Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups.
Molecular Classification of Grade 3 Endometrioid Endometrial Cancers Identifies Distinct Prognostic Subgroups.
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DOI：
10.1097/pas.0000000000001020
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发表时间：
2018-05
期刊：
影响因子：
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通讯作者：
Soslow RA
中科院分区：
文献类型：
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作者：
Bosse T;Nout RA;McAlpine JN;McConechy MK;Britton H;Hussein YR;Gonzalez C;Ganesan R;Steele JC;Harrison BT;Oliva E;Vidal A;Matias-Guiu X;Abu-Rustum NR;Levine DA;Gilks CB;Soslow RA
我们的目的是探讨分子分类是否可以用于改善3级子宫内膜样癌(EECS)的预后。3级EEC分为4个亚型：p53异常，基于突变样免疫染色(P53abn)；MMR缺陷，基于错配修复蛋白表达缺失(MMRD)；存在极外切酶结构域热点突变(POL)；无特异性分子图谱(NSMP)，这些异常均不存在。采用Kaplan-Meier方法(Log-Rank检验)以及单变量和多变量Cox比例风险模型比较患者的总体生存率(OS)和无复发生存率(RFS)。总共纳入了381名患者。中位年龄为66岁(33-96岁)。FIGO分期(2009年)：IA期171例(44.9%)，IB期120例(31.5%)，II期24例(6.3%)，III期50例(13.1%)，IV期11例(2.9%)。其中POL49例(12.9%)，p53abn 79例(20.7%)，NSMP 115例(30.2%)，MMRD 138例(36.2%)。中位随访期为6.1年(0.2~17.0)。与NSMP患者相比，极突变3级EEC(OS：危险比[HR]0.36[95%CI：0.18-0.70]，p=0.003；RFS：HR0.17[0.05-0.54]，p=0.003)预后明显好于NSMP患者；p53abn肿瘤患者的RFS明显差(HR1.73[1.09-2.74]，p0.021)；MMRD肿瘤患者有改善RFS的趋势。估计的5年OS率如下：POL 89%，MMRD 75%，NSMP69%，p53abn 55%(Log Rank p=0.001)。5年RFS率分别为：POL 96%，MMRD 77%，NSMP%，p53abn 47%(P=0.000001)。在包括年龄和FIGO分期的多变量Cox模型中，POLE和MMRD状态仍然是RFS较好的独立预后因素；P53状态是RFS较差的独立预后因素。对3级EECS的分子分类表明，这些肿瘤是子宫内膜癌分子亚型的混合体，而不是一个同质性组。分子标志物的添加确定了预后亚组，具有潜在的治疗意义。
Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrioid endometrial carcinomas (EECs). Grade 3 EECs were classified into four subgroups: p53-abnormal, based on mutant-like immunostaining (p53abn); MMR-deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall (OS), and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-Rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range 33–96). FIGO stages (2009) were as follows: IA, 171 (44.9%), IB, 120 (31.5%), II, 24 (6.3%), III, 50 (13.1%), IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range 0.2–17.0). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: Hazard Ratio [HR] 0.36 [95%CI: 0.18–0.70], p=0.003; RFS: HR 0.17 [0.05–0.54], p=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR 1.73 [1.09–2.74], p0.021); patients with MMRd tumors showed a trend towards better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log Rank p=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (p=0.000001), respectively. In a multivariable Cox model that included age and FIGO stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.