Abstract:
Under therapeutic pressure aggressive tumors evolve rapidly. Herein, a luminal B/HER2-low breast cancer was tracked for >3 years during a total of 6 largely unsuccessful therapy lines, from adjuvant to advanced settings. Targeted next generation sequencing (NGS) of the primary lesion, two metastases and 14 blood drawings suggested a striking, unprecedented coexistence of three evolution modes: punctuated, branched and convergent. Punctuated evolution of the trunk was supported by en bloc inheritance of a large set (19 distinct genes) of copy number alterations. Branched evolution was supported by the distribution of site-specific SNVs. Convergent evolution was characterized by a unique asynchronous expansion of three actionable (OncoKB level 3A) mutations at two consecutive ESR1 codons. Low or undetectable in all the sampled tumor tissues, ESR1 mutations expanded rapidly in blood during HER2/hormone double-blockade, and predicted life-threatening local progression at lung and liver metastatic foci. Dramatic clinical response to Fulvestrant (assigned off-label exclusively based on liquid biopsy) was associated with clearance of all 3 subclones and was in stark contrast to the poor therapeutic efficacy reported in large liquid biopsy-informed interventional trials. Altogether, deconvolution of the tumor phylogenetic tree, as shown herein, may help to customize treatment in breast cancers that rapidly develop refractoriness to multiple drugs.
摘要:
在治疗压力下,侵袭性肿瘤迅速发展。在这里,在总共6个基本上不成功的治疗线路中,对管腔B/HER2低乳腺癌进行了>3年的追踪,从佐剂到高级设置。原发性病变的靶向下一代测序(NGS),两个转移和14个血迹图显示了一个惊人的,三种进化模式前所未有的共存:标点符号,分支和会聚。大量拷贝数改变(19个不同的基因)的整体遗传支持了树干的标点符号进化。分支进化由位点特异性SNV的分布支持。趋同进化的特征是在两个连续的ESR1密码子处三个可操作的(OncoKB级别3A)突变的独特异步扩展。在所有取样的肿瘤组织中都低或检测不到,在HER2/激素双重阻断期间,ESR1突变在血液中迅速扩大,并预测肺和肝转移灶的危及生命的局部进展。氟维司群的显著临床反应(完全根据液体活检指定标签外)与所有3个亚克隆的清除有关,并且与大型液体活检知情介入试验中报道的不良治疗效果形成鲜明对比。总之,肿瘤系统发育树的反褶积,如本文所示,可能有助于定制治疗快速发展的多种药物难治性乳腺癌。