Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Weill Cornell Medical College, New York, New York.
Clin Cancer Res. 2020 Jul 15;26(14):3881-3888. doi: 10.1158/1078-0432.CCR-19-3959. Epub 2020 Apr 16.
We examined whether prospective molecular characterization of advanced metastatic disease can reveal grade and/or histology-specific differences to inform diagnosis and facilitate enrollment onto clinical trials.
Patients with uterine sarcoma consented to a prospective study of next-generation sequencing (NGS). Clinical annotations were extracted from their medical record. Tumor and matched normal DNA were subjected to NGS, and the genomic landscape was explored for survival correlations and therapeutic targetability.
Tumors from 107 women were sequenced and included leiomyosarcoma ( = 80), high-grade non-leiomyosarcoma ( = 22), low-grade endometrial stromal sarcoma (LG-ESS, = 4), and smooth muscle tumor of uncertain malignant potential (STUMP, = 2). Genomic profiling influenced histologic diagnosis in three cases. Common uterine leiomyosarcoma alterations were loss-of-function mutations in (56%), (51%), and (31%). Homozygous deletions of were present in 5% of these patients. alteration frequency was higher in the metastases samples as compared with the primary samples. Genomes of low-grade tumors were largely silent, while 50.5% of high-grade tumors had whole-genome duplication. Two metastatic uterine leiomyosarcoma cases were hypermutated. Both had prolonged disease-free survival. Potentially actionable mutations were identified in 48 patients (45%), 8 (17%) of whom received matched therapy with 2 achieving clinical responses. Among patients with uterine leiomyosarcoma with somatic alterations, sustained partial responses were observed with PARP inhibitor-containing therapy.
Prospective genomic profiling can contribute to diagnostic precision and inform treatment selection in patients with uterine sarcomas. There was evidence of clinical benefit in patients with uterine leiomyosarcoma with somatic alterations treated with PARP inhibitors.
我们研究了先进转移性疾病的前瞻性分子特征是否能够揭示特定于分级和/或组织学的差异，以提供诊断信息并促进临床试验入组。
患有子宫肉瘤的患者同意进行下一代测序（NGS）的前瞻性研究。从他们的病历中提取临床注释。对肿瘤和匹配的正常 DNA 进行 NGS 检测，并探索基因组景观以寻找与生存相关的相关性和治疗靶标。
对 107 名女性的肿瘤进行了测序，包括平滑肌肉瘤（ = 80）、高级别非平滑肌肉瘤（ = 22）、低级别子宫内膜间质肉瘤（LG-ESS， = 4）和平滑肌肿瘤恶性潜能不确定（STUMP， = 2）。基因组分析在三例病例中影响了组织学诊断。常见的子宫平滑肌肉瘤改变是 （56%）、 （51%）和 （31%）的功能丧失突变。这些患者中有 5%存在 的纯合缺失。在转移样本中 （ = 19）的改变频率较原发性样本高。低级别肿瘤的基因组基本上是沉默的，而 50.5%的高级别肿瘤存在全基因组复制。两例转移性子宫平滑肌肉瘤病例为高突变型。两者均有延长的无病生存期。在 48 名患者（45%）中确定了潜在的可治疗性突变，其中 8 名（17%）接受了匹配的治疗，其中 2 名患者取得了临床反应。在具有体细胞 改变的子宫平滑肌肉瘤患者中，观察到 PARP 抑制剂治疗的持续部分缓解。
前瞻性基因组分析有助于提高子宫肉瘤患者的诊断精度，并为治疗选择提供信息。在接受 PARP 抑制剂治疗的具有体细胞 改变的子宫平滑肌肉瘤患者中，观察到了临床获益的证据。
