肿瘤位置和错配修复状态对非转移性结肠癌患者临床病理特征及生存的影响

Effects of tumor location and mismatch repair on clinicopathological features and survival for non‐metastatic colon cancer:A retrospective,single center,cohort study

目的分析非转移性结肠癌不同肿瘤位置(左半结肠或右半结肠)患者的临床病理特征及生存的差异,探讨肿瘤位置和错配修复状态(MMR)对生存的影响。方法采用回顾性队列研究的方法。检索北京协和医院结直肠外科结肠癌前瞻性登记数据库2016年1月至2020年8月期间,接受根治性切除、且病理检查证实为非转移性结肠腺癌患者的病例资料和随访信息。将起源于中肠,位于回盲部、升结肠和横结肠近2/3的肿瘤定义为右半结肠癌;而将起源于后肠,位于横结肠远1/3、降结肠和乙状结肠的肿瘤定义为左半结肠癌。使用χ^(2)检验或Mann⁃Whitney U检验比较两组患者临床病理特征的差异,使用Kaplan⁃Meier曲线和Log⁃rank检验进行两组患者的生存分析并比较组间的无病生存率(DFS)和总体生存率(OS)。使用Cox回归分析生存的影响因素,使用倾向性评分匹配以调整混杂后再进行生存分析。结果共纳入856例结肠癌患者,其中肿瘤TNM分期Ⅰ期129例(15.1%),Ⅱ期391例(45.7%),Ⅲ期336例(39.3%);错配修复缺陷(dMMR)139例(16.2%)。左半结肠癌442例(51.6%,左半结肠癌组),右半结肠癌414例(48.4%,右半结肠癌组)。相比右半结肠癌,左半结肠癌患者的男性比例高[62.0%(274/442)比54.1%(224/414),χ^(2)=5.462,P=0.019],中位体质指数也高[24.2(21.9,26.6)kg/m2比23.2(21.3,25.5)kg/m2,U=78789.0,P<0.001],高、中分化腺癌比例[93.2%(412/442)比83.1%(344/414),χ^(2)=22.266,P<0.001]更高;dMMR状态[9.0%(40/442)比23.9%(99/414),χ^(2)=34.721,P<0.001]和合并脉管侵犯[24.0%(106/442)比30.2%(125/414),χ^(2)=4.186,P=0.041]比例更低。所有患者中位随访时间48(33,59)个月。Log⁃rank检验结果显示,左半结肠癌组患者与右半结肠癌组患者的DFS(P=0.668)和OS(P=0.828)差异无统计学意义。多因素Cox回归分析发现,dMMR是结肠癌患者DFS的独立保护因素(HR=0.419,95%CI:0.204~0.862,P=0.018);T3~4(HR=2.178,95%CI:1.089~4.359,P=0.028)、N+(HR=2.126,95%CI:1.443~3.133,P<0.001)和神经侵犯(HR=1.835,95%CI:1.115~3.020,P=0.017)是DFS的独立危险因素。肿瘤位置不是影响非转移性结肠癌患者DFS和OS的独立因素(均P>0.05)。亚组分析发现,在右半结肠癌组患者中,dMMR患者的DFS优于错配修复正常(pMMR)患者(HR=0.338,95%CI:0.146~0.786,P=0.012),但是两组患者的OS差异无统计学意义(HR=0.340,95%CI:0.103~1.119,P=0.076)。对DFS的独立危险因素进行倾向性得分匹配后,Log⁃rank检验结果显示,两组患者的DFS(P=0.343)和OS(P=0.658)差异无统计学意义,而dMMR患者的DFS(P=0.047)和OS(P=0.040)均优于pMMR患者。结论不同肿瘤位置的非转移性结肠癌患者其临床病理特征存在差异;但患者的生存与肿瘤位置无关,而与MMR有关,dMMR状态与更好的生存有关,在右半结肠癌患者中更为突出。

Objective To analyze the differences in clinicopathological features of colon cancers and survival between patients with right-versus left-sided colon cancers.Methods This was a retrospective cohort study.Information on patients with colon cancer from January 2016 to August 2020 was collected from the prospective registry database at Peking Union Medical College Hospital.Primary tumors located in the cecum,ascending colon,and proximal two‐thirds of the transverse colon were defined as right-sided colon cancers(RCCs),whereas primary tumors located in the distal third of the transverse colon,descending colon,or sigmoid colon were defined as left‐sided colon cancers(LCCs).Clinicopathological features were compared using theχ^(2)test or Mann‐Whitney U test.Survival was estimated by Kaplan‐Meier curves and the log‐rank test.Factors that differed significantly between the two groups were identified by multivariate survival analyses performed with the Cox proportional hazards function.One propensity score matching was performed to eliminate the effects of confounding factors.Results The study cohort comprised 856 patients,with TNM Stage I disease,391(45.7%)with Stage II,and 336(39.3%)with Stage III,including 442(51.6%)with LCC and 414(48.4%)with RCC and 129(15.1%).Defective mismatch repair(dMMR)was identified in 139 patients(16.2%).Compared with RCC,the proportion of men(274/442[62.0%]vs.224/414[54.1%],χ^(2)=5.462,P=0.019),body mass index(24.2[21.9,26.6]kg/m2 vs.23.2[21.3,25.5]kg/m2,U=78,789.0,P<0.001),and well/moderately differentiated cancer(412/442[93.2%]vs.344/414[83.1%],χ^(2)=22.266,P<0.001)were higher in the LCC than the RCC group.In contrast,the proportion of dMMR(40/442[9.0%]vs.99/414[23.9%],χ^(2)=34.721,P<0.001)and combined vascular invasion(106/442[24.0%]vs.125/414[30.2%],χ^(2)=4.186,P=0.041)were lower in the LCC than RCC group.The median follow‐up time for all patients was 48(range 33,59)months.The log‐rank test revealed no significant differences in disease-free survival(DFS)(P=0.668)or overall survival(OS)(P=0.828)between patients with LCC versus RCC.Cox proportional hazards model showed that dMMR was significantly associated with a longer DFS(HR=0.419,95%CI:0.204‒0.862,P=0.018),whereas a higher proportion of T3‐4(HR=2.178,95%CI:1.089‒4.359,P=0.028),N+(HR=2.126,95%CI:1.443‒3.133,P<0.001),and perineural invasion(HR=1.835,95%CI:1.115‒3.020,P=0.017)were associated with poor DFS.Tumor location was not associated with DFS or OS(all P>0.05).Subsequent analysis showed that RCC patients with dMMR had longer DFS than did RCC patients with pMMR(HR=0.338,95%CI:0.146‒0.786,P=0.012).However,the difference in OS between the two groups was not statistically significant(HR=0.340,95%CI:0.103‒1.119,P=0.076).After propensity score matching for independent risk factors for DFS,the log‐rank test revealed no significant differences in DFS(P=0.343)or OS(P=0.658)between patients with LCC versus RCC,whereas patient with dMMR had better DFS(P=0.047)and OS(P=0.040)than did patients with pMMR.Conclusions Tumor location is associated with differences in clinicopathological features;however,this has no impact on survival.dMMR status is significantly associated with longer survival:this association may be stronger in RCC patients.