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Worldwide, breast cancer is the most common form of cancer in women. The incidence of breast cancer increased initially, beginning in the 1970s, then levelled off over the last two decades, and recently the mortality from this disease has been slowly decreasing.1,2 When the breast cancer tumor is localized to the breast and axillary nodes,multimodality therapy is the treatment of choice, consisting of surgery, radiotherapy, and adjuvant or neoadjuvant systemic therapy with hormonal agents (tamoxifen (Tam) or an aromatase inhibitor (AI)), and/or chemotherapy.3,4 Depending on clinical and pathological criteria (including tumor size and grade, presence and number of axillary node metastases, lymphovascular invasion, and over-expression of biological markers, including estrogen receptors (ERs), progesterone receptors (PRs) and the HER2/neu receptor), as well as host factors, such as age, and co-morbidities, patients with breast cancer are roughly classified as having high-, intermediate-, or low-risk disease, which guides the recommendations for therapy.3,4
However, even after primary therapy by surgery and/or chemotherapy, the risk of recurrence remains high.5 Although, classically, breast tumor biology has been classified on the basis of hormone receptor (HR) negativity or positivity, it is now becoming clear that multiple other subtypes exist within these broad categories.6 Indeed, a subset of HRpositive tumors may be associated with early relapse due to initial or rapid development of hormone resistance, and aggressive biology.7–9 In a review of data from seven clinical trials of adjuvant therapy for early breast cancer conducted by the Eastern Cooperative Oncology Group, the greatest risk of recurrence occurred within the first three years after surgery.5 The risk was highest among women with tumors >3cm and among those who had >4 positive nodes. Interestingly, patients who had HR-negative, highly proliferative disease had a higher risk of relapse in the first five years after diagnosis; subsequently, their relapse rate sharply declined. From years 5–10, the risk was significantly greater in women with ER-positive disease.5
The Early Breast Cancer Trialists’ Collaborative Group meta-analysis has demonstrated that women with HRpositive breast cancer still have approximately 50% of their initial recurrence risk five years after diagnosis.10 However, within this subset there are groups of patients who have more rapidly proliferative, less hormonesensitive disease and potentially more bulky disease at diagnosis, which is associated with a higher risk of early relapse. Currently, there are no good biological or clinical factors to accurately assess risk of early relapse in HR-positive disease, but clearly higher stage disease, high-grade histology, lower positivity for HRs, and over-expression of the oncoprotein HER2/neu can help identify this subgroup of patients.
Types of Recurrence
The most common type of recurrence event in women with breast cancer is distant recurrence, and this risk significantly surpasses the risk for local recurrence in the majority of cases.There are several reasons for this; over the last decade more attention has been paid to achieving wider tumor-free margins at the time of surgery, and radiation is commonly employed following breast conservation surgery.11 Secondly, imaging techniques—although still far from perfect—have improved to some degree the detection of cancers in younger women or women with denser breasts, and ultrasound is routinely employed to further analyze palpable or suspected abnormalities.12 There is also the option of additional specialized testing such as magnetic resonance imaging, which can further delineate the extent of disease within the breast, including identifying multifocal disease, as well as tumors that are fully or partially mammographically occult.13 These techniques have reduced the problem of missing extensive or multifocal sites of cancer in the breast at the time of surgery, and resulted in a decrease in the rate of local recurrence risk, leaving distant risk the primary target of systemic adjuvant therapy. The one caveat to this is in inflammatory breast cancer, where the most frequent site of recurrence is local due to dermal and chest wall lymphatic invasion, but which often have subsequent or simultaneous distant recurrence as well.10 The most common initial sites of relapse for HR-positive disease are the bone, bone marrow, and soft tissue, including lymph nodes, followed by the visceral organs—including the lungs and liver, as well as brain and skin.14,15 Infiltration of the gastrointestinal tract and peritoneum can also be seen. In HR-negative disease, the most common initial site of relapse is in visceral organs.14