Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation.
Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation.
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DOI：
10.1038/ncomms13294
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发表时间：
2016-11-09
影响因子：
16.6
通讯作者：
POETIC Trial Management Group and Trialists
中科院分区：
文献类型：
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作者：
Gellert P;Segal CV;Gao Q;López-Knowles E;Martin LA;Dodson A;Li T;Miller CA;Lu C;Mardis ER;Gillman A;Morden J;Graf M;Sidhu K;Evans A;Shere M;Holcombe C;McIntosh SA;Bundred N;Skene A;Maxwell W;Robertson J;Bliss JM;Smith I;Dowsett M;POETIC Trial Management Group and Trialists
术前研究允许研究突变与雌激素受体阳性（ER+）乳腺癌对芳香化酶抑制剂（AI）的反应之间的关系，但仅限于小活检。在本研究的I期，我们对来自60名患者（40名AI治疗，20名对照）的基线、手术核心切口和血液进行外显子组测序。在不良反应者（基于Ki67变化）中，我们发现比良好反应者显著更多的体细胞突变。在约30%的肿瘤中出现了基线或手术核心的亚克隆。在第二阶段，我们将联合收割机靶向测序与第一阶段的另外28例治疗患者相结合。我们发现六个基因频繁突变：PIK3CA，TP53，CDH1，MLL3，ABCA13和FLG，配对核心之间的一致性为71%。TP53突变与不良反应相关。我们的结论是，多个活检是必要的ER+乳腺癌和TP53突变的信心突变谱与雌激素剥夺治疗的耐药性。 芳香化酶抑制剂用于治疗雌激素受体阳性乳腺癌，但患者反应的分子基础尚不清楚。在这里，作者使用来自芳香酶抑制剂临床试验的样本，并表明来自不良反应者的肿瘤比良好反应者有更多的突变，并且更频繁地携带p53突变。
Pre-surgical studies allow study of the relationship between mutations and response of oestrogen receptor-positive (ER+) breast cancer to aromatase inhibitors (AIs) but have been limited to small biopsies. Here in phase I of this study, we perform exome sequencing on baseline, surgical core-cuts and blood from 60 patients (40 AI treated, 20 controls). In poor responders (based on Ki67 change), we find significantly more somatic mutations than good responders. Subclones exclusive to baseline or surgical cores occur in ∼30% of tumours. In phase II, we combine targeted sequencing on another 28 treated patients with phase I. We find six genes frequently mutated: PIK3CA, TP53, CDH1, MLL3, ABCA13 and FLG with 71% concordance between paired cores. TP53 mutations are associated with poor response. We conclude that multiple biopsies are essential for confident mutational profiling of ER+ breast cancer and TP53 mutations are associated with resistance to oestrogen deprivation therapy. Aromatase inhibitors are used to treat oestrogen receptor positive breast cancers but the molecular basis for the response of patients is unclear. Here, the authors use samples from an aromatase inhibitor clinical trial and show that tumours from poor responders have more mutations than good responders and also more frequently harbour p53 mutations.