Time-Varying Effects of Breast Cancer Adjuvant Systemic Therapy

The benefits of breast cancer adjuvant systemic treatments are generally assumed to be proportional (or constant) over time, but limited data suggest that some treatment effects may vary with time. We therefore systematically assessed the proportional hazards assumption across all 19 breast cancer adjuvant systemic therapy trials in the National Surgical Adjuvant Breast and Bowel Project (NSABP) database. The NSABP breast cancer trials were tested for the proportionality of hazard rates between randomized treatment groups for five endpoints: overall survival, disease-free survival and recurrence, local-regional recurrence, or distant recurrence as first events. When the proportional hazards assumption did not hold, a "change point for the relative risk" technique was used to identify the temporal breakdown of the treatment effect. Time-varying treatment effects were observed in nearly half of the trials (nine of 19). In six (B-05, B-11, B-12, B-14, B-16, and B-20), novel treatment benefits diminished statistically significantly at specific time points following surgery. In B-09 and B-31, novel treatment benefits were delayed and emerged more than one year after surgery (1.57 and 1.32 years correspondingly), but the benefit in B-09 reversed after the third year of follow-up. In one trial (B-23), the initial advantage and subsequent disadvantage of one of the regimens was evident. Breast cancer adjuvant systemic therapy can have statistically significant time-varying effects, which should be considered in the design, analysis, reporting, and translation of clinical trials. These time-dependent effects will have greater relevance as the number of long-term breast cancer survivors increases.