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.

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.

• Authors: Scandinavian Breast Group Trial 9401, Minna Tanner, Jorma Isola, Tom Wiklund, Björn Erikstein, Pirkko Kellokumpu-Lehtinen, Per Malmström, Nils Wilking, Jonas Nilsson, Jonas Bergh
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 24 Issue 16 Pg. 2428-36 (Jun 01 2006) ISSN: 1527-7755 [Electronic] United States
• PMID: 16682728 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Anthracyclines (administration & dosage)
• Antigens, Neoplasm (genetics)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics)
• Breast Neoplasms (drug therapy, enzymology, genetics, 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