摘要
背景
宫颈癌是妇女最常见的恶性肿瘤之一，其发病率位居女性恶性肿瘤的第二位，在我国也居妇女恶性肿瘤的前列，近年来其发病率有上升趋势，且呈现明显年轻化趋势，宫颈癌仍是当今严重威胁妇女健康的主要疾病之一。
在宫颈癌中，有一组具有预后不良的局部晚期宫颈癌(Locally advancedcervical cancer，LACC)。LACC一般指宫颈局部肿瘤直径≥4cm的早期宫颈癌，预后较差，以往单纯手术或采用放射治疗的效果均不理想，现提倡采用多种治疗手段的综合治疗，主要包括同步放化疗、直接手术、新辅助化疗(Neoad juvantchemotherapy，NACT)+手术或放射治疗等三种方式，其中NACT的采用具有缩小肿瘤病灶，减少微转移，减少不良预后因素，可能有益于提高患者生存等意义而日趋受到重视。NACT后采取手术治疗已成为中青年局部晚期宫颈癌患者首选的治疗模式，NACT已成为宫颈癌综合治疗中的一大亮点。NACT在局部晚期宫颈癌中的近期疗效已较肯定，但影响疗效的相关临床病理因素尚缺乏系统的研究，对远期生存的影响是评价治疗价值的最主要指标，也是目前争议的焦点。
化疗是肿瘤最主要的治疗手段之一，由于肿瘤本身以及个体间异质性的存在，不同个体之间化疗疗效仍存在很大的差异，寻求疗效预测的指标是开展个体化药物治疗的基础。宫颈癌的NACT均采用铂类为基础的联合化疗。铂类药物的耐受有许多相关机制，其中DNA修复能力的改变是最主要的机制之一。
人类X射线交错互补基因1(X-ray repair cross complementing gene 1，XRCC1)和着色性干皮病基因组D(Xeroderma pigmentosum pomplementary groupD，XPD)是最主要的DNA修复基因，分别通过碱基切除修复(base excisionrepair，BER)和核苷酸切除修复(nucleotide excision repair，NER)方式参与DNA的损伤修复，其蛋白的表达可能与铂类药物耐受间存在密切的关系，但在宫颈癌NACT中，两者的表达状况与NACT疗效间的关系仍未见相关的研究。
近代药理遗传学研究表明，遗传多态性，特别是单核苷酸多态性(singlenucleotide polymorphism，SNP)是影响药物疗效个体差异的重要原因之一。XRCC1基因有3个多态性位点，分别位于密码子194(Arg-Trp)，280(Arg-His)和399(Arg-Gln)位点，XRCC1的SNP可能改变其对DNA损伤的修复能力，已成为研究肿瘤易感性及对肿瘤治疗反应性的遗传性分子指标。已有研究显示XRCC1的SNP与多种肿瘤的发生有关，也与肺小细胞肺癌、大肠癌等肿瘤铂类药物化疗的敏感性存在相关性，但在局部晚期宫颈癌中的NACT中，有关XRCC1的SNP与化疗疗效间关系的研究仍十分少见。
本研究回顾性分析我们治疗的局部晚期宫颈癌NACT的临床疗效，分析影响其疗效的可能临床病理因素，评价疗效与长期生存的关系；并进一步从XRCC1、XPD蛋白表达水平以及XRCC1 SNP的角度分析其与疗效的关系，以期揭示预测局部晚期宫颈癌NACT疗效的可能指标，为个体化化疗提供依据。
第一部分：局部晚期宫颈癌新辅助化疗价值的评价
研究目的：评价局部晚期宫颈癌新辅助化疗的近期疗效及影响疗效的临床相关因素，分析疗效与长期生存的关系。
材料与方法：回顾性分析1999．6-2007．6在浙江大学医学院附属妇产科医院接受以铂类为基础的新辅助化疗的局部肿瘤直径≥4cm的Ⅰb—Ⅱa期局部晚期宫颈癌109例。分析化疗的近期疗效，选取年龄、临床分期、分化、组织类型、治疗前肿瘤最大直径、化疗方案、疗程数、治疗前血红蛋白等8个临床参数，分析其与化疗疗效的相关性，分析不同化疗疗效者总生存率及无瘤生存率。
结果：1．109例患者中，化疗有效者为85例(CR 3例，PR 82例)，无效者24例，总有效率为77．9％。
2．化疗疗效与局部晚期宫颈癌组织类型有关，鳞癌有效率为82．3％(79／96)，腺癌为46．2％(6／13)，鳞癌有效率显著高于腺癌(X~2=9．342，P=0.002)；化疗疗效与年龄、临床分期、分化、治疗前肿瘤最大直径、化疗方案、疗程数、治疗前血红蛋白等其他因素无显著相关性(P>0．05)。
3．化疗后接受手术的102例中，化疗有效者手术后盆腔淋巴结阳性率为4．70％(4／85)，显著低于化疗无效者的23．53％(4／17)，两者差异有显著性(X~2=6．85，P=0．008)；新辅助化疗有效者宫颈间质浸润≥外1／3的比率显著低于无效者(15．29％VS 52．94％，X~2=11．87，P=0．012)；宫旁脉管阳性率两组间无显著性差异(X~2=2．06，P=0．153)。
4．109例中随访资料完整者为88例，总2年生存率为98．4％，5年生存率为86．5％；采用Log Rank方法比较生存，显示新辅助化疗有效组至随访结束全部存活，而化疗无效组1年生存率为92．9％，2年生存率为59．7％，化疗有效者生存率显著高于无效者(chi-square=7．299，P=0．007)；无瘤生存率比较显示：化疗有效组至随访结束均无瘤生存，而无效组1年无瘤生存率为88．9％，2年无瘤生存率为57．3％，化疗有效者无瘤生存率显著高于无效者(chi-square=6．814，P=0．009)。
结论：
1．NACT有效者可降低手术后盆腔淋巴结转移、宫颈外1／3间质浸润和手术后需辅助治疗的比率，提示NACT可消除或抑制微小转移灶、改善肿瘤的局部控制。
2．NACT有效的局部晚期宫颈癌患者应选择手术，并可提高生存率。
第二部分：XRCC1、XPD蛋白表达与局部晚期宫颈癌新辅助化疗疗效关系的研究
研究目的：探讨XRCC1、XPD蛋白表达与局部晚期宫颈癌新辅助化疗疗效间的相关性，旨在寻找预示化疗疗效的指标。
材料和方法：选取1996．6-2007．6在浙江大学医学院附属妇产科医院接受以铂类为基础的新辅助化疗、临床病理资料完整的肿瘤直径≥4cm的Ⅰb2-Ⅱa期子宫颈癌共99例，采用免疫组化法检测治疗前宫颈癌组织中XRCC1，XPD的蛋白表达，分析蛋白表达与新辅助化疗疗效及临床病理参数间的关系。
结果：1．XRCC1蛋白的表达在化疗无效组显著高于化疗有效组(2．99±0．38 VS1．94±0．28，t=13．64，P=0．008)。
2．XPD蛋白的表达在化疗无效组显著高于化疗有效组(2．93±0．29 VS1．78±0．39，t=11．89，P=0．007)。
3．XRCC1的表达腺癌组织中显著高于鳞癌(2．46±0．77 VS 2．10±0．45，t=-2．46，P=0．02)；盆腔淋巴结阳性者显著高于阴性者(2．52±0．77 VS2．07±0．44，t=-3．00，P=0．01)。宫颈间质浸润≥外1／3者显著高于<外1／3浸润者(2．45±0．60 VS 2．01±0．40，t=-4．14，P=0．01)；而XRCC1的表达与患者年龄、临床分期、宫旁脉管是否受累，分化、肿瘤直径等因素无关(P>0．05)。
4．XPD蛋白表达患者年龄≤35岁者组织中显著高于>35岁者(2．23±0．61 VS1．92±0．57，t=2．27，P=0．03)；腺癌显著高于鳞癌(2．44±0．72 VS 1．93±0．54，t=-3．01，P=0．01)；淋巴结阳性者显著高于阴性者(2．42±0．71 VS 1．93±0．55，t=-2．83，P=0．01)：宫颈间质浸润≥外1／3者显著高于<外1／3(2．23±0．72 VS1．89±0．50，t=-2．56，P=0．01)；XPD蛋白表达与临床分期、宫旁脉管是否受累，细胞分化及肿瘤直径等均无显著相关性(P>0．05)。
5．XRCC1蛋白与XPD蛋白表达间具有正相关性(r=0．643，p=0．001)。
结论：1．局部晚期宫颈癌NACT有效者组织中XRCC1、XPD蛋白的表达显著低于NACT无效者，提示XRCC1、XPD蛋白的高表达与铂类为基础的NACT化疗的耐药有关。
2．XRCC1、XPD蛋白表达水平的检测可作为预示局部晚期宫颈癌NACT疗效的指标之一。
第三部分：XRCC1单核苷酸多态性与局部晚期宫颈癌NACT疗效关系的研究
研究目的：探讨XRCC1单核苷酸多态性与局部晚期宫颈癌新辅助化疗疗效的关系，旨在寻找预测新辅助化疗疗效的遗传性分子指标。
材料与方法：选取1999．6-2007．6在浙江大学医学院妇产科医院接受新辅助化疗并有外周血样的局部晚期宫颈癌病例70例，采用MAMA-PCR方法检测外周血中XRCC1的codon 194、399位点的单核苷酸多态性，采用免疫组化法检测治疗前宫颈癌组织中XRCC1蛋白的表达，分析不同基因型间新辅助化疗的疗效及与XRCC1蛋白表达的关系。
结果：1．XRCC1 codon 194位点的基因型(Arg／Arg，Arg／TrP，Trp／TrP)与新辅助化疗疗效无显著性相关(X~2=1．243，P=0．07)；不同基因型间XRCC1蛋白表达无显著性差异(F=1．186，P=0．103)。
2．XRCC1 codon 399位点不同的基因型间(Arg／Arg，Arg／Gln，Gln／Gln)新辅助化疗疗效有显著性差异(X~2=2．283，P=0．03)，携带至少一个Gln等位基因者，其化疗失败的风险为基因型为Arg／Arg者的3．254倍(95％CI 0．708～14．951)；不同基因型间XRCC1蛋白的表达也有显著性差异(F=15．915，p<0．001)。至少携带一个Gln等位基因者，其XRCC1蛋白表达水平显著高于基因型为Arg/Arg者(F=2．699，P=0．009)。
结论：1．在局部晚期宫颈癌NACT中，XRCC1 codon 399位点携带至少一个Gln等位基因者，其蛋白表达和化疗失败的风险均增高，提示XRCC1 codon 399位点SNP的检测可作为预示局部晚期宫颈癌NACT化疗疗效的指标之一。
Background
Cervical carcer is the second most frequently diagnosed malignancy in womenworldwide,and also one of the most common cnacer among women in china.Recently,its incidence increased rapidly,more and more younger women suffered from it.Cervical cancer continues to be a leading cause of death in women.
The major treatment for cervical carer is surgery and radiotherapy.One sort ofhigh risk cervical carcer,which is called locally advanced cervical cancer(LACC)and is defined as an early stage cervical career with diameter larger than 4cm,LACC has apoor prognosis,the avaliable treatment for LACC contain concurrent chemoradiation,surgery,and neoadjuvant chemotherapy(NACT)+ surgery or radiotherapy.There aretheoretical advantages for the use of NACT,including decrease the loading of thetumor,reduce micro-metastatic disease,and improve the quality of life.NACT hasbeen the first considered therapy choice for young women with LACC.
Although NACT in LACC is still the subject of much controvery,manyinvestigates have reported that NACT is highly effective for patients with LACC,butthe clinical and pathological parameters which influence the effect are still unknown.Where the NACT have the survival benefit remains the focus of controvery.
Chemotherapy is the mainly therapy method for tumor,there are still differentoutcomes in different individuals as both tumors and their hosts have heterogeneity.Therefore,to search avaliable predit criterions to evaluate the response ofchemotherapy is the basic task for individual use.The regimen of NACT used for LACC is platinum-based chemotherapy,there are many mechanisms leading to theplatinum-resistance.The change of DNA repair ability is one of the most importmentmechanisms.
X-ray repair cross complementing gene 1(XRCC1)and Xeroderma pigmentosum pomplementary group D(XPD)are the major DNA repairing genes.They repair the DNA damages by base excision repair(BER)and nucleotide excision repair(NER).The expression of these two genes may be related closely to the platinum resistance.But the relationship between the expression of those two protein and the response ofNACT in LACC have not reported yet.
The pharmacological and genetic studies in resent years confirmed that the genetic polymorphism,especially the single nucleotide polymorphism(SNP),is theimportant reasons to cause the differences of individual cnacer susceptibility and therapy outcomes.There are three polymorphism sites in XRCC1,which isrespectively located on genetic codon 194(Arg-Trp),280(Arg-His)and 399(Arg-Gln).Some studies indicated that the SNP of XRCC1 related to many tumors,and alsoassociated with response to platinum-based chemotherapy in of NSCLC and carcinoma of colon.Whereas,the studies of the relationship between SNP of XRCC1and LACC is rare.
The aim of our study were to evaluate the efficacy of NACT in LACC,toanalysis the possible clinical and pathological parameters which could influence theeffect,and to assess relationship between the effect and the survival rate.Furthermore,we try to disclose the association of the expression of XRCC1 and XPD protein withthe chemotherapy response,and also the association of SNP in XRCC1 with theeffect of NACT for LACC.From these,we try to find a possible criterion to predictthe response of NACT in LACC,which can provide us with evidences to individualchemotherapy.
Part 1
Evaluation of the value of neoadjuvant chemotherapy for locallyadvanced cervical carcinoma
Objective:To evaluate the efficacy of neoadjuvant chemotherapy for locallyadvanced cervical cancer,the related clinical parameters affecting the outcome ofchemotherapy,and also the the survival.
Methods:A total of 109 patients with stageⅠb—Ⅱa of locally advanced cervicalcancers treated with neoadjuvant chemotherapy between June 1999 and June 2007 inWomen s Hospital,School of Medicine,Zhejiang University,were retrospectivelyanalysed the response of neoadjuvant chemotherapy,selected age,clinical stage,grade of differentiation,histology type,initial tumor size,chemotherapy regimens,number of courses and pre-treatment hemoglobin lever as the clinical parameters toanalysis the assosiation of the chemotherapy response and the clinical parameters,andalso analysis the difference of survival rate according to the response of NACT.
Results:
1.In 109 patients,85 cases were effective(3 complete response and 82 partialresponse),Overall response rate of neoadjuvant chemotherapy was 77.9%.
2.The clinical response was associated with histology type.The patients withsquamous cell cancer had significantly higher response rate than those withadenocarcinoma(82.3% vs 46.2%,X~2=9.342,P=0.002).the response ofneoadjuvant chemotherapy has no assosiation with age,clinical stage,grade ofdifferentiation,initial tumor size,chemotherapy regimens,number of coursesand pre-treatment hemoglobin lever.
3.The rates of positive pelvic lymph node metastasis were significantly lower incomplete or partial response patients than those in stable patients(4.70% vs23.53%,X~2=6.85,P=0.008).and also the rate of stroma invasion=outer1/3 weresignificantly lower than those<1/3(15.29% VS 52.94%,X~2=11.87,P= 0.012),while parametrial invasion has no difference(X~2=2.06,P=0.153).
4.In the 109 patients,88 patients finished the follow-up,The overall 2-year survivalrate was 98.4%,The 5-year survival rate was 86.5%;The survival rate(until thefollow-up finished)in complete or partial response group was 100%,1-yearsurvival rate and 2-year survival rate in stable disease group was 92.9% and 59.7%(chi-square=7.299,P=0.007).The disease-free survival rate in complete orpartial response group was 100%(until the follow-up finished),while 1-yeardisease-free survival rate and 2-year disease-free survival rate in stable diseasegroup was 88.9% and 57.3% respectively(chi-square=6.814,P=0.009).
Conclusions
1.NACT could decrease the rate of pelvic lymph node metastasis,the stroma invasion≥outer 1/3 and adjuvant therapy after surgery.indicated that NACT could decrease and inhibite the micro-metastasis,improve the locally control for locallyadvanced cervical carcinoma.
2.The patients who have good response to NACT should select surgery.It could beimprove the long-term survival rate.
Part 2
The Association of XRCC1 and XPD Protein Expression With the Responses toNeoadjuvant Chemotherapy in Locally Advanced Cervical Carcinoma
Objective:To asses the association between the expression of XRCC1、XPD proteinand clinical responses to neoadjuvant chemotherapy in locally advanced cervicalcancinoma.
Methods:A total of 99 patients with stageⅠb2—Ⅱa of locally advanced cervicalcancers treated with neoadjuvant chemotherapy between June 1999 and June 2007 inWomen s Hospital,School of Medicine,Zhejiang University were retrospectivelyanalysed.Immunohistochemistry method was adopted to detected the expression of XRCC1、XPD protein in pretreatment cancer tissue,the protein expression ofXRCC1、XPD and the response of NACT were analysised.and also analysised theassociation of protein expression and the clinical-pathology parameters in locallyadvanced cervical carcinoma
Results:
1.The expression of XRCC1 protein were significantly lower in effectivepatients than those in stable patients(2.99±0.38 vs 1.94±0.28,t=13.64,P=0.008).
2.The expression of XPD protein were significantly lower in effective patientsthan those in stable patients(2.93±0.29 vs 1.78±0.39,t=11.89,P=0.007).
3.The expression of XRCC1 protein in adenocarcinoma and in patients withpositive pelvic lymph node were significantly higher than those in squamous cellcancer and negative pelvic lymph node(2.23±0.61 vs 1.92±0.57,t=-2.46,P=0.02;2.52±0.77vs2.07±0.44,t=-3.00,P=0.01)).the stroma invasion≥outer 1/3 weresignificantly higher than those 0.05).
4.The expression of XPD protein in tissures of less than 35 years old patientsand in adenocarcinoma weres significantly higher than those more than 35 years andin squamous cell cancer.(2.23±0.61 VS 1.92±0.57,t=2.27,P=0.03;2.44±0.72VS1.93±-0.54,t=-3.01,P=0.01).patients with positive pelvic lymph node weresignificantly higher than those with negative pelvic lymph node(2.42±0.71 VS1.93±0.55,t=-2.83,P=0.01);the stroma invasion≥outer 1/3 were significantlyhigher than thos0.05).
Conclusions
1.The expression of XRCC1 and XPD protein were significantly lower in effectivepatients than those in stable patients,which implies the abnormal expression ofXRCC1、XPD protein may be associated with the drug-resistance ofplatinum-based neoadjuvant chemotherapy for locally advanced cervical carcinoma.
2.The expression of XRCC1、XPD protein can be considered as the index topredict the response of neoadjuvant chemotherapy in locally advanced cervicalcarcinoma.
Part 3
The Association of Single Nucleotide Polymorphism in DNA Repair GeneXRCC1 With the Effect of Neoadjuvant Chemotherapy for Locally AdvancedCervical Carcinoma
Objective:To investigate the possible associations between the effect of neoadjuvantchemotherapy for locally advanced cervical cancer and Single nucleotidepolymorphism of DNA repair gene XRCC1.
Methods:A total of 70 patients with locally advanced cervical cancers treated withneoadjuvant chemotherapy between June 1999 and June 2007 in Women s Hospital,School of Medicine,Zhejiang University were analysed.SNP of XRCC1 at codon194、399 were detected by MAMA-PCR.The contributions of different genotypesto the effect of neoadjuvant chemotherapy and XRCC1 protein expression level werecompared and analyzed.
Results:
1.Genotypes(Arg/Arg,Arg/TrP,Trp/TrP)of XRCC1 at codon 194 were notassociation with the effect of neoadjuvant chemotherapy(X~2=1.243,P=0.07);The XRCC1 protein expression level between different genotypes at codon 194 hadno siginificantly difference.(F=1.186,P=0.103).
2. Genotypes(Arg/Arg,Arg/Gln,Gln/Gln)of XRCC1 at codon 399 weresignificantly association with the effect of neoadjuvant chemotherapy(X~2=2.283,P=0.030),the risk of faliure to chemotherapy with Gln allele(Arg/Gln+Gln/Gln) were significantly higher than Arg/Arg(0R=3.254,95%CI 0.708～14.951);TheXRCC1 protein expression level between different genotypes had significantlydifference.(F=15.915,P<0.001).the expression of XRCC1 protein with Glnallele(Arg/Gln+Gln/Gln)were significantly higher than Arg/Arg(F=2.699,p=0.009).
Conclusions
1.The risk of failure to neoadjuvant chemotherapy and the expression of XRCC1protein were siginificantly increase in patients with Gln allele at codon 399 SNP,indicated that the SNP of XRCC1 gene at codon 399 can be considered as theindex to predict the response of neoadjuvant chemotherapy in locally advancedcervical carcinoma.
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