Evaluation of applying IHC4 as a prognostic model in the translational study of Intergroup Exemestane Study (IES): PathIES

Breast Cancer Res Treat. 2018 Feb;168(1):169-178. doi: 10.1007/s10549-017-4543-7. Epub 2017 Nov 24.


Background: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane.

Patients and methods: Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated.

Results: Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29-23.70) for a change from 1st quartile (Q1) to Q1-Q3 and HR of 15.54 (95% CI 3.70-65.24) for a change from Q1 to Q4.

Conclusion: In the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2-3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2-3 years and who remain disease-free after 2-3 years.

Keywords: Aromatase; Breast cancer; Prognosis.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Androstadienes / pharmacology
  • Androstadienes / therapeutic use*
  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Breast / pathology
  • Breast / surgery
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Chemotherapy, Adjuvant / methods
  • Disease-Free Survival
  • Double-Blind Method
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Immunohistochemistry
  • Mastectomy
  • Middle Aged
  • Neoplasm Recurrence, Local / epidemiology*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Recurrence, Local / prevention & control
  • Prognosis
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Tamoxifen / pharmacology
  • Tamoxifen / therapeutic use*
  • Time Factors


  • Androstadienes
  • Antineoplastic Agents, Hormonal
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Tamoxifen
  • exemestane