Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis

Patricia Cortazar, Lijun Zhang, Michael Untch, Keyur Mehta, Joseph P. Costantino, Norman Wolmark, Hervé Bonnefoi, David Cameron, Luca Gianni, Pinuccia Valagussa, Sandra M. Swain, Tatiana Prowell, Sibylle Loibl, D. Lawrence Wickerham, Jan Bogaerts, Jose Baselga, Charles Perou, Gideon Blumenthal, Jens Blohmer, Eleftherios P. MamounasJonas Bergh, Vladimir Semiglazov, Robert Justice, Holger Eidtmann, Soonmyung Paik, Martine Piccart, Rajeshwari Sridhara, Peter A. Fasching, Leen Slaets, Shenghui Tang, Bernd Gerber, Charles E. Geyer, Richard Pazdur, Nina Ditsch, Priya Rastogi, Wolfgang Eiermann, Gunter Von Minckwitz

Research output: Contribution to journalArticle

1441 Scopus citations

Abstract

Background Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. Methods We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response-ypT0 ypN0, ypT0/is ypN0, and ypT0/is-for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. Findings We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone- receptornegative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R2=0·03, 95% CI 0·00-0·25) and OS (R2=0·24, 0·00-0·70). Interpretation Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS.

Original languageEnglish (US)
Pages (from-to)164-172
Number of pages9
JournalThe Lancet
Volume384
Issue number9938
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Medicine(all)

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    Cortazar, P., Zhang, L., Untch, M., Mehta, K., Costantino, J. P., Wolmark, N., Bonnefoi, H., Cameron, D., Gianni, L., Valagussa, P., Swain, S. M., Prowell, T., Loibl, S., Wickerham, D. L., Bogaerts, J., Baselga, J., Perou, C., Blumenthal, G., Blohmer, J., ... Von Minckwitz, G. (2014). Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. The Lancet, 384(9938), 164-172. https://doi.org/10.1016/S0140-6736(13)62422-8