检测循环血肿瘤细胞及血清游离DNA表皮因子生长受体基因突变在肺癌诊断治疗中的临床意义
摘要
课题Ⅰ外周血循环肿瘤细胞(CTC)在晚期肺癌患者的预测及预后价值研究
背景
肺癌是严重威胁人类健康的疾病,其病死率居所有恶性肿瘤之首,发病率呈逐年上升趋势。肿癌患者的5年生存率仅15%,多数患者在病程中出现脑、骨、肾上腺等远隔器官转移,严重影响患者的预后。循环肿瘤细胞(circulating tumor cells,CTCs)已成为当今肿瘤界评测病情的一大可能手段。
目的
本研究目的在于探索应用免疫磁珠富集技术结合荧光细胞化学染色方法检测肺癌患者外周静脉血中CTC方法的敏感性及特异性;分析肺癌患者外周血循环肿瘤细胞水平与性别、年龄、吸烟情况、临床分期、肿瘤病理分型、等临床特征的联系;探索循环肿瘤细胞数量与远处器官转移的关联;评价循环肿瘤细胞的数量变化与影像学变化及临床疗效评价的一致性,并初步评价初始循环肿瘤细胞水平与肺癌患者生存的相关性。
方法
2007年7月至2008年4月在北京协和医院呼吸内科肿癌中心门诊明确诊断的144例肺癌患者作为研究对象。同时设立健康对照组35例、良性肿疾病对照组28例。采集肺癌患者治疗前及两对照组肘静脉血标本。应用免疫磁珠富集分离及免疫荧光细胞化学染色方法检测7.5mL静脉血中CK18+/CD45-循环肿瘤细胞(CTC计数≥2判定为检测阳性)。共随访52例入院化疗肺癌患哲治疗后CTC,并与其临床疗效、生存进行相关性分析。
结果
健康对照组纳入35例,其中2例CTC检测结果为阳性,阳性率为5.71%;良性肺疾病对照组纳入28例,仅1例检测结果为阳性,阳性率为3.57%。肺癌组纳入144例患者,未接受任何治疗前检测CTC的阳性率为64.5%(93/144)。144例肺癌患者中ⅢA期患者的CFC检测结果阳性比为32.0%(8/25),ⅢB期检测结果阳性比为56.8%(21/37),Ⅳ期为78.0%(64/82)。不同病理类型(包括腺癌、鳞癌、小细胞癌)肺癌患者的CTC检测结果阳性率分别为66.7%(76/114)、70%(7/10)、62%(10/13)。其中有52例肺癌患者进行每程化疗后的CTC随访,治疗前CTC阳性比为69.2%(36/52),治疗一程后阳性比为28.8%(15/52),最多随访6个疗程至患者结束治疗。治疗一程后的CTC水平与后续疗程CTC水平具有一致性,并且CTC水平的改变情况与疗效(疾病控制程度)高度相关。
结论
免疫磁珠阴性富集法检测循环肿瘤细胞过程简便,检测的敏感性93.1%,特异性72.8%。本研究显示CTC阳性率在肺癌患者和非肺癌患者间存在显著差异。其阳性率与有无远处转移密切相关,但与性别、年龄及肿瘤的病理类型无关。未能证明CTC数值本身与病情严重程度相关,但CTC水平越高可能提示预后不良。CTC数值在化疗前后的变化与临床疗效明确相关。化疗一程后的CTC水平与疗效高度相关。提示CTC检测结果可作为临床分期的辅助参考。
课题Ⅱ肺癌患者血清游离DNA检测EGFR基因点突变与EGFR-TKI疗效的相关性分析
背景
肺癌患者血清游离DNA含量显著高于健康人,并与原发肿瘤组织DNA具有高度一致性。既往多项涉及EGFR-TKI的大型临床研究已经证实肺癌组织ECFR基因突变情况可以预测药物疗效。
目的
验证应用肺癌患者血清游离DNA测定EGFR基因点突变的可行性,探讨该方法检测结果与肺癌患者对ECFR-TKI疗效间的相关性。
方法
收集2007年11月至2008年4月共170份呼吸内科肺癌中心门诊就诊患者4ml全血的血清样本,其中男性73例,女性97例,年龄范围40-84岁,中位年龄59岁;经检查后确诊疾病类型为,非恶性疾病20例,腺癌140例(其中细支气管肺泡癌20例),鳞癌10例。从未吸烟者81例,目前或既往吸烟者89例。采用RT-PCR技术检测其外周血清游离DNA中EGFR基因点突变情况,应用SPSS15.0软件进行统计学分析。
结果
170份血清标本中共检测到89个突变(52.3%),其中50个敏感突变(56.2%),39个耐药突变(43.8%),敏感/耐药双突变7例(4.1%)。本检测方法发现G719X为最多见的敏感突变类型(12.4%),其次是L858R、19del。T790M为最常见的耐药突变。女性突变率59.8%,显著高于男性42.4%(P＜0.05),且其敏感突变比例更高。非吸烟者与吸烟者突变率分别为58.0%和47.2%(P＜0.01),且非吸烟者的敏感突变高达83.0%。140例肺腺癌中突变检测阳性率为55.7%,BAC亚型阳性率为85%。具有敏感突变者应用EGFR-TKI的有效率为79.6%,既往有效率高达93.9%。T790M的出现多与应用EGFR-TKI有关(22/24),原发T790M发生率为2.2%。出现耐药突变T790M时61.8%的患者已表现出疾病进展,某些临床稳定者已可检测出T790M突变,提示未来出现耐药的可能。带有del、L858R突变者可有20个月以上的中位生存时间,T790M突变者中位生存仅有4个月,在敏感突变基础上继发的T790M突变常提示预后不良。
结论
应用RT-PCR方法检测肺癌患者外周血游离DNA EGFR基因点突变,取材方便,方法灵敏,可重复性好,与既往多项大型临床研究组织学测序结果高度一致,其检测结果与临床评估EGFR-TKI疗效较为符合。本研究亦提示EGFR基因突变与长期预后的可能联系。说明该方法在预测疗效、监测耐药发生方面,有良好的临床应用前景,可成为未来一线应用EGFR-TKI的筛选试验。
Background
We explored the clinical value of circulating tumor cells(CTCs) in prognosis and the assessment of treatment effects for patients with lung cancer.
Methods
In a prospective,single center and small sampling study,we tested the levels of CTC at baseline in 144 patients with emerging or recurring lung cancer and followed up 52 with CTC numbers after each cycle of chemotherapy.We then did correlation analysis between CTC variation and treatment-response evaluation based on RECIST criteria.We used AVIVABio Cancer Cell Isolating Technology,an immunomagnetic beads-based rare cell enrichment system using leukocyte depletion mechanism,to count the identified CK18+/CD45-CTCs in 7.5ml venous blood of the lung cancer patients under fluorescence microscopy.
Results
144 blood samples were collected from newly diagnosed or recurrent lung cancer patients who had been treatment-naive for at least 2 months before hospitalization. Benign respiratory diseases including tuberculosis and healthy control samples were collected,28 and 35 samples,respectively,during the same study period.The AVIVABio Technology is easy to manage and repeatable with a sensitivity of 93.1%and specificity of 72.8%in lung cancer patients.The patients with TNM stageⅢA had a CTC positive rate of 32.0%(8/25),and those ofⅢB 56.8%(21/37) andⅣ78.0%(64/82) (P＜0.01).52 patients were followed up with CTC after each cycle of chemotherapy for less than 6 cycles.After one chemo cycle,CTC positive rate fell from 69.2%(36/52) to 28.8%(15/52).Correlation analysis showed the variation of post-cycle 1 CTC was coincident with RECIST criteria by CT scan after two chemo cycles.
Conclusion
The above-mentioned method is highly sensitive and specific in detecting CTC of the patients with advanced lung cancer.CTC is closely related to the metastasis status of the tumor.The initial level of CTC and right after the therapy identified using this method has strong prognostic value.The variation of CTC in the course of chemotherapy might be a useful indicator of the chemo-response or disease-progression.
背景
肺癌是严重威胁人类健康的疾病,其病死率居所有恶性肿瘤之首,发病率呈逐年上升趋势。肿癌患者的5年生存率仅15%,多数患者在病程中出现脑、骨、肾上腺等远隔器官转移,严重影响患者的预后。循环肿瘤细胞(circulating tumor cells,CTCs)已成为当今肿瘤界评测病情的一大可能手段。
目的
本研究目的在于探索应用免疫磁珠富集技术结合荧光细胞化学染色方法检测肺癌患者外周静脉血中CTC方法的敏感性及特异性;分析肺癌患者外周血循环肿瘤细胞水平与性别、年龄、吸烟情况、临床分期、肿瘤病理分型、等临床特征的联系;探索循环肿瘤细胞数量与远处器官转移的关联;评价循环肿瘤细胞的数量变化与影像学变化及临床疗效评价的一致性,并初步评价初始循环肿瘤细胞水平与肺癌患者生存的相关性。
方法
2007年7月至2008年4月在北京协和医院呼吸内科肿癌中心门诊明确诊断的144例肺癌患者作为研究对象。同时设立健康对照组35例、良性肿疾病对照组28例。采集肺癌患者治疗前及两对照组肘静脉血标本。应用免疫磁珠富集分离及免疫荧光细胞化学染色方法检测7.5mL静脉血中CK18+/CD45-循环肿瘤细胞(CTC计数≥2判定为检测阳性)。共随访52例入院化疗肺癌患哲治疗后CTC,并与其临床疗效、生存进行相关性分析。
结果
健康对照组纳入35例,其中2例CTC检测结果为阳性,阳性率为5.71%;良性肺疾病对照组纳入28例,仅1例检测结果为阳性,阳性率为3.57%。肺癌组纳入144例患者,未接受任何治疗前检测CTC的阳性率为64.5%(93/144)。144例肺癌患者中ⅢA期患者的CFC检测结果阳性比为32.0%(8/25),ⅢB期检测结果阳性比为56.8%(21/37),Ⅳ期为78.0%(64/82)。不同病理类型(包括腺癌、鳞癌、小细胞癌)肺癌患者的CTC检测结果阳性率分别为66.7%(76/114)、70%(7/10)、62%(10/13)。其中有52例肺癌患者进行每程化疗后的CTC随访,治疗前CTC阳性比为69.2%(36/52),治疗一程后阳性比为28.8%(15/52),最多随访6个疗程至患者结束治疗。治疗一程后的CTC水平与后续疗程CTC水平具有一致性,并且CTC水平的改变情况与疗效(疾病控制程度)高度相关。
结论
免疫磁珠阴性富集法检测循环肿瘤细胞过程简便,检测的敏感性93.1%,特异性72.8%。本研究显示CTC阳性率在肺癌患者和非肺癌患者间存在显著差异。其阳性率与有无远处转移密切相关,但与性别、年龄及肿瘤的病理类型无关。未能证明CTC数值本身与病情严重程度相关,但CTC水平越高可能提示预后不良。CTC数值在化疗前后的变化与临床疗效明确相关。化疗一程后的CTC水平与疗效高度相关。提示CTC检测结果可作为临床分期的辅助参考。
课题Ⅱ肺癌患者血清游离DNA检测EGFR基因点突变与EGFR-TKI疗效的相关性分析
背景
肺癌患者血清游离DNA含量显著高于健康人,并与原发肿瘤组织DNA具有高度一致性。既往多项涉及EGFR-TKI的大型临床研究已经证实肺癌组织ECFR基因突变情况可以预测药物疗效。
目的
验证应用肺癌患者血清游离DNA测定EGFR基因点突变的可行性,探讨该方法检测结果与肺癌患者对ECFR-TKI疗效间的相关性。
方法
收集2007年11月至2008年4月共170份呼吸内科肺癌中心门诊就诊患者4ml全血的血清样本,其中男性73例,女性97例,年龄范围40-84岁,中位年龄59岁;经检查后确诊疾病类型为,非恶性疾病20例,腺癌140例(其中细支气管肺泡癌20例),鳞癌10例。从未吸烟者81例,目前或既往吸烟者89例。采用RT-PCR技术检测其外周血清游离DNA中EGFR基因点突变情况,应用SPSS15.0软件进行统计学分析。
结果
170份血清标本中共检测到89个突变(52.3%),其中50个敏感突变(56.2%),39个耐药突变(43.8%),敏感/耐药双突变7例(4.1%)。本检测方法发现G719X为最多见的敏感突变类型(12.4%),其次是L858R、19del。T790M为最常见的耐药突变。女性突变率59.8%,显著高于男性42.4%(P＜0.05),且其敏感突变比例更高。非吸烟者与吸烟者突变率分别为58.0%和47.2%(P＜0.01),且非吸烟者的敏感突变高达83.0%。140例肺腺癌中突变检测阳性率为55.7%,BAC亚型阳性率为85%。具有敏感突变者应用EGFR-TKI的有效率为79.6%,既往有效率高达93.9%。T790M的出现多与应用EGFR-TKI有关(22/24),原发T790M发生率为2.2%。出现耐药突变T790M时61.8%的患者已表现出疾病进展,某些临床稳定者已可检测出T790M突变,提示未来出现耐药的可能。带有del、L858R突变者可有20个月以上的中位生存时间,T790M突变者中位生存仅有4个月,在敏感突变基础上继发的T790M突变常提示预后不良。
结论
应用RT-PCR方法检测肺癌患者外周血游离DNA EGFR基因点突变,取材方便,方法灵敏,可重复性好,与既往多项大型临床研究组织学测序结果高度一致,其检测结果与临床评估EGFR-TKI疗效较为符合。本研究亦提示EGFR基因突变与长期预后的可能联系。说明该方法在预测疗效、监测耐药发生方面,有良好的临床应用前景,可成为未来一线应用EGFR-TKI的筛选试验。
Background
We explored the clinical value of circulating tumor cells(CTCs) in prognosis and the assessment of treatment effects for patients with lung cancer.
Methods
In a prospective,single center and small sampling study,we tested the levels of CTC at baseline in 144 patients with emerging or recurring lung cancer and followed up 52 with CTC numbers after each cycle of chemotherapy.We then did correlation analysis between CTC variation and treatment-response evaluation based on RECIST criteria.We used AVIVABio Cancer Cell Isolating Technology,an immunomagnetic beads-based rare cell enrichment system using leukocyte depletion mechanism,to count the identified CK18+/CD45-CTCs in 7.5ml venous blood of the lung cancer patients under fluorescence microscopy.
Results
144 blood samples were collected from newly diagnosed or recurrent lung cancer patients who had been treatment-naive for at least 2 months before hospitalization. Benign respiratory diseases including tuberculosis and healthy control samples were collected,28 and 35 samples,respectively,during the same study period.The AVIVABio Technology is easy to manage and repeatable with a sensitivity of 93.1%and specificity of 72.8%in lung cancer patients.The patients with TNM stageⅢA had a CTC positive rate of 32.0%(8/25),and those ofⅢB 56.8%(21/37) andⅣ78.0%(64/82) (P＜0.01).52 patients were followed up with CTC after each cycle of chemotherapy for less than 6 cycles.After one chemo cycle,CTC positive rate fell from 69.2%(36/52) to 28.8%(15/52).Correlation analysis showed the variation of post-cycle 1 CTC was coincident with RECIST criteria by CT scan after two chemo cycles.
Conclusion
The above-mentioned method is highly sensitive and specific in detecting CTC of the patients with advanced lung cancer.CTC is closely related to the metastasis status of the tumor.The initial level of CTC and right after the therapy identified using this method has strong prognostic value.The variation of CTC in the course of chemotherapy might be a useful indicator of the chemo-response or disease-progression.
引文
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