title: Time to initiation of adjuvant chemotherapy in patients with rapidly proliferating early breast cancer.
abstract: OBJECTIVE
  To evaluate the optimal time interval from definitive surgery to commencing chemotherapy in early breast cancer (EBC).
  
  
  METHODS
  The relationship between time to initiation of adjuvant chemotherapy (TTC), calculated in weeks, and disease-free (DFS) or overall survival (OS), was assessed in 921 EBC patients with rapidly proliferating tumours (thymidine labelling index >3% or G3 or Ki67 >20%), randomised in a phase III clinical trial (NCT01031030) to receive chemotherapy with or without anthracyclines (epirubicin→cyclophosphamide, methotrexate and fluorouracil (CMF) versus CMF→epirubicin versus CMF). DFS, OS and 95% confidence intervals (95% confidence interval (CI)) were calculated by the Kaplan-Meier method. Multivariate Cox analysis was performed in relation with nodal involvement, oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumour size.
  
  
  RESULTS
  At a median follow-up of 105 months (range 2-188), a prolonged TTC resulted in a significant increase in the risk of relapse: hazard ratio (HR) 1.15 (95% CI 1.02-1.30, p=0.019). Using a backward elimination procedure, TTC, tumour size and nodal involvement remained significantly associated with DFS. A time-dependent receiver-operating characteristic (ROC) curve analysis was subsequently utilised to evaluate the best cut-off for TTC, identifying 7 weeks as the best threshold for longer OS (p=0.043): 8-year OS 88% (95% CI 85-90) for patients with a TTC <7 weeks and 78% (95% CI 68-87) for the other group.
  
  
  CONCLUSIONS
  Our results confirm that a shorter TTC may reduce relapses and possibly also improve clinical outcome in patients with highly proliferating EBC.
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. Electronic address: alberto.farolfi@irst.emr.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Farolfi
authors.affiliation: Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rocca
authors.affiliation: Functional Biomorphology Laboratory, Istituto Tumori "Giovanni Paolo II"-IRCCS, Bari, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Mangia
authors.affiliation: Obstetrics and Gynaecology Unit, University of Torino Medical School, Torino, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Biglia
authors.affiliation: Department of Oncology, Per gli Infermi Hospital, Rimini, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gianni
authors.affiliation: Oncology Unit, S. Maria delle Croci Hospital, Ravenna, Italy.
authors.forename: Amelia
authors.initials: A
authors.lastname: Tienghi
authors.affiliation: Department of Medical Oncology, AUOP Palermo, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Valerio
authors.affiliation: Department of Oncology, San Filippo Neri Hospital, Roma, Italy.
authors.forename: Giampietro
authors.initials: G
authors.lastname: Gasparini
authors.affiliation: Oncology Unit, Degli Infermi Hospital, Faenza, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Amaducci
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Faedi
authors.affiliation: Oncology Unit, S. Luca Hospital, Lucca, Italy.
authors.forename: Editta
authors.initials: E
authors.lastname: Baldini
authors.affiliation: Department of Internal Medicine of the University of Genoa and Academic Unit of Medical Oncology, AOU San Martino-IST, Genoa, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rubagotti
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Maltoni
authors.affiliation: Clinical Experimental Oncology Laboratory, Istituto Tumori "Giovanni Paolo II"-IRCCS, Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D008408:Mastectomy / Q000009:adverse effects / Q000401:mortality; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors; D061665:Time-to-Treatment; D016896:Treatment Outcome
keywords: Adjuvant chemotherapy; Early breast cancer; Rapidly proliferating tumour; Time to initiation of adjuvant chemotherapy