Surrogacy Beyond Prognosis: The Importance of “Trial-Level” Surrogacy

Abstract Many candidate surrogate endpoints are currently assessed using a 2-level statistical approach, which consists in checking whether (1) the potential surrogate is associated with the final endpoint in individual patients and (2) the effect of treatment on the surrogate can be used to reliabl...

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Published in:The oncologist (Dayton, Ohio) Vol. 27; no. 4; pp. 266 - 271
Main Authors: Buyse, Marc, Saad, Everardo D, Burzykowski, Tomasz, Regan, Meredith M, Sweeney, Christopher S
Format: Journal Article
Language:English
Published: US Oxford University Press 05.04.2022
Subjects:
Biomarkers
Breast Cancer
Breast Neoplasms - pathology
Cancer
Care and treatment
Clinical trials
Diagnosis
Disease-Free Survival
Female
Humans
Medical prognosis
Methods
Neoadjuvant Therapy
Prognosis
Treatment Outcome
United States
ISSN:1083-7159, 1549-490X, 1549-490X
Online Access:Get full text
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Summary:Abstract Many candidate surrogate endpoints are currently assessed using a 2-level statistical approach, which consists in checking whether (1) the potential surrogate is associated with the final endpoint in individual patients and (2) the effect of treatment on the surrogate can be used to reliably predict the effect of treatment on the final endpoint. In some situations, condition (1) is fulfilled but condition (2) is not. We use concepts of causal inference to explain this apparently paradoxical situation, illustrating this review with 2 contrasting examples in operable breast cancer: the example of pathological complete response (pCR) and that of disease-free survival (DFS). In a previous meta-analysis, pCR has been shown to be a strong and independent prognostic factor for event-free survival (EFS) and overall survival (OS) after neoadjuvant treatment of operable breast cancer. Yet, in randomized trials, the effects of experimental treatments on pCR have not translated into predictable effects on EFS or OS, making pCR an “individual-level” surrogate, but not a “trial-level” surrogate. In contrast, DFS has been shown to be an acceptable surrogate for OS at both the individual and trial levels in early, HER2-positive breast cancer. The distinction between the prognostic and predictive roles of a tentative surrogate, not always made in the literature, avoids unnecessary confusion and allows better understanding of what it takes to validate a surrogate endpoint that is truly able to replace a final endpoint. Many candidate surrogate endpoints are currently assessed using a two-level statistical approach. This article explores tentative surrogates versus actual outcomes, focusing on the “surrogate paradox”.
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ISSN:1083-7159
1549-490X
1549-490X
DOI:10.1093/oncolo/oyac006