title: Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial.
abstract: BACKGROUND
  Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes.
  
  
  METHODS
  Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses.
  
  
  RESULTS
  Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1).
  
  
  CONCLUSIONS
  pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis.
  
  
  BACKGROUND
  EORTC 10994/BIG 1-00 Trial registration number NCT00017095.
authors.affiliation: Department of Medical Oncology, Institut Bergonié Comprehensive Cancer Centre, Université de Bordeaux, INSERM U916, Bordeaux, France h.bonnefoi@bordeaux.unicancer.fr.
authors.forename: H
authors.initials: H
authors.lastname: Bonnefoi
authors.affiliation: European Organisation for Research and Treatment of Cancer (EORTC), Brussels.
authors.forename: S
authors.initials: S
authors.lastname: Litière
authors.affiliation: Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Piccart
authors.affiliation: Department of Medical Oncology, Institut Bergonié Comprehensive Cancer Centre, Université de Bordeaux, INSERM U916, Bordeaux, France.
authors.forename: G
authors.initials: G
authors.lastname: MacGrogan
authors.affiliation: Centre George-François Leclerc, Dijon.
authors.forename: P
authors.initials: P
authors.lastname: Fumoleau
authors.affiliation: Ensemble Hospitalier de L'Institut Curie, Hopital René Huguenin, St-Cloud.
authors.forename: E
authors.initials: E
authors.lastname: Brain
authors.affiliation: Centre Paul Strauss, Strasbourg.
authors.forename: T
authors.initials: T
authors.lastname: Petit
authors.affiliation: Centre Val D'Aurelle-Paul Lamarque, Montpellier, France.
authors.forename: P
authors.initials: P
authors.lastname: Rouanet
authors.affiliation: Medical University, Gdansk, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Jassem
authors.affiliation: Centre Henri Becquerel, Rouen, France.
authors.forename: C
authors.initials: C
authors.lastname: Moldovan
authors.affiliation: Geneva University Hospital, Geneva Swiss Group for Clinical Cancer Research (SAKK), Bern.
authors.forename: A
authors.initials: A
authors.lastname: Bodmer
authors.affiliation: Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Zaman
authors.affiliation: Institute of Oncology, Ljubljana University Clinic Golnik, Golnik, Slovenia.
authors.forename: T
authors.initials: T
authors.lastname: Cufer
authors.affiliation: Institut de Cancérologie de L'Ouest (ICO), Centre René Gauducheau, Nantes Centre Paul Papin, Angers.
authors.forename: M
authors.initials: M
authors.lastname: Campone
authors.affiliation: Centre Alexis Vautrin, Nancy, France.
authors.forename: E
authors.initials: E
authors.lastname: Luporsi
authors.affiliation: Department of Clinical Sciences, Lund University, Lund Skåne Department of Oncology, Skåne University Hospital, Lund.
authors.forename: P
authors.initials: P
authors.lastname: Malmström
authors.affiliation: European Organisation for Research and Treatment of Cancer (EORTC), Brussels.
authors.forename: G
authors.initials: G
authors.lastname: Werutsky
authors.affiliation: European Organisation for Research and Treatment of Cancer (EORTC), Brussels.
authors.forename: J
authors.initials: J
authors.lastname: Bogaerts
authors.affiliation: Swedish Breast Cancer Group (SweBCG), Stockholm Department of Oncology, Karolinska Institutet, Radiumhemmet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Bergh
authors.affiliation: Cancer Services, Edinburgh University Anglo-Celtic Cooperative Oncology Group (ACCOG), Edinburgh, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Cameron
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D017024:Chemotherapy, Adjuvant / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: TP53; breast cancer; landmark analysis; neoadjuvant chemotherapy; pathological complete response