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

Abstract

A B S T R A C T PurposeAmplification 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/CEP17and 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 ϭ 1,592) or sequential A followed by C (n ϭ 1,533). ResultsAn 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 Ն 4.0). Survival was not associated with low-level HER2 amplification (ratio Ն 2; OS hazard ratio [HR], 1.14; P ϭ .39; DFS HR, 1.07; P ϭ .62), but it was associated for a ratio Ն 4 (OS HR, 1.45; P ϭ .03; DFS HR, 1.38; P ϭ .033), in which analysis was adjusted for menopausal status, hormone receptor status, treatment, number of positive nodes, and tumor size. ConclusionIn 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.

ERBB2 and TOP2A in Breast Cancer: A Comprehensive Analysis of Gene Amplification, RNA Levels, and Protein Expression and Their Influence on Prognosis and Prediction

“…The prognostic and predictive value of measuring ERBB2 and TOP2A expression has long been a matter of debate (39)(40)(41)(42)(43)(44)(45)(46). To our knowledge, however, a systematic study of ERBB2 and TOP2A in the same cohorts investigating the correlation of DNA amplification, gene and protein expression, and analyzing their prognostic relevance has so far not been published.…”

Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer

“…The correlation between TOP2A gene status/topo2a protein expression and response to anthracyclines has been addressed by a legion of studies [23,26,30,[35][36][37][38][39][40][41][42][43][44][45][46][47] and are currently a matter of considerable debate. Most studies were essentially retrospective, and included breast cancer patients treated with anthracycline combinations rather than single agent anthracycline and, therefore, the activity of the other drugs of the combination could obscure any existing relationship.…”

Combinatorial biomarker expression in breast cancer

“…Similar to ER, the HER2 status of BC narrows the pool of candidates eligible for HER2-directed therapies, but it does not definitively select those who will respond. Several studies have reported that HER2 may be a predictive marker of response to anthracycline-based chemotherapy [98][99][100][101]. It has also been suggested that HER2 positivity is predictive of better response to higher dose anthracycline-containing regimens compared with standard regimens [102,103] and to taxane compared with non-taxane-containing regimens [104,105], however, the predictive value of HER2 remains a complex subject and further validation is still required [98].…”