PO.CL01.15 · 临床研究
基于免疫组化的卵巢子宫内膜样癌预后亚分层
IHC-based prognostic sub-stratification of ovarian endometrioid carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
卵巢子宫内膜样癌（OEC）是第二常见的组织学类型，在卵巢癌中预后最为良好。与子宫内膜癌类似，OEC表现出显著的分子多样性。我们旨在通过整合免疫组化（IHC）生物标志物、临床亚分期及手术结局，开发一种实用的免疫组化预后工具。这项多机构研究纳入了来自Alberta癌症登记处（AOVT）、Mayo Clinic以及卵巢疾病及其评估研究（DOVE）的原发浸润性OEC患者。病理复核排除了误分类的高级别浆液性癌和中肾管癌，最终保留422例具有可用肿瘤标本且未接受新辅助治疗的OEC病例（AOVT N=158；DOVE N=143；Mayo N=121）。临床特征包括年龄、分期、分级、残留病灶及5年生存率。临床风险组通过结合分期和残留病灶来定义：低危（FIGO IA/IB期且无肉眼可见病灶）、中危（IC-II期且无肉眼可见病灶）、高危（III/IV期或有肉眼可见病灶）。组织微阵列采用免疫组化对TP53、PMS2、MSH6、PGR和CTNNB1进行染色，并由一名病理学家评分。肿瘤按层级分类为TP53异常（TP53abn）/PGR缺失、错配修复缺陷（MMRd，通过PMS2和MSH6判定）、核内CTNNB1（nCTNNB1）或无特异性免疫组化特征（NSIP）。采用Cox回归比较各临床风险组和生物标志物组的5年总生存（OS），并校正年龄和研究中心以生成风险比（HR）和5年生存率（5-YSR）。与低危和中危相比，高临床风险组与更差的5年OS相关（p<0.0001）。校正年龄和研究中心后，层级化免疫组化生物标志物组也与5年OS相关（p<0.0001），其中合并TP53abn/PGR缺失（n=17，HR=6.07，95% CI 2.78-13.26）、仅PGR缺失（n=55，HR=4.17，95% CI 2.19-7.94）、仅TP53abn（n=29，HR=2.04，95% CI 0.85-4.90）持续表现为更差的生存，而与NSIP（n=132）相比，核内CTNNB1（n=146，HR=0.22，95% CI 0.07-0.65）生存更佳。在低危组内，MMRd、nCTNNB1或NSIP的5年生存率超过97%，而伴TP53abn/PGR缺失或仅PR缺失的OEC 5年生存率低于75%。在中危组内，仅nCTNNB1的5年生存率超过97%。在高危组内，nCTNNB1型OEC的5年生存率为90.9%，而TP53abn/PGR缺失型仅为16.7%。这一基于免疫组化的算法在临床亚分期之外进一步细化了预后。它识别出预后不良的低危患者（TP53abn/PGR缺失、仅PGR缺失），这些患者可能从辅助治疗中获益；同时也识别出中危组内预后良好的患者，这些患者可能可以降阶梯辅助治疗。生物标志物还可能进一步改善高危组内化疗与激素治疗的患者选择。
查看英文原文 English abstract
Ovarian endometrioid carcinoma (OEC) is the second most common histotype associated with the most favorable prognosis among ovarian carcinomas. Similar to endometrial carcinoma, OEC exhibit significant molecular diversity. We aimed to develop a practical immunohistochemical (IHC) prognosticator by integrating IHC biomarkers with clinical substage, and surgical outcomes. This multi-institutional study included participants with primary invasive OEC from the Alberta Cancer Registry (AOVT), Mayo Clinic, and Disease of the Ovary and their Evaluation Study (DOVE). Pathology review excluded misclassified high-grade serous and mesonephric carcinomas leaving 422 OEC cases (AOVT N=158; DOVE N=143; Mayo N=121) with available tumor biospecimens who did not receive neoadjuvant treatment. Clinical characteristics included age, stage, grade, residual disease and 5-year survival. Clinical risk group was defined by combining stage and residual disease: Low (FIGO stage IA/IB & no macroscopic disease), Intermediate (stage IC-II& no macroscopic disease), High (stage III/IV or macroscopic disease). Tissue microarrays were stained for TP53, PMS2, MSH6, PGR, and CTNNB1 using IHC and were scored by a single pathologist. Tumors were hierarchically categorized as TP53-abnormal (TP53abn)/PGR-loss, mismatch-repair deficient (MMRd, via PMS2 and MSH6), nuclear-CTNNB1 (nCTNNB1), or no-specific-immunohistochemical-profile (NSIP). Overall survival (OS) at 5 years was compared across clinical risk and biomarker groups using Cox regression, adjusted for age and site to generate hazard ratios (HR), and 5-year survival rates (5-YSR). High clinical risk group was associated with worse 5-year OS compared to low & intermediate risk (p<0.0001). Hierarchical IHC biomarker groups were also associated with 5-year OS, adjusted for age and study site (p<0.0001), with consistently worse survival for combined TP53abn/PGR-loss (n=17, HR=6.07, 95% CI 2.78-13.26), PGR-loss only (n=55, HR=4.17, 95% CI 2.19-7.94), TP53abn only (n=29, HR=2.04, 95% CI 0.85-4.90), and better survival for nuclear-CTNNB1 (n=146, HR=0.22, 95% CI 0.07-0.65) compared to NSIP (n=132). Within the low-risk group, MMRd, nCTNNB1, or NSIP had greater than 97% 5-YSR, while OEC with TP53abn/PGR-loss or PR-loss only had less than 75% 5-YSR. Within the intermediate group, only nCTNNB1 exceeded a 5-YSR of greater than 97%. Within the high-risk group, 5YSR for nCTNNB1 OEC was 90.9%, compared to only 16.7% for TP53abn/PGR-loss. This IHC-based algorithm refines prognosis beyond clinical substage. It identifies low-risk patients with unfavorable prognosis (TP53abn/PGRloss, PGR loss only) who may benefit from adjuvant therapy, and also patients with favorable prognosis within the intermediate group for whom adjuvant therapy could be de-escalated. Further patient selection for chemo vs. hormone therapy in the high-risk group may be improved by biomarkers.
利益披露 Disclosure
G. Taengwa, None..
H. J. Atkinson, None..
B. M. McCauley, None..
S. M. Armasu, None..
C. Wang, None..
J. A. Doherty, None..
H. R. Harris, None..
E. L. Goode, None..
M. Koebel, None..
S. J. Winham, None.