Circulating Tumor Cells in Breast Cancer

  • Diana H. Liang
  • Carolyn Hall
  • Anthony LucciEmail author
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 215)


With active screening for early detection and advancements in treatment, there has been a significant decrease in mortality from breast cancer. However, a significant proportion of patients with non-metastatic breast cancer at time of diagnosis will relapse. Therefore, it is suggested that the dissemination of bloodstream tumor cells (circulating tumor cells, CTCs) undetectable by currently available diagnostic tools occurs during the early stages of breast cancer progression, and may be the potential source of micrometastases responsible for treatment failures. Here, we review the clinical significance of CTCs, as detected by the FDA-approved CellSearch® System, in both metastatic and non-metastatic breast cancer patients. Studies so far suggest that CTCs are prognostic of poorer outcomes in breast cancer patients; however, there is currently insufficient data to support use of CTC data to guide treatment. Therefore, there are ongoing studies to evaluate the utility of assessing CTC phenotypes to develop personalized breast cancer treatment, which will be reviewed in this chapter.


Breast cancer Biomarkers Prognostic factors Circulating tumor cells CTCs Liquid biopsy Micrometastases 


  1. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C et al (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):6897–6904PubMedCrossRefGoogle Scholar
  2. Arkadius Polasik AS, Friedl TWP, Rack BK, Trapp EK, Fasching PA, Taran F-A, Hartkopf AD, Schneeweiss A, Mueller V, Aktas B, Pantel K, Meier-Stiegen F, Wimberger P, Janni W, Tanja N (2016) The DETECT study concept: individualized therapy of metastatic breast cancer. J Clin Oncol 34(suppl; abstr TPS634)CrossRefGoogle Scholar
  3. Balic M, Lin H, Williams A, Datar RH, Cote RJ (2012) Progress in circulating tumor cell capture and analysis: implications for cancer management. Expert Rev Mol Diagn 12(3):303–312PubMedPubMedCentralCrossRefGoogle Scholar
  4. Banys M, Hartkopf AD, Krawczyk N, Becker S, Fehm T (2012) Clinical implications of the detection of circulating tumor cells in breast cancer patients. Biomark Med 6(1):109–118PubMedCrossRefGoogle Scholar
  5. Banys-Paluchowski M, Krawczyk N, Fehm T (2016) Potential role of circulating tumor cell detection and monitoring in breast cancer: a review of current evidence. Front Oncol 6:255PubMedPubMedCentralCrossRefGoogle Scholar
  6. Berruti A, Amoroso V, Gallo F, Bertaglia V, Simoncini E, Pedersini R et al (2014) Pathologic complete response as a potential surrogate for the clinical outcome in patients with breast cancer after neoadjuvant therapy: a meta-regression of 29 randomized prospective studies. J Clin Oncol 32(34):3883–3891CrossRefGoogle Scholar
  7. Bidard FC, Mathiot C, Delaloge S, Brain E, Giachetti S, de Cremoux P et al (2010) Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann Oncol 21(4):729–733PubMedCrossRefGoogle Scholar
  8. Bidard FC, Fehm T, Ignatiadis M, Smerage JB, Alix-Panabieres C, Janni W et al (2013) Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials. Cancer Metastasis Rev 32(1–2):179–188PubMedCrossRefGoogle Scholar
  9. Bidard FC, Proudhon C, Pierga JY (2016) Circulating tumor cells in breast cancer. Mol Oncol 10(3):418–430PubMedPubMedCentralCrossRefGoogle Scholar
  10. Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802PubMedCrossRefGoogle Scholar
  11. Budd GT, Cristofanilli M, Ellis MJ, Stopeck A, Borden E, Miller MC et al (2006) Circulating tumor cells versus imaging–predicting overall survival in metastatic breast cancer. Clin Cancer Res 12(21):6403–6409PubMedCrossRefGoogle Scholar
  12. Canzoniero JV, Park BH (2016) Use of cell free DNA in breast oncology. Biochim Biophys Acta 1865(2):266–274PubMedPubMedCentralGoogle Scholar
  13. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791PubMedCrossRefPubMedCentralGoogle Scholar
  14. Cristofanilli M, Hayes DF, Budd GT, Ellis MJ, Stopeck A, Reuben JM et al (2005) Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 23(7):1420–1430PubMedCrossRefGoogle Scholar
  15. Dave B, Mittal V, Tan NM, Chang JC (2012) Epithelial-mesenchymal transition, cancer stem cells and treatment resistance. Breast Cancer Res 14(1):202PubMedPubMedCentralCrossRefGoogle Scholar
  16. Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF et al (2013) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368(13):1199–1209PubMedCrossRefGoogle Scholar
  17. De Luca F, Rotunno G, Salvianti F, Galardi F, Pestrin M, Gabellini S et al (2016) Mutational analysis of single circulating tumor cells by next generation sequencing in metastatic breast cancer. Oncotarget 7(18):26107–26119PubMedPubMedCentralGoogle Scholar
  18. Deng G, Krishnakumar S, Powell AA, Zhang H, Mindrinos MN, Telli ML et al (2014) Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow. BMC Cancer 14:456PubMedPubMedCentralCrossRefGoogle Scholar
  19. DeSantis C, Siegel R, Bandi P, Jemal A (2011) Breast cancer statistics, 2011. CA Cancer J Clin 61(6):409–418PubMedCrossRefGoogle Scholar
  20. Ellsworth RE, Toro AL, Blackburn HL, Decewicz A, Deyarmin B, Mamula KA et al (2015) Molecular heterogeneity in primary breast carcinomas and axillary lymph node metastases assessed by genomic fingerprinting analysis. Cancer Growth Metastasis 8:15–24PubMedPubMedCentralCrossRefGoogle Scholar
  21. Ellsworth RE, Blackburn HL, Shriver CD, Soon-Shiong P, Ellsworth DL (2017) Molecular heterogeneity in breast cancer: State of the science and implications for patient care. Semin Cell Dev Biol 64:65–72PubMedCrossRefGoogle Scholar
  22. Fehm T, Muller V, Aktas B, Janni W, Schneeweiss A, Stickeler E et al (2010) HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat 124(2):403–412PubMedCrossRefGoogle Scholar
  23. Fisher B, Bauer M, Wickerham DL, Redmond CK, Fisher ER, Cruz AB et al (1983) Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update. Cancer 52(9):1551–1557PubMedCrossRefGoogle Scholar
  24. Franken B, de Groot MR, Mastboom WJ, Vermes I, van der Palen J, Tibbe AG et al (2012) Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer. Breast Cancer Res 14(5):R133PubMedPubMedCentralCrossRefGoogle Scholar
  25. Gebreamlak EP, Tse GM, Niu Y (2013) Progress in evaluation of pathologic response to neoadjuvant chemotherapy of breast cancer. Anticancer Agents Med Chem 13(2):222–226PubMedCrossRefGoogle Scholar
  26. Gilbey AM, Burnett D, Coleman RE, Holen I (2004) The detection of circulating breast cancer cells in blood. J Clin Pathol 57(9):903–911PubMedPubMedCentralCrossRefGoogle Scholar
  27. Giuliano AE, Hawes D, Ballman KV, Whitworth PW, Blumencranz PW, Reintgen DS et al (2011) Association of occult metastases in sentinel lymph nodes and bone marrow with survival among women with early-stage invasive breast cancer. JAMA 306(4):385–393PubMedPubMedCentralCrossRefGoogle Scholar
  28. Green M, Hortobagyi GN (2002). Neoadjuvant chemotherapy for operable breast cancer. Oncology (Williston Park). 16(7):871–884, 889; discussion 889–890, 892–904, 997–998Google Scholar
  29. Hall C, Krishnamurthy S, Lodhi A, Bhattacharyya A, Anderson A, Kuerer H et al (2012) Disseminated tumor cells predict survival after neoadjuvant therapy in primary breast cancer. Cancer 118(2):342–348PubMedCrossRefPubMedCentralGoogle Scholar
  30. Hall CS, Karhade M, Laubacher BA, Kuerer HM, Krishnamurthy S, DeSnyder S et al (2015) Circulating tumor cells and recurrence after primary systemic therapy in stage III inflammatory breast cancer. J Natl Cancer Inst 107(11)PubMedPubMedCentralCrossRefGoogle Scholar
  31. Hall C, Valad L, Lucci A (2016a) Circulating tumor cells in breast cancer patients. Crit Rev Oncog 21(1–2):125–139PubMedCrossRefGoogle Scholar
  32. Hall CS, Karhade MG, Bowman Bauldry JB, Valad LM, Kuerer HM, DeSnyder SM et al (2016b) Prognostic value of circulating tumor cells identified before surgical resection in nonmetastatic breast cancer patients. J Am Coll Surg 223(1):20–29PubMedPubMedCentralCrossRefGoogle Scholar
  33. Harbeck N, Thomssen C (2011) A new look at node-negative breast cancer. Oncologist 16(Suppl 1):51–60PubMedCrossRefGoogle Scholar
  34. Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-Angulo AM et al (2016) Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: american society of clinical oncology clinical practice guideline. J Clin Oncol 34(10):1134–1150PubMedPubMedCentralCrossRefGoogle Scholar
  35. Hughes AD, Mattison J, Powderly JD, Greene BT, King MR (2012) Rapid isolation of viable circulating tumor cells from patient blood samples. J Vis Exp 64:e4248Google Scholar
  36. Janni WJ, Rack B, Terstappen LW, Pierga JY, Taran FA, Fehm T et al (2016) Pooled analysis of the prognostic relevance of circulating tumor cells in primary breast cancer. Clin Cancer Res 22(10):2583–2593PubMedCrossRefGoogle Scholar
  37. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277–300PubMedCrossRefGoogle Scholar
  38. Krawczyk N, Meier-Stiegen F, Banys M, Neubauer H, Ruckhaeberle E, Fehm T (2014) Expression of stem cell and epithelial-mesenchymal transition markers in circulating tumor cells of breast cancer patients. Biomed Res Int 2014:415721PubMedPubMedCentralCrossRefGoogle Scholar
  39. Krishnamurthy S, Cristofanilli M, Singh B, Reuben J, Gao H, Cohen EN et al (2010) Detection of minimal residual disease in blood and bone marrow in early stage breast cancer. Cancer 116(14):3330–3337PubMedCrossRefGoogle Scholar
  40. Kuukasjarvi T, Karhu R, Tanner M, Kahkonen M, Schaffer A, Nupponen N et al (1997) Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res 57(8):1597–1604PubMedGoogle Scholar
  41. Liang DH, Ensor JE, Liu ZB, Patel A, Patel TA, Chang JC et al (2016) Cell-free DNA as a molecular tool for monitoring disease progression and response to therapy in breast cancer patients. Breast Cancer Res Treat 155(1):139–149PubMedCrossRefGoogle Scholar
  42. Lucci A, Hall CS, Lodhi AK, Bhattacharyya A, Anderson AE, Xiao L et al (2012) Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol. 13(7):688–695PubMedCrossRefGoogle Scholar
  43. Ma QC, Ennis CA, Aparicio S (2012) Opening Pandora’s box—the new biology of driver mutations and clonal evolution in cancer as revealed by next generation sequencing. Curr Opin Genet Dev 22(1):3–9PubMedCrossRefGoogle Scholar
  44. Mansi JL, Berger U, Easton D, McDonnell T, Redding WH, Gazet JC et al (1987) Micrometastases in bone marrow in patients with primary breast cancer: evaluation as an early predictor of bone metastases. Br Med J (Clin Res Ed) 295(6606):1093–1096CrossRefGoogle Scholar
  45. Mansi JL, Easton D, Berger U, Gazet JC, Ford HT, Dearnaley D et al (1991) Bone marrow micrometastases in primary breast cancer: prognostic significance after 6 years’ follow-up. Eur J Cancer 27(12):1552–1555PubMedCrossRefGoogle Scholar
  46. Mansi JL, Gogas H, Bliss JM, Gazet JC, Berger U, Coombes RC (1999) Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study. Lancet 354(9174):197–202PubMedCrossRefGoogle Scholar
  47. Mansi J, Morden J, Bliss JM, Neville M, Coombes RC (2016) Bone marrow micrometastases in early breast cancer-30-year outcome. Br J Cancer 114(3):243–247PubMedPubMedCentralCrossRefGoogle Scholar
  48. Mego M, Mani SA, Cristofanilli M (2010) Molecular mechanisms of metastasis in breast cancer–clinical applications. Nat Rev Clin Oncol. 7(12):693–701PubMedCrossRefGoogle Scholar
  49. Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM et al (2013) Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497(7447):108–112PubMedCrossRefGoogle Scholar
  50. Nadal R, Lorente JA, Rosell R, Serrano MJ (2013) Relevance of molecular characterization of circulating tumor cells in breast cancer in the era of targeted therapies. Expert Rev Mol Diagn. 13(3):295–307PubMedCrossRefPubMedCentralGoogle Scholar
  51. Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J et al (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94PubMedPubMedCentralCrossRefGoogle Scholar
  52. Paoletti C, Muniz MC, Thomas DG, Griffith KA, Kidwell KM, Tokudome N et al (2015) Development of circulating tumor cell-endocrine therapy index in patients with hormone receptor-positive breast cancer. Clin Cancer Res 21(11):2487–2498PubMedCrossRefPubMedCentralGoogle Scholar
  53. Pierga JY, Bidard FC, Autret A, Petit T, Andre F, Dalenc F et al (2017) Circulating tumour cells and pathological complete response: independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II trials (BEVERLY-1 and -2) of neoadjuvant chemotherapy combined with bevacizumab. Ann Oncol 28(1):103–109PubMedGoogle Scholar
  54. Schramm A, Friedl TW, Schochter F, Scholz C, de Gregorio N, Huober J et al (2016) Therapeutic intervention based on circulating tumor cell phenotype in metastatic breast cancer: concept of the DETECT study program. Arch Gynecol Obstet 293(2):271–281PubMedCrossRefPubMedCentralGoogle Scholar
  55. Shaw JA, Guttery DS, Hills A, Fernandez-Garcia D, Page K, Rosales BM et al (2017) Mutation analysis of cell-free dna and single circulating tumor cells in metastatic breast cancer patients with high circulating tumor cell counts. Clin Cancer Res 23(1):88–96PubMedCrossRefPubMedCentralGoogle Scholar
  56. Siegel RL, Miller KD, Jemal A (2017) Cancer Statistics, 2017. CA Cancer J Clin 67(1):7–30CrossRefGoogle Scholar
  57. Sloane JP, Ormerod MG, Neville AM (1980) Potential pathological application of immunocytochemical methods to the detection of micrometastases. Cancer Res 40(8 Pt 2):3079–3082PubMedGoogle Scholar
  58. Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G et al (2014) Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol 32(31):3483–3489PubMedPubMedCentralCrossRefGoogle Scholar
  59. Torres L, Ribeiro FR, Pandis N, Andersen JA, Heim S, Teixeira MR (2007) Intratumor genomic heterogeneity in breast cancer with clonal divergence between primary carcinomas and lymph node metastases. Breast Cancer Res Treat 102(2):143–155PubMedCrossRefGoogle Scholar
  60. van Dalum G, van der Stam GJ, Tibbe AG, Franken B, Mastboom WJ, Vermes I et al (2015) Circulating tumor cells before and during follow-up after breast cancer surgery. Int J Oncol 46(1):407–413PubMedCrossRefGoogle Scholar
  61. Van Poznak C, Somerfield MR, Bast RC, Cristofanilli M, Goetz MP, Gonzalez-Angulo AM et al (2015) Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: american society of clinical oncology clinical practice guideline. J Clin Oncol 33(24):2695–2704PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.M. D. Anderson Cancer Center, University of TexasHoustonUSA

Personalised recommendations