分子分型在早期子宫内膜癌及子宫内膜非典型增生患者保留生育功能治疗中的意义

Significance of molecular classification in fertility-sparing treatment of endometrial carcinoma and atypical endometrial hyperplasia

目的探讨保留生育功能治疗的早期子宫内膜癌(EC)及子宫内膜非典型增生(AEH)患者的分子分型特征,并分析其临床病理特征以及与疗效的关系。方法收集2020年6月至2021年12月于北京大学人民医院行保留生育功能治疗且采用高通量测序技术进行分子分型的早期EC和AEH患者共46例,分子分型分为4型,POLE超突变型、高度微卫星不稳定性(MSI-H)型、非特殊分子改变(NSMP)型、高拷贝型。回顾性分析早期EC和AEH患者的临床病理资料,探讨不同分子分型患者的临床病理特征及保留生育功能治疗疗效的差异。结果(1)46例患者的年龄为(32.9±5.8)岁,其中EC 40例、AEH 6例。保留生育功能治疗首选醋酸甲羟孕酮(MPA)或醋酸甲地孕酮(MA),首选药物治疗未获完全缓解(CR)时可选用或联合应用促性腺激素释放激素激动剂(GnRH-a)、左炔诺孕酮宫内缓释系统(LNG-IUS)。46例患者中,1例患者治疗未满3个月无法评价疗效,其余45例患者(包括4例治疗满3个月但不足6个月者)中保留生育功能治疗达CR 32例(71%,32/45),达到CR的中位时间为8个月(4~12个月),部分缓解(PR)6例(13%,6/45);随访期内复发8例(25%,8/32),中位复发时间为8个月(4~21个月)。(2)46例EC或AEH患者中,分子分型以NSMP型(34例,74%)为主,MSI-H型、POLE超突变型、高拷贝型分别为7例(15%)、3例(7%)、2例(4%)。4种分子分型患者的血清癌抗原125(CA125)水平、有无肿瘤家族史、错配修复(MMR)基因相关蛋白表达、细胞增殖相关核抗原(Ki-67)表达分别比较,差异均有统计学意义(P均<0.05);其中,高拷贝型患者的血清CA_(125)水平最高[为(34.3±35.2)kU/L],MSI-H型患者存在肿瘤家族史的比例(6/7)、MMR基因相关蛋白阴性表达率(7/7)、Ki-67表达(>40%者占3/3)均最高。(3)46例保留生育功能治疗患者中,NSMP型、MSI-H型、POLE超突变型、高拷贝型患者的CR率比较,差异无统计学意义[分别为76%(25/33)、3/7、2/3、2/2;χ^(2)=5.782,P=0.123];4种分子分型患者的6个月达到CR率比较,差异则有统计学意义[分别为43%(13/30)、0/6、1/3、2/2;χ^(2)=9.973,P=0.019],其中MSI-H型患者的6个月达到CR率最低。进一步对34例NSMP型患者进行生存分析显示,年龄≥30岁患者达到CR所需时间显著长于<30岁者(P=0.010)。结论分子分型与早期EC及AEH患者保留生育功能治疗的疗效相关,MSI-H型患者保留生育功能治疗的疗效不佳,NSMP型患者需要进一步细化分组以预测获益人群,而POLE超突变型、高拷贝型患者因病例数较少,有待继续临床探究。

Objective To investigate the molecular classification of endometrial carcinoma(EC)and atypical endometrial hyperplasia(AEH)treated with fertility-sparing therapy,and to analyze its relationship with clinicopathological factors and treatment efficacy.Methods A total of 46 EC and AEH patients who received fertility-sparing therapy and molecular classification tested by next generation sequencing in Peking University People's Hospital from June 2020 to December 2021,were retrospectively collected.The relationships between molecular classification and clinicopathological factors and treatment outcomes were analyzed.Results(1)Of the 46 patients,including 40 EC and 6 AEH patients,32 cases(71%,32/45)had complete response(CR)after treatment,with median CR time of 8 months,6 cases(13%,6/45)had partial response,and 8 cases(25%,8/32)had recurrence.(2)The cases were distributed as no specific molecular profile(NSMP)34 cases(74%,34/46)subtype mainly,high microsatellite instability(MSI-H)7 cases(15%,7/46),POLE ultra-mutated 3 cases(7%,3/46),and copy number high(CNH)2 cases(4%,2/46).Patients with CNH had the hightest serum cancer antigen 125(CA_(125))level[(34.3±35.2)kU/L].MSI-H subtype had more family history of tumors(6/7),more with loss of mismatch repair(MMR)protein expression by immunohistochemical(7/7),and higher nuclear antigen associated with cell proliferation(Ki-67)expression level(3/3).(3)Patients in MSI-H subgroup had the lowest CR rate at 6 months(0/6;P=0.019),and survival analysis showed that they were less likely to achieve CR than those with NSMP subtype(P=0.022).Subgroup analysis of patients with NSMP showed that age≥30 years related with longer treatment time to CR(P=0.010).In addition,CR was obtained after treatment in 2/3 POLE ultra-mutated cases and 2/2 CNH,respectively.Conclusions Molecular classification relates with the treatment response in patients with EC and AEH treated with fertility-sparing therapy.Patients with MSI-H subtype have poor treatment efficacy,and patients with NSMP need to be further studied and predict treatment benefit.However,there are few cases in POLE ultra-mutated and CNH subtypes,which need further clinical research.