Gene amplifications of PIK3CA or KRAS induce a downstream activation of the AKT-mTOR or RAF-ERK-pathways. Interactions of the active AKT pathway have been implicated in the inflammatory tumor microenvironment. Nothing is known about these interactions or prognostic power in esophageal adenocarcinoma (EAC). We retrospectively analyzed a large cohort of 685 EAC considering KRAS and PIK3CA gene amplification using fluorescence in situ hybridization (FISH) and immunohistochemistry. These results were correlated with clinical and molecular data as well as the inflammatory tumor microenvironment. Amplifications of KRAS were seen in 94 patients (17.1%), PIK3CA amplifications in 23 patients (5.0%). KRAS amplifications significantly correlated with nodal positive patients and poorer overall survival (OS) in the subgroup without neoadjuvant treatment (p = 0.004), coamplifications of Her2 (p = 0.027), and TP53 mutations (p = 0.016). PIK3CA amplifications significantly correlated with a high amount of tumor infiltrating T cells (p = 0.003) and showed a tendency to better OS (p = 0.068). A correlation with checkpoint makers (PD-L1, LAG3, VISTA, TIM3, IDO) could not be revealed. Our findings are the first to link the KRAS amplified genotype with lymphonodal positivity and poor prognosis and the PIK3CA-amplified genotype with a T cell–rich microenvironment in EAC. Future studies must show whether these two genotype subgroups can be therapeutically influenced. A dual inhibition of MEK and SHP2T could be effective in the subgroup of KRAS amplified EACs and an immune checkpoint blockade may prove to be particularly promising in the subgroup of PIK3CA-amplified EACs.

PIK3CA或KRAS的基因扩增可诱导AKT-mTOR或RAF-ERK途径的下游激活。活性AKT途径的相互作用已牵涉到炎性肿瘤微环境。关于食管腺癌（EAC）中的这些相互作用或预后能力，人们一无所知。我们回顾性分析了685个EAC的大队列，考虑了使用荧光原位杂交（FISH）和免疫组化的KRAS和PIK3CA基因扩增。这些结果与临床和分子数据以及炎性肿瘤微环境相关。94例（17.1％）PIK3CA患者出现了KRAS扩增23例（5.0％）扩增。在未接受新辅助治疗的亚组中，KRAS扩增与淋巴结阳性患者和较差的总体生存率（OS）显着相关（p  = 0.004），Her2的共扩增（p  = 0.027）和TP53突变（p  = 0.016）。PIK3CA扩增与大量的肿瘤浸润性T细胞显着相关（p  = 0.003），并显示出OS改善的趋势（p  = 0.068）。无法显示与检查点生成器（PD-L1，LAG3，VISTA，TIM3，IDO）的相关性。我们的发现是第一个将KRAS联系起来的发现EAC中具有淋巴母细胞阳性和预后较差的基因型扩增，以及具有T细胞富集微环境的PIK3CA基因型扩增。未来的研究必须表明这两个基因型亚组是否可以在治疗上受到影响。MEK和SHP2T的双重抑制在KRAS扩增的EAC的亚组中可能是有效的，免疫检查点阻断在PIK3CA扩增的EAC的亚组中可能被证明是特别有希望的。