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Molecular mechanisms of metastasis in breast cancer—clinical applications

Nature Reviews Clinical Oncology volume 7, pages 693–701 (2010)Cite this article

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Abstract

The metastatic cascade is a series of biological processes that enable the movement of tumor cells from the primary site to a distant location and the establishment of a new cancer growth. Circulating tumor cells (CTCs) have a crucial role in tumor dissemination. The role of CTCs in treatment failure and disease progression can be explained by their relation to biological processes, including the epithelial-to-mesenchymal transition and 'self seeding', defined as reinfiltration of the primary tumor or established metastasis by more aggressive CTCs. CTCs are a unique and heterogeneous cell population with established prognostic and predictive value in certain clinical situations. The possibility of collecting sequential blood samples for real-time monitoring of systemic-therapy efficacy presents new possibilities to evaluate targeted therapies based on the genomic profiling of CTCs and to improve the clinical management of patients by personalized therapy. Interruption of the metastatic cascade via the targeting of CTCs might be a promising therapeutic strategy.

Key Points

  • Circulating tumor cells (CTCs) have a crucial role in the metastatic cascade, tumor dissemination and progression

  • Experimental and clinical data suggest that the epithelial-to-mesenchymal transition has an important role in the generation of CTCs and the acquisition of resistance to therapy

  • CTCs represent a heterogeneous population of cells with different phenotypes and biological value

  • Detection of CTCs could represent a valuable prognostic and predictive factor, a tool for tumor biopsy in real time and for personalized anticancer treatment

  • Novel clinical design incorporating CTCs as short-term molecular and pharmacodynamic end points should be considered

  • Blockade of tumor dissemination and self seeding via the targeting of CTCs holds great therapeutic promise for the future

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Figure 1: Factors affecting CTCs count.
Figure 2: EMT may generate therapeutically resistant cancer stem cells.
Figure 3: Heterogeneity of CTCs based on expression of epithelial and mesenchymal antigens.

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References

  1. Jemal, A., Siegel, R., Xu, J. & Ward, E. Cancer Statistics, 2010. CA Cancer J. Clin. 60, 277–300 (2010).

    Article  PubMed  Google Scholar 

  2. Greenberg, P. A. et al. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J. Clin. Oncol. 14, 2197–2205 (1996).

    CAS  PubMed  Google Scholar 

  3. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    CAS  PubMed  Google Scholar 

  4. Pusztai, L. et al. Gene expression profiles obtained from fine-needle aspirations of breast cancer reliably identify routine prognostic markers and reveal large-scale molecular differences between estrogen-negative and estrogen-positive tumors. Clin. Cancer Res. 9, 2406–2415 (2003).

    CAS  PubMed  Google Scholar 

  5. Gianni, L. et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J. Clin. Oncol. 23, 7265–7277 (2005).

    CAS  PubMed  Google Scholar 

  6. Kakarala, M. & Wicha, M. S. Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J. Clin. Oncol. 26, 2813–2820 (2008).

    PubMed  Google Scholar 

  7. Liu, G. et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol. Cancer 5, 67 (2006).

    PubMed  PubMed Central  Google Scholar 

  8. Ishikawa, F. et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat. Biotechnol. 25, 1315–1321 (2007).

    CAS  PubMed  Google Scholar 

  9. Li, X. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl Cancer Inst. 100, 672–679 (2008).

    CAS  PubMed  Google Scholar 

  10. Gonzalez-Angulo, A. M., Hennessy, B. T. & Mills, G. B. Future of personalized medicine in oncology: a systems biology approach. J. Clin. Oncol. 28, 2777–2783 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hayes, D. F. Prognostic and predictive factors revisited. Breast 14, 493–499 (2005).

    PubMed  Google Scholar 

  12. Hortobagyi, G. N. et al. Multivariate analysis of prognostic factors in metastatic breast cancer. J. Clin. Oncol. 1, 776–786 (1983).

    CAS  PubMed  Google Scholar 

  13. Bast, R. C. Jr et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J. Clin. Oncol. 19, 1865–1878 (2001).

    PubMed  Google Scholar 

  14. Ashworth, T. R. A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aust. Med. J. 14, 146–149 (1869).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Cohen, S. J. 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. 26, 3213–3221 (2008).

    PubMed  Google Scholar 

  17. de Bono, J. S. et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin. Cancer Res. 14, 6302–6309 (2008).

    CAS  PubMed  Google Scholar 

  18. Aktas, B. et al. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 11, R46 (2009).

    PubMed  PubMed Central  Google Scholar 

  19. Reuben, J. M. et al. Circulating tumor cells and biomarkers: implications for personalized targeted treatments for metastatic breast cancer. Breast J. 16, 327–330 (2010).

    PubMed  Google Scholar 

  20. Butler, T. P. & Gullino, P. M. Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Res. 35, 512–516 (1975).

    CAS  PubMed  Google Scholar 

  21. Fidler, I. J. Metastasis: guantitative analysis of distribution and fate of tumor embolilabeled with 125 I-5-iodo-2′-deoxyuridine. J. Natl Cancer Inst. 45, 773–782 (1970).

    CAS  PubMed  Google Scholar 

  22. Wong, C. W. et al. Apoptosis: an early event in metastatic inefficiency. Cancer Res. 61, 333–338 (2001).

    CAS  PubMed  Google Scholar 

  23. Podsypanina, K. et al. Seeding and propagation of untransformed mouse mammary cells in the lung. Science 321, 1841–1844 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, 563–572 (2002).

    CAS  PubMed  Google Scholar 

  25. Yilmaz, M. & Christofori, G. Mechanisms of motility in metastasizing cells. Mol. Cancer Res. 8, 629–642 (2010).

    CAS  PubMed  Google Scholar 

  26. Dano, K. et al. Plasminogen activation and cancer. Thromb. Haemost. 93, 676–681 (2005).

    CAS  PubMed  Google Scholar 

  27. Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2, 161–174 (2002).

    CAS  PubMed  Google Scholar 

  28. Harbeck, N. et al. Urokinase-type plasminogen activator and its inhibitor type 1 predict disease outcome and therapy response in primary breast cancer. Clin. Breast Cancer 5, 348–352 (2004).

    CAS  PubMed  Google Scholar 

  29. Riisbro, R. et al. Prognostic significance of soluble urokinase plasminogen activator receptor in serum and cytosol of tumor tissue from patients with primary breast cancer. Clin. Cancer Res. 8, 1132–1141 (2002).

    PubMed  Google Scholar 

  30. Meng, S. et al. uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues. Proc. Natl Acad. Sci. USA 103, 17361–17365 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Friedl, P. & Gilmour, D. Collective cell migration in morphogenesis, regeneration and cancer. Nat. Rev. Mol. Cell Biol. 10, 445–457 (2009).

    CAS  PubMed  Google Scholar 

  32. Friedl, P. & Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188, 11–19 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Thiery, J. P. Epithelial-mesenchymal transitions in development and pathologies. Curr. Opin. Cell Biol. 15, 740–746 (2003).

    CAS  PubMed  Google Scholar 

  34. Lozano, E., Betson, M. & Braga, V. M. Tumor progression: small GTPases and loss of cell-cell adhesion. Bioessays 25, 452–463 (2003).

    CAS  PubMed  Google Scholar 

  35. Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).

    CAS  PubMed  Google Scholar 

  36. Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).

    CAS  PubMed  Google Scholar 

  37. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

    CAS  PubMed  Google Scholar 

  38. Müller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).

    PubMed  Google Scholar 

  39. Cabioglu, N. et al. CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clin. Cancer Res. 11, 5686–5693 (2005).

    CAS  PubMed  Google Scholar 

  40. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhan, M., Zhao, H. & Han, Z. C. Signalling mechanisms of anoikis. Histol. Histopathol. 19, 973–983 (2004).

    CAS  PubMed  Google Scholar 

  43. Palumbo, J. S. et al. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 96, 3302–3309 (2000).

    CAS  PubMed  Google Scholar 

  44. Palumbo, J. S. et al. Factor XIII transglutaminase supports hematogenous tumor cell metastasis through a mechanism dependent on natural killer cell function. J. Thromb. Haemost. 6, 812–819 (2008).

    CAS  PubMed  Google Scholar 

  45. Akl, E. A. et al. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database Syst. Rev. 3, CD006652 (2007).

    Google Scholar 

  46. Zielinski, C. C. & Hejna, M. Warfarin for cancer prevention. N. Engl. J. Med. 342, 1991–1993 (2000).

    CAS  PubMed  Google Scholar 

  47. Fuster, M. M., Brown, J. R., Wang, L. & Esko, J. D. A disaccharide precursor of sialyl Lewis X inhibits metastatic potential of tumor cells. Cancer Res. 63, 2775–2781 (2003).

    CAS  PubMed  Google Scholar 

  48. Kirwan, C. C., McDowell, G., McCollum, C. N., Kumar, S. & Byrne, G. J. Early changes in the haemostatic and procoagulant systems after chemotherapy for breast cancer. Br. J. Cancer 99, 1000–1006 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Mego, M. et al. Circulating tumour cells are associated with increased risk of venous thromboembolism in metastatic breast cancer patients. Br. J. Cancer 101, 1813–1816 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Norton, L. Cancer stem cells, self-seeding, and decremented exponential growth: theoretical and clinical implications. Breast Dis. 29, 27–36 (2008).

    PubMed  Google Scholar 

  51. Kim, M. Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315–1326 (2009).

    PubMed  PubMed Central  Google Scholar 

  52. Hay, E. D. An overview of epithelio-mesenchymal transformation. Acta Anat. (Basel) 154, 8–20 (1995).

    CAS  Google Scholar 

  53. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Hollier, B. G., Evans, K. & Mani, S. A. The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J. Mammary Gland Biol. Neoplasia 14, 29–43 (2009).

    PubMed  Google Scholar 

  55. Ota, I., Li, X. Y., Hu, Y. & Weiss, S. J. Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc. Natl Acad. Sci. USA 106, 20318–20323 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Bonnomet, A. et al. Epithelial-to-mesenchymal transitions and circulating tumor cells. J. Mammary Gland Biol. Neoplasia 15, 261–273 (2010).

    PubMed  Google Scholar 

  57. Shih, J. Y. et al.Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma. Clin. Cancer Res. 11, 8070–8078 (2005).

    CAS  PubMed  Google Scholar 

  58. Peinado, H. et al. Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J. Cell Sci. 117, 2827–2839 (2004).

    CAS  PubMed  Google Scholar 

  59. Labelle, M. et al. Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor beta signaling. Cancer Res. 68, 1388–1397 (2008).

    CAS  PubMed  Google Scholar 

  60. Qi, J., Chen, N., Wang, J. & Siu, C. H. Transendothelial migration of melanoma cells involves N-cadherin-mediated adhesion and activation of the beta-catenin signaling pathway. Mol. Biol. Cell 16, 4386–4397 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Milsom, C., Anderson, G. M., Weitz, J. I. & Rak, J. Elevated tissue factor procoagulant activity in CD133-positive cancer cells. J. Thromb. Haemost. 5, 2550–2552 (2007).

    CAS  PubMed  Google Scholar 

  62. Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).

    CAS  PubMed  Google Scholar 

  63. Tsuji, T. et al. Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. Cancer Res. 68, 10377–10386 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Chaffer, C. L. et al. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 66, 11271–11278 (2006).

    CAS  PubMed  Google Scholar 

  65. Tsuji, T., Ibaragi, S. & Hu, G. F. Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res. 69, 7135–7139 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kallergi, G. et al. Phosphorylated EGFR and PI3K/Akt signaling kinases are expressed in circulating tumor cells of breast cancer patients. Breast Cancer Res. 10, R80 (2008).

    PubMed  PubMed Central  Google Scholar 

  67. Fehm, T. et al. Determination of HER2 status using both serum HER2 levels and circulating tumor cells in patients with recurrent breast cancer whose primary tumor was HER2 negative or of unknown HER2 status. Breast Cancer Res. 9, R74 (2007).

    PubMed  PubMed Central  Google Scholar 

  68. Payne, R. E. et al. Measurements of EGFR expression on circulating tumor cells are reproducible over time in metastatic breast cancer patients. Pharmacogenomics 10, 51–57 (2009).

    CAS  PubMed  Google Scholar 

  69. Pestrin, M. et al. Correlation of HER2 status between primary tumors and corresponding circulating tumor cells in advanced breast cancer patients. Breast Cancer Res. Treat. 118, 523–530 (2009).

    CAS  PubMed  Google Scholar 

  70. Kallergi, G. et al. Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients. Breast Cancer Res. 11, R84 (2009).

    PubMed  PubMed Central  Google Scholar 

  71. Fehm, T. 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. 11, R59 (2009).

    PubMed  PubMed Central  Google Scholar 

  72. Dontu, G., El-Ashry, D. & Wicha, M. S. Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol. Metab. 15, 193–197 (2004).

    CAS  PubMed  Google Scholar 

  73. Rack, B. K. et al. Use of circulating tumor cells (CTC) in peripheral blood of breast cancer patients before and after adjuvant chemotherapy to predict risk for relapse: the SUCCESS trial [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a1003 (2010).

    Google Scholar 

  74. Ignatiadis, M. et al. 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 (2008).

    CAS  PubMed  Google Scholar 

  75. Hüsemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008).

    PubMed  Google Scholar 

  76. Stoecklein, N. H. et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell 13, 441–453 (2008).

    CAS  PubMed  Google Scholar 

  77. Weckermann, D. et al. Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. J. Clin. Oncol. 27, 1549–1556 (2009).

    PubMed  Google Scholar 

  78. Enderling, H., Hlatky, L. & Hahnfeldt, P. Migration rules: tumours are conglomerates of self-metastases. Br. J. Cancer 100, 1917–1925 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Ginestier, C. et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J. Clin. Invest. 120, 485–497 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Tarin, D. New insights into the pathogenesis of breast cancer metastasis. Breast Dis. 26, 13–25 (2006–2007).

    CAS  PubMed  Google Scholar 

  82. Pachmann, K. et al. Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. J. Clin. Oncol. 26, 1208–1215 (2008).

    PubMed  Google Scholar 

  83. Alix-Panabières, C. et al. Characterization and enumeration of cells secreting tumor markers in the peripheral blood of breast cancer patients. J. Immunol. Methods 299, 177–188 (2005).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Hsieh, H. B. et al. High speed detection of circulating tumor cells. Biosens. Bioelectron. 21, 1893–1899 (2006).

    CAS  PubMed  Google Scholar 

  86. Talasaz, A. H. et al. Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device. Proc. Natl Acad. Sci. USA 106, 3970–3975 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Mego, M. et al. Circulating tumor cells (CTCs) and epithelial mesenchymal transition (EMT) in breast cancer: describing the heterogeneity of microscopic disease [abstract]. Cancer Res. 69 (573 Suppl.), a3011 (2009).

    Google Scholar 

  88. Van der Auwera, I. et al. Circulating tumour cell detection: a direct comparison between the CellSearch System, the AdnaTest and CK-19/mammaglobin RT-PCR in patients with metastatic breast cancer. Br. J. Cancer 102, 276–284 (2010).

    CAS  PubMed  Google Scholar 

  89. Budd, G. T. et al. Circulating tumor cells versus imaging-predicting overall survival in metastatic breast cancer. Clin. Cancer Res. 12, 6403–6409 (2006).

    CAS  PubMed  Google Scholar 

  90. Nakamura, S. et al. Multi-center study evaluating circulating tumor cells as a surrogate for response to treatment and overall survival in metastatic breast cancer. Breast Cancer 17, 199–204 (2010).

    PubMed  Google Scholar 

  91. Nolé, F. et al. Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications. Ann. Oncol. 19, 891–897 (2008).

    PubMed  Google Scholar 

  92. Liu, M. C. et al. Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. J. Clin. Oncol. 27, 5153–5159 (2009).

    PubMed  PubMed Central  Google Scholar 

  93. Dawood, S. et al. Circulating tumor cells in metastatic breast cancer: from prognostic stratification to modification of the staging system? Cancer 113, 2422–2430 (2008).

    PubMed  Google Scholar 

  94. De Giorgi, U. et al. Circulating tumor cells and [18F]fluorodeoxyglucose positron emission tomography/computed tomography for outcome prediction in metastatic breast cancer. J. Clin. Oncol. 27, 3303–33011 (2009).

    PubMed  Google Scholar 

  95. Bidard, F. C. et al. Clinical value of circulating endothelial cells and circulating tumor cells in metastatic breast cancer patients treated first line with bevacizumab and chemotherapy. Ann. Oncol. 21, 1765–1771 (2010).

    PubMed  Google Scholar 

  96. Mego, M. et al. Predictive value of circulating tumor cells (CTCs) in metastatic breast cancer patients treated by bevacizumab-based therapy [abstract]. Cancer Res. 69 (Suppl.), a3013 (2009).

    Google Scholar 

  97. Giordano, A. et al. Prognostic value of circulating tumor cells (CTC) in metastatic breast cancer (MBC): correlation with immunohistochemically defined molecular subtypes and metastatic disease sites [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a1000 (2010).

    Google Scholar 

  98. Pierga, J. Y. et al. Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin. Cancer Res. 14, 7004–7010 (2008).

    CAS  PubMed  Google Scholar 

  99. Bidard, F. C. et al. Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann. Oncol. 21, 729–733 (2010).

    PubMed  Google Scholar 

  100. Flores, L. M. et al. 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 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Riethdorf, S. et al. 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 (2010).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge J. M. Reuben for discussions and critical input and K. Evans for critical reading of this Review. We apologize to the many researchers whose work we were unable to cite owing to space restrictions. M. Cristofanilli is the recipient of a grant from the State of Texas Rare and Aggressive Breast Cancer Research Program. M. Mego was supported by International Union Against Cancer, American Cancer Society International Fellowship for Beginning Investigators (ACSBI Award ACS/08/006). M. Cristofanilli and S. A. Mani are the recipients of a R01 grant from National Cancer Institute entitled Human breast cancer stem cell surrogates.

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Authors and Affiliations

  1. Department of Medical Oncology, Comenius University, School of Medicine, Klenova 1, Bratislava 833 10, Slovakia

    Michal Mego

  2. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA

    Sendurai A. Mani

  3. Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, 19111–2497, PA, USA

    Massimo Cristofanilli

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M. Mego researched the data for the article. All authors provided a substantial contribution to discussions of the content and writing the article. S. A. Mani and M. Cristofanilli contributed to the review and/or editing of the manuscript before submission.

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Correspondence to Massimo Cristofanilli.

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Mego, M., Mani, S. & Cristofanilli, M. Molecular mechanisms of metastasis in breast cancer—clinical applications. Nat Rev Clin Oncol 7, 693–701 (2010). https://doi.org/10.1038/nrclinonc.2010.171

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