Evolution in sites of recurrence over time in breast cancer patients treated with adjuvant endocrine therapy

Background: Hormone receptor positive breast cancer is characterized by a prolonged risk of recurrence. Extended adjuvant endocrine therapy improves disease-free survival (DFS), but no effect on overall survival has been observed. This may be explained by changes in the relative contribution of local, regional and distant recurrences as well as non-breast cancer death to DFS events over time. Patients and methods: We reviewed sequential reports of large, randomized, adjuvant endocrine therapy trials extracting the number and types of recurrences defining DFS events at each point over follow-up. Meta-regression was performed to explore the relative contribution of contralateral, loco-regional and distant recurrences as well as non-breast cancer death to DFS over time. Results: Analysis included 17 reports of 6 trials reporting outcomes between 28 and 120 months of follow-up. Over time, there was increasing contribution of contralateral breast cancer (5% of events at 20 months to 12% at 120 months; beta = 0.663, p = 0.004) and non-breast cancer death (20% of events at 20 months to 32% at 120 months; beta = 0.581, p = 0.01). There was a non-significant reduction in the contribution of distant recurrence (57% of events at 20 months to 45% at 120 months; beta = -0.397, p = 0.11), but no change in loco regional recurrence (18% of events at 20 months to 11% at 120 months; beta = -0.301, p = 0.30). Conclusions: With increasing follow-up, DFS events are increasing defined by contralateral recurrence and non breast cancer deaths with a trend for fewer distant recurrences. This may explain the limited association between DFS and overall survival with extended adjuvant endocrine therapy.