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

1235 Citations (Scopus)

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 - 2014

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Disease-Free Survival
Breast Neoplasms
Survival
Biomarkers
Triple Negative Breast Neoplasms
Neoadjuvant Therapy
PubMed
Neoplasms
Lymph Nodes
Clinical Trials
Hormones
Drug Therapy

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cortazar, P., Zhang, L., Untch, M., Mehta, K., Costantino, J. P., Wolmark, N., ... 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

Pathological complete response and long-term clinical benefit in breast cancer : The CTNeoBC pooled analysis. / Cortazar, Patricia; Zhang, Lijun; Untch, Michael; Mehta, Keyur; Costantino, Joseph P.; Wolmark, Norman; Bonnefoi, Hervé; Cameron, David; Gianni, Luca; Valagussa, Pinuccia; Swain, Sandra M.; Prowell, Tatiana; Loibl, Sibylle; Wickerham, D. Lawrence; Bogaerts, Jan; Baselga, Jose; Perou, Charles; Blumenthal, Gideon; Blohmer, Jens; Mamounas, Eleftherios P.; Bergh, Jonas; Semiglazov, Vladimir; Justice, Robert; Eidtmann, Holger; Paik, Soonmyung; Piccart, Martine; Sridhara, Rajeshwari; Fasching, Peter A.; Slaets, Leen; Tang, Shenghui; Gerber, Bernd; Geyer, Charles E.; Pazdur, Richard; Ditsch, Nina; Rastogi, Priya; Eiermann, Wolfgang; Von Minckwitz, Gunter.

In: The Lancet, Vol. 384, No. 9938, 2014, p. 164-172.

Research output: Contribution to journalArticle

Cortazar, P, Zhang, L, Untch, M, Mehta, K, Costantino, JP, Wolmark, N, Bonnefoi, H, Cameron, D, Gianni, L, Valagussa, P, Swain, SM, Prowell, T, Loibl, S, Wickerham, DL, Bogaerts, J, Baselga, J, Perou, C, Blumenthal, G, Blohmer, J, Mamounas, EP, Bergh, J, Semiglazov, V, Justice, R, Eidtmann, H, Paik, S, Piccart, M, Sridhara, R, Fasching, PA, Slaets, L, Tang, S, Gerber, B, Geyer, CE, Pazdur, R, Ditsch, N, Rastogi, P, Eiermann, W & Von Minckwitz, G 2014, 'Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis', The Lancet, vol. 384, no. 9938, pp. 164-172. https://doi.org/10.1016/S0140-6736(13)62422-8
Cortazar, Patricia ; Zhang, Lijun ; Untch, Michael ; Mehta, Keyur ; Costantino, Joseph P. ; Wolmark, Norman ; Bonnefoi, Hervé ; Cameron, David ; Gianni, Luca ; Valagussa, Pinuccia ; Swain, Sandra M. ; Prowell, Tatiana ; Loibl, Sibylle ; Wickerham, D. Lawrence ; Bogaerts, Jan ; Baselga, Jose ; Perou, Charles ; Blumenthal, Gideon ; Blohmer, Jens ; Mamounas, Eleftherios P. ; Bergh, Jonas ; Semiglazov, Vladimir ; Justice, Robert ; Eidtmann, Holger ; Paik, Soonmyung ; Piccart, Martine ; Sridhara, Rajeshwari ; Fasching, Peter A. ; Slaets, Leen ; Tang, Shenghui ; Gerber, Bernd ; Geyer, Charles E. ; Pazdur, Richard ; Ditsch, Nina ; Rastogi, Priya ; Eiermann, Wolfgang ; Von Minckwitz, Gunter. / Pathological complete response and long-term clinical benefit in breast cancer : The CTNeoBC pooled analysis. In: The Lancet. 2014 ; Vol. 384, No. 9938. pp. 164-172.
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title = "Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis",
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.",
author = "Patricia Cortazar and Lijun Zhang and Michael Untch and Keyur Mehta and Costantino, {Joseph P.} and Norman Wolmark and Herv{\'e} Bonnefoi and David Cameron and Luca Gianni and Pinuccia Valagussa and Swain, {Sandra M.} and Tatiana Prowell and Sibylle Loibl and Wickerham, {D. Lawrence} and Jan Bogaerts and Jose Baselga and Charles Perou and Gideon Blumenthal and Jens Blohmer and Mamounas, {Eleftherios P.} and Jonas Bergh and Vladimir Semiglazov and Robert Justice and Holger Eidtmann and Soonmyung Paik and Martine Piccart and Rajeshwari Sridhara and Fasching, {Peter A.} and Leen Slaets and Shenghui Tang and Bernd Gerber and Geyer, {Charles E.} and Richard Pazdur and Nina Ditsch and Priya Rastogi and Wolfgang Eiermann and {Von Minckwitz}, Gunter",
year = "2014",
doi = "10.1016/S0140-6736(13)62422-8",
language = "English (US)",
volume = "384",
pages = "164--172",
journal = "The Lancet",
issn = "0140-6736",
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number = "9938",

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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

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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