Frequency and spectrum of PIK3CA somatic mutations in breast cancer
Frequency and spectrum of PIK3CA somatic mutations in breast cancer
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DOI：
10.1186/s13058-020-01284-9
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发表时间：
2020-05-13
影响因子：
7.4
通讯作者：
Prat, Aleix
中科院分区：
文献类型：
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作者：
Martinez-Saez, Olga;Chic, Nuria;Prat, Aleix
Therascreen PIK 3CA突变检测和α特异性PI 3 K抑制剂alpelisib已获得FDA批准，用于识别和治疗晚期PIK 3CA突变（PIK 3CAmut）乳腺癌（BC）患者。然而，目前尚不清楚该检测试剂盒在多大程度上检测到BC中的大多数PIK 3CA突变。这一信息是至关重要的，因为患者和临床医生正在使用这种和其他基因组测定来指示alpelisib。方法对10项公开发表的研究中6338例BC患者的数据进行分析。主要目的是评估BC中PIK 3CA突变的比例和分布。次要目的是（1）通过计算机模拟评价therascreen面板捕获的BC中PIK 3CA突变谱;（2）评价激素受体阳性/HER 2阴性患者中PIK 3CA突变的比例和分布（HR+/HER 2-）、HER 2+和三阴性BC（TNBC）;和（3）通过Guardant B360循环肿瘤DNA（ctDNA）测定，探索在48例HR+/HER 2-晚期BC患者队列中鉴定PIK 3CA突变。结果PIK 3CAmut肿瘤患者占35.7%（2261/6338）。五种PIK 3CA突变占所有PIK 3CA突变的73%：H1047 R（35%）、E545 K（17%）、E542 K（11%）、N345 K（6%）和H1047 L（4%）。Therascreen基因列表将捕获72%的所有PIK 3CA突变和80%的具有已知PIK 3CAmut BC的患者。在患有双PIK 3CAmut肿瘤的患者中（所有PIK 3CAmut的12%），therascreen面板将捕获78%的携带1个单一PIK 3CA突变，17%的PIK 3CAmut未检测到，5%的PIK 3CA双突变。与HR+/HER 2（42%）和HER 2+（31%）BC相比，TNBC（16%）中的PIK 3CA突变率较低;然而，亚型间4种主要PIK 3CA突变的分布相似。最后，在48例晚期HR+/HER 2- BC患者的ctDNA中发现的28%的PIK 3CA突变不是therascreen面板的一部分。结论BC中的PIK 3CA突变是异质性的，并且与20%具有已知PIK 3CA突变的患者和95%具有已知双PIK 3CAmut肿瘤的患者相似，不会被therascreen面板捕获。最后，在therascreen伴随诊断测定中不存在或通过其他基于测序的测定鉴定的PIK 3CA突变的临床效用需要进一步研究。
Purpose The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA-mutated (PIK3CAmut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. Methods Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/HER2-), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2- advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay. Results Patients with PIK3CAmut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CAmut BC. Among patients with double PIK3CAmut tumors (12% of all PIK3CAmut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CAmut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2- BC were not part of the therascreen panel. Conclusion PIK3CA mutations in BC are heterogenous and similar to 20% of patients with a known PIK3CA mutation, and 95% with a known double PIK3CAmut tumor, would not be captured by the therascreen panel. Finally, the clinical utility of PIK3CA mutations not present in the therascreen companion diagnostic assay or identified by other sequencing-based assays needs further investigation.