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.
  
  
  RESULTS
  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-receptor-negative 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 (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  US Food and Drug Administration.
authors: US Food and Drug Administration, Silver Spring, MD, USA. Electronic address: patricia.cortazar@fda.hhs.gov.
authors: Patricia
authors: P
authors: Cortazar
authors: US Food and Drug Administration, Silver Spring, MD, USA.
authors: Lijun
authors: L
authors: Zhang
authors: HELIOS Klinikum, Berlin, Germany.
authors: Michael
authors: M
authors: Untch
authors: German Breast Group, Neu-Isenburg, Germany.
authors: Keyur
authors: K
authors: Mehta
authors: National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, USA.
authors: Joseph P
authors: JP
authors: Costantino
authors: National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, USA.
authors: Norman
authors: N
authors: Wolmark
authors: Institut Bergonié INSERM U916 and Université Bordeaux Segalen, Bordeaux, France.
authors: Hervé
authors: H
authors: Bonnefoi
authors: Edinburgh Cancer Research Centre, University of Edinburgh and NHS Lothian, UK.
authors: David
authors: D
authors: Cameron
authors: San Raffaele Scientific Institute, Milan, Italy.
authors: Luca
authors: L
authors: Gianni
authors: Fondazione Michelangelo, Milan, Italy.
authors: Pinuccia
authors: P
authors: Valagussa
authors: Medstar Washington Hospital Center, Washington, DC, USA.
authors: Sandra M
authors: SM
authors: Swain
authors: US Food and Drug Administration, Silver Spring, MD, USA.
authors: Tatiana
authors: T
authors: Prowell
authors: German Breast Group, Neu-Isenburg, Germany.
authors: Sibylle
authors: S
authors: Loibl
authors: National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, USA.
authors: D Lawrence
authors: DL
authors: Wickerham
authors: EORTC Headquarters, Brussels, Belgium.
authors: Jan
authors: J
authors: Bogaerts
authors: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: Jose
authors: J
authors: Baselga
authors: Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
authors: Charles
authors: C
authors: Perou
authors: US Food and Drug Administration, Silver Spring, MD, USA.
authors: Gideon
authors: G
authors: Blumenthal
authors: St Gertrauden Hospital, Berlin, Germany.
authors: Jens
authors: J
authors: Blohmer
authors: MD Anderson Cancer Center Orlando, Orlando, FL, USA.
authors: Eleftherios P
authors: EP
authors: Mamounas
authors: KarolinskaInstitutet and University Hospital, Stockholm, Sweden.
authors: Jonas
authors: J
authors: Bergh
authors: NN Petrov Research Institute of Oncology, St Petersburg, Russia.
authors: Vladimir
authors: V
authors: Semiglazov
authors: US Food and Drug Administration, Silver Spring, MD, USA.
authors: Robert
authors: R
authors: Justice
authors: University Women's Hospital, Kiel, Germany.
authors: Holger
authors: H
authors: Eidtmann
authors: National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, USA.
authors: Soonmyung
authors: S
authors: Paik
authors: Jules Bordet Institute, Brussels, Belgium.
authors: Martine
authors: M
authors: Piccart
authors: US Food and Drug Administration, Silver Spring, MD, USA.
authors: Rajeshwari
authors: R
authors: Sridhara
authors: Frauenklinik des Universitätsklinikums, Erlangen, Germany.
authors: Peter A
authors: PA
authors: Fasching
authors: EORTC Headquarters, Brussels, Belgium.
authors: Leen
authors: L
authors: Slaets
authors: US Food and Drug Administration, Silver Spring, MD, USA.
authors: Shenghui
authors: S
authors: Tang
authors: Universitäts Frauenklinik, Rostock, Germany.
authors: Bernd
authors: B
authors: Gerber
authors: Virginia Commonwealth University Massey Cancer Center, Richmond, VA, USA.
authors: Charles E
authors: CE
authors: Geyer
authors: US Food and Drug Administration, Silver Spring, MD, USA.
authors: Richard
authors: R
authors: Pazdur
authors: Hospital of the Ludwig Maximilian University of Munich, Munich, Germany.
authors: Nina
authors: N
authors: Ditsch
authors: National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA, USA.
authors: Priya
authors: P
authors: Rastogi
authors: Hospital of the Ludwig Maximilian University of Munich, Munich, Germany.
authors: Wolfgang
authors: W
authors: Eiermann
authors: German Breast Group, Neu-Isenburg, Germany.
authors: Gunter
authors: G
authors: von Minckwitz
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000473:pathology* / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000473:pathology* / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology / Q000628:therapy; D011300:Preoperative Care / Q000379:methods; D016032:Randomized Controlled Trials as Topic; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068878:Trastuzumab