Re-searching anthracycline therapy

Abstract

More than a decade of research into identification of individual predictive biomarkers for anthracyclines has been disappointing. Despite extensive attempts to identify clinically robust predictive biomarkers, the issue of the specific biological subgroup of early breast cancer patients to derive anthracycline benefit remains elusive. In particularly, the use of HER2 and the anthracycline drug target, topoisomerase II alpha (topo IIa), as sole markers has yielded inconsistent results. Regulation of topo IIa, DNA repair pathways and host features complicate the anthracycline story. See Fig. 1. We may need to abandon the quest for a sole predictive marker and re-search anthracycline activity with multifactorial predictive tools. Anthracyclines are DNA-damaging agents; however, they cannot bind directly to DNA. They bind and inhibit the topo IIa enzyme. Topoisomerase enzymes relieve the torsional stresses created by separation of the supercoiled DNA double-helix during transcription and replication. Disruption of topo IIa leads to double-strand DNA breaks, with subsequent cell death if the cell is unable to repair the damaged DNA. Theoretically, anthracyclines would be particularly active in the setting of overexpression of the topo IIa protein, coupled with impaired DNA repair. However, prediction of anthracycline benefit by topo IIa is inconsistently reported. Indeed, prediction of anthracycline activity has been reported in a conflicting mix of reports for several markers, including HER2, topo IIa and duplication of the chromosome 17 centromere. Regarding HER2, the Canadian MA.5 trial showed a significant predictive role for positive HER2 status [1]. In contrast, a substudy of the UK BR9601 trial showed improved outcomes from anthracyclines in the setting of normal HER1-3 status [2]. Many other studies showed a trend in favour of HER2, but were individually underpowered to robustly test treatment interactions [3–7]. A meta-analysis based on abstracted data from eight previously published studies concluded that anthracycline benefit was confined to HER2-positive disease [8]. However, diversity in patients, treatment and biological subtypes in the meta-analyses limit robust conclusions. A clear mechanistic link between HER2 and anthracycline activity remains elusive. Results also conflict for topo IIa, with support for [4, 5, 9–13] and against a predictive role [2, 14–16]. The Canadian MA.5 trial reported significant predictive value of pooled TOP2A aberrations, but not of TOP2A deletion or amplification independently [10]. Combined analysis of the UK NEAT/BR9601 trials showed no predictive role for TOP2A [14]. A recently presented meta-analysis assessed TOP2A in four phase III adjuvant studies comparing anthracyclines with CMF [17]. The interim analysis showed a clinically modest and statistically borderline predictive value for TOP2A amplification. The only prospective study to address this question, the TOP trial, was a single arm, single-agent neoadjuvant epirubicin analysis [9]. Whilst not yet formally published or peer reviewed, this trial is important as it is also the only trial to assess This is an invited commentary to article doi:10.1007/s10549-010-0931-y.