title: Time-varying effect and long-term survival analysis in breast cancer patients treated with neoadjuvant chemotherapy.
abstract: BACKGROUND
  Recent studies have indicated the prognostic value of tumour subtype and pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). However these results were reported after a short follow-up and using a standard Cox model which could be unsatisfactory for time-dependent factors. In the present study, we identified the prognostic factors for long-term outcome after NAC, considering that they could have an inconstant impact over time.
  
  
  METHODS
  Prognostic factors from 956 consecutive breast cancer patients treated with NAC were identified and associated with long-term outcomes. We estimated survival by a time function multivariate Cox model regression and stratified by follow-up length.
  
  
  RESULTS
  The prognostic value of tumour histological grade and hormone receptors status varied as distant recurrence-free interval (DRFI) increased. The multivariate analysis identified the following significant prognostic factors: tumour size, N stage, clinical and pathological response to NAC, hormone receptors (HR) status and histological tumour grade. The 'prognostic benefit' of low-grade and positive-HR status decreased over the years. Thus, in the early years after cancer diagnosis, the hazard ratio of distant recurrences in patients with positive-HR status increased from 0.26 (95% CI 0.1-0.4) at 6 months to 2.2 (95% CI 1.3-3.7) at 120 months. The histological tumour grade followed a similar trend. The hazard ratio of grade III patients compared with grade I was 1.83 (95% CI 1.1-2.8) at 36 months and diminished over time to 0.70 (95% CI 0.4-1.3) at 120 months. This indicates that the risk of recurrence for positive-HR patients was 74% lower at 6 months compared with the negative-hormone receptor group, but 30% higher at 5 years and more than double at 10 years. High-grade tumours presented a risk of 83% in the earlier years decreasing to 30% at 10 years versus the low-grade group.
  
  
  CONCLUSIONS
  From the present study, we conclude the importance of identifying time-dependent prognostic factors. Distant recurrence-free interval within women who receive NAC are influenced by achieving pCR and breast cancer subtype. Tumours with more aggressive biology have poorer survival during the first 5 years, but if they exceed this point their prognostic impact is no longer significant. Conversely, positive-HR patients remain at risk for distant recurrence for many years.
authors.affiliation: Department of Surgery, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Baulies
authors.affiliation: Department of Biostatistics, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Belin
authors.affiliation: 1] Department of Surgery, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [2] Craigavon Area Hospital Breast Unit, Portadown BT63 5QQ, Northern Ireland.
authors.forename: P
authors.initials: P
authors.lastname: Mallon
authors.affiliation: Department of Surgery, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Senechal
authors.affiliation: Department of Medical Oncology, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Pierga
authors.affiliation: Department of Medical Oncology, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Cottu
authors.affiliation: Department of Medical Oncology, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: M-P
authors.initials: MP
authors.lastname: Sablin
authors.affiliation: Department of Tumor Biology, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: X
authors.initials: X
authors.lastname: Sastre
authors.affiliation: Department of Biostatistics, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Asselain
authors.affiliation: Department of Surgery, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Rouzier
authors.affiliation: 1] Department of Surgery, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [2] Department of Translational Research, Residual Tumor and Response to Treatment Lab, RT2Lab, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [3] UMR932, Immunity and Cancer, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Reyal
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents