KRAS mutations in endometrial cancers: Possible prognostic and treatment implications

IF 4.5 2区 医学 Q1 OBSTETRICS & GYNECOLOGY
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引用次数: 0

Abstract

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.

Methods

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.

Results

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).

Conclusions

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.
子宫内膜癌中的 KRAS 突变:对预后和治疗的可能影响。
背景/目的:复发性或转移性子宫内膜癌(EC)患者预后较差,在接受免疫疗法或免疫化疗治疗后,治疗选择有限。KRAS突变抑制剂(KRAS-mut)已在早期实体瘤研究中显示出疗效,但在子宫内膜癌中缺乏数据。本研究描述了EC中KRAS突变相对于其他致癌基因改变的频率,以确定KRAS突变肿瘤的基因组特征,从而找到新的治疗方案:方法:对包含7870例EC的分子数据库进行查询,以确定是否存在致癌突变和免疫疗法生物标记物。比较采用Fisher-Exact/ChiSquare法(P值),并通过Benjamini-Hochberg法(q)和Wilcoxon法进行多重检验调整和成对非参数分析:KRAS突变是EC中相对常见的基因型,在16%的病例中检测到。密码子12是最常见的突变,其中G12D(31%)和G12V(27%)是最常见的亚型。免疫疗法反应生物标志物与 KRAS 突变同时存在。微卫星不稳定性高和肿瘤突变负荷高分别出现在 34.1% 和 36.5% 的 KRAS-突变患者中,而 KRAS-WT 患者的这一比例分别为 19.8% 和 16.9%(P 1%);在 8.4% 的 KRAS-突变患者和 6.4% 的 KRAS-WT 患者中分别检测到微卫星不稳定性高和肿瘤突变负荷高(P 0.05)。KRAS 突变与 Her-2 过表达成反比(1.8% 的 KRAS 突变 vs 13% 的 KRAS-WT。(p 结论:KRAS-突变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因子(TMB-高、MSI-高)存在重叠,这表明生物标记物驱动的免疫治疗组合方案是可能的。应开展临床试验来评估这些策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Gynecologic oncology
Gynecologic oncology 医学-妇产科学
CiteScore
8.60
自引率
6.40%
发文量
1062
审稿时长
37 days
期刊介绍: Gynecologic Oncology, an international journal, is devoted to the publication of clinical and investigative articles that concern tumors of the female reproductive tract. Investigations relating to the etiology, diagnosis, and treatment of female cancers, as well as research from any of the disciplines related to this field of interest, are published. Research Areas Include: • Cell and molecular biology • Chemotherapy • Cytology • Endocrinology • Epidemiology • Genetics • Gynecologic surgery • Immunology • Pathology • Radiotherapy
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