Influence of Competing Risks on Estimates of Recurrence Risk and Breast Cancer-Specific Mortality in Analyses of the Early Breast Cancer Trialists Collaborative Group

Abstract

Introduction: Early stage breast cancer is a curable disease with many patients dying of causes other than breast cancer. The influence of these competing risks of death on the interpretation of Kaplan-Meier (KM)-based analyses for other outcomes by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) are unknown. Methods: We searched the Clinical Trial Service Unit and Epidemiological Studies Unit website at Oxford University to identify all meta-analyses published by the EBCTCG between 2005 and 2018. Studies were included if they risk estimates for either breast cancer mortality and/or breast cancer recurrence based on KM analyses and reported competing events. The potential influence of competing risks was estimated using a validated multivariate linear model that predicts the difference between KM and cumulative incidence function (CIF) on estimates of breast cancer-specific outcomes. Results: The initial search identified 14 analyses published by the EBCTCG, 10 of which (71%) reported data on breast cancer and competing events. Eight of the ten studies (80%) had a relative difference between the KM and the competing risk adjusted estimates exceeding 10%. The median (range) relative difference between the KM and adjusted estimates was: 28.4% for local recurrence; 16.8% for distant recurrence, and 6.7% for breast cancer-specific mortality. There was a 2.2% relative difference between KM and CIF adjusted analyses between 0-4 years of follow-up and 18.9% beyond 10 years. Use of KM vs. CIF-based analysis did not influence treatment effect in most included studies. Conclusions: The use of KM-based methods when competing risks are present biases risk estimates in studies of early breast cancer. Future studies should exclusively use the CIF to calculate breast cancer specific outcomes. Funding: N/A Declaration of Interest: Dr. Eitan AMIR reports personal fees from Genentech/Roche, personal fees from Apobiologix, personal fees from Myriad Genetics, personal fees from Agendia, outside the submitted work. Ethical Approval: This study was exempt from institutional review board approval since it used publicly available data exclusively.