Karolina A. Kilowski , Martin F. Dietrich , Joanne Xiu , Yasmine Baca , Andrew Hinton , Sarfraz Ahmad , Thomas J. Herzog , Premal Thaker , Robert W. Holloway
{"title":"子宫内膜癌中的 KRAS 突变:对预后和治疗的可能影响。","authors":"Karolina A. Kilowski , Martin F. Dietrich , Joanne Xiu , Yasmine Baca , Andrew Hinton , Sarfraz Ahmad , Thomas J. Herzog , Premal Thaker , Robert W. Holloway","doi":"10.1016/j.ygyno.2024.10.026","DOIUrl":null,"url":null,"abstract":"<div><h3>Background/Objectives</h3><div>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.</div></div><div><h3>Methods</h3><div>A molecular database of 7870 ECs was queried for presence of oncogenic mutations and immunotherapy biomarkers. Comparisons were performed using Fisher-Exact/ChiSquare (<em>p</em>-values) and adjusted for multiple tests by Benjamini-Hochberg (q) and pairwise nonparametric analysis using Wilcoxon Method.</div></div><div><h3>Results</h3><div><em>KRAS-</em>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 <em>KRAS-</em>mut. Microsatellite instability-high and tumor mutational burden-high status were observed in 34.1% and 36.5% in <em>KRAS-</em>mut compared to 19.8% and 16.9% in <em>KRAS-</em>WT, respectively (<em>p</em> < 0.05). PD-L1 >1% was detected in 8.4% vs 6.4% of KRAS-mut vs KRAS-WT (<em>p</em> < 0.05). <em>BRCA1/2</em> mutations were detected with similar low frequency (5.9% vs 4.9%) among <em>KRAS-</em>mut and <em>KRAS-</em>WT ECs (<em>p</em> > 0.05). KRAS-mut was inversely associated with Her-2 overexpression (1.8% KRAS-mut vs 13% KRAS-WT. (<em>p</em> < 0.001).</div></div><div><h3>Conclusions</h3><div><em>KRAS-</em>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.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":"191 ","pages":"Pages 299-306"},"PeriodicalIF":4.5000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"KRAS mutations in endometrial cancers: Possible prognostic and treatment implications\",\"authors\":\"Karolina A. Kilowski , Martin F. Dietrich , Joanne Xiu , Yasmine Baca , Andrew Hinton , Sarfraz Ahmad , Thomas J. Herzog , Premal Thaker , Robert W. Holloway\",\"doi\":\"10.1016/j.ygyno.2024.10.026\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background/Objectives</h3><div>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.</div></div><div><h3>Methods</h3><div>A molecular database of 7870 ECs was queried for presence of oncogenic mutations and immunotherapy biomarkers. Comparisons were performed using Fisher-Exact/ChiSquare (<em>p</em>-values) and adjusted for multiple tests by Benjamini-Hochberg (q) and pairwise nonparametric analysis using Wilcoxon Method.</div></div><div><h3>Results</h3><div><em>KRAS-</em>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 <em>KRAS-</em>mut. Microsatellite instability-high and tumor mutational burden-high status were observed in 34.1% and 36.5% in <em>KRAS-</em>mut compared to 19.8% and 16.9% in <em>KRAS-</em>WT, respectively (<em>p</em> < 0.05). PD-L1 >1% was detected in 8.4% vs 6.4% of KRAS-mut vs KRAS-WT (<em>p</em> < 0.05). <em>BRCA1/2</em> mutations were detected with similar low frequency (5.9% vs 4.9%) among <em>KRAS-</em>mut and <em>KRAS-</em>WT ECs (<em>p</em> > 0.05). KRAS-mut was inversely associated with Her-2 overexpression (1.8% KRAS-mut vs 13% KRAS-WT. (<em>p</em> < 0.001).</div></div><div><h3>Conclusions</h3><div><em>KRAS-</em>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. 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KRAS mutations in endometrial cancers: Possible prognostic and treatment implications
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.
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