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.

Fig 1.

REMARK diagram detailing the materials used for this study. Absence of cores, core loss, absence of invasive carcinoma, and insufficient visualization of fluorescent in situ hybridization signals all contributed to absence of scores for cores within the tissue microarrays (TMAs). IHC, immunohistochemistry.

Fig 2.

The effect of HER2 gene amplification on disease-free survival. Significantly shortened disease-free survival was observed only for high-level amplification (HER2/CEP17 ratio > 4.0).

Fig 3.

The effect of any TOP2A abnormality (either TOP2A deletion or TOP2A amplification) on disease-free survival for high-level HER2-amplified instances (HER2/CEP17 ratio > 4.0). Similarly, no significant differences in overall survival were observed for TOP2A and HER2 coamplified instances, and neither overall nor disease-free survivals were significantly different when the analysis was segregated for TOP2A deletion or TOP2A amplification within the HER2-amplified group.