Adjuvant therapy for early stage breast cancer (EBC): Distant disease-free survival (DDFS) as a predictor of overall survival (OS)

Abstract

583 Background: OS advantages are often difficult to demonstrate in trials evaluating treatment for EBC, as this requires long follow-up (FU) and large trials. Results are also confounded by factors such as further treatment. DFS, the primary endpoint in many adjuvant trials, is not a consistent predictor of OS and lack of standard definitions renders its interpretation difficult. A better, quicker endpoint is needed as a surrogate for OS. Distant metastases (DM), the most common type of recurrence, are responsible for the initial peak of relapse seen at 2 years post surgery and are associated with the highest risk of death compared to locoregional and contralateral events. DDFS may be a better short-term OS predictor. Methods: The impact of common adjuvant therapies (chemotherapy [CT], tamoxifen [TAM], and aromatase inhibitors [AIs]) on DM risk and OS was examined. Results: CT trials show that improvements in DDFS often precede subsequent improvements in OS. In NSABP B14, TAM significantly improved DDFS at 4 years and OS at 10 years. In ATAC and BIG 1–98, over half of EBC recurrences are DM, but OS differences are limited by short FU. BIG 1–98 showed a significant reduction in DM risk with letrozole versus TAM, but ATAC showed no significant reduction in DM risk with anastrozole in hormone receptor-positive patients. The reason for this difference is unclear. IES initially showed a significant reduction in DM risk, which was later followed by a borderline significant OS benefit in estrogen receptor-positive/unknown patients, favoring exemestane. Conclusion: Data from several adjuvant trials show that improvements in DDFS often precede significant improvements in OS. AIs show superiority over TAM in reducing DM risk (IES, BIG 1–98). DDFS may be a better, more achievable endpoint than OS for women with EBC and could quicken the development of future adjuvant breast cancer therapies. [Table: see text] No significant financial relationships to disclose.