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Evaluation of Tumor Response, Disease Control, Progression-Free Survival, and Time to Progression As Potential Surrogate End Points in Metastatic Breast Cancer

Tomasz Burzykowski, Marc Buyse, Martine J. Piccart-Gebhart, George Sledge, James Carmichael, Hans-Joachim Lück, John R. Mackey, Jean-Marc Nabholtz, Robert Paridaens, Laura Biganzoli, Jacek Jassem, Marijke Bontenbal, Jacques Bonneterre, Stephen Chan, Gul Atalay Basaran, Patrick Therasse

From the Hasselt University, Diepenbeek; International Drug Development Institute, Louvain-la-Neuve; University Hospital Gasthuisberg, Leuven; Institut Jules Bordet; and European Organization for Research and Treatment of Cancer, Brussels, Belgium; Indiana University-Purdue University, Indianapolis, IN; Astra Zeneca, Macclesfield; and Nottingham City Hospital, United Kingdom; Medizinische Hochschule, Hannover, Germany; University of Alberta, Edmonton, Canada; Breast Cancer Research Institute–La Prandie, Valojoulx; and Centre Oscar Lambret, Lille, France; Hospital of Prato, Italy; Medical University of Gdansk, Poland; Erasmus MC, University Medical Center, Rotterdam, the Netherlands; and Marmara University Hospital, Istanbul, Turkey

Corresponding author: Tomasz Burzykowski, Hasselt University, Center for Statistics, Agoralaan, Bldg D, 3590 Diepenbeek, Belgium; e-mail: tomasz.burzykowski{at}uhasselt.be

Purpose: Overall survival (OS) can be observed only after prolonged follow-up, and any potential effect of first-line therapies on OS may be confounded by the effects of subsequent therapy. We investigated whether tumor response, disease control, progression-free survival (PFS), or time to progression (TTP) could be considered a valid surrogate for OS to assess the benefits of first-line therapies for patients with metastatic breast cancer.

Patients and Methods: Individual patient data were collected on 3,953 patients in 11 randomized trials that compared an anthracycline (alone or in combination) with a taxane (alone or in combination with an anthracycline). Surrogacy was assessed through the correlation between the end points as well as through the correlation between the treatment effects on the end points.

Results: Tumor response (survival odds ratio [OR], 6.2; 95% CI, 5.3 to 7.0) and disease control (survival OR, 5.5; 95% CI, 4.8 to 6.3) were strongly associated with OS. PFS (rank correlation coefficient, 0.688; 95% CI, 0.686 to 0.690) and TTP (rank correlation coefficient, 0.682; 95% CI, 0.680 to 0.684) were moderately associated with OS. Response log ORs were strongly correlated with PFS log hazard ratios (linear coefficient [], 0.96; 95% CI, 0.73 to 1.19). Response and disease control log ORs and PFS and TTP log hazard ratios were poorly correlated with log hazard ratios for OS, but the confidence limits of were too wide to be informative.

Conclusion: No end point could be demonstrated as a good surrogate for OS in these trials. Tumor response may be an acceptable surrogate for PFS.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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