Skip to main content

Advertisement

Log in

Distant metastases do not metastasize

  • NON-THEMATIC REVIEW
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Distant metastases (MET) are for most solid cancers decisive life-threatening events. Data about MET-free survival and survival after MET show a strong dependency on the kind of cancer and the prognostic features. Nonetheless, within biological subgroups, the MET process is very homogenous. Therefore, the growth rate can be estimated from initiation of MET to MET diagnosis and to time of death. Based on the known volume doubling time of breast cancer, the time of the first possible dissemination can also be estimated. Important consequences of these MET-initiation estimates are the hypotheses that almost all MET are initiated before removal of the primary tumor and that MET do not metastasize in a clinically relevant magnitude. Although breast cancer data were primarily used to form these hypotheses, the discussed MET process can be generalized to all solid cancers. The impact of these hypotheses on diagnostic, curative and palliative treatment, aftercare, and especially on clinical research would be important.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

BC:

Breast cancer

MET:

(Distant) metastasization

pLN:

(Positive) lymph node

PT:

Primary tumor

TC(D):

Tumor cell (dissemination)

VD(T):

Volume doubling (time)

References

  1. Chambers, A. F., Groom, A. C., & MacDonald, I. C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nature Reviews. Cancer, 2(8), 563–572. doi:10.1038/nrc865.

    Article  CAS  PubMed  Google Scholar 

  2. Fidler, I. J. (2003). The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nature Reviews. Cancer, 3(6), 453–458. doi:10.1038/nrc1098.

    Article  CAS  PubMed  Google Scholar 

  3. Munich Cancer Registry. http://www.Tumorregister-muenchen.De/facts/specific_analysis.Php.

  4. Curado, M., Edwards, B., Shin, H., Storm, H., Ferlay, J., Heanue, M., et al. (2007). Cancer incidence in five continents, vol. Ix. Lyon: IARC Scientific Publication No.160.

  5. Nguyen, D. X., Bos, P. D., & Massague, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nature Reviews. Cancer, 9(4), 274–284. doi:10.1038/nrc2622.

    Article  CAS  PubMed  Google Scholar 

  6. Weinberg, R. (2007). The biology of cancer. New York: Garland Science.

    Google Scholar 

  7. Sugarbaker, E. V., Cohen, A. M., & Ketcham, A. S. (1971). Do metastases metastasize? Annals of Surgery, 174(2), 161–166.

    Article  CAS  PubMed  Google Scholar 

  8. Tait, C. R., Dodwell, D., & Horgan, K. (2004). Do metastases metastasize? The Journal of Pathology, 203(1), 515–518. doi:10.1002/path.1544.

    Article  PubMed  Google Scholar 

  9. Sobin, L., Gospodarowicz, M., & Wittekind, C. (Eds.). (2009). Uicc: TNM classification of malignant tumors (7th ed.). Wiley-Blackwell: New York.

    Google Scholar 

  10. Leong, S. P., Cady, B., Jablons, D. M., Garcia-Aguilar, J., Reintgen, D., Jakub, J., et al. (2006). Clinical patterns of metastasis. Cancer and Metastasis Reviews, 25(2), 221–232. doi:10.1007/s10555-006-8502-8.

    Article  PubMed  Google Scholar 

  11. Sarfati, D., Blakely, T., & Pearce, N. (2010). Measuring cancer survival in populations: relative survival vs cancer-specific survival. International Journal of Epidemiology, 39(2), 598–610. doi:10.1093/ije/dyp392.

    Article  PubMed  Google Scholar 

  12. Benson, J. R., & della Rovere, G. Q. (2007). Management of the axilla in women with breast cancer. The Lancet Oncology, 8(4), 331–348. doi:10.1016/S1470-2045(07)70103-1.

    Article  PubMed  Google Scholar 

  13. Michaelson, J. S., Silverstein, M., Wyatt, J., Weber, G., Moore, R., Halpern, E., et al. (2002). Predicting the survival of patients with breast carcinoma using tumor size. Cancer, 95(4), 713–723. doi:10.1002/cncr.10742.

    Article  PubMed  Google Scholar 

  14. Perou, C. M., Sorlie, T., Eisen, M. B., van de Rijn, M., Jeffrey, S. S., Rees, C. A., et al. (2000). Molecular portraits of human breast tumours. Nature, 406(6797), 747–752. doi:10.1038/35021093.

    Article  CAS  PubMed  Google Scholar 

  15. Sotiriou, C., & Pusztai, L. (2009). Gene-expression signatures in breast cancer. The New England Journal of Medicine, 360(8), 790–800. doi:10.1056/NEJMra0801289.

    Article  CAS  PubMed  Google Scholar 

  16. Bernards, R., & Weinberg, R. A. (2002). A progression puzzle. Nature, 418(6900), 823. doi:10.1038/418823a.

    Article  CAS  PubMed  Google Scholar 

  17. Balic, M., Lin, H., Young, L., Hawes, D., Giuliano, A., McNamara, G., et al. (2006). Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clinical Cancer Research, 12(19), 5615–5621. doi:10.1158/1078-0432.CCR-06-0169.

    Article  CAS  PubMed  Google Scholar 

  18. Clarke, M. F., & Fuller, M. (2006). Stem cells and cancer: two faces of eve. Cell, 124(6), 1111–1115. doi:10.1016/j.cell.2006.03.011.

    Article  CAS  PubMed  Google Scholar 

  19. Chojniak, R., & Younes, R. N. (2003). Pulmonary metastases tumor doubling time: assessment by computed tomography. American Journal of Clinical Oncology, 26(4), 374–377. doi:10.1097/01.COC.0000026481.38654.52.

    Article  PubMed  Google Scholar 

  20. Finlay, I. G., Meek, D., Brunton, F., & McArdle, C. S. (1988). Growth rate of hepatic metastases in colorectal carcinoma. The British Journal of Surgery, 75(7), 641–644.

    Article  CAS  PubMed  Google Scholar 

  21. Peer, P. G., van Dijck, J. A., Hendriks, J. H., Holland, R., & Verbeek, A. L. (1993). Age-dependent growth rate of primary breast cancer. Cancer, 71(11), 3547–3551.

    Article  CAS  PubMed  Google Scholar 

  22. Kuroishi, T., Tominaga, S., Morimoto, T., Tashiro, H., Itoh, S., Watanabe, H., et al. (1990). Tumor growth rate and prognosis of breast cancer mainly detected by mass screening. Japanese Journal of Cancer Research, 81(5), 454–462.

    CAS  PubMed  Google Scholar 

  23. Richards, M. A., Westcombe, A. M., Love, S. B., Littlejohns, P., & Ramirez, A. J. (1999). Influence of delay on survival in patients with breast cancer: a systematic review. Lancet, 353(9159), 1119–1126. doi:S0140673699021431.

    Article  CAS  PubMed  Google Scholar 

  24. Engel, J., Eckel, R., Kerr, J., Schmidt, M., Furstenberger, G., Richter, R., et al. (2003). The process of metastasisation for breast cancer. European Journal of Cancer, 39(12), 1794–1806. doi:S0959804903004222.

    Article  CAS  PubMed  Google Scholar 

  25. Aguirre-Ghiso, J. A. (2007). Models, mechanisms and clinical evidence for cancer dormancy. Nature Reviews. Cancer, 7(11), 834–846. doi:10.1038/nrc2256.

    Article  CAS  PubMed  Google Scholar 

  26. Naumov, G. N., Folkman, J., Straume, O., & Akslen, L. A. (2008). Tumor-vascular interactions and tumor dormancy. APMIS, 116(7–8), 569–585. doi:10.1111/j.1600-0463.2008.01213.x.

    Article  CAS  PubMed  Google Scholar 

  27. Husemann, Y., Geigl, J. B., Schubert, F., Musiani, P., Meyer, M., Burghart, E., et al. (2008). Systemic spread is an early step in breast cancer. Cancer Cell, 13(1), 58–68. doi:10.1016/j.ccr.2007.12.003.

    Article  PubMed  Google Scholar 

  28. Meng, S., Tripathy, D., Frenkel, E. P., Shete, S., Naftalis, E. Z., Huth, J. F., et al. (2004). Circulating tumor cells in patients with breast cancer dormancy. Clinical Cancer Research, 10(24), 8152–8162. doi:10.1158/1078-0432.CCR-04-1110.

    Article  PubMed  Google Scholar 

  29. Cristofanilli, M., Budd, G. T., Ellis, M. J., Stopeck, A., Matera, J., Miller, M. C., et al. (2004). Circulating tumor cells, disease progression, and survival in metastatic breast cancer. The New England Journal of Medicine, 351(8), 781–791. doi:10.1056/NEJMoa040766.

    Article  CAS  PubMed  Google Scholar 

  30. Pachmann, K., Camara, O., Kavallaris, A., Krauspe, S., Malarski, N., Gajda, M., et al. (2008). Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. Journal of Clinical Oncology, 26(8), 1208–1215. doi:10.1200/JCO.2007.13.6523.

    Article  PubMed  Google Scholar 

  31. Townson, J. L., & Chambers, A. F. (2006). Dormancy of solitary metastatic cells. Cell Cycle, 5(16), 1744–1750. doi:2864.

    CAS  PubMed  Google Scholar 

  32. Wikman, H., Vessella, R., & Pantel, K. (2008). Cancer micrometastasis and tumour dormancy. APMIS, 116(7–8), 754–770. doi:10.1111/j.1600-0463.2008.01033.x.

    Article  CAS  PubMed  Google Scholar 

  33. Birkeland, S. A., & Storm, H. H. (2002). Risk for tumor and other disease transmission by transplantation: a population-based study of unrecognized malignancies and other diseases in organ donors. Transplantation, 74(10), 1409–1413. doi:10.1097/01.TP.0000034717.19606.B5.

    Article  PubMed  Google Scholar 

  34. Logan, P. T., Fernandes, B. F., Di Cesare, S., Marshall, J. C., Maloney, S. C., & Burnier, M. N., Jr. (2008). Single-cell tumor dormancy model of uveal melanoma. Clinical & Experimental Metastasis, 25(5), 509–516. doi:10.1007/s10585-008-9158-2.

    Article  Google Scholar 

  35. Heyn, C., Ronald, J. A., Ramadan, S. S., Snir, J. A., Barry, A. M., MacKenzie, L. T., et al. (2006). In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain. Magnetic Resonance in Medicine, 56(5), 1001–1010. doi:10.1002/mrm.21029.

    Article  PubMed  Google Scholar 

  36. Hölzel, D., Eckel, R., & Engel, J. (2009). [Colorectal cancer metastasis: frequency, prognosis, and consequences]. Chirurg, 80(4), 331–340. doi:10.1007/s00104-008-1603-x.

    Article  PubMed  Google Scholar 

  37. Kim, M. Y., Oskarsson, T., Acharyya, S., Nguyen, D. X., Zhang, X. H., Norton, L., et al. (2009). Tumor self-seeding by circulating cancer cells. Cell, 139(7), 1315–1326. doi:10.1016/j.cell.2009.11.025.

    Article  PubMed  Google Scholar 

  38. Fisher, B., Anderson, S., Fisher, E. R., Redmond, C., Wickerham, D. L., Wolmark, N., et al. (1991). Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet, 338(8763), 327–331.

    Article  CAS  PubMed  Google Scholar 

  39. Fisher, B., & Anderson, S. J. (2010). The breast cancer alternative hypothesis: is there evidence to justify replacing it? Journal of Clinical Oncology, 28(3), 366–374. doi:10.1200/JCO.2009.26.8292.

    Article  PubMed  Google Scholar 

  40. Chambers, A. F., Naumov, G. N., Vantyghem, S. A., & Tuck, A. B. (2000). Molecular biology of breast cancer metastasis. Clinical implications of experimental studies on metastatic inefficiency. Breast Cancer Research, 2(6), 400–407.

    Article  CAS  PubMed  Google Scholar 

  41. Glaves, D., Huben, R. P., & Weiss, L. (1988). Haematogenous dissemination of cells from human renal adenocarcinomas. British Journal of Cancer, 57(1), 32–35.

    CAS  PubMed  Google Scholar 

  42. van de Vijver, M. J., He, Y. D., van’t Veer, L. J., Dai, H., Hart, A. A., Voskuil, D. W., et al. (2002). A gene-expression signature as a predictor of survival in breast cancer. The New England Journal of Medicine, 347(25), 1999–2009. doi:10.1056/NEJMoa021967.

    Article  PubMed  Google Scholar 

  43. Bos, P. D., Zhang, X. H., Nadal, C., Shu, W., Gomis, R. R., Nguyen, D. X., et al. (2009). Genes that mediate breast cancer metastasis to the brain. Nature, 459(7249), 1005–1009. doi:10.1038/nature08021.

    Article  CAS  PubMed  Google Scholar 

  44. Liu, R., Wang, X., Chen, G. Y., Dalerba, P., Gurney, A., Hoey, T., et al. (2007). The prognostic role of a gene signature from tumorigenic breast-cancer cells. The New England Journal of Medicine, 356(3), 217–226. doi:10.1056/NEJMoa063994.

    Article  CAS  PubMed  Google Scholar 

  45. Kang, Y., Siegel, P. M., Shu, W., Drobnjak, M., Kakonen, S. M., Cordon-Cardo, C., et al. (2003). A multigenic program mediating breast cancer metastasis to bone. Cancer Cell, 3(6), 537–549. doi:S1535610803001326.

    Article  CAS  PubMed  Google Scholar 

  46. Fisher, B. (1980). Laboratory and clinical research in breast cancer—a personal adventure: the David A. Karnofsky memorial lecture. Cancer Research, 40(11), 3863–3874.

    CAS  PubMed  Google Scholar 

  47. Talmadge, J. E., Wolman, S. R., & Fidler, I. J. (1982). Evidence for the clonal origin of spontaneous metastases. Science, 217(4557), 361–363.

    Article  CAS  PubMed  Google Scholar 

  48. Fidler, I. J. (1973). The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. European Journal of Cancer, 9(3), 223–227.

    CAS  PubMed  Google Scholar 

  49. Klein, C. A. (2009). Parallel progression of primary tumours and metastases. Nature Reviews. Cancer, 9(4), 302–312. doi:10.1038/nrc2627.

    Article  CAS  PubMed  Google Scholar 

  50. Pantel, K., & Brakenhoff, R. H. (2004). Dissecting the metastatic cascade. Nature Reviews. Cancer, 4(6), 448–456. doi:10.1038/nrc1370.

    Article  CAS  PubMed  Google Scholar 

  51. Palmieri, D., Chambers, A. F., Felding-Habermann, B., Huang, S., & Steeg, P. S. (2007). The biology of metastasis to a sanctuary site. Clinical Cancer Research, 13(6), 1656–1662. doi:10.1158/1078-0432.CCR-06-2659.

    Article  CAS  PubMed  Google Scholar 

  52. Mehta, M. P., Tsao, M. N., Whelan, T. J., Morris, D. E., Hayman, J. A., Flickinger, J. C., et al. (2005). The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. International Journal of Radiation Oncology, Biology, Physics, 63(1), 37–46. doi:10.1016/j.ijrobp.2005.05.023.

    PubMed  Google Scholar 

  53. Aoyama, H., Shirato, H., Tago, M., Nakagawa, K., Toyoda, T., Hatano, K., et al. (2006). Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA, 295(21), 2483–2491. doi:10.1001/jama.295.21.2483.

    Article  CAS  PubMed  Google Scholar 

  54. Holmgren, L., O’Reilly, M. S., & Folkman, J. (1995). Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Natural Medicines, 1(2), 149–153.

    Article  CAS  Google Scholar 

  55. Steeg, P. S. (2006). Tumor metastasis: mechanistic insights and clinical challenges. Natural Medicines, 12(8), 895–904. doi:10.1038/nm1469.

    Article  CAS  Google Scholar 

  56. Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial. Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC) Edinburgh (1987). Lancet, 2(8552), 171–175. doi:S0140-6736(87)90762-8.

  57. de Boer, M., van Deurzen, C. H., van Dijck, J. A., Borm, G. F., van Diest, P. J., Adang, E. M., et al. (2009). Micrometastases or isolated tumor cells and the outcome of breast cancer. The New England Journal of Medicine, 361(7), 653–663. doi:10.1056/NEJMoa0904832.

    Article  PubMed  Google Scholar 

  58. Veronesi, U., Marubini, E., Mariani, L., Valagussa, P., & Zucali, R. (1999). The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial. European Journal of Cancer, 35(9), 1320–1325. doi:S0959-8049(99)00133-1.

    Article  CAS  PubMed  Google Scholar 

  59. Fisher, B., Anderson, S., Bryant, J., Margolese, R. G., Deutsch, M., Fisher, E. R., et al. (2002). Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. The New England Journal of Medicine, 347(16), 1233–1241. doi:10.1056/NEJMoa022152.

    Article  PubMed  Google Scholar 

  60. Morton, D. L., Thompson, J. F., Cochran, A. J., Mozzillo, N., Elashoff, R., Essner, R., et al. (2006). Sentinel-node biopsy or nodal observation in melanoma. The New England Journal of Medicine, 355(13), 1307–1317. doi:10.1056/NEJMoa060992.

    Article  CAS  PubMed  Google Scholar 

  61. Hartgrink, H. H., van de Velde, C. J., Putter, H., Bonenkamp, J. J., Klein Kranenbarg, E., Songun, I., et al. (2004). Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial. Journal of Clinical Oncology, 22(11), 2069–2077. doi:10.1200/JCO.2004.08.026.

    Article  CAS  PubMed  Google Scholar 

  62. Adam, R., Delvart, V., Pascal, G., Valeanu, A., Castaing, D., Azoulay, D., et al. (2004). Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg, 240(4), 644–657. doi:00000658-200410000-00010. discussion 657–648.

    PubMed  Google Scholar 

  63. Fisher, B., & Fisher, E. R. (1966). Transmigration of lymph nodes by tumor cells. Science, 152(727), 1397–1398.

    Article  CAS  PubMed  Google Scholar 

  64. Aoi, T., Yae, K., Nakagawa, M., Ichisaka, T., Okita, K., Takahashi, K., et al. (2008). Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science, 321(5889), 699–702. doi:10.1126/science.1154884.

    Article  CAS  PubMed  Google Scholar 

  65. Zahl, P. H., Maehlen, J., & Welch, H. G. (2008). The natural history of invasive breast cancers detected by screening mammography. Archives of Internal Medicine, 168(21), 2311–2316. doi:10.1001/archinte.168.21.2311.

    Article  PubMed  Google Scholar 

  66. Chlebowski, R. T., Kuller, L. H., Prentice, R. L., Stefanick, M. L., Manson, J. E., Gass, M., et al. (2009). Breast cancer after use of estrogen plus progestin in postmenopausal women. The New England Journal of Medicine, 360(6), 573–587. doi:10.1056/NEJMoa0807684.

    Article  CAS  PubMed  Google Scholar 

  67. Paget, S. (1889). The distribution of secondary growths in cancer of the breast. Lancet, 1, 571–573.

    Article  Google Scholar 

  68. Naumov, G. N., Wilson, S. M., MacDonald, I. C., Schmidt, E. E., Morris, V. L., Groom, A. C., et al. (1999). Cellular expression of green fluorescent protein, coupled with high-resolution in vivo videomicroscopy, to monitor steps in tumor metastasis. Journal of Cell Science, 112(Pt 12), 1835–1842.

    CAS  PubMed  Google Scholar 

  69. Kienast, Y., von Baumgarten, L., Fuhrmann, M., Klinkert, W. E., Goldbrunner, R., Herms, J., et al. (2010). Real-time imaging reveals the single steps of brain metastasis formation. Nature Medicine, 16(1), 116–122. doi:10.1038/nm.2072.

    Article  CAS  PubMed  Google Scholar 

  70. Hoon, D. S., Kitago, M., Kim, J., Mori, T., Piris, A., Szyfelbein, K., et al. (2006). Molecular mechanisms of metastasis. Cancer and Metastasis Reviews, 25(2), 203–220. doi:10.1007/s10555-006-8500-x.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the many doctors and clinicians who cooperate within the complex network of the Munich Cancer Registry despite the back-breaking medical bureaucracy for the daily health care. It is our duty to provide an adequate evaluation of the submitted data for outcomes, quality management and innovative treatments.

Conflict of interest

We declare that we have no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dieter Hölzel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hölzel, D., Eckel, R., Emeny, R.T. et al. Distant metastases do not metastasize. Cancer Metastasis Rev 29, 737–750 (2010). https://doi.org/10.1007/s10555-010-9260-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-010-9260-1

Keywords

Navigation