Abstract
BackgroundHER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy.MethodsIn a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry).ResultsHER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02-0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel.ConclusionsThis study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12611000506998.
Highlights
Adjuvant chemotherapy is known to prolong diseasefree survival (DFS) and overall survival (OS) in patients with early-stage breast cancer (EBCTCG [1])
Patients and tissues Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples were retrospectively collected from 367 patients that had participated in a phase III trial (HE 10/97); in that trial, 595 eligible high-risk breast cancer patients were randomized to receive postoperative dose-dense sequential chemotherapy with 3 cycles of epirubicin 110 mg/m2, followed by 3 cycles of paclitaxel (TaxolTM, Bristol-Myers Squibb, Princeton, NJ, USA) 250 mg/m2, followed by 3 cycles of intensified CMF (E-TCMF, experimental arm) or four cycles of epirubicin followed by 4 cycles of CMF (E-CMF, control arm), at the same doses as in the E-T-CMF arm
With the exception of high tumor grade and HER2 protein overexpression, which were more common in the E-T-CMF arm, basic clinicopathological characteristics were well balanced when the 352 analyzed patients were stratified by adjuvant chemotherapy arm (Table 2)
Summary
Adjuvant chemotherapy is known to prolong diseasefree survival (DFS) and overall survival (OS) in patients with early-stage breast cancer (EBCTCG [1]). Most relevant studies and a meta-analysis [9] provided compelling evidence that the benefit from adjuvant anthracyclines is restricted to the HER2-positive subgroup of patients. These results have been challenged by other investigators, especially in patients with metastatic disease [10,11]. Taken together, these findings raise the possibility that other than HER2 genes, located on chromosome 17, may be key regulators of anthracycline responsiveness [7]. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy
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