Skip to main content

Advertisement

SpringerLink
Log in

Detection of cerebrospinal fluid tumor cells and its clinical relevance in leptomeningeal metastasis of breast cancer

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Circulating tumor cells are commonly observed in the peripheral blood of advanced breast cancer patients. We tested the feasibility of tumor cell detection in the cerebrospinal fluid (CSF) and studied its clinical relevance in leptomeningeal metastasis (LM) of breast cancer. CSF samples were collected from 38 metastatic breast cancer patients known or suspected to have LM. Control CSF samples were collected from 14 individuals without solid tumor malignancy. We used a modified CellSearch™ assay and an alternative EPCAM-based method involving immunomagnetic enrichment followed by flow cytometry (IE/FC) to enumerate CSF tumor cells (CSFTCs). CSFTCs were assayed at time of LM diagnosis and over the course of LM-directed therapy. We analyzed a total of 102 CSF samples with modified CellSearch™. The CSFTC counts were strongly correlated with the corresponding IE/FC results (Pearson’s r = 0.94). Twenty-eight out of 30 samples in which malignant cells were identified by CSF cytology were CSFTC-positive by modified CellSearch™. Baseline CSFTC levels from 21 patients eventually diagnosed with LM were significantly higher than the controls (p = 0.0202), whereas 13 patients deemed not to have LM showed CSFTC results indistinguishable from the controls. In patients with serial samples, it was possible to monitor CSFTC levels as a potential biomarker of treatment response. CSFTC detection using a modified CellSearch™ assay demonstrated high sensitivity in detecting malignant cells in CSF and may be a promising method for diagnosing LM and monitoring LM during treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Chamberlain MC (2004) Neoplastic meningitis. Semin Neurol 24(4):363–374. doi:10.1055/s-2004-861531

    Article  PubMed  Google Scholar 

  2. Scott BJ, Kesari S (2013) Leptomeningeal metastases in breast cancer. Am J Cancer Res 3(2):117–126

    PubMed Central  CAS  PubMed  Google Scholar 

  3. Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM (2010) Leptomeningeal metastases in the MRI era. Neurology 74(18):1449–1454. doi:10.1212/WNL.0b013e3181dc1a69

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Frisk G, Svensson T, Backlund LM, Lidbrink E, Blomqvist P, Smedby KE (2012) Incidence and time trends of brain metastases admissions among breast cancer patients in Sweden. Br J Cancer 106(11):1850–1853. doi:10.1038/bjc.2012.163

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Lin NU, Winer EP (2007) Brain metastases: the HER2 paradigm. Clin Cancer Res 13(6):1648–1655. doi:10.1158/1078-0432.CCR-06-2478

    Article  CAS  PubMed  Google Scholar 

  6. Altundag K, Bondy ML, Mirza NQ, Kau SW, Broglio K, Hortobagyi GN, Rivera E (2007) Clinicopathologic characteristics and prognostic factors in 420 metastatic breast cancer patients with central nervous system metastasis. Cancer 110(12):2640–2647. doi:10.1002/cncr.23088

    Article  CAS  PubMed  Google Scholar 

  7. Kim HJ, Im SA, Keam B, Kim YJ, Han SW, Kim TM, Oh DY, Kim JH, Lee SH, Chie EK, Han W, Kim DW, Kim TY, Noh DY, Heo DS, Park IA, Bang YJ, Ha SW (2012) Clinical outcome of central nervous system metastases from breast cancer: differences in survival depending on systemic treatment. J Neuro-oncol 106(2):303–313. doi:10.1007/s11060-011-0664-8

    Article  Google Scholar 

  8. Gauthier H, Guilhaume MN, Bidard FC, Pierga JY, Girre V, Cottu PH, Laurence V, Livartowski A, Mignot L, Dieras V (2010) Survival of breast cancer patients with meningeal carcinomatosis. Ann Oncol 21(11):2183–2187. doi:10.1093/annonc/mdq232

    Article  CAS  PubMed  Google Scholar 

  9. de Azevedo CR, Cruz MR, Chinen LT, Peres SV, Peterlevitz MA, de Azevedo Pereira AE, Fanelli MF, Gimenes DL (2011) Meningeal carcinomatosis in breast cancer: prognostic factors and outcome. J Neuro-oncol 104(2):565–572. doi:10.1007/s11060-010-0524-y

    Article  Google Scholar 

  10. Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS (1993) Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group. J Clin Oncol 11(3):561–569

    CAS  PubMed  Google Scholar 

  11. Chamberlain MC (1998) Leptomeningeal metastases: a review of evaluation and treatment. J Neurooncol 37(3):271–284

    Article  CAS  PubMed  Google Scholar 

  12. Kaplan JG, DeSouza TG, Farkash A, Shafran B, Pack D, Rehman F, Fuks J, Portenoy R (1990) Leptomeningeal metastases: comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias. J Neuro-oncol 9(3):225–229

    Article  CAS  Google Scholar 

  13. Balm M, Hammack J (1996) Leptomeningeal carcinomatosis. Presenting features and prognostic factors. Arch Neurol 53(7):626–632

    Article  CAS  PubMed  Google Scholar 

  14. Glantz MJ, Cole BF, Glantz LK, Cobb J, Mills P, Lekos A, Walters BC, Recht LD (1998) Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer 82(4):733–739

    Article  CAS  PubMed  Google Scholar 

  15. Straathof CS, de Bruin HG, Dippel DW, Vecht CJ (1999) The diagnostic accuracy of magnetic resonance imaging and cerebrospinal fluid cytology in leptomeningeal metastasis. J Neurol 246(9):810–814

    Article  CAS  PubMed  Google Scholar 

  16. Deisenhammer F, Bartos A, Egg R, Gilhus NE, Giovannoni G, Rauer S, Sellebjerg F, Force ET (2006) Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. Eur J Neurol 13(9):913–922. doi:10.1111/j.1468-1331.2006.01493.x

    Article  CAS  PubMed  Google Scholar 

  17. Chamberlain MC, Glantz M, Groves MD, Wilson WH (2009) Diagnostic tools for neoplastic meningitis: detecting disease, identifying patient risk, and determining benefit of treatment. Semin Oncol 36(4 Suppl 2):S35–S45. doi:10.1053/j.seminoncol.2009.05.005

    Article  PubMed  Google Scholar 

  18. 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(20):6897–6904

    Article  PubMed  Google Scholar 

  19. Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkins RG, Haber DA, Toner M (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450(7173):1235–1239. doi:10.1038/nature06385

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Todenhofer T, Hennenlotter J, Feyerabend S, Aufderklamm S, Mischinger J, Kuhs U, Gerber V, Fetisch J, Schilling D, Hauch S, Stenzl A, Schwentner C (2012) Preliminary experience on the use of the Adnatest(R) system for detection of circulating tumor cells in prostate cancer patients. Anticancer Res 32(8):3507–3513

    PubMed  Google Scholar 

  21. Tanaka F, Yoneda K, Kondo N, Hashimoto M, Takuwa T, Matsumoto S, Okumura Y, Rahman S, Tsubota N, Tsujimura T, Kuribayashi K, Fukuoka K, Nakano T, Hasegawa S (2009) Circulating tumor cell as a diagnostic marker in primary lung cancer. Clin Cancer Res 15(22):6980–6986. doi:10.1158/1078-0432.CCR-09-1095

    Article  CAS  PubMed  Google Scholar 

  22. Gallagher DJ, Milowsky MI, Ishill N, Trout A, Boyle MG, Riches J, Fleisher M, Bajorin DF (2009) Detection of circulating tumor cells in patients with urothelial cancer. Ann Oncol 20(2):305–308. doi:10.1093/annonc/mdn627

    Article  CAS  PubMed  Google Scholar 

  23. Danila DC, Heller G, Gignac GA, Gonzalez-Espinoza R, Anand A, Tanaka E, Lilja H, Schwartz L, Larson S, Fleisher M, Scher HI (2007) Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 13(23):7053–7058. doi:10.1158/1078-0432.CCR-07-1506

    Article  CAS  PubMed  Google Scholar 

  24. Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse M, Mitchell E, Miller MC, Doyle GV, Tissing H, Terstappen LW, Meropol NJ (2008) Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 26(19):3213–3221. doi:10.1200/JCO.2007.15.8923

    Article  PubMed  Google Scholar 

  25. 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(8):781–791

    Article  CAS  PubMed  Google Scholar 

  26. Ignatiadis M, Xenidis N, Perraki M, Apostolaki S, Politaki E, Kafousi M, Stathopoulos EN, Stathopoulou A, Lianidou E, Chlouverakis G, Sotiriou C, Georgoulias V, Mavroudis D (2007) Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. J Clin Oncol 25(33):5194–5202. doi:10.1200/JCO.2007.11.7762

    Article  PubMed  Google Scholar 

  27. Lucci A, Hall CS, Lodhi AK, Bhattacharyya A, Anderson AE, Xiao L, Bedrosian I, Kuerer HM, Krishnamurthy S (2012) Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol 13(7):688–695. doi:10.1016/S1470-2045(12)70209-7

    Article  PubMed  Google Scholar 

  28. Bidard FC, Peeters DJ, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, de Lascoiti AF, De Mattos-Arruda L, Ignatiadis M, Lebofsky R, van Laere SJ, Meier-Stiegen F, Sandri MT, Vidal-Martinez J, Politaki E, Consoli F, Bottini A, Diaz-Rubio E, Krell J, Dawson SJ, Raimondi C, Rutten A, Janni W, Munzone E, Caranana V, Agelaki S, Almici C, Dirix L, Solomayer EF, Zorzino L, Johannes H, Reis-Filho JS, Pantel K, Pierga JY, Michiels S (2014) Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol 15(4):406–414. doi:10.1016/S1470-2045(14)70069-5

    Article  PubMed  Google Scholar 

  29. de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14(19):6302–6309

    Article  PubMed  Google Scholar 

  30. Garcia JA, Rosenberg JE, Weinberg V, Scott J, Frohlich M, Park JW, Small EJ (2007) Evaluation and significance of circulating epithelial cells in patients with hormone-refractory prostate cancer. BJU Int 99(3):519–524. doi:10.1111/j.1464-410X.2007.06659.x

    Article  PubMed  Google Scholar 

  31. Magbanua MJ, Carey LA, DeLuca A, Hwang J, Scott JH, Rimawi MF, Mayer EL, Marcom PK, Liu MC, Esteva FJ, Park JW, Rugo HS, Translational Breast Cancer Research C (2015) Circulating tumor cell analysis in metastatic triple-negative breast cancers. Clin Cancer Res 21(5):1098–1105. doi:10.1158/1078-0432.CCR-14-1948

    Article  CAS  PubMed  Google Scholar 

  32. Magbanua MJ, Sosa EV, Roy R, Eisenbud LE, Scott JH, Olshen A, Pinkel D, Rugo HS, Park JW (2013) Genomic profiling of isolated circulating tumor cells from metastatic breast cancer patients. Cancer Res 73(1):30–40. doi:10.1158/0008-5472.CAN-11-3017

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Chamberlain M, Soffietti R, Raizer J, Ruda R, Brandsma D, Boogerd W, Taillibert S, Groves MD, Le Rhun E, Junck L, van den Bent M, Wen PY, Jaeckle KA (2014) Leptomeningeal metastasis: a response assessment in neuro-oncology critical review of endpoints and response criteria of published randomized clinical trials. Neuro-oncology 16(9):1176–1185. doi:10.1093/neuonc/nou089

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. 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(10):752–760

    Article  PubMed Central  PubMed  Google Scholar 

  35. 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. doi:10.1186/1472-6890-12-21

    Article  PubMed Central  PubMed  Google Scholar 

  36. 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(17):1598–1605. doi:10.1212/WNL.0b013e31828f183f discussion 1603

    Article  PubMed Central  PubMed  Google Scholar 

  37. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, Shioda T, Ramaswamy S, Ting DT, Lin CP, Toner M, Haber DA, Maheswaran S (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158(5):1110–1122. doi:10.1016/j.cell.2014.07.013

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Magbanua MJ, Park JW (2013) Isolation of circulating tumor cells by immunomagnetic enrichment and fluorescence-activated cell sorting (IE/FACS) for molecular profiling. Methods 64(2):114–118. doi:10.1016/j.ymeth.2013.07.029

    Article  CAS  PubMed  Google Scholar 

  39. Magbanua MJ, Sosa EV, Scott JH, Simko J, Collins C, Pinkel D, Ryan CJ, Park JW (2012) Isolation and genomic analysis of circulating tumor cells from castration resistant metastatic prostate cancer. BMC Cancer 12:78. doi:10.1186/1471-2407-12-78

    Article  PubMed Central  PubMed  Google Scholar 

  40. 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(23):7134–7143. doi:10.1158/0008-5472.CAN-13-2051

    Article  CAS  PubMed  Google Scholar 

  41. Magbanua MJ, Melisko M, Park JW (2014) Molecular characterization of cerebrospinal fluid tumor cells associated with leptomeningeal carcinomatosis. Cancer Cell Microenviron 1:109–113. doi:10.14800/ccm.167

    Google Scholar 

  42. Magbanua MJ, Roy R, Sosa EV, Hauranieh L, Kablanian A, Eisenbud LE, Ryazantsev A, Au A, Scott JH, Melisko M, Park JW (2014) Genome-wide copy number analysis of cerebrospinal fluid tumor cells and their corresponding archival primary tumors. Genom Data 2:60–62. doi:10.1016/j.gdata.2014.04.003

    Article  PubMed Central  PubMed  Google Scholar 

  43. Palma JA, Fernandez-Torron R, Esteve-Belloch P, Fontes-Villalba A, Hernandez A, Fernandez-Hidalgo O, Gallego Perez-Larraya J, Martinez-Vila E (2013) Leptomeningeal carcinomatosis: prognostic value of clinical, cerebrospinal fluid, and neuroimaging features. Clin Neurol Neurosurg 115(1):19–25. doi:10.1016/j.clineuro.2012.03.048

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Venkata Sai Vemula, Louai Hauranieh, and Eduardo Sosa for technical assistance.

Grant support

UCSF Research Allocation Program (M.E. Melisko). The Breast Cancer Research Foundation (M.J.M. Magbanua). Bay Area Breast Cancer Translational (SPORE) P50 CA58207 (J.W. Park).

Author information

Author notes

    Authors and Affiliations

    1. Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 2340 Sutter Street, San Francisco, CA, 94115, USA

      Jin Sun Lee, Michelle E. Melisko, Mark Jesus M. Magbanua, Andrea T. Kablanian, Janet H. Scott, Hope S. Rugo & John W. Park

    Authors
    1. Jin Sun Lee
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Michelle E. Melisko
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Mark Jesus M. Magbanua
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Andrea T. Kablanian
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Janet H. Scott
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Hope S. Rugo
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. John W. Park
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to John W. Park.

    Ethics declarations

    Conflicts of interest

    None.

    Ethics and consent

    The study protocol was approved by the Committee on Human Research at the University of California San Francisco. All patients gave informed consent for participation in this study.

    Additional information

    Jin Sun Lee, Michelle E. Melisko, and Mark Jesus M. Magbanua have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 15 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Lee, J.S., Melisko, M.E., Magbanua, M.J.M. et al. Detection of cerebrospinal fluid tumor cells and its clinical relevance in leptomeningeal metastasis of breast cancer. Breast Cancer Res Treat 154, 339–349 (2015). https://doi.org/10.1007/s10549-015-3610-1

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10549-015-3610-1

    Keywords

    Search

    Navigation