Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.

Epidermal growth factor receptor mutation analysis in cytological specimens and responsiveness to gefitinib in advanced non-small cell lung cancer patients

Background： Epidermal growth factor receptor（EGFR） mutation is the key predictor of EGFR tyrosine kinase inhibitors（TKIs） efficacy in non-small cell lung cancer（NSCLC）. We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.Methods： A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system（ARMS）. We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate（ORR）, disease control rate（DCR） and progression free survival（PFS）.Results： Of all patients, EGFR mutation rate was 28.6%（60/210） by direct sequencing and 45.2%（95/210） by ARMS（P〈0.001） respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR（48.0% vs. 80.9%, P=0.004） and shorter median PFS（7.4 vs. 10.5 months, P=0.009） as compared with that of EGFR mutation positive patients by both detection methods. Conclusions： Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.

Associations Between Epidermal Growth Factor Receptor Gene Mutation and Serum Tumor Markers in Advanced Lung Adenocarcinomas: A Retrospective Study

Objective To investigate the associations between epidermal growth factor receptor （EGFR） gene mutations and serum tumor markers in advanced lung adenocarcinomas. Methods We investigated the association between EGFR gene mutations and clinical features, including serum tumor marker levels, in 97 advanced lung adenocarcinomas patients who did not undergo the treatment of EGlaR tyrosine kinase inhibitors. EGFR gene mutation was detected by real-time PCR at exons 18, 19, 20, and 21. Serum tumor marker concentrations were analyzed by chemiluminescence assay kit at the same time. Results EGFR gene mutations were detected in 42 （43%） advanced lung adenocarcinoma patients. Gender （P=0.003）, smoking status （P=0.001）, and abnormal serum status of carcinoembryonic antigen （CEA, P=0.028） were significantly associated with EGFR gene mutation incidence. Multivariate analysis showed the abnormal CEA level in serum was independently associated with the incidence of EGFR gene mutation （P=0.046） with an odds ratio of 2.613 （95% Ch 1.018-6.710）. However, receiver operating characteristic （ROC） curve analysis revealed CEA was not an ideal predictive marker for EGFR gene mutation status in advanced lung adenocarcinoma （the area under the ROC curve was 0.608, P=0.069）. Conclusions EGFR gene mutation status is significantly associated with serum CEA status in advanced lung adenocarcinmoas. However, serum CEA is not an ideal predictor for EGFR mutation.

Gender Does Not Have a Potential Predictive Value for the Presence of Epidermal Growth Factor Receptor Mutation in Lung Adenocarcinoma

Background: Previous studies reported that non-small cell carcinoma patients characterized by female gender, never-smoking status and adenocarcinoma histology were more likely to harbor epidermal growth factor receptor (EGFR) mutations. However, some studies failed to find the relationship between EGFR mutation and gender. Methods: One hundred and eighty-four consecutive patients (90 men and 94 women) of resected lung adenocarcinoma were studied retrospectively. Since the smoking rate is significantly higher in men, we assumed that gender difference might be a seeming factor affected by smoking. Therefore we subdivided the patients into 2 groups: never- and ever-smokers. Results: The number of ever-smokers was 94.44% in men, whereas 8.51% in women. EGFR mutation was positive in 48.9%. For overall patients, EGFR mutation status was associated with gender, pStage, pT status, lepidic dominant histologic subtype, pure/mixed groundglass opacity (GGO) on computed tomography (CT) and smoking status. However, in ever-smokers, EGFR mutation status was associated with lepidic histologic subtype and GGO on CT, but not others including gender. Similar results were also found in never-smokers, and gender was not also related to EGFR mutation in never smokers. Conclusion: The EGFR mutational frequency among men and women was not significantly different when lung adenocarcinoma patients were stratified into never- and ever-smokers.

Relationship between epidermal growth factor receptor gene mutation and copy number in Chinese patients with non-small cell lung cancer

Epidermal growth factor receptor(EGFR) gene mutation and copy number are useful predictive markers that guide the selection of non-small cell lung cancer(NSCLC) patients for EGFR-targeting therapy.This study aimed to investigate the correlation between EGFR gene mutation and copy number and clinicopathologic characteristics of Chinese patients with NSCLC.NSCLC specimens collected from 205 patients between November 2009 and January 2011 were selected to detect EGFR gene mutations with real-time polymerase chain reaction(RT-PCR) and to detect EGFR gene copy number with fluorescence in situ hybridization(FISH).EGFR mutations primarily occurred in females,non-smokers,and patients with adenocarinomas(all P < 0.001).Tissues from 128(62%) patients were FISH-positive for EGFR,including 37(18%) with gene amplification and 91(44%) with high polysomy.EGFR gene mutation was correlated with FISH-positive status(R = 0.340,P < 0.001).Multivariate analysis showed that not smoking(OR = 5.910,95% CI = 2.363-14.779,P < 0.001) and having adenocarcinoma(OR = 0.122,95% CI = 0.026-0.581,P = 0.008) were favorable factors for EGFR gene mutation.These results show a high frequency of EGFR FISH positivity in NSCLC tissues from Chinese patients and a significant relevance between EGFR gene mutations and FISH-positive status.Among the FISH-positive samples,EGFR gene mutation occurred more frequently in samples with gene amplification compared to those with high polysomy,suggesting that EGFR mutation and gene amplification should be used as clinical decision parameters to predict response to EGFR-targeting therapy.

Coexistence of anaplastic lymphoma kinase rearrangement in lung adenocarcinoma harbouring epidermal growth factor receptor mutation:A single-center study

BACKGROUND Accumulating evidences confirm that epidermal growth factor receptor(EGFR)mutation and anaplastic lymphoma kinase(ALK)rearrangement have coexisted in lung adenocarcinoma(LUAD).However,Its biological mechanism,clinicopathological features,and optimization of targeted drugs have not yet been completely elucidated.AIM To explore the clinical profile of LUAD patients with co-mutations of EGFR and ALK genes,with hopes of scientifically guiding similar patients towards selected,targeted drugs.METHODS Two hundred and thirty-seven LUAD patients were enrolled.EGFR mutations were detected by the amplification refractory mutation system-peptide nucleic acid technique,while the expression of ALK rearrangement was screened by the 5′/3′imbalance strategy for reverse transcription followed by quantitative polymerase chain reaction analysis.The clinicopathological features of these patients were analysed retrospectively,and the follow-up data were collected.RESULTS There were six cases with co-mutations of EGFR and ALK genes,which were more common in women,non-smoking and stage IV LUAD patients with bone metastasis,hence a positive rate of 2.53%(6/237).EGFR-tyrosine kinase inhibitors(EGFR-TKIs)were their preferred drugs for targeted therapy in these patients,with progression-free survival ranging from two months to six months.CONCLUSION In Gannan region,the positive rate of co-mutations of EGFR and ALK genes in LUAD patients is relatively high,and the co-mutations are more common in women,non-smoking and stage IV patients with bone metastasis.These patients prefer EGFR-TKIs as their preferred targeted drugs,but the therapeutic effect is not good.EGFR/ALK dual-TKIs may be more effective targeted drugs,which needs further study.

Plasma fibrinogen levels are associated with epidermal growth factor receptor gene mutation in Chinese patients with non-small cell lung cancer

Objective： The plasma fibrinogen levels had not only been used as an independent prognostic parameter for the patients with non-small cell lung cancer （NSCLC）, but also as a promising biomarker for evaluating the efficacy of chemotherapy. This study aimed to investigate the correlation between the plasma fibrinogen levels and epidermal growth factor receptor （EGFR） gene mutation and clinical-pathological characteristics of Chinese patients with NSCLC. Methods： In this retrospective study, NSCLC specimens collected from 352 patients between November 2009 and November 2011 were selected to detect EGFR gene mutation with real-time polymerase chain reaction （RT-PCR）. In these specimens, 308 ones were also detected EGFR gene copy number with fluorescence in situ hybridization （FISH）. Coagulation makers were examined prior to the operations. The association between the plasma fibrinogen levels and EGFR gene mutation and clinical-pathological characteristics were analyzed using SPSS 16.0 software. Results： The median pre-operation plasma fibrinogen level was 3.55 g/L （109/352） patients with higher plasma fibrinogen level （〉 4.0 g/L）. The lower plasma fibrinogen levels correlated significantly with EGFR gene mutations （P 〈 0.001）, the similar result was seen in platelet counts （P = 0.026）. A linear correlation was found between the plasma fibrinogen levels and the platelet counts in NSCLC patients （R^2 = 0.209, P 〈 0.001）. Pre-peration plasma fibrinogen levels correlated with gender （P 〈 0.001）, smoking status （P 〈 0.001 ）, and histology （P 〈 0.001 ）. There were significant link between the above clinical-pathological characteristics and EGFR gene mutations. In addition, EGFR gene mutation was correlated with FISH-positive status （P 〈 0.001）. Moreover, both plasma fibrinogen level （P = 0.024） and the EGFR gene copy number （P = 0.040） had significant relationships with the pathological TNM stage. Conclusion： This study showed that a significant relevance between plasma fibrinogen levels and EGFR gene mutations. The plasma fibrinogen level might be as a clinical decision parameter for evaluating the efficacy of anti-EGFR tyrosine kinase inhibitors （TKIs） in NSCLC. The patients of NSCLC had higher indicate have poor benefits from anti-EFGR TKIs. In addition, pre-operation plasma fibrinogen level could be used as an indepedent prognostic biomarker for the patients with NSCLC.

Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer

BACKGROUND Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor(EGFR)-mutated non-small cell lung cancer(NSCLC).AIM To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.METHODS This multicenter,open-label,pilot randomized controlled trial enrolled 68 EGFRmutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy+icotinib groups.RESULTS The median progression-free survival in the icotinib alone and chemotherapy+icotinib groups was 8.0 mo(95%CI:3.84-11.63)and 13.4 mo(95%CI:10.18-16.33),respectively(P=0.0249).No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen(all P>0.05).CONCLUSION A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.

Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer

The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase III clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them.

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

First-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer(NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858 R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Secondgeneration EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.

Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer

Administration of monoclonal antibodies(mAbs)against epidermal growth factor receptor(EGFR)such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer(mCRC).However,the efficacy of these mAbs is limited due to genetic variation among patients,in particular K-ras mutations.The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC.Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF,MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors.Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation,our understanding of their mode of action is limited.Rational drug development based on stringent preclinical data,biomarker validation,and proper selection of patients is of paramount importance in the treatment of mCRC.In this review,we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFRRas-ERK and PI3K signalings.

Epidermal growth factor receptor and metastatic colorectal cancer:Insights into target therapies

Colorectal cancer(CRC)has high incidence and mortality worldwide.In 2012,CRC was the second most prevalent cancer among males(9%)and the third among females(8%).In recent decades,standard chemotherapies protocols combining 5-fluorouracil,leucovorin,irinotecan and oxaliplatin were important for improve survival in this set of patients.Further,biological drugs throughout epidermal growth factor receptor(EGFR)pathways showed interesting results in metastatic disease(mCRC)control when in association to standard chemotherapy regimens.Cetuximab and panitumumab are two cornerstones for mCRC treatment and are both approved in Europe and United States based on previous results phaseⅢtrials.This paper will briefly summarize those anti-EGFR therapies framework in mCRC and discusses some issues in this regard.

Clinical efficacy and drug resistance of anti-epidermal growth factor receptor therapy in colorectal cancer

Colorectal cancer(CRC) ranked third in cancer related death and its incidence has been increasing worldwide. In recent decades important therapeutic advances have been developed in treatment of metastatic CRC(mCRC), such as monoclonal antibodies against epidermal growth factor receptor(anti-EGFR), which provided additional clinical benefits in mCRC. However, anti-EGFR therapies have limited usage due to approximately 95% of patients with KRAS mutated mCRC do not response to anti-EGFR treatment. Thus, KRAS mutation is predictive of nonresponse to anti-EGFR therapies but it alone is not a sufficient basis to decide who should not be received such therapies because; approximately fifty percent(40%-60%) of CRC patients with wild-type KRAS mutation also have poor response to anti-EGFR based treatment. This fact leads us to suspect that there must be other molecular determinants of response to anti-EGFR therapies which have not been identified yet. Current article summarizes the clinical efficacy of anti-EGFR therapies and also evaluates its resistance mechanisms.

Dramatic response to immunotherapy in an epidermal growth factor receptor-mutant non-small cell lung cancer: A case report

BACKGROUND The advent of immune checkpoint inhibitors(ICIs)has revolutionized the management of several types of solid cancers,including lung cancer,by boosting the body's natural tumor killing response.However,it is undeniable that only a small proportion of non-small cell lung cancer(NSCLC)patients with epidermal growth factor receptor(EGFR)mutations can achieve long-term responses and benefit from immunotherapy.CASE SUMMARY Herein,we report the case of a 48-year-old man diagnosed with stage IV lung adenocarcinoma with an EGFR L858R mutation who was administered pembrolizumab monotherapy followed by pemetrexed and achieved a 10-month progression-free survival interval.In this case report,we show that ICIs were effective for our patient with EGFR-mutated NSCLC and discuss the characteristics of patients who can benefit from immunotherapy.CONCLUSION We suggest that patients with EGFR-mutated NSCLC with high PD-L1 expression(defined as≥25%),the L858R mutation,smoking history,or pemetrexed pretreatment may benefit from immunotherapy.

Epidermal growth factor receptor compound and concomitant mutations:advances in precision treatment strategies

Epidermal growth factor receptor(EGFR)mutations are common oncogenic driver mutations in patients with non-small cell lung cancer(NSCLC).The application of EGFR-tyrosine kinase inhibitors(TKIs)is beneficial for patients with advanced and early-stage NSCLC.With the development of next-generation sequencing technology,numerous patients have been found to have more than one genetic mutation in addition to a single EGFR mutation;however,the efficacy of conventional EGFR-TKIs and the optimal treatments for such patients remain largely unknown.Thus,we review the incidence,prognosis,and current treatment regimens of EGFR compound mutations and EGFR concomitant mutations to provide treatment recommendations and guidance for patients with these mutations.

Identification of EGFR kinase domain mutations among lung cancer patients in China:implication for targeted cancer therapy

Lung cancer is one of the leading causes of death with one of the lowest survival rates. However, a subset of lung cancer patients who are of Asian origin and carry somatic mutations in epidermal growth factor receptor or EGFR have responded remarkable well to two tyrosine kinase inhibitors, gefitinib and erlotinib. While EGFR mutation profiles have been reported from Japan, South Korea, and Taiwan, there is no such report from mainland of China where the largest pool of patients reside. In this report, we identified ten somatic mutations from a total of 41 lung cancer patients in China. Among them, seven mutations were found in 17 adenocarcinomas. In contrast to previous reports, eight of these mutations are deletions in exon 19 and two of these deletions are homozygous. These results suggest that a large portion of Chinese adenocarcinoma patients could benefit from gefitinib or erlotinib. This unique mutation profile provides a rationale to develop the next generation of EGFR inhibitors more suitable for the Chinese population.

Comparison of three methods for detecting epidermal growth factor receptor mutations in plasma DNA samples of Chinese patients with advanced non-small cell lung cancer

Background Epidermal growth factor receptor （EGFR） mutations can predict tumor response to tyrosine kinase inhibitors （TKIs）. Detecting EGFR mutations in plasma DNA samples in patients with advanced non-small cell lung cancer is challenging and promising. We compared three methods for detecting plasma EGFR mutations, including direct DNA sequencing, denaturing high-performance liquid chromatography （DHPLC） and Scorpions Amplification Refractory Mutation System （Scorpions ARMS）.Methods Plasma DNA samples from 73 patients with stage ⅢB to Ⅳ adenocarcinoma were analyzed for EGFR mutations in exons 19 （deletion mutation） and 21（L858R mutation） using direct DNA sequencing, DHPLC and Scorpions ARMS. Sensitivities of the three methods were compared and the relationship between EGFR mutations and patients＇survival was analyzed.Results In 73 patients, we detected EGFR mutations in 5 samples （6.9%） by direct DNA sequencing, in 22 samples （30.1%） by DHPLC, and in 28 samples （38.4%） by Scorpions ARMS. EGFR mutations were found in 13 samples in exon 19 and in 9 samples in exon 21 by DHPLC, while we found mutations in 15 samples in exon 19 and in 13 samples in exon 21 by Scorpions ARMS. Among the 73 patients, there was 90.4% concordance between DHPLC and Scorpions ARMS （66/73, K=0.79, P=0.07）. Of the 73 patients, 46 patients were treated with gefitinib, including 18 patients with mutations and 28 patients without mutations as determined by Scorpions ARMS. The 18 patients with mutations had a significantly longer progression-free survival （PFS） time （median PFS was 21.0 months） than the 28 patients without mutations （median PFS was 7.0 months） （P=0.022）.Conclusions Among the three methods for detecting EGFR mutations in plasma DNA samples of patients with advanced lung adenocarcinoma, direct gene sequencing had the lowest sensitivity, while Scorpion ARMS showed the highest mutation detecting capability. DHPLC is slightly less sensitive than Scorpion ARMS. EGFR mutations in exons 19（deletion mutation） and 21 （L858R mutation） predict a longer PFS.

Impact of smoking status and pathologic type on epidermal growth factor receptor mutations in lung cancer

Background Epidermal growth factor receptor （EGFR） responsive to the treatment with tyrosine kinase inhibitors. large series of lung carcinomas. mutations in lung carcinomas can make the disease more We aimed to evaluate the prevalence of EGFR mutations in a Methods We examined 1195 consecutive lung cancer patients for EGFR mutations in exons 18, 19, and 21 using direct sequencing of polymerase chain reaction products. A detailed smoking history was obtained. Patients were categorized as never smokers （〈100 lifetime cigarettes）, former smokers （quit 〉1 year ago）, or current smokers （quit 〈1 year ago）. Results There were EGFR mutations in 9 （4.5%） of 201 squamous carcinomas, in 1 （2%） of 50 large cell carcinomas, and in 1 （2.3%） of 44 small cell carcinomas that were investigated. Three hundred and twenty-seven mutations were found in the series of 858 adenocarcinomas （38.1%）. Among 858 lung adenocarcinomas, we detected EGFR mutations in 250 （48.6%） of 514 never smokers, 39 （33.9%） of 115 former smokers, and 38 （16.6%） of 229 current smokers. Significantly fewer EGFR mutations were found in people who smoked for more than 15 pack-years （P=-0.0002） or stopped smoking less than 15 years ago （P=0.033） compared with individuals who never smoked. Conclusions Adenocarcinoma is the most frequent EGFR mutation pathologic type in lung cancer. The likelihood of EGFR mutations in exons 18, 19 and 21 decreases as the number of pack-years increases. Mutations were less common in people who smoked for more than 15 pack-years or who stopped smoking cigarettes less than 15 years ago. These data can assist clinicians in assessing the likelihood of exons 18, 19, or 21 EGFR mutations in Chinese patients with lung cancer when mutational analysis is not feasible.

Low Correspondence of EGFR Mutations in Tumor Tissue And Paired Serum of Non-Small-Cell Lung Cancer Patients

Objective： Epidermal growth factor receptor （EGFR） mutations are strong determinants of tumor response to EGFR tyrosine kinase inhibitors in non-small-cell lung cancer （NSCLC） patients. The aim of this study was to evaluate the correspondence between EGFR mutations in non-small-cell lung cancer tissues and in circulating DNA. Methods： The research was conducted in 50 non-small-cell lung cancer patients who had undergone curative surgery, and in whom both serum and neoplastic tissues were available. Meanwhile sera of 33 cases of advanced NSCLC patients were also analyzed. DNA were extracted from each sample. Mutations of EGFR in exonl8-21 were examined by PCR amplification method and direct sequencing. Results： EGFR mutations were detected in 15 （30%） of 50 neoplastic tissue samples, 6 cases were in-frame deletion del E746-A750 in exonl9, 9 cases were substitution in exon 21 （all were L858R except one was L861Q）, but no mutated DNA resulted in paired serum circulating DNA samples of 50 resectable patients. As the 33 advanced NSCLC patients, EGFR mutations were detected in only 2 serum circulating DNA samples, all were L858R mutation in exon 21. Conclusion： These data indicated that it was difficult to identify EGFR mutations in circulating DNA of NSCLC patients. The use of EGFR mutation in serum as a clinical method for decision making of TKI therapy is unsatisfactory.

Management of tyrosine kinase inhibitor resistance in lung cancer with EGFR mutation

The identification of driver mutations and drugs that inhibit their activity has been a major therapeutic advance for patients with advanced lung adenocarcinoma. Unfortunately, the success of these drugs is limited by the universal development of resistance. Treatment failure can result from inadequate drug exposure or selection of resistant malignant clones. Clinically distinct mechanisms of disease progression have been identified and can inform treatment decisions. Investigations into the biochemical mechanisms of tyrosine kinase inhibitor resistance may provide additional therapeutic targets by which the efficacy of targeted therapy can be improved.