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

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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Figure 1: Size versus time chart of metastasis development.
Figure 2: Hazard rate for recurrence of breast cancer in patients undergoing mastectomy (Milan series).
Figure 3: Outline of the metastatic process of breast cancer.
Figure 4: Hazard rate for death of breast cancer patients: comparison between untreated patients and patients undergoing mastectomy.
Figure 5: Outline of the hypothesized dynamics of metastasis development in premenopausal patients with breast cancer.
Figure 6: Outline of the hypothesized dynamics of metastasis development in postmenopausal patients with breast cancer.
Figure 7: Pattern of CMF-sensitive and CMF-refractory recurrences occurring in the first 4 years following mastectomy.

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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.

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Correspondence to Romano Demicheli.

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Demicheli, R., Retsky, M., Hrushesky, W. et al. Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures. Nat Rev Clin Oncol 4, 699–710 (2007). https://doi.org/10.1038/ncponc0999

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  • DOI: https://doi.org/10.1038/ncponc0999

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