Molecular profiling of ER+ metastatic breast cancers to reveal association of genomic alterations with acquired resistance to CDK4/6 inhibitors.
Molecular profiling of ER+ metastatic breast cancers to reveal association of genomic alterations with acquired resistance to CDK4/6 inhibitors.
复制标题
ER 转移性乳腺癌的分子谱分析揭示基因组改变与 CDK4/6 抑制剂获得性耐药性的关联。
DOI：
--
复制
发表时间：
2019
影响因子：
45.3
通讯作者：
S. Chandarlapaty
中科院分区：
文献类型：
--
作者：
P. Razavi;C. H. Anjos;David N. Brown;Li Qing;Christina Ping;J. Herbert;Jodecy Colon;Dazhi Liu;Maiya J Mao;L. Norton;M. Scaltriti;D. Solit;M. Robson;J. Reis;K. Jhaveri;S. Chandarlapaty
1009 背景：ER+ 转移性乳腺癌 (MBC) 的基因组分析揭示了与抗雌激素治疗和内分泌抵抗相关的高度普遍的基因组改变（例如 ESR1、NF1、ERBB2）。目前尚不清楚在暴露于现在标准的 CDK4/6 抑制剂 (CDK4/6i) 后是否观察到任何此类获得性基因组改变。方法：为了确定与 CDK4/6i + 抗雌激素组合获得性耐药相关的基因组改变，我们前瞻性地对来自 845 名 MBC 患者的 1059 例 ER+ 乳腺癌进行了肿瘤和匹配的正常测序，这些患者收集了 CDK4/6i 治疗前 (n = 838) 或治疗后 (n = 221)，包括 110 对治疗前和治疗后对。我们进行了基因富集分析，以确定与 CDK4/6i 初始样本相比，CDK4/6i 后样本中更常见的致癌突变和拷贝数改变，并进一步将这些结果与单独激素治疗后数据集的结果进行比较。结果：CDK4/6i 后样本是在暴露于 CDK4/6i 加芳香酶抑制剂 (51%)、加氟维司群 (28%) 或多种/其他 (21%) 后收集的。除了先前与单独激素治疗耐药相关的改变之外，我们的分析还确定了在 CDK4/6i 后肿瘤中特异性富集的多个基因。其中，与 CDK4/6i 初始样本相比，RB1 的功能丧失改变在 CDK4/6i 后显着丰富（7.9% vs. 2.7%，p 值 = 1.5e-5）。 CDK4/6i 后肿瘤中的大多数 RB1 突变具有杂合性丢失 (LOH)，而 LOH 在 CDK4/6i 初治肿瘤中并不常见。此外，PI3K/AKT 信号传导（不包括 PIK3CA）、细胞周期（例如 CDKN2A 丢失）和 Hippo 信号传导效应器的多重改变在 CDK4/6i 后肿瘤中更为常见。结论：这项对 CDK4/6i 后和前的 MBC 进行的大型临床基因组分析揭示了暴露于 CDK4/6i 后多个基因组病变丰富，强调了与治疗相关的基因组进化是一种反复出现的现象，并确定了具有强大潜力改变后续治疗方案益处的独特基因组子集。
1009 Background: Genomic profiling of ER+ metastatic breast cancer (MBC) has revealed highly prevalent genomic alterations (e.g. ESR1, NF1, ERBB2) associated with exposure to antiestrogen therapy and endocrine resistance. It is not known whether any such acquired genomic alterations are observed after exposure to now standard CDK4/6 inhibitors (CDK4/6i). Methods: To identify genomic alterations associated with acquired resistance to CDK4/6i + antiestrogen combinations, we prospectively performed tumor and matched normal sequencing on 1059 ER+ breast cancers from 845 MBC patients collected prior to (n = 838) or post-treatment with CDK4/6i (n = 221), including 110 pre- and post-treatment pairs. We performed gene enrichment analyses to identify the oncogenic mutations and copy number alterations that were more frequent in post-CDK4/6i samples compared to CDK4/6i-naïve samples and further compared these results to those of post-hormone alone therapy datasets. Results: The post-CDK4/6i samples were collected following exposure to CDK4/6i plus aromatase inhibitors (51%), plus fulvestrant (28%), or multiple/other (21%). Along with alterations previously associated with resistance to hormonal therapy alone, our analysis identified multiple genes to be specifically enriched in the post-CDK4/6i tumors. Among these, loss-of-function alterations in RB1 were significantly enriched in the post-CDK4/6i compared to CDK4/6i-naïve samples (7.9% vs. 2.7%, p-value = 1.5e-5). The majority of the RB1 mutations in the post-CDK4/6i tumors had loss of heterozygosity (LOH), while LOH was uncommon in the CDK4/6i-naive tumors. Additionally, multiple alterations in effectors of PI3K/AKT signaling (excluding PIK3CA), cell cycle (such as CDKN2A loss) and in Hippo signaling were more frequent in the post-CDK4/6i tumors. Conclusions: This large clinico-genomic analysis of the post- and pre-CDK4/6i MBCs reveals multiple genomic lesions to be enriched after exposure to CDK4/6i, highlighting therapy-related genomic evolution as a recurrent phenomenon and identifying unique genomic subsets that have strong potential to alter the benefit of subsequent lines of therapies.