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Breast cancer remains the most common malignancy among women, with an average lifetime risk of approximately 10%. Despite the continued rise in incidence of the disease, with almost half a million deaths annually worldwide, mortality rates have fallen over the past two decades. This is testimony to the success of interventional strategies such as screening and adjuvant systemic therapies that permit diagnosis of breast cancer prior to de novo formation of micrometastases or the obliteration of established foci of disease at distant sites. It is this burden of micrometastatic disease outside the breast that represents the most fundamental and challenging aspect of breast cancer treatment.
In accordance with Fisher’s hypothesis of biological predeterminism, these micrometastatic foci can remain dormant and be activated many years after initial diagnosis.1 It is now acknowledged that not all cases of early breast cancer are systemic at the outset with distant micrometastases pre-existent at presentation. Breast cancer is a heterogeneous disease with a variable and unpredictable natural history. We have entered a new era in breast cancer management where disease is ‘small’ and more likely to be confined to the breast and regional nodes.2 This ‘stage migration’ is attributable to a combination of heightened public awareness and screening programmes and has led to an increased proportion of smaller-sized (<2cm) node-negative tumours. Some of these tumours will behave in a Halstedian manner with minimal proclivity for haematogenous dissemination and the formation of micrometastases at an early stage in the neoplastic continuum. A spectrum, or intermediate paradigm, is emerging that encompasses elements of Fisher and Halsted but is less restrictive than either hypothesis in pure form.3
Modern methods of molecular profiling may permit tumours to be assigned to one group or another based on biological behaviour, with appropriate intensities of locoregional and systemic treatments. Those patients without micrometastatic disease at presentation do not require adjuvant systemic therapy and fewer than 10% of those receiving chemotherapy for node-negative disease derive any benefit. It may be surmised that as tumour size has fallen progressively in recent years, a lower proportion of patients will have micrometastases at the time of diagnosis and a correspondingly greater proportion will have disease limited to the locoregional tissues. For these patients, inadequate primary locoregional treatment will lead to higher rates of local recurrence, which under these circumstances represents a determinant of distant disease and can directly affect survival by acting as a source for micrometastases.4 The biphasic pattern of recurrence with peaks at one to two and four to five years suggests that dormant micrometastases may be stimulated by the act of primary surgery, which can remove sources of angiostatin with
initiation of microangiogenesis and the dissemination of tumour cells. Administration of antiangiogenic agents in a pre-surgical schedule may suppress this angiogenic kick-start and interrupt the ‘conversation’ between breast cancer and endothelial cells.5