Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in HER2–Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti–HER2 Therapy

Pathologic complete response (pCR) has prognostic importance and is frequently used as a primary end point, but doubts remain about its validity as a surrogate for event-free survival (EFS) and overall survival (OS) in human epidermal growth factor receptor 2 (HER2)–positive, early breast cancer.

We obtained individual-patient data from randomized trials of neoadjuvant anti-HER2 therapy that enrolled at least 100 patients, had data for pCR, EFS, and OS, and a median follow-up of at least 3 years. We quantified the patient-level association between pCR (defined as ypT0/Tis ypN0) and both EFS and OS using odds ratios (ORs, with ORs >1.00 indicating a benefit from achieving a pCR). We quantified the trial-level association between treatment effects on pCR and on EFS and OS using R2 (with values above 0.75 considered as indicating strong associations).


Eleven of 15 eligible trials had data for analysis (3,980 patients, with a median follow-up of 62 months). Considering all trials, we found strong patient-level associations, with ORs of 2.64 (95% CI, 2.20 to 3.07) for EFS and 3.15 (95% CI, 2.38 to 3.91) for OS; however, trial-level associations were weak, with an unadjusted R2 of 0.23 (95% CI, 0 to 0.66) for EFS and 0.02 (95% CI, 0 to 0.17) for OS. We found qualitatively similar results when grouping trials according to different clinical questions, when analyzing only patients with hormone receptor–negative disease, and when using a more stringent definition of pCR (ypT0 ypN0).

Although pCR may be useful for patient management, it cannot be considered as a surrogate for EFS or OS in neoadjuvant trials of HER2-positive, operable breast cancer.


“Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2–Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti–Human Epidermal Growth Factor Receptor 2 Therapy” has been published in DOI: 10.1200/JCO.22.02363 Journal of Clinical Oncology

Published online March 28, 2023.

By Pierre Squifflet, MSc; Everardo D. Saad, MD; Sibylle Loibl, MD; Marion T. van Mackelenbergh, MD; Michael Untch, MD; Priya Rastogi, MD; Luca Gianni, MD; Andreas Schneeweiss, MD; Pierfranco Conte, MD; Martine Piccart, MD; Hervé Bonnefoi, MD; Christian Jackisch, MD; Valentina Nekljudova, PhD; Gong Tang, PhD; Pinuccia Valagussa, MD; Colin Neate, MD; Richard Gelber, PhD; Coralie Poncet, PhD; Dominik Heinzmann, MD; Carsten Denkert, MD; Charles E. Geyer Jr, MD; Javier Cortes, MD; Valentina Guarneri, MD; Evandro de Azambuja, MD; David Cameron, MD; Gustavo Ismael, MD; Norman Wolmark, MD; Patricia Cortazar, MD; Marc Buyse, ScD; and on behalf of the CTNeoBC Project.