The Risk of Early Recurrence and Distant Metastases: Lessons from the Monotherapy Adjuvant Aromatase Inhibitor Trials with a Focus on BIG 1-98

European Oncological Disease, 2006;1(2):24-7 DOI:


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.