Skip to main content
SpringerLink
Log in

Challenges and Opportunities in the Use of CTCs for Companion Diagnostic Development

  • Chapter
  • First Online:
Book cover Minimal Residual Disease and Circulating Tumor Cells in Breast Cancer

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 195))

Abstract

Circulating tumor cells offer promise as a surrogate source of cancer cells that can be obtained in real time and may provide opportunities to evaluate predictive biomarkers that can guide treatment decisions. In this review, we consider some of the technical hurdles around CTC numbers and suitability of various CTC capture and analysis platforms for biomarker evaluation. In addition, we consider the potential regulatory hurdles to development of CTC-based diagnostics. Finally, we suggest a path for co-development of anticancer therapeutics with CTC-based diagnostics that could enable clinical validation and qualification of CTC-based assays as companion diagnostics.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ashworth T (1869) A case of cancer in which cells similar to those in the tumors were seen in the blood after death. Aust Med J 14:146

    Google Scholar 

  2. Attard G, de Bono JS (2011) Utilizing circulating tumor cells: challenges and pitfalls. Curr Opin Genet Dev 21:50–58

    Article  PubMed  CAS  Google Scholar 

  3. Punnoose EA, Atwal SK, Spoerke JM, Savage H, Pandita A, Yeh RF, Pirzkall A, Fine BM, Amler LC, Chen DS, Lackner MR (2011) Molecular biomarker analyses using circulating tumor cells. PloS one 5:e12517

    Article  Google Scholar 

  4. Maheswaran S, Haber DA (2010) Circulating tumor cells: a window into cancer biology and metastasis. Curr Opin Genet Dev 20(1):96–99

    Google Scholar 

  5. Pantel K, Alix-Panabieres C (2010) Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med 16:398–406

    Article  PubMed  Google Scholar 

  6. 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

    Article  PubMed  CAS  Google Scholar 

  7. Cristofanilli M, Hayes DF, Budd GT, Ellis MJ, Stopeck A, Reuben JM, Doyle GV, Matera J, Allard WJ, Miller MC, Fritsche HA, Hortobagyi GN, Terstappen LW (2005) Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 23:1420–1430

    Article  PubMed  Google Scholar 

  8. Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen LW (2006) Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 12:4218–4224

    Article  PubMed  CAS  Google Scholar 

  9. Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR, Taplin ME, Bubley GJ, Kheoh T, Haqq C, Molina A, Anand A, Koscuiszka M, Larson SM, Schwartz LH, Fleisher M, Scher HI (2010) Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol 28:1496–1501

    Article  PubMed  CAS  Google Scholar 

  10. Reid AH, Attard G, Danila DC, Oommen NB, Olmos D, Fong PC, Molife LR, Hunt J, Messiou C, Parker C, Dearnaley D, Swennenhuis JF, Terstappen LW, Lee G, Kheoh T, Molina A, Ryan CJ, Small E, Scher HI, de Bono JS (2010) Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol 28:1489–1495

    Article  PubMed  CAS  Google Scholar 

  11. Bidard FC, Mathiot C, Delaloge S, Brain E, Giachetti S, de Cremoux P, Marty M, Pierga JY (2010) Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann Oncol 21:729–733

    Article  PubMed  Google Scholar 

  12. Ignatiadis M, Kallergi G, Ntoulia M, Perraki M, Apostolaki S, Kafousi M, Chlouverakis G, Stathopoulos E, Lianidou E, Georgoulias V, Mavroudis D (2008) Prognostic value of the molecular detection of circulating tumor cells using a multimarker reverse transcription-PCR assay for cytokeratin 19, mammaglobin A, and HER2 in early breast cancer. Clin Cancer Res 14:2593–2600

    Article  PubMed  CAS  Google Scholar 

  13. Philip R, Carrington L, Chan M (2011) US FDA perspective on challenges in co-developing in vitro companion diagnostics and targeted cancer therapeutics. Bioanalysis 3:383–389

    Article  PubMed  CAS  Google Scholar 

  14. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726

    Article  PubMed  CAS  Google Scholar 

  15. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, Antipin Y, Mitsiades N, Landers T, Dolgalev I, Major JE, Wilson M, Socci ND, Lash AE, Heguy A, Eastham JA, Scher HI, Reuter VE, Scardino PT, Sander C, Sawyers CL, Gerald WL (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell 18:11–22

    Article  PubMed  CAS  Google Scholar 

  16. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, Arora VK, Le C, Koutcher J, Scher H, Scardino PT, Rosen N, Sawyers CL (2011) Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19:575–586

    Article  PubMed  CAS  Google Scholar 

  17. Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky D, Isaacs WB, Bova GS (1998) Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res 58:204–209

    PubMed  CAS  Google Scholar 

  18. Dupont Jensen J, Laenkholm AV, Knoop A, Ewertz M, Bandaru R, Liu W, Hackl W, Barrett JC, Gardner H (2010) PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res 17:667–677

    Article  PubMed  Google Scholar 

  19. Agulnik M, Oza AM, Pond GR, Siu LL (2006) Impact and perceptions of mandatory tumor biopsies for correlative studies in clinical trials of novel anticancer agents. J Clin Oncol 24:4801–4807

    Article  PubMed  Google Scholar 

  20. Miller MC, Doyle GV, Terstappen LW (2010) Significance of circulating tumor cells detected by the cellSearch system in patients with metastatic breast colorectal and prostate cancer. J Oncol 2010:617421

    PubMed  Google Scholar 

  21. Mikolajczyk SD, Millar LS, Tsinberg P, Coutts SM, Zomorrodi M, Pham T, Bischoff FZ, Pircher TJ (2011) Detection of EpCAM-negative and cytokeratin-negative circulating tumor cells in peripheral blood. J Oncol 2011:252361

    PubMed  Google Scholar 

  22. Sieuwerts AM, Kraan J, Bolt J, van der Spoel P, Elstrodt F, Schutte M, Martens JW, Gratama JW, Sleijfer S, Foekens JA (2009) Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst 101:61–66

    PubMed  CAS  Google Scholar 

  23. Coumans FA, Doggen CJ, Attard G, de Bono JS, Terstappen LW (2010) All circulating EpCAM + CK + CD45- objects predict overall survival in castration-resistant prostate cancer. Ann Oncol 21:1851–1857

    Google Scholar 

  24. Marrinucci D, Bethel K, Bruce RH, Curry DN, Hsieh B, Humphrey M, Krivacic RT, Kroener J, Kroener L, Ladanyi A, Lazarus NH, Nieva J, Kuhn P (2007) Case study of the morphologic variation of circulating tumor cells. Hum Pathol 38:514–519

    Article  PubMed  Google Scholar 

  25. Marrinucci D, Bethel K, Lazar D, Fisher J, Huynh E, Clark P, Bruce R, Nieva J, Kuhn P (2010) Cytomorphology of circulating colorectal tumor cells: a small case series. J Oncol 2010:861341

    Google Scholar 

  26. Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A’Hern R, Levink R, Coumans F, Moreira J, Riisnaes R, Oommen NB, Hawche G, Jameson C, Thompson E, Sipkema R, Carden CP, Parker C, Dearnaley D, Kaye SB, Cooper CS, Molina A, Cox ME, Terstappen LW, de Bono JS (2009) Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res 69:2912–2918

    Article  PubMed  CAS  Google Scholar 

  27. 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

    Article  PubMed  Google Scholar 

  28. Leversha MA, Han J, Asgari Z, Danila DC, Lin O, Gonzalez-Espinoza R, Anand A, Lilja H, Heller G, Fleisher M, Scher HI (2009) Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin Cancer Res 15:2091–2097

    Article  PubMed  CAS  Google Scholar 

  29. Hofman V, Long E, Ilie M, Bonnetaud C, Vignaud JM, Flejou JF, Lantuejoul S, Piaton E, Mourad N, Butori C, Selva E, Marquette CH, Poudenx M, Sibon S, Kelhef S, Venissac N, Jais JP, Mouroux J, Molina TJ, Vielh P, Hofman P (2012) Morphological analysis of circulating tumour cells in patients undergoing surgery for non-small cell lung carcinoma using the isolation by size of epithelial tumour cell (ISET) method. Cytopathology 23(1):30–38.

    Article  PubMed  CAS  Google Scholar 

  30. 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 450:1235–1239

    Article  PubMed  CAS  Google Scholar 

  31. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, Digumarthy S, Muzikansky A, Irimia D, Settleman J, Tompkins RG, Lynch TJ, Toner M, Haber DA (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359:366–377

    Article  PubMed  CAS  Google Scholar 

  32. Yu M, Stott S, Toner M, Maheswaran S, Haber DA (2011) Circulating tumor cells: approaches to isolation and characterization. J cell Biol 192:373–382

    Article  PubMed  CAS  Google Scholar 

  33. Stott SL, Hsu CH, Tsukrov DI, Yu M, Miyamoto DT, Waltman BA, Rothenberg SM, Shah AM, Smas ME, Korir GK, Floyd FP Jr, Gilman AJ, Lord JB, Winokur D, Springer S, Irimia D, Nagrath S, Sequist LV, Lee RJ, Isselbacher KJ, Maheswaran S, Haber DA, Toner M (2011) Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci U S A 107:18392–18397

    Article  Google Scholar 

  34. Stott SL, Lee RJ, Nagrath S, Yu M, Miyamoto DT, Ulkus L, Inserra EJ, Ulman M, Springer S, Nakamura Z, Moore AL, Tsukrov DI, Kempner ME, Dahl DM, Wu CL, Iafrate AJ, Smith MR, Tompkins RG, Sequist LV, Toner M, Haber DA, Maheswaran S (2011) Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl Med 2:25ra23

    Google Scholar 

  35. Helzer KT, Barnes HE, Day L, Harvey J, Billings PR, Forsyth A (2009) Circulating tumor cells are transcriptionally similar to the primary tumor in a murine prostate model. Cancer Res 69:7860–7866

    Article  PubMed  CAS  Google Scholar 

  36. Talasaz AH, Powell AA, Huber DE, Berbee JG, Roh KH, Yu W, Xiao W, Davis MM, Pease RF, Mindrinos MN, Jeffrey SS, Davis RW (2009) Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device. Proc Natl Acad Sci U S A 106:3970–3975

    Article  PubMed  CAS  Google Scholar 

  37. Riethdorf S, Muller V, Zhang L, Rau T, Loibl S, Komor M, Roller M, Huober J, Fehm T, Schrader I, Hilfrich J, Holms F, Tesch H, Eidtmann H, Untch M, von Minckwitz G, Pantel K (2010) Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res 16:2634–2645

    Article  PubMed  CAS  Google Scholar 

  38. Fehm T, Muller V, Aktas B, Janni W, Schneeweiss A, Stickeler E, Lattrich C, Lohberg CR, Solomayer E, Rack B, Riethdorf S, Klein C, Schindlbeck C, Brocker K, Kasimir-Bauer S, Wallwiener D, Pantel K (2010) HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat 124:403–412

    Article  PubMed  CAS  Google Scholar 

  39. Flores LM, Kindelberger DW, Ligon AH, Capelletti M, Fiorentino M, Loda M, Cibas ES, Janne PA, Krop IE (2010) Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer. Br J Cancer 102:1495–1502

    Article  PubMed  CAS  Google Scholar 

  40. Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, Beitsch P, Khan A, Euhus D, Osborne C, Frenkel E, Hoover S, Leitch M, Clifford E, Vitetta E, Morrison L, Herlyn D, Terstappen LW, Fleming T, Fehm T, Tucker T, Lane N, Wang J, Uhr J (2004) HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A 101:9393–9398

    Article  PubMed  CAS  Google Scholar 

  41. Pestrin M, Bessi S, Galardi F, Truglia M, Biggeri A, Biagioni C, Cappadona S, Biganzoli L, Giannini A, Di Leo A (2009) Correlation of HER2 status between primary tumors and corresponding circulating tumor cells in advanced breast cancer patients. Breast Cancer Res Treat 118:523–530

    Article  PubMed  CAS  Google Scholar 

  42. Pantel K, Brakenhoff RH, Brandt B (2008) Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8:329–340

    Article  PubMed  CAS  Google Scholar 

  43. Hayashi N, Yamauchi H (2011) Role of circulating tumor cells and disseminated tumor cells in primary breast cancer. Breast cancer. (Tokyo, Japan)

    Google Scholar 

  44. Taube SE, Clark GM, Dancey JE, McShane LM, Sigman CC, Gutman SI (2009) A perspective on challenges and issues in biomarker development and drug and biomarker codevelopment. J Natl Cancer Inst 101:1453–1463

    Article  PubMed  Google Scholar 

  45. Clinical Laboratory Improvement Amendments (CLIA) (1988) Clinical Laboratory Improvement Amendments (CLIA) US Department of Health and Human Services. URL: https://www.cms.gov/clia/

  46. Wistuba II, Gelovani JG, Jacoby JJ, Davis SE, Herbst RS (2011) Methodological and practical challenges for personalized cancer therapies. Nat Rev 8:135–141

    CAS  Google Scholar 

  47. Danila D, Fleisher M, Scher H (2011) Circulating tumor cells as biomarkers in prostate cancer. Clin Cancer Res 17:3903–3912

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Garret Hampton and Andrea Pirzkall for their comments on the manuscript and useful discussions.

Author information

Authors and Affiliations

  1. Department of Oncology Biomarker Development, Genentech, Inc, South San Francisco, CA, USA

    Elizabeth A. Punnoose & Mark R. Lackner

Authors
  1. Elizabeth A. Punnoose
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark R. Lackner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark R. Lackner .

Editor information

Editors and Affiliations

  1. , Breast Cancer Translational Res. Lab., Institut Jules Bordet, Boulevard de Waterloo 125, Brussels, 1000, Belgium

    Michail Ignatiadis

  2. , Breast Cancer Translational Res. Lab., Institut Jules Bordet, Boulevard de Waterloo 125, Brussels, 1000, Belgium

    Christos Sotiriou

  3. Zentrum für Experimentelle Medizin, Inst. Tumorbiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, Hamburg, 20246, Germany

    Klaus Pantel

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Punnoose, E.A., Lackner, M.R. (2012). Challenges and Opportunities in the Use of CTCs for Companion Diagnostic Development. In: Ignatiadis, M., Sotiriou, C., Pantel, K. (eds) Minimal Residual Disease and Circulating Tumor Cells in Breast Cancer. Recent Results in Cancer Research, vol 195. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28160-0_22

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-28160-0_22

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-28159-4

  • Online ISBN: 978-3-642-28160-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation