Validation of the IHC4 breast cancer prognostic algorithm using multiple approaches on the multinational TEAM clinical trial

John M S Bartlett*, Jason Christiansen, Mark Gustavson, David L. Rimm, Tammy Piper, Cornelis J H Van De Velde, Annette Hasenburg, Dirk G. Kieback, Hein Putter, Christos J. Markopoulos, Luc Y. Dirix, Caroline Seynaeve, Daniel W. Rea

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


Context. - Hormone receptors HER2/neu and Ki-67 are markers of residual risk in early breast cancer. An algorithm (IHC4) combining these markers may provide additional information on residual risk of recurrence in patients treated with hormone therapy. Objective. - To independently validate the IHC4 algorithm in the multinational Tamoxifen Versus Exemestane Adjuvant Multicenter Trial (TEAM) cohort, originally developed on the trans-ATAC (Arimidex, Tamoxifen, Alone or in Combination Trial) cohort, by comparing 2 methodologies. Design. - The IHC4 biomarker expression was quantified on TEAM cohort samples (n = 2919) by using 2 independent methodologies (conventional 3,3′-diaminobezidine [DAB] immunohistochemistry with image analysis and standardized quantitative immunofluorescence [QIF] by AQUA technology). The IHC4 scores were calculated by using the same previously established coefficients and then compared with recurrence-free and distant recurrence- free survival, using multivariate Cox proportional hazards modeling. Results. - The QIF model was highly significant for prediction of residual risk (P <.001), with continuous model scores showing a hazard ratio (HR) of 1.012 (95% confidence interval [95% CI]: 1.010-1.014), which was significantly higher than that for the DAB model (HR: 1.008, 95% CI: 1.006-1.009); P <.001). Each model added significant prognostic value in addition to recognized clinical prognostic factors, including nodal status, in multivariate analyses. Quantitative immunofluorescence, however, showed more accuracy with respect to overall residual risk assessment than the DAB model. Conclusions. - The use of the IHC4 algorithm was validated on the TEAM trial for predicting residual risk in patients with breast cancer. These data support the use of the IHC4 algorithm clinically, but quantitative and standardized approaches need to be used.

Original languageEnglish
Pages (from-to)66-74
Number of pages9
JournalArchives of Pathology and Laboratory Medicine
Issue number1
Publication statusPublished - 1 Jan 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medical Laboratory Technology
  • Medicine(all)


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