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Open Access 01-07-2020 | Magnetic Resonance Imaging | Clinical Study

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

Authors: Rachna Malani, Martin Fleisher, Priya Kumthekar, Xuling Lin, Antonio Omuro, Morris D. Groves, Nancy U. Lin, Michelle Melisko, Andrew B. Lassman, Suriya Jeyapalan, Andrew Seidman, Anna Skakodub, Adrienne Boire, Lisa M. DeAngelis, Marc Rosenblum, Jeffrey Raizer, Elena Pentsova

Published in: Journal of Neuro-Oncology | Issue 3/2020

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.

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Herrlinger U, Forschler H, Kuker W, Meyermann R, Bamberg M, Dichgans J, Weller M (2004) Leptomeningeal metastasis: survival and prognostic factors in 155 patients. J Neurol Sci 223:167–178. https://doi.org/10.1016/j.jns.2004.05.008CrossRefPubMed

Wasserstrom WR, Glass JP, Posner JB (1982) Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 49:759–772CrossRef

Glass JP, Melamed M, Chernik NL, Posner JB (1979) Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology. Neurology 29:1369–1375. https://doi.org/10.1212/wnl.29.10.1369CrossRefPubMed

Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM (2010) Leptomeningeal metastases in the MRI era. Neurology 74:1449–1454. https://doi.org/10.1212/WNL.0b013e3181dc1a69CrossRefPubMedPubMedCentral

Liu MC, Shields PG, Warren RD, Cohen P, Wilkinson M, Ottaviano YL, Rao SB, Eng-Wong J, Seillier-Moiseiwitsch F, Noone AM, Isaacs C (2009) Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. J Clin Oncol 27:5153–5159. https://doi.org/10.1200/JCO.2008.20.6664CrossRefPubMedPubMedCentral

Maheswaran S, Haber DA (2010) Circulating tumor cells: a window into cancer biology and metastasis. Curr Opin Genet Dev 20:96–99. https://doi.org/10.1016/j.gde.2009.12.002CrossRefPubMedPubMedCentral

Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW (2004) Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10:6897–6904. https://doi.org/10.1158/1078-0432.CCR-04-0378CrossRefPubMed

Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791. https://doi.org/10.1056/NEJMoa040766CrossRefPubMed

Le Rhun E, Massin F, Tu Q, Bonneterre J, Bittencourt Mde C, Faure GC (2012) Development of a new method for identification and quantification in cerebrospinal fluid of malignant cells from breast carcinoma leptomeningeal metastasis. BMC Clin Pathol 12:21. https://doi.org/10.1186/1472-6890-12-21CrossRefPubMedPubMedCentral

10.

Lee JS, Melisko ME, Magbanua MJ, Kablanian AT, Scott JH, Rugo HS, Park JW (2015) Detection of cerebrospinal fluid tumor cells and its clinical relevance in leptomeningeal metastasis of breast cancer. Breast Cancer Res Treat 154:339–349. https://doi.org/10.1007/s10549-015-3610-1CrossRefPubMed

11.

Lin X, Fleisher M, Rosenblum M, Lin O, Boire A, Briggs S, Bensman Y, Hurtado B, Shagabayeva L, DeAngelis LM, Panageas KS, Omuro A, Pentsova EI (2017) Cerebrospinal fluid circulating tumor cells: a novel tool to diagnose leptomeningeal metastases from epithelial tumors. Neuro Oncol 19:1248–1254. https://doi.org/10.1093/neuonc/nox066CrossRefPubMedPubMedCentral

12.

Nayak L, Fleisher M, Gonzalez-Espinoza R, Lin O, Panageas K, Reiner A, Liu CM, Deangelis LM, Omuro A (2013) Rare cell capture technology for the diagnosis of leptomeningeal metastasis in solid tumors. Neurology 80:1598–1605. https://doi.org/10.1212/WNL.0b013e31828f183f(discussion 1603)CrossRefPubMedPubMedCentral

13.

Le Rhun E, Weller M, Brandsma D, Van den Bent M, de Azambuja E, Henriksson R, Boulanger T, Peters S, Watts C, Wick W, Wesseling P, Ruda R, Preusser M, Board EE, Committee EG (2017) EANO-ESMO clinical practice Guidelines for diagnosis, treatment and follow-up of patients with leptomeningeal metastasis from solid tumours. Ann Oncol 28:iv84–iv99. https://doi.org/10.1093/annonc/mdx221CrossRefPubMed

14.

Chamberlain M, Junck L, Brandsma D, Soffietti R, Ruda R, Raizer J, Boogerd W, Taillibert S, Groves MD, Rhun EL, Walker J, van den Bent M, Wen PY, Jaeckle KA (2016) Leptomeningeal metastases: a RANO proposal for response criteria. Neuro Oncol. https://doi.org/10.1093/neuonc/now183CrossRefPubMedPubMedCentral

15.

Le Rhun E, Devos P, Boulanger T, Smits M, Brandsma D, Ruda R, Furtner J, Hempel JM, Postma TJ, Roth P, Snijders TJ, Winkler F, Winklhofer S, Castellano A, Hattingen E, Capellades J, Gorlia T, Van den Bent M, Wen PY, Bendszus M, Weller M, European Organisation for R, Treatment of Cancer Brain Tumor Group Central Nervous System Metastases C, the EBTGIC (2019) The RANO Leptomeningeal Metastasis Group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal. Neuro-oncology 21:648–658. https://doi.org/10.1093/neuonc/noz024CrossRefPubMedPubMedCentral

16.

Boire A, Brandsma D, Brastianos PK, Le Rhun E, Ahluwalia M, Junck L, Glantz M, Groves MD, Lee EQ, Lin N, Raizer J, Ruda R, Weller M, Van den Bent MJ, Vogelbaum MA, Chang S, Wen PY, Soffietti R (2019) Liquid biopsy in central nervous system metastases: a RANO review and proposals for clinical applications. Neuro Oncol 21:571–584. https://doi.org/10.1093/neuonc/noz012CrossRefPubMedPubMedCentral

17.

Kumthekar P, Gradishar W, Lin N, Pentsova E, Groves M, Jeyapalan S, Melisko M, Grimm S, Lassman A, Raizer J (2018) Intrathecal (It) traztuzumab (T) for the treatment of leptomeningeal metastases (Lm) in patients (Pts) with human epidermal growth factor receptor 2-positive (Her2+) cancer: a Multicenter Phase 1/2 Study. Neuro-Oncology 20:58–i58CrossRef

18.

Magbanua MJ, Melisko M, Roy R, Sosa EV, Hauranieh L, Kablanian A, Eisenbud LE, Ryazantsev A, Au A, Scott JH, Park JW (2013) Molecular profiling of tumor cells in cerebrospinal fluid and matched primary tumors from metastatic breast cancer patients with leptomeningeal carcinomatosis. Cancer Res 73:7134–7143. https://doi.org/10.1158/0008-5472.CAN-13-2051CrossRefPubMed

19.

Patel AS, Allen JE, Dicker DT, Peters KL, Sheehan JM, Glantz MJ, El-Deiry WS (2011) Identification and enumeration of circulating tumor cells in the cerebrospinal fluid of breast cancer patients with central nervous system metastases. Oncotarget 2:752–760CrossRef

20.

Gill CM, Brastianos PK (2019) Management of leptomeningeal carcinomatosis and challenges of trial design. Curr Opin Oncol 31:508–513. https://doi.org/10.1097/CCO.0000000000000574CrossRefPubMed

21.

Morikawa A, Jordan L, Rozner R, Patil S, Boire A, Pentsova E, Seidman AD (2016) Characteristics and outcomes of patients with breast cancer with leptomeningeal metastasis. Clin Breast Cancer. https://doi.org/10.1016/j.clbc.2016.07.002CrossRefPubMedPubMedCentral

22.

Glantz MJ, Jaeckle KA, Chamberlain MC, Phuphanich S, Recht L, Swinnen LJ, Maria B, LaFollette S, Schumann GB, Cole BF, Howell SB (1999) A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 5:3394–3402PubMed

23.

Niikura N, Liu J, Hayashi N, Mittendorf EA, Gong Y, Palla SL, Tokuda Y, Gonzalez-Angulo AM, Hortobagyi GN, Ueno NT (2012) Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J Clin Oncol 30:593–599. https://doi.org/10.1200/JCO.2010.33.8889CrossRefPubMed

Title: Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer
Authors: Rachna Malani
Martin Fleisher
Priya Kumthekar
Xuling Lin
Antonio Omuro
Morris D. Groves
Nancy U. Lin
Michelle Melisko
Andrew B. Lassman
Suriya Jeyapalan
Andrew Seidman
Anna Skakodub
Adrienne Boire
Lisa M. DeAngelis
Marc Rosenblum
Jeffrey Raizer
Elena Pentsova
Publication date: 01-07-2020
Publisher: Springer US
Keywords: Magnetic Resonance Imaging
Magnetic Resonance Imaging
Metastasis
Trastuzumab
Biomarkers
Published in: Journal of Neuro-Oncology / Issue 3/2020
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-020-03555-z

At a glance: The STEP trials

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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