title: Time dependence of biomarkers: non-proportional effects of immunohistochemical panels predicting relapse risk in early breast cancer.
abstract: BACKGROUND
  We investigated the impact of follow-up duration to determine whether two immunohistochemical prognostic panels, IHC4 and Mammostrat, provide information on the risk of early or late distant recurrence using the Edinburgh Breast Conservation Series and the Tamoxifen vs Exemestane Adjuvant Multinational (TEAM) trial.
  
  
  METHODS
  The multivariable fractional polynomial time (MFPT) algorithm was used to determine which variables had possible non-proportional effects. The performance of the scores was assessed at various lengths of follow-up and Cox regression modelling was performed over the intervals of 0-5 years and >5 years.
  
  
  RESULTS
  We observed a strong time dependence of both the IHC4 and Mammostrat scores, with their effects decreasing over time. In the first 5 years of follow-up only, the addition of both scores to clinical factors provided statistically significant information (P<0.05), with increases in R(2) between 5 and 6% and increases in D-statistic between 0.16 and 0.21.
  
  
  CONCLUSIONS
  Our analyses confirm that the IHC4 and Mammostrat scores are strong prognostic factors for time to distant recurrence but this is restricted to the first 5 years after diagnosis. This provides evidence for their combined use to predict early recurrence events in order to select those patients who may/will benefit from adjuvant chemotherapy.
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: J
authors.initials: J
authors.lastname: Stephen
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: G
authors.initials: G
authors.lastname: Murray
authors.affiliation: Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Cameron
authors.affiliation: Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: J
authors.initials: J
authors.lastname: Thomas
authors.affiliation: Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: I H
authors.initials: IH
authors.lastname: Kunkler
authors.affiliation: Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: W
authors.initials: W
authors.lastname: Jack
authors.affiliation: Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: G R
authors.initials: GR
authors.lastname: Kerr
authors.affiliation: Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: T
authors.initials: T
authors.lastname: Piper
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: C L
authors.initials: CL
authors.lastname: Brookes
authors.affiliation: Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: D W
authors.initials: DW
authors.lastname: Rea
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: C J H
authors.initials: CJ
authors.lastname: van de Velde
authors.affiliation: Department of Gynecological Oncology, University Hospital, Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hasenburg
authors.affiliation: Department of Surgery, Athens University Medical School, Athens, Greece.
authors.forename: C
authors.initials: C
authors.lastname: Markopoulos
authors.affiliation: Oncology Center, St Augustinus, Antwerp, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Dirix
authors.affiliation: Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Seynaeve
authors.affiliation: 1] Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK [2] Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: J M S
authors.initials: JM
authors.lastname: Bartlett
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D012306:Risk
chemical_list: D014408:Biomarkers, Tumor