Originally published as JCO Early Release 10.1200/JCO.2008.20.1566 on July 20 2009

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Tubbs, R. Articles by Hayes, D. F. PubMed PubMed Citation Articles by Tubbs, R. Articles by Hayes, D. F. Related Articles Related Editorial Social Bookmarking                            What's this?

Outcome of Patients With Early-Stage Breast Cancer Treated With Doxorubicin-Based Adjuvant Chemotherapy As a Function of HER2 and TOP2A Status

From the Department of Molecular Pathology and Taussig Cancer Center, Cleveland Clinic, Cleveland; and Cancer and Leukemia Group B, Ohio State University, Arthur James Cancer Center Hospital, Columbus, OH; Cancer Research and Biostatistics; Fred Hutchinson Cancer Research Center; and Phenopath Laboratories, Seattle, WA; Department of Pathology, University of Texas, Health Science Center at San Antonio, San Antonio, TX; Eastern Cooperative Oncology Group, Cancer Pavilion, Indiana University Medical Center, Indianapolis, IN; North Central Cancer Treatment Group, Medical Oncology, Mayo Clinic, Rochester, MN; University of California, Los Angeles Medical Center, Santa Monica, CA; Loyola University Medical Center, Maywood, IL; Arizona Cancer Center, Tucson, AZ; and University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.

Corresponding author: Raymond R. Tubbs, DO, Department of Molecular Pathology, Cleveland Clinic, Lerner College of Medicine, 9500 Euclid Ave, L30, Cleveland, OH 44195; e-mail: TubbsR{at}ccf.org.

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 4.0). Survival was not associated with low-level HER2 amplification (ratio 2; OS hazard ratio [HR], 1.14; P = .39; DFS HR, 1.07; P = .62), but it was associated for a ratio 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.

Supported in part by Public Health Service Cooperative Agreement Grants No. CA32102, CA38926, CA49883, CA21155, CA77658, CA25224, CA31946, CA32291, CA37891, CA35431, CA45377, CA58416, CA22433, CA58686, CA46113, CA04919, CA46441, CA58861, CA46282, CA35261, CA27057, CA76132, CA35192, CA76447, CA76462, CA45450, CA76429, CA63845, CA12644, CA20319, CA63844, CA45560, CA58415, CA14028, CA58658, CA42777, CA35119, CA35090, CA35117, CA13612, CA16385, CA67575, CA68183, CA46368, CA04920, CA74647, and CA52654, awarded by the National Cancer Institute, Department of Health and Human Services; by Amgen; and by the Breast Cancer Research Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Editorial

• Are HER2 and TOP2A Useful As Prognostic or Predictive Biomarkers for Anthracycline-Based Adjuvant Chemotherapy for Breast Cancer?
  Kathleen I. Pritchard
  JCO 2009 27: 3875-3876 [Full Text]

This article has been cited by other articles:

				Can Anthracycline Response Be Predicted from HER2 and TOP2A Status of Breast Tumors? Journal Watch Oncology and Hematology, October 6, 2009; 2009(1006): 2 - 2. [Full Text]

				K. I. Pritchard Are HER2 and TOP2A Useful As Prognostic or Predictive Biomarkers for Anthracycline-Based Adjuvant Chemotherapy for Breast Cancer? J. Clin. Oncol., August 20, 2009; 27(24): 3875 - 3876. [Full Text] [PDF]