Lee Sarah S, Secord Angeles Alvarez, Friedman Steven, Hade Erinn M, Smitherman Carson, Bisht Nikita, Borden Lindsay, Jackson Amanda L, Backes Floor, Thaker Premal, Arend Rebecca, Wright Jason D, Corr Bradley, Ko Emily, Konecny Gottfried, Podwika Sarah, Bae-Jump Victoria, Hacker Kari E, Pothuri Bhavana
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Perlmutter Cancer Center, New York University Langone Health, New York, NY, United States.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Durham, NC, United States.
Gynecol Oncol. 2025 Aug;199:152-158. doi: 10.1016/j.ygyno.2025.07.006. Epub 2025 Jul 11.
Mismatch repair deficiency (dMMR), high microsatellite instability (MSI-H), and high tumor mutation burden (TMB-H) are predictive and prognostic biomarkers in endometrial cancer. We aimed to characterize the racial/ethnic distribution of molecular markers and the clinical characteristics among endometrial cancer patients with TMB-H and MSI-H/dMMR.
The Endometrial Cancer Molecularly Targeted Therapy Consortium is a centrally verified clinical and molecular repository. Patients with endometrial cancer who underwent tumor profiling were included. TMB-H was defined as ≥10-12 mutations per megabase. MSI-H was determined by next-generation sequencing or polymerase chain reaction, and dMMR by loss of MLH1, MSH2, MSH6, or PMS2 on immunohistochemistry. Tumor biomarker positivity was defined as TMB-H and/or MSI-H/dMMR. Overall survival was assessed using Kaplan-Meier and Cox proportional hazard models.
Among 742 patients, 22 % (n = 164) were biomarker positive: 12 % (n = 87) had both TMB-H and MSI-H/dMMR, 8 % (n = 63) had MSI-H/dMMR alone, and 2 % (n = 14) had 14 TMB-H alone. Only 9 % of non-Hispanic Black patients had biomarker positive tumors compared to 26 % of patients from other racial/ethnic groups. Pathogenic POLE mutations were rare (<1 %, n = 5). Patients with TMB-H had a higher proportion of high-risk histologies (43 %) than those with MSI-H/dMMR (24 %). Biomarker positive tumors were associated with a lower risk of death compared to biomarker negative tumors (aHR 0.63, 95 % CI: 0.46, 0.88).
Less than 10 % of non-Hispanic Black patients with endometrial cancer had TMB-H and/or MSI-H/dMMR, and biomarker positivity was associated with improved survival. Prospective studies are necessary to elucidate how these molecular differences impact treatment and outcomes.
错配修复缺陷（dMMR）、高度微卫星不稳定（MSI-H）和高肿瘤突变负荷（TMB-H）是子宫内膜癌的预测和预后生物标志物。我们旨在描述分子标志物的种族/民族分布以及TMB-H和MSI-H/dMMR子宫内膜癌患者的临床特征。
子宫内膜癌分子靶向治疗联盟是一个经过集中验证的临床和分子资料库。纳入接受肿瘤分析的子宫内膜癌患者。TMB-H定义为每兆碱基≥10-12个突变。MSI-H通过下一代测序或聚合酶链反应确定，dMMR通过免疫组织化学检测MLH1、MSH2、MSH6或PMS2的缺失来确定。肿瘤生物标志物阳性定义为TMB-H和/或MSI-H/dMMR。使用Kaplan-Meier和Cox比例风险模型评估总生存期。
在742例患者中，22%（n = 164）生物标志物呈阳性：12%（n = 87）同时具有TMB-H和MSI-H/dMMR，8%（n = 63）仅具有MSI-H/dMMR，2%（n = 14）仅具有TMB-H。与其他种族/民族的26%患者相比，只有9%的非西班牙裔黑人患者肿瘤生物标志物呈阳性。致病性POLE突变很少见（<1%，n = 5）。TMB-H患者的高危组织学比例（43%）高于MSI-H/dMMR患者（24%）。与生物标志物阴性肿瘤相比，生物标志物阳性肿瘤的死亡风险较低（风险比0.63，95%置信区间：0.46，0.88）。
不到10%的非西班牙裔黑人子宫内膜癌患者具有TMB-H和/或MSI-H/dMMR，且生物标志物阳性与生存期改善相关。有必要进行前瞻性研究以阐明这些分子差异如何影响治疗和结局。
