Topoisomerase IIalpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401

J Clin Oncol. 2006 Jun 1;24(16):2428-36. doi: 10.1200/JCO.2005.02.9264. Epub 2006 May 8.

Abstract

Purpose: Amplification of the HER-2/neu and topoisomerase IIalpha (TOP2A) genes has been linked to the effects of anthracyclines. Their role in predicting the outcome of anthracycline-based adjuvant chemotherapy for breast cancer patients has remained controversial.

Patients and methods: The present substudy of the Scandinavian Breast Group trial 9401, in which an epirubicin-based regimen (nine courses of tailored and dose-escalated fluorouracil, epirubicin, and cyclophosphamide [FEC]) was compared with three or four courses of standard FEC followed by bone marrow-supported high-dose chemotherapy (cyclophosphamide, thiotepa, and carboplatin), included high-risk breast cancer patients (with eight or more positive axillary lymph nodes or at least five nodes with additional poor prognostic indicators). Amplification of HER-2/neu was determined retrospectively in paraffin-embedded tumor tissue sections by chromogenic in situ hybridization. TOP2A was tested only in HER-2/neu-amplified tumors.

Results: HER-2/neu amplification alone, which was present in 32.7% of the tumors, was a strong prognostic factor for short relapse-free (P = .0034) and overall survival (P = .0008) but showed no direct association with treatment assignment. TOP2A coamplification, which was present in 37% of HER-2/neu-amplified tumors, was associated with better relapse-free survival in patients treated with tailored and dose-escalated FEC (hazard ratio [HR] = 0.45; P = .049). A statistical multivariate Cox's regression analysis confirmed the predictive significance of TOP2A coamplification (HR = 0.30; P = .020) in HER-2/neu-amplified tumors. There was no such association in patients with HER-2/neu-amplified tumors without TOP2A gene amplification.

Conclusion: Coamplification of HER-2/neu and TOP2A may define a subgroup of high-risk breast cancer patients who benefit from individually tailored and dose-escalated adjuvant anthracyclines.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracyclines / administration & dosage*
  • Antigens, Neoplasm / genetics*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Chemotherapy, Adjuvant
  • Clinical Trials as Topic
  • DNA Topoisomerases, Type II / genetics*
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Amplification*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • In Situ Hybridization
  • Lymphatic Metastasis
  • Multivariate Analysis
  • Odds Ratio
  • Poly-ADP-Ribose Binding Proteins
  • Predictive Value of Tests
  • Prognosis
  • Proportional Hazards Models
  • Receptor, ErbB-2 / genetics*
  • Scandinavian and Nordic Countries
  • Treatment Outcome

Substances

  • Anthracyclines
  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Receptor, ErbB-2
  • DNA Topoisomerases, Type II
  • TOP2A protein, human