Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, 564 03, Thessaloniki, Macedonia, Greece.
J Transl Med. 2012 Oct 23;10:212. doi: 10.1186/1479-5876-10-212.
The vast majority of patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab eventually develop resistance to this agent. There is an unmet need therefore, for identifying biological markers with possible prognostic/predictive value in such patients. The aim of this study was to investigate the prognostic role of topoisomerase II alpha gene (TOP2A) amplification and protein (TopoIIa) expression in patients treated with trastuzumab-containing regimens.
Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 225 eligible patients treated with trastuzumab. Protein expression of ER, PgR, Ki67, PTEN, HER2 and TopoIIa were centrally assessed by immunohistochemistry. HER2 and TOP2A gene amplification was evaluated by fluorescence in situ hybridization. PIK3CA mutations were identified by single nucleotide polymorphism genotyping. Survival was evaluated from the initiation of trastuzumab as 1st line treatment to the date of last follow-up or death.
Among the 225 samples analyzed, only 137 (61%) were found to be HER2-positive. TOP2A was amplified in 41% and deleted in 16% of such tumors. TOP2A gene amplification was more frequent in ER-negative tumors. TopoIIa protein expression was observed in the majority (65%) of the samples and was associated with ER-positive status, high Ki67 expression, presence of PTEN protein and PIK3CA mutations. Median follow-up for patients treated in the 1st line was 51 months. Survival was more prolonged with trastuzumab-containing treatment in HER2-positive patients (50 months, log-rank, p=0.007). TOP2A non-amplified or deleted tumors were associated with increased risk for death compared to TOP2A amplified tumors (HR=2.16, Wald's p=0.010 and HR=2.67, p=0.009, respectively). In multivariate analysis, a significant interaction of TOP2A with anthracycline treatment (either in the adjuvant or the 1st line setting) was observed for survival (Wald's p=0.015). Among the TOP2A amplified subgroup, anthracycline-treated patients were associated with decreased risk for death.
TOP2A gene amplification was shown to be a favorable prognostic marker in HER2-positive MBC patients treated with trastuzumab, such an effect however, appears to rather be related to treatment with anthracyclines (predictive marker for benefit from anthracyclines). The results of the present retrospective study warrant validation in larger cohorts of patients treated in the context of randomized trials.
接受曲妥珠单抗治疗的 HER2 阳性转移性乳腺癌（MBC）患者绝大多数最终会对该药物产生耐药性。因此，需要确定具有此类患者可能的预后/预测价值的生物学标志物。本研究旨在研究拓扑异构酶 II ɑ 基因（TOP2A）扩增和蛋白（TopoIIa）表达在接受曲妥珠单抗治疗的患者中的预后作用。
回顾性收集了 225 名接受曲妥珠单抗治疗的合格患者的福尔马林固定石蜡包埋肿瘤组织样本。通过免疫组织化学法对 ER、PgR、Ki67、PTEN、HER2 和 TopoIIa 蛋白表达进行中心评估。通过荧光原位杂交评估 HER2 和 TOP2A 基因扩增。通过单核苷酸多态性基因分型鉴定 PIK3CA 突变。从曲妥珠单抗作为一线治疗开始至最后一次随访或死亡的日期评估生存情况。
在分析的 225 个样本中，仅发现 137 个（61%）为 HER2 阳性。其中 41%的肿瘤存在 TOP2A 扩增，16%的肿瘤存在 TOP2A 缺失。TOP2A 基因扩增在 ER 阴性肿瘤中更为常见。大多数（65%）样本中观察到 TopoIIa 蛋白表达，与 ER 阳性状态、高 Ki67 表达、PTEN 蛋白存在和 PIK3CA 突变相关。一线治疗的患者中位随访时间为 51 个月。在 HER2 阳性患者中，接受曲妥珠单抗治疗的患者生存时间更长（50 个月，对数秩检验，p=0.007）。与 TOP2A 扩增的肿瘤相比，TOP2A 非扩增或缺失的肿瘤死亡风险增加（HR=2.16，Wald's p=0.010 和 HR=2.67，p=0.009）。多变量分析显示，TOP2A 与蒽环类药物治疗（辅助治疗或一线治疗）之间存在显著的相互作用（Wald's p=0.015）。在 TOP2A 扩增亚组中，接受蒽环类药物治疗的患者死亡风险降低。
TOP2A 基因扩增被证明是接受曲妥珠单抗治疗的 HER2 阳性 MBC 患者的有利预后标志物，但这种作用似乎与蒽环类药物治疗有关（蒽环类药物获益的预测标志物）。本回顾性研究的结果需要在接受随机试验治疗的更大患者队列中进行验证。
