TY - JOUR
T1 - Pathological complete response and long-term clinical benefit in breast cancer
T2 - The CTNeoBC pooled analysis
AU - Cortazar, Patricia
AU - Zhang, Lijun
AU - Untch, Michael
AU - Mehta, Keyur
AU - Costantino, Joseph P.
AU - Wolmark, Norman
AU - Bonnefoi, Hervé
AU - Cameron, David
AU - Gianni, Luca
AU - Valagussa, Pinuccia
AU - Swain, Sandra M.
AU - Prowell, Tatiana
AU - Loibl, Sibylle
AU - Wickerham, D. Lawrence
AU - Bogaerts, Jan
AU - Baselga, Jose
AU - Perou, Charles
AU - Blumenthal, Gideon
AU - Blohmer, Jens
AU - Mamounas, Eleftherios P.
AU - Bergh, Jonas
AU - Semiglazov, Vladimir
AU - Justice, Robert
AU - Eidtmann, Holger
AU - Paik, Soonmyung
AU - Piccart, Martine
AU - Sridhara, Rajeshwari
AU - Fasching, Peter A.
AU - Slaets, Leen
AU - Tang, Shenghui
AU - Gerber, Bernd
AU - Geyer, Charles E.
AU - Pazdur, Richard
AU - Ditsch, Nina
AU - Rastogi, Priya
AU - Eiermann, Wolfgang
AU - Von Minckwitz, Gunter
N1 - Funding Information:
This project was partly funded by the US Food and Drug Administration. We thank Janet Woodcock, who provided financial support for the CTNeoBC pooled analysis; all the patients, Breast Cancer Cooperative Groups, investigators, pathologists, and statisticians who participated in the neoadjuvant trials; and Jo Anne Zujewski for her help.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1016/S0140-6736(13)62422-8
DO - 10.1016/S0140-6736(13)62422-8
M3 - Article
C2 - 24529560
AN - SCOPUS:84904188903
SN - 0140-6736
VL - 384
SP - 164
EP - 172
JO - The Lancet
JF - The Lancet
IS - 9938
ER -