Iida Yasushi, Churchman Michael, Hollis Robert L, Taylor Sarah, Bartos Clare, Croy Ian, Gentleman William, Rye Tzyvia, Nirsimloo Rachel, Herrington C Simon, Gourley Charlie, Okamoto Aikou, Thomson John P
Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan.
Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
Gynecol Oncol. 2025 Jul;198:66-74. doi: 10.1016/j.ygyno.2025.05.016. Epub 2025 May 27.
Clear cell ovarian carcinoma (CCOC) is generally associated with a favourable prognosis, however up to 30 % of low-stage cases relapse within five years. The benefit of adjuvant chemotherapy in early-stage disease (FIGO IA-IC1) remains uncertain. This study aimed to identify molecular and immune markers associated with relapse in a well-characterized CCOC cohort.
We analyzed 85 CCOC cases identified through the Edinburgh Ovarian Cancer Database. Targeted DNA sequencing assessed genomic alterations, while CD3 and CD8 immunohistochemistry evaluated tumour immune infiltration. Tumours were stratified by stage (IA-IC1, IC2-II, III-IV), and progression-free survival (PFS) analysis included stage, age, genomic features, and immune markers.
Common genomic alterations included ARID1A (49 %) and PIK3CA (42 %) mutations, PIK3-AKT pathway perturbations (60 %), and mismatch repair-related mutational signatures (25.9 %). Genomic features were not significantly associated with tumour stage; however, low-stage tumours (IA-IC1) were enriched in CD3+ (40 % cases) and CD8+ (29 % cases) tumour-infiltrating lymphocytes (TILs) compared to higher-stage tumours (IC2-II: 13 %/7 %; III-IV: 9 %/0 %). In univariate analysis, low CD3+ TIL levels were significantly associated with reduced PFS (HR = 4.4, P = 0.042), and ARID1A wild-type status was linked to poorer PFS in low-stage tumours (HR = 7.2, P = 0.088). Notably, the combination of ARID1A wild-type status and CD3+ TIL depletion identified a high-risk subgroup with increased relapse risk (HR = 11.7, P = 0.051).
The combination of ARID1A wild-type status and low CD3+ TIL levels suggests higher relapse risk in low-stage CCOC. These findings warrant further investigation into targeted and immune-based therapies for high-risk early-stage patients.
透明细胞卵巢癌（CCOC）通常预后良好，然而高达30%的低分期病例会在五年内复发。早期疾病（FIGO IA - IC1）辅助化疗的益处仍不确定。本研究旨在确定在一个特征明确的CCOC队列中与复发相关的分子和免疫标志物。
我们分析了通过爱丁堡卵巢癌数据库确定的85例CCOC病例。靶向DNA测序评估基因组改变，而CD3和CD8免疫组化评估肿瘤免疫浸润。肿瘤按分期（IA - IC1、IC2 - II、III - IV）分层，无进展生存期（PFS）分析包括分期、年龄、基因组特征和免疫标志物。
常见的基因组改变包括ARID1A（49%）和PIK3CA（42%）突变、PIK3 - AKT通路紊乱（60%）以及错配修复相关的突变特征（25.9%）。基因组特征与肿瘤分期无显著相关性；然而，与高分期肿瘤（IC2 - II：13%/7%；III - IV：9%/0%）相比，低分期肿瘤（IA - IC1）中CD3 +（40%病例）和CD8 +（29%病例）肿瘤浸润淋巴细胞（TILs）更为丰富。在单因素分析中，低CD3 + TIL水平与PFS降低显著相关（HR = 4.4，P = 0.042），并且ARID1A野生型状态与低分期肿瘤中较差的PFS相关（HR = 7.2，P = 0.088）。值得注意的是，ARID1A野生型状态和CD3 + TIL耗竭的组合确定了一个复发风险增加的高风险亚组（HR = 11.7，P = 0.051）。
ARID1A野生型状态和低CD3 + TIL水平的组合表明低分期CCOC复发风险更高。这些发现值得对高危早期患者的靶向治疗和基于免疫的治疗进行进一步研究。
