HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy

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.

Paeonol alleviates epirubicin-induced renal injury in mice by regulating Nrf2 and NF-κB pathways

“…Epirubicin (Epi), an anticancer anthracycline antibiotic, is being successfully used for the treatment of various malignant neoplasms, including breast cancer, lung cancer and other solid tumors (Fountzilas et al, 2012;Pasello et al, 2015). Unfortunately, the clinical application of epirubicin is limited by its dose-dependent toxicities in normal tissues, such as the heart, liver and kidney (Baldini et al, 2004;ElSheikh et al, 2012).…”

Topoisomerase II-alfa gene as a predictive marker of response to anthracyclines in breast cancer

“…However, other published data do not support this association. More recently, it has been hypothesized that the amplification of HER-2 is just a surrogate marker for the amplification of TOP2A gene, the real determinant of increased activity of anthracyclines [6,19,20,22].…”

“…[2][3][4][5][6][7][8][9][10][11][12]. In vitro studies have shown that TOP2A alterations are frequent in tumor cells and determine a greater sensitivity to the action of anthracyclines [10][11][12]27].…”

Recent Progress in HER2 Associated Breast Cancer

“…Joyfully, about the mutant mechanism, researchers newly reported a case that a breast cancer patient harboring an activating EGFR mutation clinically benefiting from EGFR-targeted treatment (Ali et al, 2014). The immune way ADCC (Nahta, 2012) multiple mAbs HER2 internalization (Ben-Kasu et al, 2009) anti-HER2 vaccine Peptide-based/DNA-based/ anti-idiotypic (Cao et al, 2013;Tagliabue and Campiglio, 2014) Trastuzumab mitogenic signaling (Schroeder et al, 2014;Kawajiri et al, 2015) ADCC 188Re-labeled HYNIC-trastuzuma radioactivity dose-dependent fashion (Luo et al, 2015) 64Cu-DOTA-trastuzumab metastatic breast cancer (Mortimer et al, 2014) Trastuzumab resistance Upregulation of HER3 (Nahta, 2012;Brady et al, 2014;Rimawi et al, 2014;Zang et al, 2014;Nam et al, 2015) miRNAs (miRNA-21, miR-7, miR-200c) (Bai et al, 2014;Chen and Bourguignon, 2014;Huynh and Jones, 2014; H E R 2 c o p y n u m b e r / dimerization status Interaction between HER2 and other ERBB (Lee et al, 2015) autophagy (Yeh et al, 2014) Anthracyclines HER2/TOP2A (Fountzilas et al, 2012) S-222611 ERBB family dimmers (Spicer et al, 2015) NCT Increase pCR rates (Shinde et al, 2015) Flotillin reduction of ErbB2-ErbB3 (Asp and Pust, 2014) CC apoptosis/ proliferation (Khan et al, 2015) Taspase1 Cyclins E, A, and B (Dong et al, 2014) Combined therapy Trastuzumab, carboplatin, paclitaxel (Shinde et al, 2015) Trastuzumab, MK-2206 (Hudis et al, 2013) Trastuzumab, lapatinib (Rimawi et al, 2014;Scaltriti et al, 2014;Schroeder et al, 2014) lapatinib , BYL719 (Brady et al, 2014) AZD8931, paclitaxel (Kurata et al, 2014) Hsp90, laptinib ( …”

“…Anthracyclines and taxanes which targeted on HER2/ TOP2A are currently considered to be essential drugs in adjuvant chemotherapy (Fountzilas et al, 2012), which is commonly used to treat patients with locally advanced or inflammatory breast cancer (LABC); S-222611, an oral reversible, novel, selective and potent dual tyrosine kinase inhibitor of EGFR and HER2, in a dose-dependent way, providing effective blockade of all possible signalingactive ERBB family dimers (Spicer et al, 2015); NCT -Platinum-containing neoadjuvant chemotherapy, may increase Pathologic complete response (pCR) rates in HER2 (+) breast cancers (Shinde et al, 2015). largely because these tumors have defective DNA-repair pathways ; paclitaxel has demonstrated efficacy in the metastatic breast cancer (Shinde et al, 2015); Aiso, depletion of lipid raft-associated flotillin (flotillin-1 and flotillin-2) resulted in down-regulation of ErbB3 and a selective reduction of ErbB2-ErbB3 receptor complexes, with the flotillin-2 induced effection being mediated by Akt and MAPK signaling cascades (Asp et al, 2014).…”