Reducing the risk of distant metastases: a better end point in adjuvant aromatase inhibitor breast cancer trials?

For women with hormone receptor-positive disease, the third-generation aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, are more effective than tamoxifen in improving disease-free survival (DFS) when used initially or as adjuvant therapy following two to three years of tamoxifen or after tamoxifen has been completed. Demonstrating improvement in overall survival (OS), or breast cancer-associated mortality, however, requires long follow-up in large numbers of patients. Subsequent crossover to another treatment following disease recurrence further confounds the assessment of OS benefit. DFS is the primary end point of most adjuvant trials, but the definition varies among trials, making cross-trial comparisons difficult. Importantly, DFS benefit does not always correlate with OS benefit. Distant metastasis is a well-recognized predictor of breast cancer-associated mortality, and AIs have shown greater efficacy over tamoxifen in reducing distant metastatic events and improving distant DFS (DDFS). A small proportion of initially treated early breast cancer patients may already have micrometastatic tumor deposits that can result in the rapid development of distant metastases. Thus, early identification and aggressive treatment of such patients with the most effective adjuvant therapies is a major goal. This review discusses the efficacy of the AIs in improving DDFS in the different adjuvant settings and explores whether significant improvements in DDFS correlate with meaningful improvements in OS or breast cancer-associated mortality. Significant DDFS improvement may be a quicker, better end point in clinical trials, leading to a more efficient, faster assessment of treatment efficacy.