Breast Cancer Res Treat (2008) 109:567–572 571 A )%19000 ( ty 80 i l ib 70 ab 60 rop 50 e 40 om 30 tcu 20 O 10 0 B ) 100 (% 90 ty 80 i l ib 70 ab 60 rop 50 e 40 om 30 tcu 20 O 10 0 0 0 2 2 4 6 8 10 DSS / OS DFI / DFS DSS DFI OS DFS 4 6 Follow-up (year) 8 10 Fig. 1 Inﬂuence of survival deﬁnitions on estimated outcome probability in breast cancer patients 50 years or less of age (A), and over 70 years of age (B). Both by Kaplan–Meier method (solid line) and competing risk analysis (dotted line). DSS: disease speciﬁc survival; OS: overall survival; DFI: disease free interval; DFS: disease free survival. Contralateral breast cancer was ignored in the deﬁnition of relapse. outcome could inﬂuence the results of a trial. We can illustrate this with data from the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial, in which 6241 patients were included in the 2 relevant arms of this trial [12, 13]. After a median follow-up of 68 months, 831 pa- tients have died (411 patients treated with anastrozole and 420 patients treated with tamoxifen). More patients who were treated with tamoxifen died from breast cancer than patients who were treated with anastrozole (265 vs. 235), whereas fewer patients who received tamoxifen died from a cause not related to breast cancer (155 vs. 176). Treat- ment with anastrozole also led to a reduction in disease recurrences (402 vs. 498). A considerable part of this reduction was caused by the difference in occurrence of contralateral breast cancers (35 vs. 59). Consequently, anastrozole led to an improvement in disease free survival (Hazard Rate (HR) 0.87, P = 0.01), and an even better improvement in disease free interval (HR 0.79, P = 0.0005). Overall survival was similar for anastrozole and tamoxifen treated patients (HR 0.97), whereas disease speciﬁc survival was 12% better in the anastrozole group, although this was not signiﬁcant (HR 0.88, P = 0.20). These data from the ATAC trial illustrate that a clear deﬁnition of survival endpoints, including the contribution of non-disease related death and the contribution of con- tralateral breast cancer to the estimated disease recurrence rate are crucial for a correct interpretation of outcome analyses in clinical trials. These data also demonstrate that a signiﬁcant difference in disease free survival is not automatically followed by a signiﬁcant difference in overall survival. The Kaplan–Meier method for estimating survival has repeatedly been criticised for possible biases in the esti- mation of event rates [8, 9, 11, 14]. In the presence of competing events, cumulative incidence functions of the events of interest are probably evaluated more appropri- ately by taking into account other events within a com- peting risk framework. In general, event rates derived using the Kaplan–Meier approach are larger than estimates accounting for competing risks, [8, 9, 11] and differences between Kaplan–Meier and competing risk approaches can become substantial when the competing risk event is re- lated to or is a result of the underlying disease. But, as presented by Satagopan et al. ignoring the informative censoring mechanism does not substantially inﬂuence the estimates of breast cancer-speciﬁc mortality [15]. We present similar results in our estimations of disease-speciﬁc survival and disease free survival. However, differences became more substantial when relatively more patients were censored due to competing events. Although not the subject of our current analyses, it is probably more likely that ignoring of the informative censoring mechanism will substantially inﬂuence the estimates of local recurrence. Conclusion Clear deﬁnitions of endpoints and competing events are crucial for the correct interpretation and reliable compari- son of outcome studies. In the present study on patients with early breast cancer, the inclusion of contralateral breast cancer and/or non-disease related death substantially inﬂuenced estimates of recurrent disease rate and survival, speciﬁcally in elder patients and patients with a good prognosis. Bias generated by the Kaplan–Meier approach due to informative censoring of contralateral breast cancer or non-disease related death was limited. References 1. Altman DG, De Stavola BL, Love SB, Stepniewska KA (1995) Review of survival analyses published in cancer journals. Br J Cancer 72:511–518 2. Altman DG, De Stavola BL, Love SB, Stepniewska KA (1998) Polychemotherapy for early breast cancer: an overview of the 123