
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