Ⅰ-Ⅲ期三阴性乳腺癌病人接受保乳手术或乳房切除术的预后分析.pdf

论著371.外科理论与实践2 0 2 3年第2 8 卷第4期I期三阴性乳腺癌病人接受保乳手术或乳房切除术的预后分析朱巧俐，苗伊鸣2*，陈小松（1.温州医科大学附属衢州医院（衢州市人民医院）乳甲外科，浙江衢州324000;2.上海交通大学医学院附属瑞金医院普外科乳腺疾病诊治中心，上海200025)摘要 目目的：探讨I期三阴性乳腺癌（triple-negativebreast cancer,TNBC)病人接受保乳手术(breast-con-serving surgery,BCS)或乳房切除术(mastectomy，M)对病人无病生存(disease free survival,DFS）和总生存（overllsur-vival,0S)的影响。方法：收集2 0 0 9 年1月至2 0 18 年12 月上海交通大学医学院附属瑞金医院乳腺疾病诊治中心收治的8 44例可手术III期TNBC病人，根据手术方式分为BCS组和M组。采用COX回归分析评估病人的临床特征和手术方式对病人DFS和OS的影响。进一步应用倾向性评分匹配平衡两组病人间存在的基线特征差异，评估两组手术的预后差异。结果：533例（6 3.15%)接受M,311例（36.8 5%)接受BCS。与M组相比，年轻、肿瘤小、淋巴结阴性、HER2表达缺失(HER2-0)的病人更多接受BCS。中位随访时间7 2 个月。多因素分析表明，M组病人的OS率低于BCS组病人（HR=2.02,95%CI:1.043.91,P=0.038），但两组DFS差异无统计学意义（HR=1.42,95%CI:0.942.15P=0.100)。将病人T分期、N分期(pN)和年龄等因素进行倾向性评分匹配平衡后,BCS组和M组病人OS率(P=0.114)和DFS率(P=0.124)差异无统计学意义。结论：在I期TNBC病人中,年轻、肿瘤小、淋巴结阴性和HER2-0病人更多选择BCS。匹配相关临床病理指标后,TNBC病人接受BCS或M手术方式的预后差异无统计学意义。关键词：乳腺癌；三阴性；保乳手术；乳房切除术中图分类号：R737.9文献标志码：A文章编号：10 0 7-9 6 10(2 0 2 3)0 4-0 37 1-0 7D0I:10.16139/j.1007-9610.2023.04.014Prognostic analysis of breast-conserving surgery or mastectomy in patients with stage I-II triple-negativebreastcancerZHUQiaoli,MIAOYiming,CHENXiaosong1.Department of Breast and Tyroid Surgery,Quzhou Affiliated Hospital of Wenzhou Medical University,Quzhou Peoples Hos-pital,Zhejiang Quzhou 324000,China;2.Department of General Surgery,Comprehensive Breast Health Center,Rujin Hospi-tal,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaAbstractObjective:To investigate the effect of breast-conserving surgery(BCS)or mastectomy(M)in patientswith stage I-II triple-negative breast cancer(TNBC)on disease free survival(DFS)and overall survival(OS).Methods:A total of 844 patients with stage I-II TNBC who were admitted to Comprehensive Breast Health Center,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine from January 2009 to December 2018 were collected and divided intoBCS and M groups according to the surgical method.COX regression analysis was used to evaluate the influence of clinicalcharacteristics and surgical methods on DFS and OS of the patients.The propensity score was further used to balance thedifferences in baseline characteristics between the two groups of patients,and to evaluate the differences in the prognosis oftwo groups of patients.Results:There were 533 patients(63.15%)underwent M and 311 patients(36.85%)underwentBCS.Patients with younger age,smaller tumor size,negative lymph node,and loss of HER2 expression(HER2-0)weremore tend to BCS group compared to M group.Median follow-up time was 72 months.Multivariate COX analysis showedthat the OS of M group was lower than that of BCS group(HR=2.02,95%CI:1.04-3.91,P=0.038),but there was no sig-nificant difference in DFS between the two groups(HR=1.42,95%CI:0.94-2.15,P=0.100).After propensity score match-ing for factors such as T stage,N stage and age,the results showed that there was no significant difference in OS(P=0.114)and DFS(P=0.124)between BCS and M groups.Conclusions:Among patients with stage I-II TNBC,patients with*共同第一作者通信作者：陈小松，E-mail：c h e n x i a o s o n g 0 156 h o t ma i l.c o m372J Surg Concepts Pract 2023,Vol.28,No.4younger age,smaller tumor,negative lymph node,and HER2-0 were more likely to choose BCS.After propensity scorematching for relevant clinicopathological parameters,the results indicated that there was no significant difference in OS andDFS of the TNBC patients undergoing BCS or M surgery.Key words:Breast cancer;Triple-negative;Breast-conserving surgery;Mastectomy乳腺癌是女性最常见的恶性肿瘤。2 0 2 0 年最新数据显示，乳腺癌已取代肺癌，成为全球发病率第一的癌症。三阴性乳腺癌（triple-negativebreast cancer,TNBC）占所有乳腺癌病人的10%15%2。目前乳腺癌外科治疗常用手术包括保乳手术（breast-conserving surgery,BCS）和乳房切除术（ma s t e c t o my，M）。既往研究报道，对于接受BCS的病人，TNBC较其他分子分型乳腺癌具有更高的局部区域复发(local regional recurrence,LRR)率3;但在TNBC病人中,BCS与M相比,无远处转移生存或总生存（overall survival，O S）差异无统计学意义。本研究计划入组I期TNBC病人,评估临床病理参数对BCS选择的影响,并分析BCS与M组病人之间预后是否有差异。1资料和方法1.1排除标准纳入2 0 0 9 年1月1日至2 0 18 年12 月31日在上海交通大学医学院附属瑞金医院乳腺疾病诊治中心手术并病理确诊为TNBC的乳腺癌病人。排除标准：男性乳腺癌；接受I/期乳房重建；免疫组织化学（immunohistochemistry，IH C）人表皮生长因子受体2(human epidermal growth factor re-ceptor-2,HER2)+，但荧光原位杂交(fluores-cence in situ hybridization,FISH)检测阳性;初诊IV期的病人；接受新辅助治疗的病人。8 51例TNBC乳腺癌病人中排除1例男性乳腺癌,6 例I/I期乳房重建，共纳入8 44例。使用倾向性评分，对采取两种手术方式的乳腺癌病人进行匹配，以消除两组间的基线差异，从而最小化选择偏倚和变量的影响。设定0.2 作为卡钳值，依据病人年龄、BMI、术后肿瘤大小(pT）、p N分期（pN）、K i-6 7 指数、HER2状态、病理类型、组织学分级及辅助化疗情况进行1:1匹配。匹配后BCS和M组各有2 57 例1.2数据收集数据来源于上海交通大学乳腺癌数据库(Shanghai Jiao Tong University Breast Cancer Data-base,SJTU-BCDB)。数据库提供预后数据和随访信息。收集病人确诊时的临床特征、病理特征及手术方式。包括年龄、体质量指数（bodymass index，BMI）、月经状态、HER2表达程度、病理类型、组织学分级以及pT、p N、K i-6 7 状态和术后化疗状况。随访病人的无病生存(disease-free survival,DFS)及OS。D FS事件定义为发生乳腺癌复发转移（局部或远处转移)或新发生的对侧乳腺癌、第二原发肿瘤或由于任何原因引起的死亡。OS事件定义为任何原因导致死亡的事件。BMI值根据中国成人超重和肥胖症预防控制指南4的标准分类如下。正常：18.5 kg/mBMI24 kg/m;超重:BMI24 kg/m;低体重：BMI18.5kg/m。病人的pT和pN分期参照美国癌症联合会(American Joint Committee on Cancer,AJCC)第8 版5。HER2表达程度表示如下。HER2-O:HER2表达缺失；HER2低表达：HER2+/FISH检测阴性。1.3随访通过门诊复查、电话随访等方式，术后2 年内每3个月随访1次；术后3 5年每半年随访1次；术后超过5年，每年随访1次。随访截止时间为2 0 2 1年12 月31日。随访资料来源于SJTU-BCDB。1.4统计学方法采用R语言(3.6.3,https:/www.r-project.org/)统计学软件进行相关统计。计数资料采用频数及百分比进行描述，计量资料采用均数标准差进行描述。两组手术病人间的基线特征比较采用卡方检验或Fisher精确检验。采用多因素Logistic回归分析评估各临床病理因素与不同手术方式选择的相关性。使用Kaplan-Meier曲线及Log-rank分析比较两组间的生存差异。采用COX回归分析进行单因素及多因素回归分析，评价不同手术方式及临床病理因素对病人OS及DFS的影响，并计算风险比(hazard ratio,HR）及9 5%置信区间（confidence in-terval,CI)。P 0.0 5为差异有统计学意义。对倾向性评分匹配后的数据采用Kaplan-Meier法进行生存分析，同时配合Log-rank检验评估不同手术方式与OS及DFS间的关联，373外科理论与实践2 0 2 3年第2 8 卷第4期2结果2.1人组病人的临床特征及两组病人间基线差异本研究共纳人8 44例I期TNBC病人，311例（36.8 5%）接受BSC，533例接受M（6 3.15%）（见表1)。对病人临床特征与手术方式选择的关系进行单因素分析。与M组相比,BCS组年龄较小(P0.001);绝经前病人较多(P=0.004)。BCS组HER2-0的比例较高（P=0.007）、p T 2 3期肿瘤较少（P0.001）淋巴结阳性病人较少（P0.001）。BM I值、病理类型、组织学分级、Ki-67水平及术后化疗状况两组差异无统计学意义。表1I Il期TNBC病人临床病理特征分析xs/n(%)Tab 1Clinicopathological characteristics for stage I-IITNBC patients xs/n(%)Flx2FactorsBCS(n=311)M(n=533)PvaluevalueAge(years)53.6813.0557.2311.8516.30.001BMI(kg/m)23.103.0123.012.790.20.671Menopause statusn(%)Pre-menopause128(41.16)167(31.33)8.30.004Post-menopause183(58.84)366(68.67)pTn(%)T192(61.74)226(42.40)29.40.001T2.3119(38.26)307(57.60)pNn(%)Negative250(80.39)358(67.17)17.014%269(86.50)443(83.11)Pathologictypingln(%)DCIS5(1.61)11(2.07)IDC290(93.25)490(91.93)0.50.776Othersn(%)16(5.14)32(6.00)GradingI-I59(18.97)129(24.20)200(64.31)322(60.41)3.10.211Unknown52(16.72)82(15.39)Chemotherapyln(%)No41(13.18)63(11.82)0.30.561Yes270(86.82)470(88.18)多因素分析提示,TNBC病人手术方式选择与病人年龄（OR=1.02,P=0.013）、p T（O R=2.17,P0.001)、p N（O R=1.8 4,P 0.0 0 1）、H E R2 状态（OR=1.42,P=0.023)存在显著相关性，而与月经状态(0 R=0.99,P=0.967)无显著相关性（见表2）。提示年龄大、肿瘤大、淋巴结阳性、HER2低表达的TNBC更多选择M。表2 1 川期TNBC病人M组相关临床病理因素的多因素Logistic回归分析Tab 2Logistic regression analysis for mastectomy instage I-II TNBC patientsFactorsOR95%CIPvalueAge(years)60 us.601.021.01-1.040.013Menopause status0.990.63-1.570.967post-menopause vs.pre-menopausepT T2.3 us.T,2.171.61-2.910.001pNNpositiveus.Nnegative1.841.30-2.590.001HER2HER2lowvs.HER2-01.421.051.920.0232.2手术方式对TNBC病人预后的影响中位随访7 2 个月，整组人群的5年DFS率为87.55%，5年0 S率为9 3.48%，5年LRR率为3.55%。M组的5年DFS率为8 4.9 9%，5年0 S率为9 1.2 7%，5年LRR率为2.7 9%；BCS组的5年DFS率为91.89%，5年0 S率为9 7.16%，5年LRR率为5.14%。BCS与M组相比,LRR率较高，但未达到统计学差异（P=0.083）。将年龄、BMI、月经状态、HER2表达、病理类型、组织学分级、pT、p N、K i-6 7 状态及化疗状况纳人单因素COX分析,发现pT、p N、手术方式与TNBC的OS显著相关,而pT、p N、手术方式、术后化疗状态及Ki-67水平与TNBC的DFS显著相关(见表3)。多因素分析发现，pT、p N与TNBC病人DFS和OS都显著相关（P0.05），而手术方式仅与病人0 S相关(HR=2.02,95%CI:1.043.91,P=0.038)(见表4)。2.3临床病理参数倾向性评分匹配后，手术方式对TNBC预后的影响考虑到BCS组与M组间病人临床病理特征存在差异，故采用倾向性评分匹配方法消除组间差异后行进一步分析。依据年龄、BMI、月经状态、pT、pN、H E R2、K i-6 7、病理类型、病理组织学分级及术后化疗情况行倾向性评分匹配，以减少选择偏倚。经过倾向性评分匹配后，两组病人临床病理指标具有较好的一致性(见表5)。374J Surg Concepts Pract 2023,Vol.28,No.4表3I期TNBC病人OS及DFS的单因素COX回归分析Tab 3Univariate COX regression analysis for OS andDFS in stage I-II TNBCpatientsOSDFSFactorsPvaluePvalueAge(years)60 vs.600.070.158Menopause status0.090.061post-menopause vs.pre-menopauseBMI(kg/m)0.7730.60524vs.18.5,240.4730.69818.5 vs.18.5,240.9670.375Pathologic typing0.5890.507IDC us.DCIS0.780.725Others us.DCIS0.7230.333pT T,2-3 us.T,0.0010.001pNNpositiveus.Nnegative0.00114%us.14%0.1190.045Chemotherapy Yes us.No0.1120.049Surgical approach M us.BCS0.0020.005基于倾向性评分匹配后的数据进行进一步分析。Kaplan-Meier曲线提示,BCS组与M组I期乳腺癌病人的5年0 S率分别为9 7.2 0%和9 4.55%（P=0.114）；5年DFS率分别为9 1.7 9%和8 7.9 3%（P=0.124）（见图1）。基于倾向性评分匹配后的数据进行单因素COX回归分析提示，M组与BCS组的OS率(HR=1.84,95%CI:0.853.96,P=0.120)和DFS率(HR=1.47,95%CI:0.902.41,P=0.127)差异无统计学意义。表5PSM后行BCS及M的 期TNBC病人临床病理特征比较xs/n(%)Tab 5 Clinical-pathological characteristics for stage I-IITNBC patients underwent BCS or M after PSM x+s/n(%)BCSMF/2FactorsPvalue(n=257)(n=257)valueAge(years)54.7912.76)56.0211.67)1.30.253BMI(kg/m)23.113.00)23.142.82)0.00.912Menopause statusn(%)Pre-menopause100(38.91)87(33.85)1.40.233Post-menopause157(61.09)170(66.15)pTn(%)lT148(57.59)145(56.42)0.70.789T2.3109(42.41)112(43.58)pNn(%)Negative202(78.60)208(80.93)0.40.51Positive55(21.40)49(19.07)HER2n(%)HER20103(40.08)107(41.63)0.10.72HER2low154(59.92)150(58.37)Ki-67n(%)14%34(13.23)42(16.34)1.00.3214%223(86.77)215(83.66)Pathologic typingn(%)DCIS5(1.95)6(2.34)0.30.854IDC242(94.16)243(94.55)Others10(3.89)8(3.11)Gradingln(%)lI-II52(20.23)47(18.29)1.30.528168(65.37)164(63.81)Unknown37(14.40)46(17.90)Chemotherapyn(%)No30(11.67)39(15.18)1.40.244Yes227(88.33%)218(84.82%)表4I期TNBC病人OS及DFS的多因素COX回归分析Tab 4Multivariate COX regression analysis for OS and DFS in stage I-II TNBC patientsOSDFSFactorsHR95%CIPvalueHR95%CIPvalueAge(years)60 us.601.370.64-2.910.419/Menopause statusPost-menopause vs.pre-menopause1.230.53-2.840.6261.330.9-1.970.155Surgical approachM us.BCS2.021.04-3.910.0381.420.94-2.150.100pT T.2.us.T,2.021.17-3.480.0111.821.25-2.650.002ChemotherapyYes us.No/0.580.350.940.026pNNPositiveus.N Negative3.221.96-5.3014%Us.14%0.670.44-1.040.076375外科理论与实践2 0 2 3年第2 8 卷第4期A.1.00B1.000.750.75Probabiliy ofosPrababilityof oFs0.500.50GroupGroup0.25P0.001C.25P=0.005BCSBCSM+M0.000.0012243648607284961081201321441224384860728496108120132144Fallowuptime(months)Folowuptime(months)NumberatriskNumberatriskBCS311309307285242198157117785527144BCS311306298275230186144107715025134M533528513478404340273223170131884918M53351648745138232125820716012380 47141224364860728496108120132144D1224364日728496108120132144Followuptime(months)Fallowuptime(months)D1.001000.750.75Probabilily ofosProhabilityof DFs0.500.60GroupGroup0.25P=0.1140.25P=0.124BCSBCSMM0.000.00122430486072849610812013214412243048GO728486108120132144Fllowuptime(months)Followuptime(months)NumberatriskNumberatriskBCS257255253240208171138100634121124BCS2572522442301981621289359 4020114M257257251240208174 137107756139248M257249240229196 16412910171573723812243848607284961081201321441224384880728406108 120132144Followuptime(months)Followuptime(months)Kaplan-Meier survival analysis for early stage TNBC patients underwent BCS or M before and after PSMA:OS before PSM;B:DFS before PSM;C:OS after PSM;D:DFS after PSM.图1倾向性评分匹配前后接受BCS或M的生存分析Fig1The relationship between different surgical approach and survival outcome in stage I-II TNBC patients before andafter PSM3讨论本研究比较TNBC病人接受BCS与M手术的相关临床病理指标的影响因素，并分析其对预后的影响。进一步采用倾向性评分匹配消除组间差异后,BCS与M组病人预后差异无统计学意义。这提示，对于TNBC病人，BCS是安全的手术方式。肿瘤的临床分期、年龄以及其他临床病理指标可能影响病人手术方式的选择，对于分期较早或较年轻的病人，更多会选择BCS。此外,医疗资源的可及性、病人的认识、对医师的专业培训以及病灶位置等，也会影响BCS的比例7。本研究纳入TNBC病人，发现年龄和肿瘤分期等因素会影响手术方式的选择,这与既往研究报道的结果相似。早期研究表明,BCS联合放疗治疗效果与M相当18。NSABPB-06和Milan等多个随机对照研究均证明，BCS联合放疗与M治疗早期乳腺癌具有相似的预后9-11。达近年研究表明，与M相比，BCS不仅改善美学效果，而且可能存在生存获益12-16。2 0 16 年,Lan-cetOncology发表的一项大型队列研究表明，与M相比，BCS联合放疗提高10 年OS率117。本研究提示,TNBC病人中,总体人群、BCS组和M组病人的5年LRR率分别为3.55%、5.14%和2.7 9%。BCS组与M组相比,LRR率较高,但未达到统计学差异,与既往的研究结果3类似,提示BCS组的病人更易发生局部区域复发。然而进一步对OS率及DFS率分析，并未显示BCS组的预后更差，提示BCS在TNBC病人中安全可行。鉴于BCS组与M组病人间临床病理特征存在显著差异，本研究采用倾向性评分匹配平衡组间临床病理参数的差异,发现BCS组与M组病人的DFS率和OS率差异无统计学意义，提示不同手术方式对I期TNBC病人的预后无显著影响。刘晓静等18-19 研究M+前哨淋巴结活检术、BCS+前哨淋巴结活检术、改良根治术和BCS+腋窝淋巴结清扫术4种不同手术方式对TNBC预后的影响，发现4种手术方式病人的DFS率和OS率差异均无统计学意:376:J Surg Concepts Pract 2023,Vol.28,No.4义，与本研究结果一致。吕文芝等2 0 对共计包括5487例TNBC病人的10 项研究进行荟萃分析，发现接受BCS的TNBC病人OS率明显高于接受M者，但DFS率差异无统计学意义，也与本研究的结果相似。可能与接受BCS组病人的临床分期较早、系统综合治疗及较年轻有关(6.2 1当然，本研究也存在一些不足：未对腋窝淋巴结手术方式（前哨淋巴结活检或淋巴结清扫)再进一步细化分组对比，没有对比TNBC新辅助化疗后BCS与M两者预后的差异。且本研究是一项回顾性研究，不能完全排除选择偏倚。因此，需进行前瞻性研究证实相关结论。综上所述,在I期TNBC病人中,年轻、肿瘤小、淋巴结阴性、HER2-0的病人更倾向选择BCS。匹配相关临床病理指标后,TNBC病人接受BCS与M手术对其预后无显著影响。参考文献1 SUNG H,FERLAY J,SIEGEL R L,et al.Global CancerStatistics 2020:GLOBOCAN estimates of incidence andmortality worldwide for 36 cancers in 185 countriesJ.CA Cancer J Clin,2021,71(3):209-249.2 DASS S A,TAN K L,SELVA RAJAN R,et al.Triplenegative breast cancer:a review of present and 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