Multifactorial approach to predicting resistance to anthracyclines

J Clin Oncol. 2011 Apr 20;29(12):1578-86. doi: 10.1200/JCO.2010.31.2231. Epub 2011 Mar 21.

Abstract

Purpose: Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER) -negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-α (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines.

Patients and methods: The TOP trial included 149 patients, 139 of whom were evaluable for response prediction analyses. The primary end point was pathologic complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC (European Organisation for Research and Treatment of Cancer) 10994/BIG (Breast International Group) 00-01 and MDACC (MD Anderson Cancer Center) 2003-0321 neoadjuvant trials were used for validation purposes.

Results: A pCR was obtained in 14% of the evaluable patients in the TOP trial. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (P ≤ .001 v P ≤ .33). We developed an anthracycline-based score (A-Score) combining three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value ([NPV]; NPV, 0.98; 95% CI, 0.90 to 1.00) overall and in the human epidermal growth factor receptor 2 (HER2) -negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based arms of the two validation trials (BIG 00-01: NPV, 0.83; 95% CI, 0.64 to 0.94 and MDACC 2003-0321: NPV, 1.00; 95% CI, 0.80 to 1.00).

Conclusion: Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible adverse effects.

Trial registration: ClinicalTrials.gov NCT00017095 NCT00336791.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / therapeutic use*
  • Antigens, Neoplasm / analysis
  • Antigens, Neoplasm / genetics
  • Biomarkers, Tumor / analysis
  • Biopsy
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Chemotherapy, Adjuvant
  • DNA Topoisomerases, Type II / analysis
  • DNA Topoisomerases, Type II / genetics
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • Drug Resistance, Neoplasm* / genetics
  • Epirubicin / adverse effects
  • Epirubicin / therapeutic use*
  • Europe
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Middle Aged
  • Neoadjuvant Therapy
  • Odds Ratio
  • Patient Selection
  • Poly-ADP-Ribose Binding Proteins
  • Predictive Value of Tests
  • Prospective Studies
  • Receptor, ErbB-2 / analysis
  • Receptors, Estrogen / analysis
  • Reproducibility of Results
  • Risk Assessment
  • Risk Factors
  • Texas
  • Treatment Failure

Substances

  • Antibiotics, Antineoplastic
  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Receptors, Estrogen
  • Epirubicin
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • DNA Topoisomerases, Type II
  • TOP2A protein, human

Associated data

  • ClinicalTrials.gov/NCT00017095
  • ClinicalTrials.gov/NCT00336791