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Tumor Biology

, Volume 37, Issue 4, pp 4263–4273 | Cite as

A headlight on liquid biopsies: a challenging tool for breast cancer management

  • Daniela Massihnia
  • Alessandro Perez
  • Viviana Bazan
  • Giuseppe Bronte
  • Marta Castiglia
  • Daniele Fanale
  • Nadia Barraco
  • Antonina Cangemi
  • Florinda Di Piazza
  • Valentina Calò
  • Sergio Rizzo
  • Giuseppe Cicero
  • Gianni Pantuso
  • Antonio RussoEmail author
Review

Abstract

Breast cancer is the most frequent carcinoma and second most common cause of cancer-related mortality in postmenopausal women. The acquisition of somatic mutations represents the main mechanism through which cancer cells overcome physiological cellular signaling pathways (e.g., PI3K/Akt/mTOR, PTEN, TP53). To date, diagnosis and metastasis monitoring is mainly carried out through tissue biopsy and/or re-biopsy, a very invasive procedure limited only to certain locations and not always feasible in clinical practice. In order to improve disease monitoring over time and to avoid painful procedure such as tissue biopsy, liquid biopsy may represent a new precious tool. Indeed, it represents a basin of “new generation” biomarkers that are spread into the bloodstream from both primary and metastatic sites. Moreover, elevated concentrations of circulating tumor DNA (ctDNA) as well as circulating tumor cells (CTCs) have been found in blood plasma of patients with various tumor types. Nowadays, several new approaches have been introduced for the detection and characterization of CTCs and ctDNA, allowing a real-time monitoring of tumor evolution. This review is focused on the clinical relevance of liquid biopsy in breast cancer and will provide an update concerning CTCs and ctDNA utility as a tool for breast cancer patient monitoring during the course of disease.

Keywords

Liquid biopsy Breast cancer Circulating tumor cells CTCs Circulating tumor DNA ctDNA 

Notes

Compliance with ethical guidelines

Conflicts of interest

None

References

  1. 1.
    Bombonati A, Sgroi DC. The molecular pathology of breast cancer progression. J Pathol. 2011;223(2):307–17.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Fanale D, Amodeo V, Corsini LR, Rizzo S, Bazan V, Russo A. Breast cancer genome-wide association studies: there is strength in numbers. Oncogene. 2012;31(17):2121–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Russo A, Calo V, Bruno L, Schiro V, Agnese V, Cascio S, et al. Is BRCA1-5083del19, identified in breast cancer patients of Sicilian origin, a Calabrian founder mutation? Breast Cancer Res Treat. 2009;113(1):67–70.CrossRefPubMedGoogle Scholar
  5. 5.
    Fanale D, Bazan V, Caruso S, Castiglia M, Bronte G, Rolfo C, et al. Hypoxia and human genome stability: downregulation of BRCA2 expression in breast cancer cell lines. Biomed Res Int. 2013;2013:746858.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ottini L, Capalbo C, Rizzolo P, Silvestri V, Bronte G, Rizzo S, et al. HER2-positive male breast cancer: an update. Breast Cancer (Dove Med Press). 2010;2:45–58.Google Scholar
  7. 7.
    Fanale D, Bazan V, Corsini LR, Caruso S, Insalaco L, Castiglia M, et al. HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions. Breast Cancer Res Treat. 2013;140(3):505–17.CrossRefPubMedGoogle Scholar
  8. 8.
    Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869–74.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rutgers E, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v8–30.CrossRefPubMedGoogle Scholar
  10. 10.
    Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Yadav BS, Chanana P, Jhamb S. Biomarkers in triple negative breast cancer: a review. World J Clin Oncol. 2015;6(6):252–63.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hurvitz S, Mead M. Triple-negative breast cancer: advancements in characterization and treatment approach. Curr Opin Obstet Gynecol. 2016;28(1):59–69.PubMedGoogle Scholar
  13. 13.
    Nik-Zainal S, Van Loo P, Wedge DC, Alexandrov LB, Greenman CD, Lau KW, et al. The life history of 21 breast cancers. Cell. 2012;149(5):994–1007.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007;7(11):834–46.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009;9(4):302–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Sadovska L, Eglitis J, Line A. Extracellular Vesicles as Biomarkers and Therapeutic Targets in Breast Cancer. Anticancer Res. 2015;35(12):6379–90.PubMedGoogle Scholar
  17. 17.
    Yu DD, Wu Y, Shen HY, Lv MM, Chen WX, Zhang XH, et al. Exosomes in development, metastasis and drug resistance of breast cancer. Cancer Sci. 2015;106(8):959–64.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Green TM, Alpaugh ML, Barsky SH, Rappa G, Lorico A. Breast cancer-derived extracellular vesicles: characterization and contribution to the metastatic phenotype. Biomed Res Int. 2015;2015:634865.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Corsini LR, Bronte G, Terrasi M, Amodeo V, Fanale D, Fiorentino E, et al. The role of microRNAs in cancer: diagnostic and prognostic biomarkers and targets of therapies. Expert Opin Ther Targets. 2012;16 Suppl 2:S103–109.CrossRefPubMedGoogle Scholar
  20. 20.
    Franchina T, Amodeo V, Bronte G, Savio G, Ricciardi GR, Picciotto M, et al. Circulating miR-22, miR-24 and miR-34a as novel predictive biomarkers to pemetrexed-based chemotherapy in advanced non-small cell lung cancer. J Cell Physiol. 2014;229(1):97–9.PubMedGoogle Scholar
  21. 21.
    Amodeo V, Bazan V, Fanale D, Insalaco L, Caruso S, Cicero G, et al. Effects of anti-miR-182 on TSP-1 expression in human colon cancer cells: there is a sense in antisense? Expert Opin Ther Targets. 2013;17(11):1249–61.CrossRefPubMedGoogle Scholar
  22. 22.
    Bronte F, Bronte G, Fanale D, Caruso S, Bronte E, Bavetta MG, et al. HepatomiRNoma: the proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma. Crit Rev Oncol Hematol. 2016;97:312–21.CrossRefPubMedGoogle Scholar
  23. 23.
    Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458(7239):719–24.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    D’Anneo A, Carlisi D, Emanuele S, Buttitta G, Di Fiore R, Vento R, et al. Parthenolide induces superoxide anion production by stimulating EGF receptor in MDA-MB-231 breast cancer cells. Int J Oncol. 2013;43(6):1895–900.PubMedGoogle Scholar
  25. 25.
    Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res. 2011;13(2):R21.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Di Fiore R, Drago-Ferrante R, D’Anneo A, Augello G, Carlisi D, De Blasio A, et al. In human retinoblastoma Y79 cells okadaic acid-parthenolide co-treatment induces synergistic apoptotic effects, with PTEN as a key player. Cancer Biol Ther. 2013;14(10):922–31.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7(8):606–19.CrossRefPubMedGoogle Scholar
  28. 28.
    Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt and apoptosis: size matters. Oncogene. 2003;22(56):8983–98.CrossRefPubMedGoogle Scholar
  29. 29.
    Fingar DC, Salama S, Tsou C, Harlow E, Blenis J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 2002;16(12):1472–87.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163–75.CrossRefPubMedGoogle Scholar
  31. 31.
    Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003;11(4):895–904.CrossRefPubMedGoogle Scholar
  32. 32.
    Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.CrossRefGoogle Scholar
  33. 33.
    Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86.CrossRefPubMedGoogle Scholar
  34. 34.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.CrossRefPubMedGoogle Scholar
  35. 35.
    Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004;64(21):7678–81.CrossRefPubMedGoogle Scholar
  36. 36.
    Oshiro C, Kagara N, Naoi Y, Shimoda M, Shimomura A, Maruyama N, et al. PIK3CA mutations in serum DNA are predictive of recurrence in primary breast cancer patients. Breast Cancer Res Treat. 2015;150(2):299–307.CrossRefPubMedGoogle Scholar
  37. 37.
    Samuels Y, Diaz Jr LA, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell. 2005;7(6):561–73.CrossRefPubMedGoogle Scholar
  38. 38.
    Cuorvo LV, Verderio P, Ciniselli CM, Girlando S, Decarli N, Leonardi E, et al. PI3KCA mutation status is of limited prognostic relevance in ER-positive breast cancer patients treated with hormone therapy. Virchows Arch. 2014;464(1):85–93.CrossRefPubMedGoogle Scholar
  39. 39.
    Langerod A, Zhao H, Borgan O, Nesland JM, Bukholm IR, Ikdahl T, et al. TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res. 2007;9(3):R30.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Nakopoulou LL, Alexiadou A, Theodoropoulos GE, Lazaris AC, Tzonou A, Keramopoulos A. Prognostic significance of the co-expression of p53 and c-erbB-2 proteins in breast cancer. J Pathol. 1996;179(1):31–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Kogan-Sakin I, Tabach Y, Buganim Y, Molchadsky A, Solomon H, Madar S, et al. Mutant p53(R175H) upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells. Cell Death Differ. 2011;18(2):271–81.CrossRefPubMedGoogle Scholar
  42. 42.
    Reis-Filho JS, Drury S, Lambros MB, Marchio C, Johnson N, Natrajan R, et al. ESR1 gene amplification in breast cancer: a common phenomenon? Nat Genet. 2008;40(7):809–10. author reply 810–802.CrossRefPubMedGoogle Scholar
  43. 43.
    Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20(7):1757–67.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45(12):1439–45.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sausen M, Parpart S, Diaz Jr LA. Circulating tumor DNA moves further into the spotlight. Genome Med. 2014;6(5):35.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Diaz Jr LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579–86.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Stroun M, Maurice P, Vasioukhin V, Lyautey J, Lederrey C, Lefort F, et al. The origin and mechanism of circulating DNA. Ann N Y Acad Sci. 2000;906:161–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–37.CrossRefPubMedGoogle Scholar
  49. 49.
    Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MH, et al. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med. 2015;7(8):1034–47.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Kohler C, Radpour R, Barekati Z, Asadollahi R, Bitzer J, Wight E, et al. Levels of plasma circulating cell free nuclear and mitochondrial DNA as potential biomarkers for breast tumors. Mol Cancer. 2009;8:105.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Catarino R, Ferreira MM, Rodrigues H, Coelho A, Nogal A, Sousa A, et al. Quantification of free circulating tumor DNA as a diagnostic marker for breast cancer. DNA Cell Biol. 2008;27(8):415–21.CrossRefPubMedGoogle Scholar
  52. 52.
    Sorenson GD, Pribish DM, Valone FH, Memoli VA, Bzik DJ, Yao SL. Soluble normal and mutated DNA sequences from single-copy genes in human blood. Cancer Epidemiol Biomarkers Prev. 1994;3(1):67–71.PubMedGoogle Scholar
  53. 53.
    Board RE, Wardley AM, Dixon JM, Armstrong AC, Howell S, Renshaw L, et al. Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Res Treat. 2010;120(2):461–7.CrossRefPubMedGoogle Scholar
  54. 54.
    Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368(13):1199–209.CrossRefPubMedGoogle Scholar
  55. 55.
    Esposito A, Bardelli A, Criscitiello C, Colombo N, Gelao L, Fumagalli L, et al. Monitoring tumor-derived cell-free DNA in patients with solid tumors: clinical perspectives and research opportunities. Cancer Treat Rev. 2014;40(5):648–55.CrossRefPubMedGoogle Scholar
  56. 56.
    Jung M, Klotzek S, Lewandowski M, Fleischhacker M, Jung K. Changes in concentration of DNA in serum and plasma during storage of blood samples. Clin Chem. 2003;49(6 Pt 1):1028–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Umetani N, Kim J, Hiramatsu S, Reber HA, Hines OJ, Bilchik AJ, et al. Increased integrity of free circulating DNA in sera of patients with colorectal or periampullary cancer: direct quantitative PCR for ALU repeats. Clin Chem. 2006;52(6):1062–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem. 2015;61(1):112–23.CrossRefPubMedGoogle Scholar
  59. 59.
    Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10(8):472–84.CrossRefPubMedGoogle Scholar
  60. 60.
    Schwarzenbach H. Circulating nucleic acids as biomarkers in breast cancer. Breast Cancer Res. 2013;15(5):211.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Beaver JA, Jelovac D, Balukrishna S, Cochran RL, Croessmann S, Zabransky DJ, et al. Detection of cancer DNA in plasma of patients with early-stage breast cancer. Clin Cancer Res. 2014;20(10):2643–50.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Higgins MJ, Jelovac D, Barnathan E, Blair B, Slater S, Powers P, et al. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res. 2012;18(12):3462–9.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Madic J, Kiialainen A, Bidard FC, Birzele F, Ramey G, Leroy Q, et al. Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients. Int J Cancer. 2015;136(9):2158–65.CrossRefPubMedGoogle Scholar
  64. 64.
    Rolfo C, Castiglia M, Hong D, Alessandro R, Mertens I, Baggerman G, et al. Liquid biopsies in lung cancer: the new ambrosia of researchers. Biochim Biophys Acta. 2014;1846(2):539–46.PubMedGoogle Scholar
  65. 65.
    Krebs MG, Hou JM, Ward TH, Blackhall FH, Dive C. Circulating tumour cells: their utility in cancer management and predicting outcomes. Ther Adv Med Oncol. 2010;2(6):351–65.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, 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):6897–904.CrossRefPubMedGoogle Scholar
  67. 67.
    Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer. 2008;8(5):329–40.CrossRefPubMedGoogle Scholar
  68. 68.
    Sun YF, Yang XR, Zhou J, Qiu SJ, Fan J, Xu Y. Circulating tumor cells: advances in detection methods, biological issues, and clinical relevance. J Cancer Res Clin Oncol. 2011;137(8):1151–73.CrossRefPubMedGoogle Scholar
  69. 69.
    Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781–91.CrossRefPubMedGoogle Scholar
  70. 70.
    Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, 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):3213–21.CrossRefPubMedGoogle Scholar
  71. 71.
    Pantel K, Alix-Panabieres C, Riethdorf S. Cancer micrometastases. Nat Rev Clin Oncol. 2009;6(6):339–51.CrossRefPubMedGoogle Scholar
  72. 72.
    Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147(2):275–92.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Cortesi E, Palleschi M, Magri V, Naso G. The promise of liquid biopsy in cancer: a clinical perspective. Chin J Cancer Res. 2015;27(5):488–90.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Lianidou ES, Markou A, Strati A. The Role of CTCs as Tumor Biomarkers. Adv Exp Med Biol. 2015;867:341–67.CrossRefPubMedGoogle Scholar
  75. 75.
    Lucci A, Hall CS, Lodhi AK, Bhattacharyya A, Anderson AE, Xiao L, et al. Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol. 2012;13(7):688–95.CrossRefPubMedGoogle Scholar
  76. 76.
    Franken B, de Groot MR, Mastboom WJ, Vermes I, van der Palen J, Tibbe AG, et al. Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer. Breast Cancer Res. 2012;14(5):R133.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014;158(5):1110–22.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339(6119):580–4.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL, Turnbull JD, et al. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res. 2011;9(8):997–1007.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983–8.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555–67.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Alunni-Fabbroni M, Sandri MT. Circulating tumour cells in clinical practice: methods of detection and possible characterization. Methods. 2010;50(4):289–97.CrossRefPubMedGoogle Scholar
  83. 83.
    Tibbe AG, Miller MC, Terstappen LW. Statistical considerations for enumeration of circulating tumor cells. Cytometry A. 2007;71(3):154–62.CrossRefPubMedGoogle Scholar
  84. 84.
    Vona G, Sabile A, Louha M, Sitruk V, Romana S, Schutze K, et al. Isolation by size of epithelial tumor cells: a new method for the immunomorphological and molecular characterization of circulatingtumor cells. Am J Pathol. 2000;156(1):57–63.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Lin HK, Zheng S, Williams AJ, Balic M, Groshen S, Scher HI, et al. Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin Cancer Res. 2010;16(20):5011–8.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Paterlini-Brechot P, Benali NL. Circulating tumor cells (CTC) detection: clinical impact and future directions. Cancer Lett. 2007;253(2):180–204.CrossRefPubMedGoogle Scholar
  87. 87.
    Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, et al. HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A. 2004;101(25):9393–8.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Witzig TE, Bossy B, Kimlinger T, Roche PC, Ingle JN, Grant C, 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):1085–91.PubMedGoogle Scholar
  89. 89.
    Mejean A, Vona G, Nalpas B, Damotte D, Brousse N, Chretien Y, et al. Detection of circulating prostate derived cells in patients with prostate adenocarcinoma is an independent risk factor for tumor recurrence. J Urol. 2000;163(6):2022–9.CrossRefPubMedGoogle Scholar
  90. 90.
    Zach O, Kasparu H, Krieger O, Hehenwarter W, Girschikofsky M, Lutz D. Detection of circulating mammary carcinoma cells in the peripheral blood of breast cancer patients via a nested reverse transcriptase polymerase chain reaction assay for mammaglobin mRNA. J Clin Oncol. 1999;17(7):2015–9.CrossRefPubMedGoogle Scholar
  91. 91.
    de Cremoux P, Extra JM, Denis MG, Pierga JY, Bourstyn E, Nos C, et al. Detection of MUC1-expressing mammary carcinoma cells in the peripheral blood of breast cancer patients by real-time polymerase chain reaction. Clin Cancer Res. 2000;6(8):3117–22.PubMedGoogle Scholar
  92. 92.
    Hauch S, Zimmermann S, Lankiewicz S, Zieglschmid V, Bocher O, Albert WH. The clinical significance of circulating tumour cells in breast cancer and colorectal cancer patients. Anticancer Res. 2007;27(3A):1337–41.PubMedGoogle Scholar
  93. 93.
    Stathopoulou A, Vlachonikolis I, Mavroudis D, Perraki M, Kouroussis C, Apostolaki S, et al. Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. J Clin Oncol. 2002;20(16):3404–12.CrossRefPubMedGoogle Scholar
  94. 94.
    Stathopoulou A, Ntoulia M, Perraki M, Apostolaki S, Mavroudis D, Malamos N, et al. A highly specific real-time RT-PCR method for the quantitative determination of CK-19 mRNA positive cells in peripheral blood of patients with operable breast cancer. Int J Cancer. 2006;119(7):1654–9.CrossRefPubMedGoogle Scholar
  95. 95.
    Bidard FC, Fehm T, Ignatiadis M, Smerage JB, Alix-Panabieres C, Janni W, et al. Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials. Cancer Metastasis Rev. 2013;32(1–2):179–88.CrossRefPubMedGoogle Scholar
  96. 96.
    Tseng JY, Yang CY, Liang SC, Liu RS, Jiang JK, Lin CH. Dynamic changes in numbers and properties of circulating tumor cells and their potential applications. Cancers (Basel). 2014;6(4):2369–86.CrossRefGoogle Scholar
  97. 97.
    Fehm T, Hoffmann O, Aktas B, Becker S, Solomayer EF, Wallwiener D, et al. Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Res. 2009;11(4):R59.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Fernandez SV, Bingham C, Fittipaldi P, Austin L, Palazzo J, Palmer G, et al. TP53 mutations detected in circulating tumor cells present in the blood of metastatic triple negative breast cancer patients. Breast Cancer Res. 2014;16(5):445.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Daniela Massihnia
    • 1
  • Alessandro Perez
    • 1
  • Viviana Bazan
    • 1
  • Giuseppe Bronte
    • 1
  • Marta Castiglia
    • 1
  • Daniele Fanale
    • 1
  • Nadia Barraco
    • 1
  • Antonina Cangemi
    • 1
  • Florinda Di Piazza
    • 1
  • Valentina Calò
    • 1
  • Sergio Rizzo
    • 1
  • Giuseppe Cicero
    • 1
  • Gianni Pantuso
    • 1
  • Antonio Russo
    • 1
    Email author
  1. 1.Department of Surgical, Oncological and Oral Sciences, Section of Medical OncologyUniversity of PalermoPalermoItaly

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