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Circulating Tumor Cells in Colorectal Cancer: Past, Present, and Future Challenges

  • Gastrointestinal Malignancies
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Opinion statement

Recent advances in immunomagnetic separation and flow cytometry have made the detection and characterization of circulating tumor cells (CTC) a reality. This technology has already demonstrated prognostic significance in breast and prostate cancer. In the current review, we will review the historical and current data regarding the enumeration and identification of CTC in colorectal cancer. With immunomagnetic separation techniques, CTC can reliably and reproducibly be identified within 1 to 2 cells in a 7.5 mL sample of peripheral blood. Prospective studies have demonstrated a significant adverse impact on survival with the presence of ≥3 CTC per 7.5 mL blood. Approximately one quarter of patients with metastatic disease will be categorized in this poor prognosis group. In addition, change in number of cells on treatment has prognostic significance. While CTC enumerated through immunomagnetic separation are a clear prognostic factor for patients with mCRC, the future challenge is to study whether treatment decision-making should be impacted by their level. Low cell yield in mCRC is a potential hinderance to answering these important clinical questions at present. CTC can also be isolated and studied with flow cytometry, FISH, and RT-PCR, allowing real-time assessment of tumor biology. Future advances in this field will improve both the detection and manipulation of these cells. Improvements in detection and characterization of CTC will hopefully lead to refinement of the surgical and chemotherapeutic treatment of colorectal cancer.

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References and Recommended Reading

Papers of particular interest, published recently, has been highlighted as: • Of importance •• Of major importance

  1. Jemal A, et al.: Cancer statistics, 2008. CA Cancer J Clin 2008, 58(2):71–96.

    Article  PubMed  Google Scholar 

  2. Hochster HS, et al.: Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 2008, 26(21):3523–3529.

    Article  CAS  PubMed  Google Scholar 

  3. Sanoff HK, et al.: Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol 2008, 26(35):5721–5727.

    Article  CAS  PubMed  Google Scholar 

  4. Tournigand C, et al.: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004, 22(2):229–237.

    Article  CAS  PubMed  Google Scholar 

  5. Van Cutsem E, et al.: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009, 360(14):1408–1417.

    Article  PubMed  Google Scholar 

  6. Amado RG, et al.: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008, 26(10):1626–1634.

    Article  CAS  PubMed  Google Scholar 

  7. Van Cutsem E, et al.: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. J Clin Oncol, 2008, 26(May 20 suppl; abstr 2)

  8. Falcone A, et al.: FOLFOXIRI (irinotecan, oxaliplatin, and infusional 5FU/LV) in combination with bevacizumab (BV) in the first-line treatment of metastatic colorectal cancer (mCRC): a phase II study by the G.O.N.O. group. J Clin Oncol, 2008, 26(May 20 suppl; abstr 4031)

  9. Ashworth TR: Aust Med J 1869, 14:146

  10. Pelkey TJ, Frierson HF Jr, Bruns DE: Molecular and immunological detection of circulating tumor cells and micrometastases from solid tumors. Clin Chem 1996, 42(9):1369–1381.

    CAS  PubMed  Google Scholar 

  11. Racila E, et al.: Detection and characterization of carcinoma cells in the blood. Proc Natl Acad Sci USA 1998, 95(8):4589–4594.

    Article  CAS  PubMed  Google Scholar 

  12. Koelink PJ, et al.: Circulating cell death products predict clinical outcome of colorectal cancer patients. BMC Cancer 2009, 9:88.

    Article  PubMed  Google Scholar 

  13. Allen-Mersh TG, et al.: Role of circulating tumour cells in predicting recurrence after excision of primary colorectal carcinoma. Br J Surg 2007, 94(1):96–105.

    Article  CAS  PubMed  Google Scholar 

  14. Gala JL, et al.: Expression of prostate-specific antigen and prostate-specific membrane antigen transcripts in blood cells: implications for the detection of hematogenous prostate cells and standardization. Clin Chem 1998, 44(3):472–481.

    CAS  PubMed  Google Scholar 

  15. Smith MR, Biggar S, Hussain M: Prostate-specific antigen messenger RNA is expressed in non-prostate cells: implications for detection of micrometastases. Cancer Res 1995, 55(12):2640–2644.

    CAS  PubMed  Google Scholar 

  16. Lopez-Guerrero JA, et al.: Minimal illegitimate levels of cytokeratin K19 expression in mononucleated blood cells detected by a reverse transcription PCR method (RT-PCR). Clin Chim Acta 1997, 263(1):105–116.

    Article  CAS  PubMed  Google Scholar 

  17. Molnar B, et al.: Molecular detection of circulating cancer cells. Role in diagnosis, prognosis and follow-up of colon cancer patients. Dig Dis 2003, 21(4):320–325.

    Article  PubMed  Google Scholar 

  18. Molnar B, et al.: Circulating tumor cell clusters in the peripheral blood of colorectal cancer patients. Clin Cancer Res 2001, 7(12):4080–4085.

    CAS  PubMed  Google Scholar 

  19. Witzig TE, et al.: Detection of circulating cytokeratin-positive cells in the blood of breast cancer patients using immunomagnetic enrichment and digital microscopy. Clin Cancer Res 2002, 8(5):1085–1091.

    PubMed  Google Scholar 

  20. Allard WJ, et al.: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004, 10(20):6897–6904.

    Article  PubMed  Google Scholar 

  21. Cohen SJ, et al.: Isolation and characterization of circulating tumor cells in patients with metastatic colorectal cancer. Clin Colorectal Cancer 2006, 6(2):125–132.

    Article  CAS  PubMed  Google Scholar 

  22. Cohen SJ, et al.: Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 2008, 26(19):3213–3221.

    Article  PubMed  Google Scholar 

  23. Groot M, et al.: Circulating tumor cells (CTC) in newly diagnosed breast or colorectal cancers. J Clin Oncol 2007, 25(18S: June 20 Suppl: abstr 14512)

  24. Hiraiwa K, et al.: Clinical significance of circulating tumor cells in blood from patients with gastrointestinal cancers. Ann Surg Oncol 2008, 15(11):3092–3100.

    Article  PubMed  Google Scholar 

  25. Sastre J, et al.: Circulating tumor cells in colorectal cancer: correlation with clinical and pathological variables. Ann Oncol 2008, 19(5):935–938.

    Article  CAS  PubMed  Google Scholar 

  26. Cristofanilli M, et al.: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004, 351(8):781–791.

    Article  CAS  PubMed  Google Scholar 

  27. Moreno JG, et al.: Changes in circulating carcinoma cells in patients with metastatic prostate cancer correlate with disease status. Urology 2001, 58(3):386–392.

    Article  CAS  PubMed  Google Scholar 

  28. Krivacic RT, et al.: A rare-cell detector for cancer. Proc Natl Acad Sci USA 2004, 101(29):10501–10504.

    Article  CAS  PubMed  Google Scholar 

  29. Nagrath S, et al.: Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 2007, 450(7173):1235–1239.

    Article  CAS  PubMed  Google Scholar 

  30. Maheswaran S, et al.: Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008, 359(4):366–377.

    Article  CAS  PubMed  Google Scholar 

  31. Cohen SJ, et al.: Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol 2009, 20(7):1223–1229.

    Google Scholar 

  32. Tol J, et al.: Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009, 360(6):563–572.

    Article  CAS  PubMed  Google Scholar 

  33. Koopman M, et al.: Circulating tumor cells (CTC) in advanced colorectal cancer (ACC) patients undergoing 1st line treatment with chemotherapy, bevacizumab and cetuximab as an important and early predictor of survival. Ann Oncol 2008, 19(suppl 8: viii 166)

  34. Wong SC, et al.: Clinical significance of cytokeratin 20-positive circulating tumor cells detected by a refined immunomagnetic enrichment assay in colorectal cancer patients. Clin Cancer Res 2009, 15(3):1005–1012.

    Article  CAS  PubMed  Google Scholar 

  35. Matsusaka S, et al.: Use of circulating tumor cells and circulating endothelial cells as surrogate markers for FOLFOX4 with or without bevacizumab in mCRC. ASCO Gastrointestinal Cancers Symp, 2009 (abstr 345)

  36. Hurwitz H, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350(23):2335–2342.

    Article  CAS  PubMed  Google Scholar 

  37. Falcone A, et al.: Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007, 25(13):1670–1676.

    Article  CAS  PubMed  Google Scholar 

  38. Fong Y, et al.: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999, 230(3):309–318; discussion 318–321.

    Article  CAS  PubMed  Google Scholar 

  39. http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed March 11, 2009

  40. Nordlinger B, et al.: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet 2008, 371(9617):1007–1016.

    Article  CAS  PubMed  Google Scholar 

  41. Andre T, et al.: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004, 350(23):2343–2351.

    Article  CAS  PubMed  Google Scholar 

  42. Wolmark N, et al.: A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: results of NSABP Protocol C-08. J Clin Oncol 2009, 27(18 suppl; abstr LBA4)

  43. Kerr D, et al.: A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study. J Clin Oncol 2009, 27(15 suppl; abstr 4000)

  44. de Bono JS, et al.: Potential applications for circulating tumor cells expressing the insulin-like growth factor-I receptor. Clin Cancer Res 2007, 13(12):3611–3616.

    Article  PubMed  Google Scholar 

  45. Guo J, et al.: Detection of cytokeratin 20 mRNA in the peripheral blood of patients with colorectal cancer by immunomagnetic bead enrichment and real-time reverse transcriptase-polymerase chain reaction. J Gastroenterol Hepatol 2005, 20(8):1279–1284.

    Article  CAS  PubMed  Google Scholar 

  46. Lim HJ, et al.: EGFR staining of circulating tumor cells (CTCs) from patients with metastatic colorectal cancer. ASCO Gastrointestinal Cancers Symp 2009 (abstr 373)

  47. Van Cutsem E, et al.: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007, 25(13):1658–1664.

    Article  PubMed  Google Scholar 

  48. Hendlisz A, et al.: Modulation and prognostic value of epidermal growth factor receptor (EGFR) expression in circulating tumor cells (CTCs) during chemotherapy (CT) in patients with metastatic colorectal cancer. J Clin Oncol 2008, 26(May 20 suppl; abstr 15038)

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  1. Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA

    Benjamin P. Negin MD & Steven J. Cohen MD

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Correspondence to Steven J. Cohen MD.

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Negin, B.P., Cohen, S.J. Circulating Tumor Cells in Colorectal Cancer: Past, Present, and Future Challenges. Curr. Treat. Options in Oncol. 11, 1–13 (2010). https://doi.org/10.1007/s11864-010-0115-3

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