Background: Nonsurgical treatment options are increasingly needed for endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC). Despite promising initial response rates, prospective long-term data and determinants for relapse are limited. Methods: Follow-up data from patients in our prospective phase II trial of LIUD for AH/G1EEC were collected from medical records. Spatial transcriptomics (Nanostring GeoMX digital spatial profiling) with in silico cell type deconvolution and pathway analyses were employed on longitudinal biopsy samples from five patients across pre-treatment, on-treatment, and relapse. Results: Of 43 participants exhibiting initial response to LIUD, 41 had follow-up data. Sixteen (39%) experienced relapse. Clinical factors associated with shorter response duration included younger age, initial diagnosis of G1EEC, lack of response at six months, premenopausal status, and Hispanic ethnicity (p<0.05), but only six-month response status remained a significant predictor in a multivariate model (p=0.023). LIUD increased abundance of NK cells (DMCP-counter score=46.13, FDR=0.004) and cytotoxic lymphocytes (DMCP-counter score=277.67, FDR=0.004), as well as lymphocyte cytotoxicity markers PRF1 (log2FC=1.62, FDR=0.025) and GZMA (log2FC=2.47, FDR=0.008). NK cells were reduced at relapse (DMCP-counter score=-55.96, FDR=0.02). Immune-related pathways (IFNα-response and TGFβ-signaling) were enriched at relapse (FDR<0.05). IDO1 expression, reflecting immune exhaustion, was upregulated at relapse (FDR<0.05). Conclusions: Upfront resistance and relapse after initial response to LIUD for AH/G1EEC impacts nearly half of patients, remaining a major hurdle for non-surgical treatment of AH/G1EEC. Molecular studies evaluating longitudinal biopsies from a small cohort implicate immune mechanisms at relapse, including reversal of progestin-related immunomodulation and increased immune exhaustion.

中文翻译：

---

左炔诺孕酮宫内节育器治疗不典型增生和早期子宫内膜癌的长期随访显示以免疫衰竭为特征的复发


背景：子宫内膜不典型增生（AH）和子宫内膜样子宫内膜癌（EEC）越来越需要非手术治疗方案。尽管初始缓解率令人鼓舞，但预期的长期数据和复发的决定因素仍然有限。方法：从医疗记录中收集 LIUD 治疗 AH/G1EEC 前瞻性 II 期试验中患者的随访数据。对五名患者治疗前、治疗中和复发期间的纵向活检样本进行了空间转录组学（Nanostring GeoMX 数字空间分析）以及计算机细胞类型解卷积和通路分析。结果：在 43 名对 LIUD 表现出初步反应的参与者中，41 名有后续数据。十六人 (39%) 经历过复发。与较短的缓解持续时间相关的临床因素包括年龄较小、G1EEC 的初始诊断、六个月时缺乏缓解、绝经前状态和西班牙裔种族 (p<0.05)，但在多变量模型中，只有六个月的缓解状态仍然是显着的预测因素（p=0.023）。 LIUD增加了NK细胞（DMCP计数=46.13，FDR=0.004）和细胞毒性淋巴细胞（DMCP计数=277.67，FDR=0.004）以及淋巴细胞细胞毒性标记物PRF1（log2FC=1.62，FDR=0.025）的丰度和 GZMA（log2FC=2.47，FDR=0.008）。 NK 细胞在复发时减少（DMCP 计数=-55.96，FDR=0.02）。免疫相关通路（IFNα 反应和 TGFβ 信号传导）在复发时丰富（FDR<0.05）。反映免疫衰竭的 IDO1 表达在复发时上调 (FDR<0.05)。结论：AH/G1EEC 的 LIUD 初步缓解后的前期耐药和复发影响了近一半的患者，这仍然是 AH/G1EEC 非手术治疗的主要障碍。 评估一小群纵向活检的分子研究表明复发时的免疫机制，包括孕激素相关免疫调节的逆转和免疫衰竭的增加。