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

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

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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 ≥ 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.

Original languageEnglish (US)
Pages (from-to)3881-3886
Number of pages6
JournalJournal of Clinical Oncology
Volume27
Issue number24
DOIs
StatePublished - Aug 20 2009

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tubbs, R., Barlow, W. E., Budd, G. T., Swain, E., Porter, P., Gown, A., Yeh, I. T., Sledge, G., Shapiro, C., Ingle, J., Haskell, C., Albain, K. S., Livingston, R., & Hayes, D. F. (2009). Outcome of patients with early-stage breast cancer treated with doxorubicin-based adjuvant chemotherapy as a function of HER2 and TOP2A status. Journal of Clinical Oncology, 27(24), 3881-3886. https://doi.org/10.1200/JCO.2008.20.1566