| 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 patientsSubject and Method1 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.Results1 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 patientsSubject and Method1 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.Results1 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 %.Conclusion1 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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