Kilowski Karolina A, Dietrich Martin F, Xiu Joanne, Baca Yasmine, Hinton Andrew, Ahmad Sarfraz, Herzog Thomas J, Thaker Premal, Holloway Robert W
Gynecologic Oncology Program, AdventHealth Cancer Institute, Orlando, FL, USA.
Cancer Care Centers of Brevard, US Oncology Network, Rockledge, FL, USA.
Gynecol Oncol. 2024 Dec;191:299-306. doi: 10.1016/j.ygyno.2024.10.026. Epub 2024 Nov 4.
BACKGROUND/OBJECTIVES: Patients with recurrent or metastatic endometrial cancer (EC) have poor prognoses with limited therapeutic options following immunotherapy or immunochemotherapy treatments. Inhibitors of KRAS mutations (KRAS-mut) have shown efficacy in early solid tumor studies, but data in EC are lacking. This study describes the frequency of KRAS-mut relative to other oncogenic alterations in EC to identify genomic characteristics of KRAS-mut tumors that could lead to novel therapeutic options.
A molecular database of 7870 ECs was queried for presence of oncogenic mutations and immunotherapy biomarkers. Comparisons were performed using Fisher-Exact/ChiSquare (p-values) and adjusted for multiple tests by Benjamini-Hochberg (q) and pairwise nonparametric analysis using Wilcoxon Method.
KRAS-mut is a relatively frequent genotype in EC, detected in 16% of cases. Codon 12 was most frequently mutated, with G12D (31%) and G12V (27%) the most common subtypes. Biomarkers of immunotherapy response co-occur with KRAS-mut. Microsatellite instability-high and tumor mutational burden-high status were observed in 34.1% and 36.5% in KRAS-mut compared to 19.8% and 16.9% in KRAS-WT, respectively (p < 0.05). PD-L1 >1% was detected in 8.4% vs 6.4% of KRAS-mut vs KRAS-WT (p < 0.05). BRCA1/2 mutations were detected with similar low frequency (5.9% vs 4.9%) among KRAS-mut and KRAS-WT ECs (p > 0.05). KRAS-mut was inversely associated with Her-2 overexpression (1.8% KRAS-mut vs 13% KRAS-WT. (p < 0.001).
KRAS-mut represents a genotypically distinct group of ECs. Overlap exists with genomic predictors (TMB-high, MSI-high) of immunotherapy response, suggesting a possible biomarker-driven combination option with immunotherapy. Clinical trials to evaluate these strategies should be developed.
背景/目的：复发或转移性子宫内膜癌（EC）患者预后较差，免疫治疗或免疫化疗后的治疗选择有限。KRAS突变抑制剂（KRAS-mut）在早期实体瘤研究中已显示出疗效，但EC方面的数据尚缺乏。本研究描述了KRAS-mut相对于EC中其他致癌改变的频率，以确定KRAS-mut肿瘤的基因组特征，从而可能带来新的治疗选择。
查询了一个包含7870例EC的分子数据库，以确定致癌突变和免疫治疗生物标志物的存在情况。使用Fisher精确检验/卡方检验（p值）进行比较，并通过Benjamini-Hochberg方法（q）对多重检验进行校正，以及使用Wilcoxon方法进行成对非参数分析。
KRAS-mut是EC中相对常见的基因型，在16%的病例中被检测到。密码子12最常发生突变，G12D（31%）和G12V（27%）是最常见的亚型。免疫治疗反应的生物标志物与KRAS-mut同时出现。KRAS-mut中微卫星高度不稳定和肿瘤突变负荷高状态分别为34.1%和36.5%，而KRAS-WT中分别为19.8%和16.9%（p<0.05）。KRAS-mut中8.4%检测到PD-L1>1%，KRAS-WT中为6.4%（p<0.05）。KRAS-mut和KRAS-WT ECs中BRCA1/2突变的检测频率相似（5.9%对4.9%）（p>0.05）。KRAS-mut与Her-2过表达呈负相关（KRAS-mut为1.8%，KRAS-WT为13%。（p<0.001）。
KRAS-mut代表了一组基因型不同的EC。与免疫治疗反应的基因组预测指标（高肿瘤突变负荷、高度微卫星不稳定）存在重叠，提示可能存在生物标志物驱动的免疫治疗联合方案。应开展评估这些策略的临床试验。
