晚期或复发性子宫内膜癌中的PIK3CA突变：来自II期MITO END-3研究的探索性分子分析。
完整摘要 · 中文译文
目的：免疫治疗联合化疗可显著改善晚期子宫内膜癌（EC）的无进展生存期，尤其是在微卫星高度不稳定（MSI-H）的病例中。尽管如此，对于免疫治疗后的复发性子宫内膜癌，迫切需要新的治疗选择。PI3K通路在包括子宫内膜癌在内的妇科肿瘤中频繁发生改变，代表了一个潜在的治疗靶点。 患者与方法：在MITO END-3试验的一项预先计划的转化分析中，我们回顾性分析了107例具有适合下一代测序（NGS）分析（FoundationOne CDx）样本的患者的基因组异常，重点关注PIK3CA突变状态。 结果：在我们的分析中，四个最常发生突变的基因是TP53、PIK3CA、ARID1A和PTEN。在51.4%（55/107例患者）的组织样本中检测到PIK3CA突变。共观察到68种不同的PIK3CA突变，其中64种被认为是致病性的，4种被归类为意义不明的变异，2例患者同时存在两种不同的致病性突变。最常见的PIK3CA突变位于激酶结构域，最常见的是H1047R（11/68）和H1047Y（3/68），以及螺旋结构域，包括E545K（4/68）和E542K（3/68）。值得注意的是，根据目前乳腺癌文献，MITO END-3中报告的68种不同PIK3CA突变中有24种被认为可预测对alpelisib的PI3K抑制治疗的反应。有趣的是，在所有癌症基因组图谱分类中均观察到PIK3CA突变。 结论：在这项事后 来自MITO END-3试验的事后分析，我们确认了PIK3CA突变在子宫内膜癌（EC）中的高发生率，使该肿瘤成为临床试验中测试PI3K抑制剂的理想候选对象。
完整摘要 · 英文原文
PURPOSE: Immunotherapy with chemotherapy significantly improves progression-free survival in advanced endometrial cancer (EC), especially in microsatellite instability-high (MSI-H) cases. Despite this, for recurrent EC in the postimmunotherapy setting, new treatment options are urgently needed. The PI3K pathway is frequently altered in gynecologic cancers, including EC, representing a potential treatment target. PATIENTS AND METHODS: In a preplanned translational analysis of the MITO END-3, we retrospectively analyzed the genomic abnormalities of 107 patients with samples eligible for next-generation sequencing (NGS) analysis (FoundationOne CDx) with a focus on PIK3CA mutational status. RESULTS: In our analysis, the four most frequently mutated genes were TP53, PIK3CA, ARID1A, and PTEN. PIK3CA mutations were detected in 51.4% (55/107 patients) of tissue samples. A total of 68 different PIK3CA mutations were observed, of which 64 were considered pathogenic and four were classified as variants of unknown significance, with the co-occurrence of two different pathogenic mutations in 2 patients. The most frequent PIK3CA mutations were found in the kinase domain, most commonly H1047R (11/68) and H1047Y (3/68), and in the helical domain, including E545K (4/68) and E542K (3/68). Notably, 24 different PIK3CA mutations out of 68 reported in MITO END-3 are considered predictive of response to PI3K inhibition with alpelisib according to current literature in breast cancer. Interestingly, PIK3CA mutations were observed in all The Cancer Genome Atlas categories. CONCLUSION: In this post hoc analysis from the MITO END-3 trial, we confirmed the high frequency of PIK3CA mutations in EC, establishing this tumor as an ideal candidate for testing of PI3K inhibitors in clinical trials.