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Breast cancer remains a leading cause of morbidity and mortality in women,1 mainly due to the propensity of primary breast tumors to metastasize to regional and distant sites and the failure of effective clinical management of metastatic disease.2,3 Primary therapy for breast cancer usually involves surgical resection of the tumor (lumpectomy or mastectomy), alone or in combination with local radiotherapy. As discussed in later chapters, factors such as tumor size, grade, lymph node involvement, and hormonal status provide valuable information for prognosis. If the patient is felt to have a reasonably high probability of harboring micrometastases, then adjuvant systemic drug therapy (cytotoxic or hormonal) is usually recommended.4 This adjuvant approach has several problems, including both unnecessary treatment of patients who may have been truly cured by their primary treatment alone, as well as the fact that many patients may relapse despite treatment (adjuvant therapy typically only reduces the risk of recurrence by 25-30%).5 A better understanding of the biology of metastasis can improve clinical management and provide the potential for developing novel prognostic and/or therapeutic strategies to combat metastatic breast cancer. This chapter will review what is currently known about the metastatic process, including the timing and steps involved the metastatic cascade, the organ-specific nature of breast cancer metastasis, the contribution of specific molecular factors to metastatic disease, and the issue of tumor dormancy.

Timing of Metastasis—an Early or Late Event in Breast Cancer?

The prevailing paradigm of cancer development suggests that tumor cells sequentially accumulate multiple genetic mutations that allow them to evolve from a nonmalignant epithelial cell to a highly aggressive cancer cell, a process called multistep carcinogenesis.6,7 Until recently, it was believed that metastasis was therefore a late event in disease progression, such that additive genetic mutations allowed cancer cells to acquire the capacity to escape from the primary tumor and disseminate to distant organs as a final step in carcinogenesis. Certainly, the clinical reality that patients with large primary breast cancers are more likely to die from metastasis than patients with small tumors8 was believed to reflect the late onset of metastatic spread. However, experimental and clinical observations have challenged this idea, and suggested that metastatic dissemination may in fact be an early event in the overall evolution of breast cancer.9 For example, the observation that metastases can develop in patients with small primary tumors, before the diagnosis of the primary tumor, or even in the absence of a detectable primary tumor (so-called cancers of unknown origin)10,11 indicates that a successful metastatic cell does not necessarily need to undergo a lengthy evolution within the primary site in order to be deadly. Furthermore, recent studies have indicated that the presence of individual tumor cells in the blood or bone marrow of breast cancer patients is an important early indicator of the potential for metastatic disease and poor prognosis.12 Finally, global gene expression analyses of primary breast cancers ...

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