Review Article | Published:

Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures

Nature Clinical Practice Oncology volume 4, pages 699710 (2007) | Download Citation

Subjects

Abstract

Primary tumor removal, usually considered intrinsically beneficial, can perturb metastatic homeostasis, and for some patients results in the acceleration of metastatic cancer. The continuous-growth model is required to yield to an interrupted-growth model, the implications of which are episodes of tumor dormancy. This Review analyzes the recent evolution of two paradigms related to the development of breast cancer metastases. The evolution of the paradigms described herein is supported by a growing body of findings from experimental models, and is required to explain breast cancer recurrence dynamics for patients undergoing surgery with or without adjuvant chemotherapy.

Key points

  • Established tumor growth models that assume continuous growth of a tumor fail to explain clinical findings from breast cancer patients with local or distant recurrence; such discrepancies may be explained by tumor dormancy

  • The hazard rate for tumor recurrence soon after surgery displays a pattern that is related to menopausal status: a two-peaked hazard function for premenopausal patients and a single wider peak for postmenopausal patients

  • It has been confirmed that in patients receiving adjuvant chemotherapy, recurrence risk is reduced at the first and third years for both menopausal statuses

  • Subclinical metastases might be induced to grow by the conversion of single noncycling G0 cells or by the switching of avascular micrometastatic foci to active angiogenesis

  • Assuming a triggering effect of surgical removal of the primary tumor, the early sharp recurrence peak seen in premenopausal patients can be ascribed to the switching of micrometastatic foci to the angiogenic phenotype, while the following broader peak might result from interruption of dormancy of a number of single cells

  • For postmenopausal patients, the accelerating effects of surgery are much more modest

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References

  1. 1.

    (1964) Dynamics of tumour growth. Br J Cancer 18: 490–502

  2. 2.

    (1977) Growth Kinetics of Tumours. Oxford: Clarendon Press

  3. 3.

    et al. (1989) An exponential-Gompertzian description of LoVo cell tumor growth from in vivo and in vitro data. Cancer Res 49: 6543–6546

  4. 4.

    (1971) Kinetics of mammary tumor cell growth and implications for therapy. Cancer 28: 1479–1499

  5. 5.

    and (1977) Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 61: 1307–1317

  6. 6.

    et al. (1994) Local recurrences following mastectomy: support for the concept of tumor dormancy. J Natl Cancer Inst 86: 45–48

  7. 7.

    et al. (1996) Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: further support about the concept of tumor dormancy. Breast Cancer Res Treat 41: 177–185

  8. 8.

    et al. (2004) Menopausal status dependence of the timing of breast cancer recurrence after surgical removal of the primary tumour. Breast Cancer Res 6: R689–R696

  9. 9.

    et al. (1999) Does breast cancer exist in a state of chaos? Eur J Cancer 35: 886–891

  10. 10.

    et al. (2001) Angiogenesis sustains tumor dormancy in patients with breast cancer treated with adjuvant chemotherapy. Breast Cancer Res Treat 65: 71–75

  11. 11.

    et al. (2005) Hazard rates of recurrence following diagnosis of primary breast cancer. Breast Cancer Res Treat 89: 173–178

  12. 12.

    et al. (2005) Improvement of breast cancer relapse prediction in high risk intervals using artificial neural networks. Breast Cancer Res Treat 94: 265–272

  13. 13.

    et al. (1999) Comparative analysis of breast cancer recurrence risk for patients receiving adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF): data supporting the occurrence of 'cures'. Breast Cancer Res Treat 53: 209–215

  14. 14.

    (1972) Observations on the mortality from carcinoma of the breast. Br J Cancer 45: 31–38

  15. 15.

    et al. (1991) Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet 338: 327–331

  16. 16.

    et al. (1993) Age as prognostic factor in premenopausal breast carcinoma. Lancet 341: 1039–1043

  17. 17.

    et al. (1995) Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events. J Natl Cancer Inst 87: 19–27

  18. 18.

    et al. (1996) Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14: 2738–2746

  19. 19.

    et al. (1998) Time-dependence of hazard ratios for prognostic factors in primary breast cancer. Breast Cancer Res Treat 52: 227–237

  20. 20.

    et al. (1999) Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst 91: 80–85

  21. 21.

    et al. (1999) Local failure is responsible for the decrease in survival for patients with breast cancer treated with conservative surgery and postoperative radiotherapy. J Clin Oncol 17: 101–109

  22. 22.

    and (1999) The shape of age-incidence curves of female breast cancer by hormone receptor status. Cancer Causes Control 10: 431–437

  23. 23.

    et al. (2005) Distinct breast cancer incidence and prognostic patterns in the NCI's SEER program: suggesting a possible link between etiology and outcome. Breast Cancer Res Treat 90: 127–137

  24. 24.

    et al. (1954) The dormant cancer cell. BMJ 2: 607–609

  25. 25.

    and (1959) Experimental evidence in support of the dormant tumor cell. Science 130: 918–919

  26. 26.

    et al. (1991) Cancer dormancy: studies of the murine BCL1 lymphoma. Cancer Res 51: 5045s–5053s

  27. 27.

    et al. (1991) A prolactin dependent, metastasising rat mammary carcinoma as a model for endocrine-related tumour dormancy. Br J Cancer 64: 463–468

  28. 28.

    et al. (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153: 865–873

  29. 29.

    et al. (1992) Unusual growth characteristics of human melanoma xenografts in the nude mouse: a model for desmoplasia, dormancy and progression. Br J Cancer 65: 487–490

  30. 30.

    and (1981) Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J Natl Cancer Inst 67: 51–56

  31. 31.

    et al. (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1: 149–153

  32. 32.

    et al. (2002) Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res 62: 2162–2168

  33. 33.

    et al. (2003) Prolonged dormancy and site-specific growth potential of cancer cells spontaneously disseminated from nonmetastatic breast tumors as revealed by labeling with green fluorescent protein. Clin Cancer Res 9: 3808–3814

  34. 34.

    et al. (2001) Biological behavior of human breast cancer micrometastases. Clin Cancer Res 7: 2434–2439

  35. 35.

    (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27–31

  36. 36.

    et al. (2006) A model of human tumor dormancy: angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst 98: 316–325

  37. 37.

    et al. (2004) Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth. Cancer Res 64: 7336–7345

  38. 38.

    et al. (1990) Development of micrometastases: earliest events detected with bacterial lacZ gene-tagged tumor cells. J Natl Cancer Inst 82: 1497–1503

  39. 39.

    et al. (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 85: 1419–1424

  40. 40.

    and (1989) The biology of tumor metastasis. Semin Oncol 16: 106–115

  41. 41.

    (1991) Molecular mechanisms of cancer metastasis: tumor and host properties and the role of oncogenes and suppressor genes. Curr Opin Oncol 3: 75–92

  42. 42.

    et al. (1994) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339: 58–61

  43. 43.

    et al. (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79: 315–328

  44. 44.

    et al. (1997) Proposal for a new model of breast cancer metastatic development. Ann Oncol 8: 1075–1080

  45. 45.

    et al. (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2: 563–572

  46. 46.

    et al. (1997) Computer simulation of a breast cancer metastasis model. Breast Cancer Res Treat 45: 193–202

  47. 47.

    and (1910) Frequency of visceral metastases in tumor bearing mice following surgical removal of their tumor [French]. Bull Assoc Fr Etud Cancer 3: 19–23

  48. 48.

    (1950) Some observations on the natural behavior of cancer in man. N Engl J Med 242: 167–172

  49. 49.

    et al. (1976) Effects of surgery on the cell kinetics of residual tumor. Cancer Treat Rep 60: 1749–1760

  50. 50.

    et al. (1982) Tumor cell proliferation and sequential chemotherapy after partial tumor resection in C3H/HeJ mammary tumors. Breast Cancer Res Treat 2: 323–329

  51. 51.

    et al. (1982) Effect of surgical removal on the growth and kinetics of residual tumor. Cancer Res 39: 3861–3865

  52. 52.

    et al. (1991) Surgically induced cytokinetic responses in experimental rat mammary tumor models. Cancer 68: 759–767

  53. 53.

    et al. (1989) Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 49: 1996–2001

  54. 54.

    et al. (1983) Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res 43: 1488–1492

  55. 55.

    et al. (2001) A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Res 61: 5575–5579

  56. 56.

    et al. (2006) Interruption of tumor dormancy by a transient angiogenic burst within the tumor microenvironment. Proc Natl Acad Sci USA 103: 4216–4221

  57. 57.

    et al. (1998) Stimulation of tumour angiogenesis by proximal wounds: spatial and temporal analysis by MRI. Br J Cancer 77: 440–447

  58. 58.

    et al. (1999) Stimulation of tumour growth by wound-derived growth factors. Br J Cancer 79: 1392–1398

  59. 59.

    et al. (2003) Role of HER2 in wound-induced breast carcinoma proliferation. Lancet 362: 527–533

  60. 60.

    et al. (2001) Does surgery modify growth kinetics of breast cancer micrometastases? Br J Cancer 85: 490–492

  61. 61.

    et al. (1962) Natural history of untreated breast cancer (1805–1933). BMJ 2: 213–221

  62. 62.

    et al. (1998) Estimate of tumor growth time for breast cancer local recurrences: rapid growth after wake-up? Breast Cancer Res Treat 51: 133–137

  63. 63.

    et al. (1989) Menstrual influence on surgical cure of breast cancer. Lancet 334: 949–952

  64. 64.

    et al. (2005) Cancer growth and spread are saltatory and phase-locked to the reproductive cycle through mediators of angiogenesis. Mol Cancer Ther 4: 1065–1075

  65. 65.

    et al. (2005) Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process. Ann Oncol 16: 1449–1457

  66. 66.

    et al. (2003) Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res Treat 82: 199–206

  67. 67.

    et al. (2000) Lack of effect of adjuvant chemotherapy on the elimination of single dormant cells in bone marrow of high-risk breast cancer patients. J Clin Oncol 18: 80–86

  68. 68.

    Early Breast Cancer Trialists' Collaborative Group (1998) Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 352: 930–942

  69. 69.

    (2002) The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res 4: 197–201

  70. 70.

    and (2002) Reproductive factors and breast cancer risk: do they differ according to age at diagnosis? Breast Cancer Res Treat 72: 107–115

  71. 71.

    et al. (2005) Distinct breast cancer incidence and prognostic patterns in the NCI's SEER program: suggesting a possible link between etiology and outcome. Breast Cancer Res Treat 90: 127–137

  72. 72.

    et al. (1998) Changing estrogen and progesterone receptor pattern in breast carcinoma during menstrual cycle and menopause. Cancer 83: 698–705

  73. 73.

    et al. (2003) Fluctuation of intratumor biological variables as a function of menstrual timing of surgery for breast cancer in premenopausal patients. Ann Oncol 14: 962–964

  74. 74.

    and (2001) Estrogen and angiogenesis: a review. Arterioscler Thromb Vasc Biol 21: 6–12

  75. 75.

    (2003) Variability of vascular endothelial growth factor in normal human breast tissue in vivo during the menstrual cycle. J Clin Endocrinol Metab 88: 2695–2698

  76. 76.

    (2005) Positive correlation between estradiol and vascular endothelial growth factor but not fibroblast growth factor-2 in normal breast tissue in vivo. Clin Cancer Res 11: 8036–8041

  77. 77.

    (2005) Sex steroid regulation of angiogenesis in breast tissue. Angiogenesis 8: 127–136

  78. 78.

    et al. (2005) Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1 and VEGFR-2 in breast cancer and endothelial cells. Br J Cancer 93: 1005–1010

  79. 79.

    et al. (2001) Circulating levels of endostatin in cancer patients. Oncol Rep 8: 405–409

  80. 80.

    et al. (1995) Angiogenesis in invasive breast carcinoma: is it associated with parameters of prognostic significance? Histopathology 26: 165–169

  81. 81.

    et al. (1997) Angiogenesis in breast cancer is related to age but not to other prognostic factors. Pathol Res Pract 193: 267–273

  82. 82.

    et al. (2005) Daily coordination of cancer growth and circadian clock gene expression. Breast Cancer Res Treat 91: 47–60

  83. 83.

    et al. (2006) Circadian clock coordinates cancer cell cycle progression, thymidylate synthase (TS), and 5-fluorouracil (5-FU) therapeutic index. Mol Cancer Ther 5: 2023–2033

  84. 84.

    et al. (2002) Fertility cycle influence on surgical breast cancer cure. Breast Cancer Res Treat 75: 65–72

  85. 85.

    (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186

  86. 86.

    et al. (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug resistant cancer. Cancer Res 60: 1878–1886

  87. 87.

    et al. (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10: 8152–8162

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Acknowledgements

We wish to thank Dr Franca Fossati Bellani, Department of Medical Oncology, National Cancer Institute of Milan, for his long-lasting, friendly and generous contribution, as well as helpful comments and critical appraisal of this manuscript.

Author information

Affiliations

  1. R Demicheli is Senior Medical Researcher, Department of Medical Oncology, National Cancer Institute of Milan, Italy.

    • Romano Demicheli
  2. MW Retsky is Lecturer in Surgery, Department of Vascular Biology, Children's Hospital and Harvard Medical School, Boston, MA, USA.

    • Michael W Retsky
  3. WJM Hrushesky is Senior Clinician Investigator, Research Service, Dorn VA Medical Center, The University of South Carolina, Columbia, SC, USA.

    • William JM Hrushesky
  4. M Baum is Professor Emeritus of Surgery, University College London, London, UK.

    • Michael Baum

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Romano Demicheli.

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DOI

https://doi.org/10.1038/ncponc0999

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