Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients.
Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients.
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对 4854 名患者的系统分析揭示了 ESR1 野生型转移性乳腺癌中激酶融合的富集。
DOI：
10.1016/j.annonc.2020.04.008
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hechtman,JF
中科院分区：
文献类型：
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作者：
Ross,DS;Liu,B;Schram,AM;Razavi,P;Lagana,SM;Zhang,Y;Scaltriti,M;Bromberg,JF;Ladanyi,M;Hyman,DM;Drilon,A;Zehir,A;Benayed,R;Chandarlapaty,S;Hechtman,JF
背景激酶融合在乳腺癌（BC）中是罕见的，并且特征性不强。我们的目的是在一个大型的晚期BC患者队列中描述激酶融合的特征。患者和方法通过Memorial Sloan Kettering-可操作的癌症靶点的综合突变谱分析，（MSK-IMPACT）靶向的DNAseq和MSK-Fusion靶向的RNAseq。（0.6%）例患者存在融合：11例FGFR（5例FGFR 2、3例FGFR 3、3例FGFR 1）、5例BRAF、4例NTRK 1、2例RET、2例ROS 1、1例ALK、1例ERBB 2和1例MET。在15例（56%）融合阳性BC中存在内分泌治疗史; 15例病例中有8例有可用的治疗前样本，其中6例为融合阴性。所有融合阳性BC样本均未携带ESR 1热点突变。两名患者acquiredLMNA-NTRK 1融合和转移性疾病接受larotrectinib和表现出临床benefit.ConclusionKinase融合在BC是非常罕见的，似乎是丰富的耐药，转移性癌和相互排斥与ESR 1突变。本研究扩大了激活丝裂原活化蛋白激酶（MAPK）信号转导的遗传改变的范围，在这种情况下可以替代ESR 1突变。内分泌治疗后进展时的分子检测应包括融合检测，特别是在缺乏ESR 1热点改变的情况下，以努力确定可能提供实质性临床获益的其他治疗选择。
BackgroundKinase fusions are rare and poorly characterized in breast cancer (BC). We aimed to characterize kinase fusions within a large cohort of advanced BC.Patients and methodsA total of 4854 patients with BC were analyzed by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) targeted DNAseq and MSK-Fusion targeted RNAseq during the study time period.ResultsTwenty-seven of 4854 (0.6%) patients harbored fusions: 11FGFR(fiveFGFR2, threeFGFR3, threeFGFR1), fiveBRAF, fourNTRK1, twoRET, twoROS1, oneALK, oneERBB2,and oneMET. A history of endocrine therapy was present in 15 (56%) of fusion-positive BC; eight of the 15 cases had available pre-treatment samples, of which six were fusion-negative. None of the fusion-positive BC samples harboredESR1hotspot mutations. Two patients with acquiredLMNA-NTRK1fusions and metastatic disease received larotrectinib and demonstrated clinical benefit.ConclusionKinase fusions in BC are extremely rare, and appear to be enriched in hormone-resistant, metastatic carcinomas and mutually exclusive withESR1mutations. The present study expands the spectrum of genetic alterations activating mitogen-activated protein kinase (MAPK) signaling that can substitute forESR1mutations in this setting. Molecular testing at progression after endocrine therapy should include fusion testing, particularly in the absence ofESR1hotspot alterations, in an effort to identify additional therapeutic options which may provide substantial clinical benefit.