Abstract P2-16-01: Relationship between overall survival and surrogate measures in patients with metastatic breast cancer treated with chemotherapy
Authors: Culakova E , Poniewierski MS , Crawford J , Dale DC , Lyman GH 
Published: March 2017

Abstract
Background: While metastatic breast cancer (MBC) is considered an incurable disease, nearly one-fifth of patients live longer than five years following diagnosis. In an effort to identify novel agents earlier, surrogate end points of overall survival (OS) such as response or progression are often employed in randomized controlled trials (RCTs). The goal of this analysis is to evaluate patterns of outcome reporting and the relationship of OS with surrogate measures in RCTs of patients with MBC.
Methods: The analysis was based on data from a systematic review of patients with MBC evaluating the clinical impact of chemotherapy intensity on survival. Reports of phase 2-3 RCTs published between 1990-2013 comparing more intense chemotherapy regimens (higher dose intensity or use of additional agents) with less intense were identified. For each RCT, clinical, treatment, demographic and outcome data were extracted. Outcomes evaluated included OS, progression free survival (PFS), and time to progression (TTP) with a focus on median survival and hazard ratios (HRs) as measures of treatment effect. Survival post progression (SPP) was calculated as the difference between median survival and median progression free time. The relations between various outcome measures were estimated utilizing weighted Pearson correlation coefficient (CORR) adjusted by Fisher's transformation. Weights were assigned proportionally to the sample size of individual RCTs.
Results: The review identified 70 eligible RCTs including 15,043 patients with MBC. Average median OS, PFS, and TTP were 19.2, 6.9, and 8.1 months reported in 96%, 60%, and 43% of studies, respectively. Progression could be determined in 66 studies, while 6 RCTs provided both outcomes. TTP was more often utilized in earlier studies (65% in 1990-2000, 35% in 2001-2008, and 33% in 2009-2013) and it was superseded by PFS in later years (20%, 70% and 81%, respectively). Only 37%, 33%, and 11% of RCTs reported HRs for OS, PFS, and TTP, respectively. HRs were more often available in recent publications (20% in 1990-2000, 22% in 2001-2008, 63% in 2009-2013 provided HR for OS). The correlation between reported HR and HR estimated by the ratio of arm-specific median survival times was high for OS (CORR=0.87, 95%CI: 0.73-0.94) and TTP (CORR=0.92, 95%CI: 0.61-0.99) and slightly lower for PFS (CORR=0.72, 95%CI: 0.44-0.87). The relationship between OS and surrogate measures (PFS, TTP) was weaker. The correlation between HR for OS and PFS was 0.49 (95%CI: 0.21-0.69) and for OS and TTP it was 0.26 (95%CI: -0.13-0.58). Survival time following progression was dependent on treatment type and was longer in less intense arms than more intense (mean SPP: 12.4 months vs. 11.4 months, P=0.0155).
Conclusions: In RCTs of patients with MBC treated with chemotherapy, when HR is not reported and if necessary statistical conditions are met, the HR approximated by ratio of median survival times may be a suitable proxy estimate. In agreement with other reports, neither PFS nor TTP are acceptable surrogate outcomes for OS in MBC, as survival following progression may be substantial. In these patients, crossover and post-trial treatments may influence the relationship between OS and surrogate measures.
Citation Format: Culakova E, Poniewierski MS, Crawford J, Dale DC, Lyman GH. Relationship between overall survival and surrogate measures in patients with metastatic breast cancer treated with chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-16-01.