Outcome of patients with early-stage breast cancer treated with doxorubicin-based adjuvant chemotherapy as a function of HER2 and TOP2A status.

Abstract

PURPOSE:

Amplification and deletion of the TOP2A gene have been reported as positive predictive markers of response to anthracycline-based therapy. We determined the status of the HER2 and TOP2A genes in a large cohort of breast cancer patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C).

PATIENTS AND METHODS:

TOP2A/CEP17 and HER2/CEP17 fluorescent in situ hybridization (FISH) were performed on tissue microarrays (TMAs) constructed from 2,123 of the 3,125 women with moderate-risk primary breast cancer who received equivalent doses of either concurrent adjuvant chemotherapy with A plus C (n = 1,592) or sequential A followed by C (n = 1,533).

RESULTS:

An abnormal TOP2A genotype was identified for 153 (9.4%) of 1,626 patients (4.0% amplified; 5.4% deleted). An abnormal HER2 genotype was identified for 303 (20.4%) of 1,483 patients (18.8% amplified; 1.6% deleted). No significant differences in either overall survival (OS) or disease-free survival (DFS) were identified for TOP2A. In univariate analysis, OS and DFS rates were strongly and adversely associated only with higher levels of HER2 amplification (ratio > or = 4.0). Survival was not associated with low-level HER2 amplification (ratio > or = 2; OS hazard ratio [HR], 1.14; P = .39; DFS HR, 1.07; P = .62), but it was associated for a ratio > or = 4 (OS HR, 1.45; P = .03; DFS HR, 1.38; P = .033), in which analysis was adjusted for menopausal status, hormone receptor status, treatment, number of positive nodes, and tumor size.

CONCLUSION:

In this population of patients with early-stage breast cancer who were treated with adjuvant AC chemotherapy, TOP2A abnormalities were not associated with outcome. HER2 high-level amplification was a prognostic marker in anthracycline-treated patients.

• Authors: Raymond Tubbs, William E Barlow, G Thomas Budd, Eric Swain, Peggy Porter, Allen Gown, I-Ten Yeh, George Sledge, Charles Shapiro, James Ingle, Charles Haskell, Kathy S Albain, Robert Livingston, Daniel F Hayes
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 24 Pg. 3881-6 (Aug 20 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19620488 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• DNA-Binding Proteins
• Poly-ADP-Ribose Binding Proteins
• Doxorubicin
• ERBB2 protein, human
• Receptor, ErbB-2
• DNA Topoisomerases, Type II
• TOP2A protein, human

Topics

• Antigens, Neoplasm (analysis, genetics)
• Breast Neoplasms (chemistry, drug therapy, genetics)
• Chemotherapy, Adjuvant
• Chromosomes, Human, Pair 17
• DNA Topoisomerases, Type II (analysis, genetics)
• DNA-Binding Proteins (analysis, genetics)
• Doxorubicin (therapeutic use)
• Female
• Gene Amplification
• Gene Dosage
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence
• Neoplasm Staging
• Poly-ADP-Ribose Binding Proteins
• Receptor, ErbB-2 (analysis, genetics)
• Tissue Array Analysis
• Treatment Outcome