肺腺癌EGFR基因突变和TKI疗效与血清肿瘤标记物的相关性
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摘要
背景和目的：肺癌是最常见的恶性肿瘤之一,是男性发病率最高的肿瘤,发病率和死亡率分别约35.5和31.2/10万人；也是女性常见的肿瘤类型,在中国,女性肺癌患病率已上升到21/10万人。最新统计显示全球新诊断的肺癌约占癌症病人的13%,死亡率已经达到了18%。中国的肺癌发病率约为61.4/10万人,其中约80%为非小细胞肺癌,多数发现已经是晚期,预后差,中位生存期约6～12月,1年生存率约20%～50%；诊断后的5年生存率低于15%。早期患者可通过手术切除而痊愈,但其中70%以上患者发现时已经是局部侵犯或远隔转移而无法手术。现对进展期患者的治疗方案的选择非常有限,多采用含铂类化疗药物为基础的方案进行一线治疗,但只能延长生存期而不能治愈,中位生存期仅8～10月；二线化疗方案的有效率约16.3%,三线方案仅2.3%,中位生存期仅4个月。同时患者往往要忍受化疗药物所带来的毒副作用,部分患者因耐药而导致抗肿瘤治疗的失败。为了提高肺癌患者的治疗效果和延长生存时间,亟需探讨新的治疗方法。随着对肺癌生物学的进一步认识,在肺癌的治疗策略上有了很大的进展,其中表皮生长因子受体(epidermal growth factor receptor, EGFR)已成为肺癌治疗的热点之一。
ECFR是原癌基因c-erb-1(HER-1)表达的具有酪氨酸激酶活性的受体,在许多肿瘤中呈高表达和/或发生突变,进而通过信号转导来控制肿瘤细胞的增殖和分化；同时参与肿瘤的新生血管生成、局部侵袭和和远处转隔。自EGFR酪氨酸激酶抑制(epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI)在临床上应用以来,发现有较好的疾病控制率,且不良反应相对较小,从而引起广泛的关注。研究发现该类药物在女性、不吸烟者、亚洲人种和肺腺癌患者中疗效更好,其原因可能和EGFR基因突变有关,故检测是否有基因的突变来预测EGFR-TKI的有效性。现对EGFR基因突变的检测是可行的,但是由于有时肺癌组织标本量的不足和原发灶标本的获取困难等因素限制了EGFR基因突变检测的实用性。虽检测血中EGFR突变目前是可行的,但肿瘤状态的不均一性,其检测的结果并不总能代表原发灶的生物学特点；且先前接受过化疗的病人EGFR基因的状态是否会发生改变等诸多因素及昂贵的检测费用降低了其检测价值。
而相对检测简单、无创、经济及重复性好的血清学肿瘤标记物的检测是否可预测EGFR-TKI对肺癌治疗效果了?目前发现有多个标记物可能有预测作用,如癌胚抗原(Carcinoembryonic antigen, CEA)、多肽特异性抗原(TPS)、双向调节因子(Amphiregulin)和转化生长因子α(TGF-α)等,其中以CEA研究较多,并且应用价值较大。但有关肺腺癌中EGFR基因突变和EGFR-TKI疗效与多个常见肿瘤血清标记物的相关性研究,迄今国内外未见报道。为探讨EGFR基因突变和EGFR-TKI的疗效与肿瘤标记物检测的相关性及意义,本试验从以下两个部分进行系统的研究。
第一部分EGFR-TKI治疗肺腺癌疗效与血清肿瘤标记物的相关性对象和方法
1对象和EGFR-TKI服药方法选取2007年1月1日至2010年12月31日期间在河南省人民医院住院或门诊经病理学证实的肺腺癌患者,筛查具有完整的临床资料和蛋白芯片-化学发光法检测的血清肿瘤标记物结果的患者,其中48例申请赠药注册的服用EGFR-TKI进展期肺腺癌患者(ⅢB,Ⅳ期)进行疗效分析及预后因素的判断；应用EGFR-TKI治疗患者口服吉非替尼(250mg/d)或(厄洛替尼150mg/d),直至肿瘤进展或因毒副反应无法耐受而停药。
2 EGFR-TKI疗效的判定定期复查相关指标,据实体瘤客观疗效评价标准1.0版进行疗效判定,计算疾病有效率(response rate, RR)和疾病控制率(disease control rate, DCR)。记录患者的无进展生存期(progression free surviva, PFS)和总生存期(overall survival, OS)。
3血清肿瘤标记物检测抽取空腹静脉血2ml,析出血清后蛋白芯片-化学发光法进行多种肿瘤标记物(包括糖链抗原19-9,神经元特异性烯醇化酶,癌胚抗原,糖链抗原242,铁蛋白,人绒毛膜促性腺激素,甲胎蛋白,游离型前列腺特异性抗原,前列腺特异性抗原,癌抗原125,人生长激素和癌抗原15-3)检测。
4统计学方法使用SPSS 12.0统计学软件进行数据处理。计量资料以均数±标准差表示,独立样本进行方差齐性检验后采用t检验或校正t检验进行统计；计数资料以率表示,采用χ2检验进行分析。疗效相关因素分析采用单因素χ2检验或Fisher精确检验和多因素Logistic回归法；生存分析采用Kaplan-Meier法、Log-rank检验以及Cox多因素回归模型。所有显著性水平都采用双侧检验；P<0.05差异有统计学意义。
结果
1 EGFR-TKI的临床疗效应用EGFR-TKI治疗的48例患者中CR(完全缓解)2例(4.2%),PR(部分缓解)26例(54.2%),SD(稳定)3例(6.3%),PD(进展)17例(35.4%)。RR为58.3%,DCR为65.6%。
2 PR+CR组和PD+SD组间的血清肿瘤标记物水平、PFS和OS间的比较统计结果显示PR+CR组患者的CA-199和CEA血清水平显著高于PD+SD组患者的血清水平(P<0.05)；且前组的OS,PFS明显长于后者(P<0.05)。
3 PR+CR+PD组和PD组间的血清肿瘤标记物、PFS和OS间的比较PR+CR+PD组患者的CA-199,CEA和CA125的血清水平较PD组高(P<0.05)；两组间的OS和PFS有显著性差异(P<0.05)。
4 RR与患者临床特征的关系单因素χ2检验显示：RR与患者是否吸烟和血清CEA、CA125、CA242水平是否升高有关；Logistic多因素回归分析显示：不吸烟、ECFR-TKI治疗前血清CEA、CA199水平升高患者治疗的有效率明显高于吸烟、治疗前血清CEA、CA199水平处于正常范围内者,差异具有统计学意义(P<0.05)。
5 DCR与患者临床特征的关系单因素χ2检验显示：DCR与患者吸烟史和治疗前血清CEA、CA199水平是否升高相关；Logistic多因素回归分析显示：EGFR-TKI治疗前CEA血清水平升高的患者的DCR明显高于不升高者,具有统计学差异(P<0.05)。
6生存分析应用ECFR-TKI治疗患者的中位PFS为8.6(1～18)个月,中位OS为13.2(2～26)个月,1年生存率为61.4%。Kaplan-Meier生存曲线显示：吸烟史、血清CEA、CA199水平是否升高对患者的生存有显著影响。Log-rank检验显示：不吸烟、治疗前血清CA199、CEA水平升高的者的PFS和OS均较长(P<0.05)。Cox多因素生存分析提示：EGFR-TKI治疗前血清CA199和CEA的水平是影响生存的独立因素。
第二部分肺腺癌EGFR基因突变与血清肿瘤标记物的相关性
对象和方法
1对象收集和筛查2009年1月1日至2010年12月31日期间于河南省人民医院呼吸科、肿瘤科、胸外科和河南省胸部肿瘤诊治中心住院有病理学证据和完整临床资料的70例肺腺癌患者。根据1999年世界卫生组织(WHO)肺及胸膜肿瘤组织学类型修订方案进行肺癌病理分型鉴别；据国际抗癌联盟(UICC)1997年制定的TNM分期标准进行临床分期。
2血清肿瘤标记物检测抽取空腹静脉血2ml,析出血清后蛋白芯片-化学发光法进行多种肿瘤标记物(包括糖链抗原19-9,神经元特异性烯醇化酶,癌胚抗原,糖链抗原242,铁蛋白,人绒毛膜促性腺激素,甲胎蛋白,游离型前列腺特异性抗原,前列腺特异性抗原,癌抗原125,人生长激素和癌抗原15-3)检测。
3 EGFR基因突变分析据文献提取石蜡包埋标本DNA,优化PCR法进行EGFR基因扩增,琼脂糖凝胶电泳鉴定后进行DNA测序。
4统计学方法使用SPSS 12.0统计学软件进行数据处理。计量资料以均数±标准差表示,独立样本进行方差齐性检验后采用t检验或校正t检验进行统计；计数资料以率表示,采用χ2检验进行分析。EGFR基因突变和各因素间的相关性分析采用χ2检验或Fisher精确检验和多因素Logistic回归法。绘制受试者工作特征曲线(ROC)分析筛选后的肿瘤标记物对EGFR基因突变的预测价值。所有显著性水平都采用双侧检验；P<0.05差异有统计学意义。
结果
1 EGFR基因突变特点70例标本共检测到EGFR基因突变27例(38.6%,27/70)。其中外显子19基因突变15例；外显子21基因突变12例。
2 EGFR基因突变组和野生组间血清肿瘤标记物水平的比较有EGFR基因突变组的CA199,CEA和CA242的血清水平明显高于野生组,有统计学差异(P<0.05)；CA125和CA153的血清水平两组无明显差异。
3临床特征与EGFR基因突变间关系单因素χ2检验显示：EGFR基因突变与患者的性别、吸烟史及血清CA199、CEA、CA242水平是否升高相关(P<0.05)；和年龄、PS评分、血清CA125和CA153水平无关。进一步logistic多因素分析显示不吸烟者、Ⅲ+Ⅳ期、血清CEA和CA242水平升高者的EGFR基因突变率高(P<0.05)。
4绘制ROC曲线并计算曲线下面积CEA和CA242的曲线下面积及95%CI分别为0.814(0.707～0.922)和0.769(0.646～0.891),曲线下面积差异有统计学意义(P<0.05)。当CEA的分界点取5.00ng/ml时,其预测EGFR基因突变的敏感性Se=70.4%,特异性Sp=74.4%；CA242分界点取20.00 U/ml时,敏感性Se=37%,特异性Sp=95.3%。
结论
1 EGFR-TKI治疗肺腺癌的疗效优于以铂类药物为基础的化疗方案,不吸烟的患者获益更大；
2本研究发现应用EGFR-TKI治疗前患者血清CEA, CA199水平升高者有着更高的疾病控制率(DCR)和缓解率(RR)；患者的无进展生存期(PFS)和总生存期(OS)更长；治疗前血清CA199和CEA的水平可预测EGFR-TKI治疗肺腺癌患者的疗效；
3吸烟肺腺癌患者的EGFR突变率低；
4本研究发现血清水平CEA, CA242升高的肺腺癌患者的EGFR基因突变率高；同期的血清CEA、CA242水平,尤其是CEA,可预测EGFR基因突变。
Background and objective:Lung cancer is one of the most common tumors, the highest incidence of male cancer incidence and mortality rates were 35.5 and 31.2 per 100,000 people. It is also common in female, and the rates of Chinese women has risen to 21 per100,000 people. The latest statistics show Lung cancer accounts for 13%(1.6 million) of the total cases and 18%(1.4 million) of the deaths in the world。In China, lung cancer incidence rate is 61.4 100,000 people, of which about 80% are non-small cell lung cancer, and most patients found have an advanced stage, whose prognosis is poor and median survival of approximately is about 6 to 12 months; 1-year survival rate is about 20-50% and 5-year survival after diagnosis less than 15%. Early stage patients can be cured by surgery, but 70% of patients detected are at local invasion or distant metastasis, surgery can not be done. The treatment of choice in these patients is very limited and the main choice of drugs containing platinum based first-line chemotherapy treatment, but only prolong survival,not be cured, in which median survival was only from 8 to 10 month; second-line chemotherapy treatment was 16.3% and third-line programs only 2.3%, median survival was only 4 months. Furthermore the patients often can not tolerate the side effects of chemotherapy and reduce the quality of life. Only small part patients benefit from the chemotherapy and the majority are ineffective due to drug resistance. In order to improve treatment and prolong survival time, new therapies is need. With a better understanding of cancer biology, diagnosis and treatment strategies in lung cancer has been a great progress, and epidermal growth factor receptor (EGFR) are studied in a wide range.
ECFR is a proto-oncogene c-erb-1 (HER-1) expression of receptors with tyrosine kinase activity, found in many tumors over-expression and/or mutations, transducting signal to control the proliferation and differentiation of tumor; also involving in angiogenesis, tumor invasion and local or distant metastasis. EGFR tyrosine kinase inhibition in clinical practice has been found to have better disease control rate, and adverse reactions are relatively small. So targeted therapy is another option in addition to conventional treatment. Good effect are found in women, nonsmokers, Asian ethnicity and adenocarcinoma, which may be related to EGFR mutations. Gene mutation could predict the effectiveness of EGFR-TKI, but how to detect EGFR gene is a prbolem. Insufficient sample or difficult to obtain specimens of the primary tumor led to the failure of detection and monitoring of EGFR mutation. Detection of EGFR mutations in blood cells is now feasible, but the results can not be fully representative of the primary tumor because of tumor heterogeneity, and we do not know if there will be changes in EGFR mutations after chemotherapy. So many questions like before and expensive testing costs reduced the value of genetic testing. Serological detection of tumor markers is relatively simple, noninvasive, economic, and reproducible. Currently there are several markers predicting the efficacy of EGFR-TKI, such as carcinoembryonic antigen (CEA), polypeptide specific antigen (TPS), Amphiregulin and transforming growth factor-α(TGF-α), and CEA was studied mostly and found to predict the effect of TKI. But the correlation on EGFR mutations and EGFR-TKI efficacy with serum level of tumor markers in lung adenocarcinoma patients has not been reported at home and abroad. To investigate the EGFR mutation and EGFR-TKI efficacy with detection of tumor markers and find their significance, the study include the following two parts.
The first part Correlation between efficacy of the EGFR tyrosine kinase inhibitor and serum tumor markers in lung adenocarcinoma patients
Subject and Method
1 Subject and Medication methods From January 1,2007 to December 2010 31, the patient of with adenocarcinoma confirmed by pathology in Henan province people's hospital, who had complete clinical data and the results of serum tumor marker were selected to analysis.48 cases with advanced adenocarcinoma (ⅢB,Ⅳperiod) taking EGFR-TKI and checking in the donated medicine were seleted to assess the efficacy and prognostic factors,Application of EGFR-TKI treatment of patients treated with gefitinib (250mg/d) or (erlotinib 150mg/d) until disease progression or intolerable side effects,and checking relevant indicators regularly.
2 Therapeutic evaluation According to the solid tumor objective response evaluation criteria 1.0 to determine the efficacy of drugs to calculate response rate (RR) and disease control rate (DCR), And record the time of progression-free survival (PFS) and overall survival (OS).
3 Detection of serum tumor markers Tumor marks were detected by protein chip-chemiluminescence way after 2ml venous blood distilled and separated out.
4 Statistical Method Using SPSS 12.0 statistical software for data processing. Measurement data were described as mean±standard deviation, t test or t'test was used for statistics in independent samples after testing homogeneity of variance.Count data described as a rate,and clinical factors were analyzed by single factorχ2 test or Fisher exact test and multivariate Logistic regression. Kaplan-Meier, Log-rank test and Cox regression model were used to survival analysis. All significance levels were used two-sided test, and P<0.05 was considered statistically significant.
Results
1 Clinical outcomes EGFR-TKI treatment of 48 patients achieved CR (complete response) in 2 cases (4.2%), PR (partial response) of 26 cases (54.2%), SD (stable) in 3 cases (6.3%), PD (progress) 17 cases (35.4%) RR为58.3%, DCR为65.6%。RR was 58.3%, DCR was 65.6%.
2 Comparison of serum tumor markers, PFS and OS between the PR+CR group and the PD+SD Statistics showed that the serum CA-199 and CEA levels in PR and CR groups were significantly higher than the PD and SD groups (P<0.05); and OS, PFS of the former group was significantly longer than the latter (P<0.05).
3 Comparison of serum tumor markers, PFS and OS between PR+CR+PD group and the PD Between the PR+CR+PD group the lever of CA-199, CEA and CA125 in serum were higher than the PD group (P<0.05). OS and PFS between the two groups showed significant differences (P<0.05).
4 Relationship between RR and clinical features A single factorχ2 test showed that:RR was related to the smoking and levels of serum CEA, CA125, CA242. Multivariate logistic regression analysis showed that:the RR in the patients of non-smoke, high serum CEA, CA199 level had a better outcome than the patients of smoke, low serum CEA, CA199 level. The difference was statistically significant (P <0.05).
5 Relationship between DCR and clinical features A single factorχ2 test showed that:DCR was related to the smoking and levels of serum CEA, CA199, but multivariate logistic regression analysis showed that:the DCR in the patients of high serum CEA level had a better outcome than the patients of low serum CEA level. The difference was statistically significant (P<0.05).
6 Survival analysis EGFR-TKI treatment for patients with a median PFS was 8.6 (1～18) months, the median OS was 13.2 (2～26) months and 1 year survival rate was 61.4%. Kaplan-Meier survival curves showed that smoking history, serum CEA, CA199 levels had significant effect on the survival of patients.And log-rank test showed tha before treatment the PFS and OS in no-smok, high serum CA199, CEA level patients were longer (P<0.05).Cox multivariate survival analysis indicated that the serum levels of CA199 and CEA were independent factors EGFR-TKI pretreatment affecting survival.
The second part Correlation between mutation of EGFR and serum tumor markers in lung adenocarcinoma patients
Subject and Method
1 Subject From January 1,2009 to December 31,2010,70 patients confirmed by pathology from Department of Respiratory Medicine, oncology and thoracic surgery,in the Henan province people's hospital.
2 Detection of serum tumor markers Tumor marks were detected by protein chip-chemiluminescence way after 2ml venous blood distilled and separated out.
3 Detection of EGFR gene mutation DNA was extracted from paraffin-embedded samples, After EGFR gene amplified by PCR, the products were analyzed in agarose gel electrophoresis and sequenced.
4 Statistical Method Using SPSS 12.0 statistical software for data processing. Measurement data were described as mean±standard deviation, t test or t'est was used for statistics in independent samples after testing homogeneity of variance.Count data described as a rate,and clinical factors were analyzed by single factorχ2 test or Fisher exact test and multivariate Logistic regression. The methods ofχ2 test, Fisher exact test and multivariate Logistic regression were used to analysis the correlation between EGFR mutations and factors. Receiver operating characteristic curve (ROC) was draw to assess the value of tumor marker in predicting EGFR mutation. All significance levels were used two-sided test, and P<0.05 was considered statistically significant.
Results
1 Characteristics of EGFR mutations In 70 specimens,27 (38.6%,27/70)were detected to have EGFR gene mutations, in which exon 19 of EGFR gene mutations detected in 15 cases; exon 21 EGFR mutation detected in 12 cases.
2 Comparison of serum tumor markers between the EGFR mutation group and the wild The serum levels of CA199, CEA and CA242 in EGFR mutation group were higher than these in the wild with significant difference (P<0.05). The CA125 and CA153 were no significant differences between the two groups.
3 Relationship between clinical characteristics and EGFR gene mutation A single factorχ2 test showed that EGFR mutations was associated with gender, smoking history and serological CA199, CEA, CA242 level (P<0.05), not with age, PS score, serological CA125 or CA153 levels. Further multivariate logistic analysis shown that the patient with non-smoking, inⅢ+Ⅳperoid, high serological CEA and CA242 level had higher rate in the EGFR gene mutation (P<0.05).
4 Draw the ROC curve and calculate the area under the curve The areas of CEA and CA242 under the curve and 95% CI were 0.814 (0.707～0.922) and 0.769 (0.646～0.891) each, area under the curve was significantly. When the CEA cut-off point for the 5.00 ng/ml, the sensitivity Se=70.4%, specificity Sp=74.4%; and CA242 cutoff point of 20.00 U/ml, the sensitivity Se= 37%, specificity Sp= 95.3 %.
Conclusion
1 EGFR-TKI treatment of lung adenocarcinoma is more effective than platinum-based chemotherapy drugs, and patients who do not smoke benefit more;
2 The patient who had high level of CEA, CA199 before application of targeted therapy would have a higher disease control rate and remission rate, longer progression-free survival and overall survival, So serum levels of CA199 and CEA before treatmeng can be used to forecast EGFR-TKI treatment efficacy in patients with lung adenocarcinoma;
3 The patients who smoke had a lower mutations in EGFR in lung adenocarcinoma;
4 The EGFR gene mutation happened more in the patient who had a high serum levels of CEA, CA242, which might predict the rate of EGFR mutation.
ECFR是原癌基因c-erb-1(HER-1)表达的具有酪氨酸激酶活性的受体,在许多肿瘤中呈高表达和/或发生突变,进而通过信号转导来控制肿瘤细胞的增殖和分化；同时参与肿瘤的新生血管生成、局部侵袭和和远处转隔。自EGFR酪氨酸激酶抑制(epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI)在临床上应用以来,发现有较好的疾病控制率,且不良反应相对较小,从而引起广泛的关注。研究发现该类药物在女性、不吸烟者、亚洲人种和肺腺癌患者中疗效更好,其原因可能和EGFR基因突变有关,故检测是否有基因的突变来预测EGFR-TKI的有效性。现对EGFR基因突变的检测是可行的,但是由于有时肺癌组织标本量的不足和原发灶标本的获取困难等因素限制了EGFR基因突变检测的实用性。虽检测血中EGFR突变目前是可行的,但肿瘤状态的不均一性,其检测的结果并不总能代表原发灶的生物学特点；且先前接受过化疗的病人EGFR基因的状态是否会发生改变等诸多因素及昂贵的检测费用降低了其检测价值。
而相对检测简单、无创、经济及重复性好的血清学肿瘤标记物的检测是否可预测EGFR-TKI对肺癌治疗效果了?目前发现有多个标记物可能有预测作用,如癌胚抗原(Carcinoembryonic antigen, CEA)、多肽特异性抗原(TPS)、双向调节因子(Amphiregulin)和转化生长因子α(TGF-α)等,其中以CEA研究较多,并且应用价值较大。但有关肺腺癌中EGFR基因突变和EGFR-TKI疗效与多个常见肿瘤血清标记物的相关性研究,迄今国内外未见报道。为探讨EGFR基因突变和EGFR-TKI的疗效与肿瘤标记物检测的相关性及意义,本试验从以下两个部分进行系统的研究。
第一部分EGFR-TKI治疗肺腺癌疗效与血清肿瘤标记物的相关性对象和方法
1对象和EGFR-TKI服药方法选取2007年1月1日至2010年12月31日期间在河南省人民医院住院或门诊经病理学证实的肺腺癌患者,筛查具有完整的临床资料和蛋白芯片-化学发光法检测的血清肿瘤标记物结果的患者,其中48例申请赠药注册的服用EGFR-TKI进展期肺腺癌患者(ⅢB,Ⅳ期)进行疗效分析及预后因素的判断；应用EGFR-TKI治疗患者口服吉非替尼(250mg/d)或(厄洛替尼150mg/d),直至肿瘤进展或因毒副反应无法耐受而停药。
2 EGFR-TKI疗效的判定定期复查相关指标,据实体瘤客观疗效评价标准1.0版进行疗效判定,计算疾病有效率(response rate, RR)和疾病控制率(disease control rate, DCR)。记录患者的无进展生存期(progression free surviva, PFS)和总生存期(overall survival, OS)。
3血清肿瘤标记物检测抽取空腹静脉血2ml,析出血清后蛋白芯片-化学发光法进行多种肿瘤标记物(包括糖链抗原19-9,神经元特异性烯醇化酶,癌胚抗原,糖链抗原242,铁蛋白,人绒毛膜促性腺激素,甲胎蛋白,游离型前列腺特异性抗原,前列腺特异性抗原,癌抗原125,人生长激素和癌抗原15-3)检测。
4统计学方法使用SPSS 12.0统计学软件进行数据处理。计量资料以均数±标准差表示,独立样本进行方差齐性检验后采用t检验或校正t检验进行统计；计数资料以率表示,采用χ2检验进行分析。疗效相关因素分析采用单因素χ2检验或Fisher精确检验和多因素Logistic回归法；生存分析采用Kaplan-Meier法、Log-rank检验以及Cox多因素回归模型。所有显著性水平都采用双侧检验；P<0.05差异有统计学意义。
结果
1 EGFR-TKI的临床疗效应用EGFR-TKI治疗的48例患者中CR(完全缓解)2例(4.2%),PR(部分缓解)26例(54.2%),SD(稳定)3例(6.3%),PD(进展)17例(35.4%)。RR为58.3%,DCR为65.6%。
2 PR+CR组和PD+SD组间的血清肿瘤标记物水平、PFS和OS间的比较统计结果显示PR+CR组患者的CA-199和CEA血清水平显著高于PD+SD组患者的血清水平(P<0.05)；且前组的OS,PFS明显长于后者(P<0.05)。
3 PR+CR+PD组和PD组间的血清肿瘤标记物、PFS和OS间的比较PR+CR+PD组患者的CA-199,CEA和CA125的血清水平较PD组高(P<0.05)；两组间的OS和PFS有显著性差异(P<0.05)。
4 RR与患者临床特征的关系单因素χ2检验显示：RR与患者是否吸烟和血清CEA、CA125、CA242水平是否升高有关；Logistic多因素回归分析显示：不吸烟、ECFR-TKI治疗前血清CEA、CA199水平升高患者治疗的有效率明显高于吸烟、治疗前血清CEA、CA199水平处于正常范围内者,差异具有统计学意义(P<0.05)。
5 DCR与患者临床特征的关系单因素χ2检验显示：DCR与患者吸烟史和治疗前血清CEA、CA199水平是否升高相关；Logistic多因素回归分析显示：EGFR-TKI治疗前CEA血清水平升高的患者的DCR明显高于不升高者,具有统计学差异(P<0.05)。
6生存分析应用ECFR-TKI治疗患者的中位PFS为8.6(1～18)个月,中位OS为13.2(2～26)个月,1年生存率为61.4%。Kaplan-Meier生存曲线显示：吸烟史、血清CEA、CA199水平是否升高对患者的生存有显著影响。Log-rank检验显示：不吸烟、治疗前血清CA199、CEA水平升高的者的PFS和OS均较长(P<0.05)。Cox多因素生存分析提示：EGFR-TKI治疗前血清CA199和CEA的水平是影响生存的独立因素。
第二部分肺腺癌EGFR基因突变与血清肿瘤标记物的相关性
对象和方法
1对象收集和筛查2009年1月1日至2010年12月31日期间于河南省人民医院呼吸科、肿瘤科、胸外科和河南省胸部肿瘤诊治中心住院有病理学证据和完整临床资料的70例肺腺癌患者。根据1999年世界卫生组织(WHO)肺及胸膜肿瘤组织学类型修订方案进行肺癌病理分型鉴别；据国际抗癌联盟(UICC)1997年制定的TNM分期标准进行临床分期。
2血清肿瘤标记物检测抽取空腹静脉血2ml,析出血清后蛋白芯片-化学发光法进行多种肿瘤标记物(包括糖链抗原19-9,神经元特异性烯醇化酶,癌胚抗原,糖链抗原242,铁蛋白,人绒毛膜促性腺激素,甲胎蛋白,游离型前列腺特异性抗原,前列腺特异性抗原,癌抗原125,人生长激素和癌抗原15-3)检测。
3 EGFR基因突变分析据文献提取石蜡包埋标本DNA,优化PCR法进行EGFR基因扩增,琼脂糖凝胶电泳鉴定后进行DNA测序。
4统计学方法使用SPSS 12.0统计学软件进行数据处理。计量资料以均数±标准差表示,独立样本进行方差齐性检验后采用t检验或校正t检验进行统计；计数资料以率表示,采用χ2检验进行分析。EGFR基因突变和各因素间的相关性分析采用χ2检验或Fisher精确检验和多因素Logistic回归法。绘制受试者工作特征曲线(ROC)分析筛选后的肿瘤标记物对EGFR基因突变的预测价值。所有显著性水平都采用双侧检验；P<0.05差异有统计学意义。
结果
1 EGFR基因突变特点70例标本共检测到EGFR基因突变27例(38.6%,27/70)。其中外显子19基因突变15例；外显子21基因突变12例。
2 EGFR基因突变组和野生组间血清肿瘤标记物水平的比较有EGFR基因突变组的CA199,CEA和CA242的血清水平明显高于野生组,有统计学差异(P<0.05)；CA125和CA153的血清水平两组无明显差异。
3临床特征与EGFR基因突变间关系单因素χ2检验显示：EGFR基因突变与患者的性别、吸烟史及血清CA199、CEA、CA242水平是否升高相关(P<0.05)；和年龄、PS评分、血清CA125和CA153水平无关。进一步logistic多因素分析显示不吸烟者、Ⅲ+Ⅳ期、血清CEA和CA242水平升高者的EGFR基因突变率高(P<0.05)。
4绘制ROC曲线并计算曲线下面积CEA和CA242的曲线下面积及95%CI分别为0.814(0.707～0.922)和0.769(0.646～0.891),曲线下面积差异有统计学意义(P<0.05)。当CEA的分界点取5.00ng/ml时,其预测EGFR基因突变的敏感性Se=70.4%,特异性Sp=74.4%；CA242分界点取20.00 U/ml时,敏感性Se=37%,特异性Sp=95.3%。
结论
1 EGFR-TKI治疗肺腺癌的疗效优于以铂类药物为基础的化疗方案,不吸烟的患者获益更大；
2本研究发现应用EGFR-TKI治疗前患者血清CEA, CA199水平升高者有着更高的疾病控制率(DCR)和缓解率(RR)；患者的无进展生存期(PFS)和总生存期(OS)更长；治疗前血清CA199和CEA的水平可预测EGFR-TKI治疗肺腺癌患者的疗效；
3吸烟肺腺癌患者的EGFR突变率低；
4本研究发现血清水平CEA, CA242升高的肺腺癌患者的EGFR基因突变率高；同期的血清CEA、CA242水平,尤其是CEA,可预测EGFR基因突变。
Background and objective:Lung cancer is one of the most common tumors, the highest incidence of male cancer incidence and mortality rates were 35.5 and 31.2 per 100,000 people. It is also common in female, and the rates of Chinese women has risen to 21 per100,000 people. The latest statistics show Lung cancer accounts for 13%(1.6 million) of the total cases and 18%(1.4 million) of the deaths in the world。In China, lung cancer incidence rate is 61.4 100,000 people, of which about 80% are non-small cell lung cancer, and most patients found have an advanced stage, whose prognosis is poor and median survival of approximately is about 6 to 12 months; 1-year survival rate is about 20-50% and 5-year survival after diagnosis less than 15%. Early stage patients can be cured by surgery, but 70% of patients detected are at local invasion or distant metastasis, surgery can not be done. The treatment of choice in these patients is very limited and the main choice of drugs containing platinum based first-line chemotherapy treatment, but only prolong survival,not be cured, in which median survival was only from 8 to 10 month; second-line chemotherapy treatment was 16.3% and third-line programs only 2.3%, median survival was only 4 months. Furthermore the patients often can not tolerate the side effects of chemotherapy and reduce the quality of life. Only small part patients benefit from the chemotherapy and the majority are ineffective due to drug resistance. In order to improve treatment and prolong survival time, new therapies is need. With a better understanding of cancer biology, diagnosis and treatment strategies in lung cancer has been a great progress, and epidermal growth factor receptor (EGFR) are studied in a wide range.
ECFR is a proto-oncogene c-erb-1 (HER-1) expression of receptors with tyrosine kinase activity, found in many tumors over-expression and/or mutations, transducting signal to control the proliferation and differentiation of tumor; also involving in angiogenesis, tumor invasion and local or distant metastasis. EGFR tyrosine kinase inhibition in clinical practice has been found to have better disease control rate, and adverse reactions are relatively small. So targeted therapy is another option in addition to conventional treatment. Good effect are found in women, nonsmokers, Asian ethnicity and adenocarcinoma, which may be related to EGFR mutations. Gene mutation could predict the effectiveness of EGFR-TKI, but how to detect EGFR gene is a prbolem. Insufficient sample or difficult to obtain specimens of the primary tumor led to the failure of detection and monitoring of EGFR mutation. Detection of EGFR mutations in blood cells is now feasible, but the results can not be fully representative of the primary tumor because of tumor heterogeneity, and we do not know if there will be changes in EGFR mutations after chemotherapy. So many questions like before and expensive testing costs reduced the value of genetic testing. Serological detection of tumor markers is relatively simple, noninvasive, economic, and reproducible. Currently there are several markers predicting the efficacy of EGFR-TKI, such as carcinoembryonic antigen (CEA), polypeptide specific antigen (TPS), Amphiregulin and transforming growth factor-α(TGF-α), and CEA was studied mostly and found to predict the effect of TKI. But the correlation on EGFR mutations and EGFR-TKI efficacy with serum level of tumor markers in lung adenocarcinoma patients has not been reported at home and abroad. To investigate the EGFR mutation and EGFR-TKI efficacy with detection of tumor markers and find their significance, the study include the following two parts.
The first part Correlation between efficacy of the EGFR tyrosine kinase inhibitor and serum tumor markers in lung adenocarcinoma patients
Subject and Method
1 Subject and Medication methods From January 1,2007 to December 2010 31, the patient of with adenocarcinoma confirmed by pathology in Henan province people's hospital, who had complete clinical data and the results of serum tumor marker were selected to analysis.48 cases with advanced adenocarcinoma (ⅢB,Ⅳperiod) taking EGFR-TKI and checking in the donated medicine were seleted to assess the efficacy and prognostic factors,Application of EGFR-TKI treatment of patients treated with gefitinib (250mg/d) or (erlotinib 150mg/d) until disease progression or intolerable side effects,and checking relevant indicators regularly.
2 Therapeutic evaluation According to the solid tumor objective response evaluation criteria 1.0 to determine the efficacy of drugs to calculate response rate (RR) and disease control rate (DCR), And record the time of progression-free survival (PFS) and overall survival (OS).
3 Detection of serum tumor markers Tumor marks were detected by protein chip-chemiluminescence way after 2ml venous blood distilled and separated out.
4 Statistical Method Using SPSS 12.0 statistical software for data processing. Measurement data were described as mean±standard deviation, t test or t'test was used for statistics in independent samples after testing homogeneity of variance.Count data described as a rate,and clinical factors were analyzed by single factorχ2 test or Fisher exact test and multivariate Logistic regression. Kaplan-Meier, Log-rank test and Cox regression model were used to survival analysis. All significance levels were used two-sided test, and P<0.05 was considered statistically significant.
Results
1 Clinical outcomes EGFR-TKI treatment of 48 patients achieved CR (complete response) in 2 cases (4.2%), PR (partial response) of 26 cases (54.2%), SD (stable) in 3 cases (6.3%), PD (progress) 17 cases (35.4%) RR为58.3%, DCR为65.6%。RR was 58.3%, DCR was 65.6%.
2 Comparison of serum tumor markers, PFS and OS between the PR+CR group and the PD+SD Statistics showed that the serum CA-199 and CEA levels in PR and CR groups were significantly higher than the PD and SD groups (P<0.05); and OS, PFS of the former group was significantly longer than the latter (P<0.05).
3 Comparison of serum tumor markers, PFS and OS between PR+CR+PD group and the PD Between the PR+CR+PD group the lever of CA-199, CEA and CA125 in serum were higher than the PD group (P<0.05). OS and PFS between the two groups showed significant differences (P<0.05).
4 Relationship between RR and clinical features A single factorχ2 test showed that:RR was related to the smoking and levels of serum CEA, CA125, CA242. Multivariate logistic regression analysis showed that:the RR in the patients of non-smoke, high serum CEA, CA199 level had a better outcome than the patients of smoke, low serum CEA, CA199 level. The difference was statistically significant (P <0.05).
5 Relationship between DCR and clinical features A single factorχ2 test showed that:DCR was related to the smoking and levels of serum CEA, CA199, but multivariate logistic regression analysis showed that:the DCR in the patients of high serum CEA level had a better outcome than the patients of low serum CEA level. The difference was statistically significant (P<0.05).
6 Survival analysis EGFR-TKI treatment for patients with a median PFS was 8.6 (1～18) months, the median OS was 13.2 (2～26) months and 1 year survival rate was 61.4%. Kaplan-Meier survival curves showed that smoking history, serum CEA, CA199 levels had significant effect on the survival of patients.And log-rank test showed tha before treatment the PFS and OS in no-smok, high serum CA199, CEA level patients were longer (P<0.05).Cox multivariate survival analysis indicated that the serum levels of CA199 and CEA were independent factors EGFR-TKI pretreatment affecting survival.
The second part Correlation between mutation of EGFR and serum tumor markers in lung adenocarcinoma patients
Subject and Method
1 Subject From January 1,2009 to December 31,2010,70 patients confirmed by pathology from Department of Respiratory Medicine, oncology and thoracic surgery,in the Henan province people's hospital.
2 Detection of serum tumor markers Tumor marks were detected by protein chip-chemiluminescence way after 2ml venous blood distilled and separated out.
3 Detection of EGFR gene mutation DNA was extracted from paraffin-embedded samples, After EGFR gene amplified by PCR, the products were analyzed in agarose gel electrophoresis and sequenced.
4 Statistical Method Using SPSS 12.0 statistical software for data processing. Measurement data were described as mean±standard deviation, t test or t'est was used for statistics in independent samples after testing homogeneity of variance.Count data described as a rate,and clinical factors were analyzed by single factorχ2 test or Fisher exact test and multivariate Logistic regression. The methods ofχ2 test, Fisher exact test and multivariate Logistic regression were used to analysis the correlation between EGFR mutations and factors. Receiver operating characteristic curve (ROC) was draw to assess the value of tumor marker in predicting EGFR mutation. All significance levels were used two-sided test, and P<0.05 was considered statistically significant.
Results
1 Characteristics of EGFR mutations In 70 specimens,27 (38.6%,27/70)were detected to have EGFR gene mutations, in which exon 19 of EGFR gene mutations detected in 15 cases; exon 21 EGFR mutation detected in 12 cases.
2 Comparison of serum tumor markers between the EGFR mutation group and the wild The serum levels of CA199, CEA and CA242 in EGFR mutation group were higher than these in the wild with significant difference (P<0.05). The CA125 and CA153 were no significant differences between the two groups.
3 Relationship between clinical characteristics and EGFR gene mutation A single factorχ2 test showed that EGFR mutations was associated with gender, smoking history and serological CA199, CEA, CA242 level (P<0.05), not with age, PS score, serological CA125 or CA153 levels. Further multivariate logistic analysis shown that the patient with non-smoking, inⅢ+Ⅳperoid, high serological CEA and CA242 level had higher rate in the EGFR gene mutation (P<0.05).
4 Draw the ROC curve and calculate the area under the curve The areas of CEA and CA242 under the curve and 95% CI were 0.814 (0.707～0.922) and 0.769 (0.646～0.891) each, area under the curve was significantly. When the CEA cut-off point for the 5.00 ng/ml, the sensitivity Se=70.4%, specificity Sp=74.4%; and CA242 cutoff point of 20.00 U/ml, the sensitivity Se= 37%, specificity Sp= 95.3 %.
Conclusion
1 EGFR-TKI treatment of lung adenocarcinoma is more effective than platinum-based chemotherapy drugs, and patients who do not smoke benefit more;
2 The patient who had high level of CEA, CA199 before application of targeted therapy would have a higher disease control rate and remission rate, longer progression-free survival and overall survival, So serum levels of CA199 and CEA before treatmeng can be used to forecast EGFR-TKI treatment efficacy in patients with lung adenocarcinoma;
3 The patients who smoke had a lower mutations in EGFR in lung adenocarcinoma;
4 The EGFR gene mutation happened more in the patient who had a high serum levels of CEA, CA242, which might predict the rate of EGFR mutation.
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