摘要

Abstract Background Chemotherapeutic agents such as anthracyclines and taxanes are commonly used in the neoadjuvant setting. Bevacizumab is an antibody which binds to vascular endothelial growth factor A (VEGFA) and inhibits its receptor interaction, thus obstructing the formation of new blood vessels. Methods A phase II randomized clinical trial of 123 patients with Her2-negative breast cancer was conducted, with patients treated with neoadjuvant chemotherapy (fluorouracil (5FU)/epirubicin/cyclophosphamide (FEC) and taxane), with or without bevacizumab. Serial biopsies were obtained at time of diagnosis, after 12 weeks of treatment with FEC ± bevacizumab, and after 25 weeks of treatment with taxane ± bevacizumab. A time course study was designed to investigate the genomic landscape at the three time points when tumor DNA alterations, tumor percentage, genomic instability, and tumor clonality were assessed. Substantial differences were observed with some tumors changing mainly between diagnosis and at 12 weeks, others between 12 and 25 weeks, and still others changing in both time periods. Results In both treatment arms, good responders (GR) and non-responders (NR) displayed significant difference in genomic instability index (GII) at time of diagnosis. In the combination arm, copy number alterations at 25 loci at the time of diagnosis were significantly different between the GR and NR. An inverse aberration pattern was also observed between the two extreme response groups at 6p22-p12 for patients in the combination arm. Signs of subclonal reduction were observed, with some aberrations disappearing and others being retained during treatment. Increase in subclonal amplification was observed at 6p21.1, a locus which contains the VEGFA gene for the protein which are targeted by the study drug bevacizumab. Of the 13 pre-treatment samples that had a gain at VEGFA, 12 were responders. Significant decrease of frequency of subclones carrying gains at 17q21.32-q22 was observed at 12 weeks, with the peak occurring at TMEM100, an ALK1 receptor signaling-dependent gene essential for vasculogenesis. This implies that cells bearing amplifications of VEGFA and TMEM100 are particularly sensitive to this treatment regime. Conclusions Taken together, these results suggest that heterogeneity and subclonal architecture influence the response to targeted treatment in combination with chemotherapy, with possible implications for clinical decision-making and monitoring of treatment efficacy. Trial registration NCT00773695. Registered 15 October 2008

译文

摘要背景化疗药物，如蒽环类药物和紫杉类药物，通常用于新辅助治疗。贝伐单抗是一种与血管内皮生长因子 A (VEGFA) 结合并抑制其受体相互作用的抗体，因此阻碍了新血管的形成。方法对 123 例 Her2-negative 乳腺癌患者进行了 II 期随机临床试验，患者接受了新辅助化疗 (氟尿嘧啶 (5FU)/表阿霉素/环磷酰胺 (FEC) 和紫杉烷), 有或没有贝伐单抗。在诊断时、 FEC ± bevacizumab 治疗 12 周后以及紫杉烷 ± bevacizumab 治疗 25 周后获得一系列活检。设计了一项时间进程研究，以调查在评估肿瘤 DNA 改变、肿瘤百分比、基因组不稳定性和肿瘤克隆性的三个时间点的基因组景观。一些肿瘤主要在诊断和 12 周之间发生变化，其他肿瘤在 12 周和 25 周之间发生变化，还有一些肿瘤在两个时间段发生变化。结果在两个治疗组中，良好反应者 (GR) 和无反应者 (NR) 在诊断时显示基因组不稳定指数 (GII) 有显著差异。在组合臂中，诊断时 25 个位点的拷贝数改变在 GR 和 NR 之间有显著差异。在两个极端反应组之间也观察到一个相反的像差模式，在 6p22-p12 的组合臂的患者中。观察到亚克隆减少的迹象，一些畸变消失，另一些在治疗期间保留。在 6p21.1 处观察到亚克隆扩增的增加，该位点包含研究药物贝伐单抗靶向的蛋白质的 VEGFA 基因。在 VEGFA 有所增加的 13 个预处理样本中，12 个是响应者。在 12 周内观察到在 17q21.32-q22 携带收益的亚克隆的频率显著下降，峰值出现在 TMEM100，一种对血管生成至关重要的 ALK1 受体信号依赖基因。这意味着携带 VEGFA 和 TMEM100 扩增的细胞对这种治疗方案特别敏感。综上所述，这些结果表明异质性和亚克隆结构影响对联合化疗的靶向治疗的反应，可能对临床决策和治疗疗效监测产生影响。试用注册 nct00773695。注册 2008年10月15日