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.
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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
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.
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.
Munich Cancer Registry. http://www.Tumorregister-muenchen.De/facts/specific_analysis.Php.
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.
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.
Weinberg, R. (2007). The biology of cancer. New York: Garland Science.
Sugarbaker, E. V., Cohen, A. M., & Ketcham, A. S. (1971). Do metastases metastasize? Annals of Surgery, 174(2), 161–166.
Tait, C. R., Dodwell, D., & Horgan, K. (2004). Do metastases metastasize? The Journal of Pathology, 203(1), 515–518. doi:10.1002/path.1544.
Sobin, L., Gospodarowicz, M., & Wittekind, C. (Eds.). (2009). Uicc: TNM classification of malignant tumors (7th ed.). Wiley-Blackwell: New York.
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.
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.
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.
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.
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.
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.
Bernards, R., & Weinberg, R. A. (2002). A progression puzzle. Nature, 418(6900), 823. doi:10.1038/418823a.
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.
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.
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.
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.
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.
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.
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.
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.
Aguirre-Ghiso, J. A. (2007). Models, mechanisms and clinical evidence for cancer dormancy. Nature Reviews. Cancer, 7(11), 834–846. doi:10.1038/nrc2256.
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.
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.
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.
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.
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.
Townson, J. L., & Chambers, A. F. (2006). Dormancy of solitary metastatic cells. Cell Cycle, 5(16), 1744–1750. doi:2864.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Glaves, D., Huben, R. P., & Weiss, L. (1988). Haematogenous dissemination of cells from human renal adenocarcinomas. British Journal of Cancer, 57(1), 32–35.
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.
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.
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.
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.
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.
Talmadge, J. E., Wolman, S. R., & Fidler, I. J. (1982). Evidence for the clonal origin of spontaneous metastases. Science, 217(4557), 361–363.
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.
Klein, C. A. (2009). Parallel progression of primary tumours and metastases. Nature Reviews. Cancer, 9(4), 302–312. doi:10.1038/nrc2627.
Pantel, K., & Brakenhoff, R. H. (2004). Dissecting the metastatic cascade. Nature Reviews. Cancer, 4(6), 448–456. doi:10.1038/nrc1370.
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.
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.
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.
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.
Steeg, P. S. (2006). Tumor metastasis: mechanistic insights and clinical challenges. Natural Medicines, 12(8), 895–904. doi:10.1038/nm1469.
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.
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.
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.
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.
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.
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.
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.
Fisher, B., & Fisher, E. R. (1966). Transmigration of lymph nodes by tumor cells. Science, 152(727), 1397–1398.
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.
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.
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.
Paget, S. (1889). The distribution of secondary growths in cancer of the breast. Lancet, 1, 571–573.
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.
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.
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.
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.
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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
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DOI: https://doi.org/10.1007/s10555-010-9260-1