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Patients with operable non-small cell lung cancer (NSCLC) receiving neoadjuvant or adjuvant chemotherapy have a very limited improvement in 5-year survival rate. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have made a breakthrough in the treatment of EGFR-mutant advanced NSCLC, which shed light for the exploration of perioperative targeted therapy in NSCLC patients. Significant progress has been made in the research of targeted therapy of the first and third generation EGFR-TKI in perioperative patients. The availability of novel potent and less toxic targeted therapy has brought new treatments for the operable NSCLC. This article reviews the progress and existing problems of adjuvant and neoadjuvant targeted therapy in NSCLC harboring EGFR mutation.
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Objective:To investigate the correlations of β-catenin expression with the efficacy of tyrosine kinase inhibitor (TKI) and prognosis of patients with advanced lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations.Methods:The clinical data of 125 patients with stage Ⅲ B-Ⅳ lung adenocarcinoma who were treated with first-line EGFR-TKI treatment in the 901st Hospital of Joint Logistic Support Force of Chinese PLA from January 2016 to December 2019 were collected. The expression of β-catenin protein was detected by immunohistochemistry, and subtypes of EGFR mutations were detected by amplification refractory mutation system (ARMS). Correlations of β-catenin expression with clinicopathological features, efficacy of EGFR-TKI and prognosis were analyzed. Twenty-eight pairs of specimens were selected before EGFR-TKI treatment and after resistance to EGFR-TKI to observe the changes of β-catenin expression. Results:Among 125 advanced lung adenocarcinoma patients with EGFR mutations, there were 60 cases of EGFR 19 del, 55 cases of L858R mutation and 10 cases of rare sensitive mutation; 79 cases (63.2%) had reduced membranous expression of β-catenin, 66 cases (52.8%) had ectopic expression in cytoplasm and 28 cases (22.4%) had ectopic expression in nucleus. The positive rates of Napsin A protein in the groups with different abnormal expression patterns of β-catenin were lower than those in the corresponding normal expression groups (all P < 0.001). Patients with International Association for the Study of Lung Cancer (IASLC) grade Ⅲ showed more frequent translocation in cytoplasma and nucleus of β-catenin than patients with IASLC gradeⅠ-Ⅱ (ectopic expression in cytoplasm: χ2 = 3.99, P = 0.046,ectopic expression in nucleus: χ2 = 11.07, P = 0.001). The objective remission rate (ORR) in patients with reduced membranous expression of β-catenin and ectopic expression in nucleus was lower than that in patients with normal membranous expression ( χ2 = 4.66, P = 0.031) and negative ectopic expression in nucleus ( χ2 = 10.22, P = 0.001), and the disease control rate (DCR) in patients with ectopic expression in nucleus was lower than that in the corresponding normal expression group ( χ2 = 10.95, P = 0.001). Patients with ectopic expression of β-catenin in nucleus and cytoplasma had worse progression-free survival (PFS) and overall survival (OS) than the corresponding cytoplasmic and nuclear ectopic expression negative groups (both P < 0.05). Multivariate Cox regression analysis showed that nuclear β-catenin ectopic expression was an independent risk factor for both PFS and OS (PFS: HR = 2.088, 95% CI 1.331-3.274, P = 0.001; OS: HR = 3.656, 95% CI 1.795-7.444, P<0.001). β-catenin membranous expression was reduced in 11 of 28 tissue samples that underwent secondary biopsy compared with pre-treatment ( P = 0.049). Conclusions:β-catenin expression in advanced lung adenocarcinoma with EGFR-sensitive mutations can be used as a molecular marker to predict the efficacy of EGFR-TKI and prognosis of patients.
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Objective:To investigate the diagnostic values of human epididymis protein 4 (HE4), endothelial cell specific molecule-1 (ESM-1) and epidermal growth factor receptor (EGFR) for lung cancer.Methods:The clinical data of 90 patients with lung cancer and 50 patients with benign lung diseases diagnosed by the pathological examination in Tangshan People's Hospital from December 2019 to January 2021 were retrospectively analyzed, and 40 healthy physical examiners in the same period were selected as the controls. The serum HE4 levels were detected by electrochemiluminescence method. The serum ESM-1 and EGFR levels were tested by enzyme-linked immunosorbent assay. The differences in serum HE4, ESM-1 and EGFR levels between the three groups were compared; logistic regression analysis was used to screen out the effective indicators for the diagnosis of lung cancer and to construct a prediction model for the diagnosis of lung cancer. Using pathological diagnosis result as the gold standard, the receiver operating characteristic (ROC) curve was drawn, and the diagnostic efficacy of indicators for lung cancer was evaluated.Results:The levels of serum HE4 in lung cancer group, benign lung diseases group and healthy control group were 119.55 pmol/L (82.06 pmol/L, 189.00 pmol/L), 58.84 pmol/L (45.62 pmol/L, 69.41 pmol/L) and 42.67 pmol/L (37.09 pmol/L, 51.84 pmol/L), the levels of ESM-1 were 33.00 ng/ml (25.85 ng/ml, 47.40 ng/ml), 20.14 ng/ml (11.93 ng/ml, 28.90 ng/ml) and 15.39 ng/ml (11.84 ng/ml, 20.19 ng/ml), and the levels of EGFR were 46.60 pg/ml (37.45 pg/ml, 58.98 pg/ml), 32.77 pg/ml (26.27 pg/ml, 40.86 pg/ml) and 30.43 pg/ml (27.54 pg/ml, 35.75 pg/ml), and the differences in each indicator among the three groups were statistically significant (all P < 0.001). The levels of serum HE4, ESM-1 and EGFR in lung cancer group were higher than those in benign lung diseases group and healthy control group. In patients with lung cancer, logistic regression analysis was performed with HE4 (X 1), ESM-1 (X 2) and EGFR (X 3) as the independent variables and pathological diagnosis as the dependent variable, and a lung cancer prediction regression model was established: P = 0.171X 1+0.351X 2+0.184X 3-24.660. The accuracy of this model in predicting lung cancer could reach 98.5%, and serum HE4, ESM-1 and EGFR were risk factors for the occurrence of lung cancer (all P < 0.05). The area under ROC curve from high to low was HE4 (0.960), ESM-1 (0.942) and EGFR (0.859). The diagnostic sensitivity of serum HE4 63.67 pmol/L for lung cancer was 86.7%, and the specificity was 97.5%. Both serum HE4 ( r = 0.304, P = 0.004) and ESM-1 ( r = 0.416, P < 0.001) were correlated with EGFR. Conclusions:Serum HE4, ESM-1 and EGFR can be used as effective indicators for the diagnosis of lung cancer, and the prediction model established based on the three serum tumor markers is of good value for the diagnosis and prediction of lung cancer.
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Objective:To explore the clinical efficacy of CT-guided 125I seed implantation in patients with oligometastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations (EGFRm+ ) without progression after first-line EGFR-tyrosine kinase inhibitors (TKIs) treatment. Methods:From January 2015 to January 2019, 89 eligible patients (38 males, 51 females; age: (62±11) years) in the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. They were divided into 2 groups according to different treatment methods. The 125I seeds were implanted for oligometastatic lesions and/or primary tumors without progression after first-line EGFR-TKIs therapy in local consolidation treatment group (Group A, n=32). The maintenance treatment group (Group B, n=57) only received EGFR-TKIs until disease progression. The progression-free survival (PFS) and overall survival (OS) of the 2 groups were estimated by Kaplan-Meier curves, and were compared by using log-rank test. Complications in Group A were observed. Results:The follow-up time of the group A and group B were 36.5(31.0, 43.3) months and 30.0(24.0, 35.0) months respectively. The median PFS and OS in group A were 15.0(95% CI: 12.8-17.2 ) months and 37.0(95% CI: 33.9-40.1) months, both of which were significantly longer than those in group B (12.0(95% CI: 10.9-13.1) months and 31.0(95% CI: 28.9-33.1) months; χ2 values: 8.80, 7.15, P values: 0.003, 0.007). In Group A, the total incidence of complications in CT-guided 125I seed implantation was 21.9%(7/32), and the common complications and adverse events were pneumothorax and hemoptysis. Only 1 patient underwent chest tube insertion, and the rest were treated with conservative treatment. No operation related death occurred. Conclusion:CT-guided 125I seed implantation is safe and feasible for patients with EGFRm+ oligometastatic NSCLC without progression after first-line EGFR-TKIs treatment, and can prolong the PFS and OS of patients.
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Objective:To evaluate the value of radiomic fusion features combined with extreme gradient boosting (XGBoost) machine learning models based on 18F-FDG PET/CT images in the prediction of human epidermal growth factor receptor 2 (HER2) expression status in breast cancer. Methods:18F-FDG PET/CT images of 210 patients with primary breast cancer (all females; age 52(46, 60) years; 95 HER2-positive and 115 HER2-negative) in Tianjin Medical University Cancer Institute and Hospital between January 2012 and December 2019 were retrospectively analyzed. About 70% of the HER2-positive and HER2-negative groups were randomly selected using Python 3.7.1 software as a training set ( n=147; 67 HER2-positive and 80 HER2-negative, age: 52(46, 60) years vs 55(45, 62) years) and 30% as a test set ( n=63; 28 HER2-positive and 35 HER2-negative, age: 54(43, 65) years vs 52(45, 61) years). After tumor segmentation on CT and PET images being finished, CT and PET radiomic features were extracted respectively. PET/CT fusion features (including PET/CT splicing features and PET/CT mean features) were obtained through post-processing. The support vector machine (SVM) model and XGBoost model were established. The selected features were input to predict the expression status of HER2 in primary breast cancer lesions, and the prediction efficiency of the model was evaluated by ROC curve. The Delong test was used to compare the predictive effectiveness of different models and radiomic features, and the calibration curve of the machine learning model with the highest prediction efficiency was plotted. Results:Compared with SVM model, XGBoost model had better prediction performance ( z values: 2.26-3.54, P values: 0.016-0.040) when four kinds of radiomic features (CT features, PET features, PET/CT splicing features and PET/CT mean features) were input. ROC curve analysis showed that PET/CT mean features with XGBoost machine learning model had the best performance in predicting the expression status of HER2, and the maximum AUC was 0.83 (95% CI: 0.73-0.93), which was superior to CT features (0.75(95% CI: 0.63-0.88); z=3.57, P=0.027), PET features (0.73(95% CI: 0.60-0.86); z=2.64, P=0.034) and PET/CT splicing features (0.74(95% CI: 0.60-0.87); z=2.49, P=0.037). Conclusion:XGBoost machine learning model based on PET/CT radiomics fusion features is expected to predict HER2 expression status in patients with breast cancer.
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Objective:To investigate the effect of a short hairpin RNA (shRNA) targeting epidermal growth factor receptor (EGFR) combined with sirolimus on proliferation and apoptosis of the human cutaneous squamous cell carcinoma cell line Colo-16, and to explore underlying mechanisms.Methods:Cultured Colo-16 cells were divided into 5 groups: normal cell group receiving conventional culture and treatment with phosphate-buffered saline (PBS) , negative control group transfected with a shRNA-NC-expressing plasmid and treated with PBS, sirolimus group receiving conventional culture and sirolimus treatment, EGFR shRNA group transfected with an EGFR shRNA-expressing plasmid and treated with PBS, and combined group transfected with an EGFR shRNA-expressing plasmid and treated with sirolimus. Methyl thiazol tetrazolium (MTT) assay was performed to evaluate cellular proliferative activity in the above groups from 24 to 96 hours, and flow cytometry to detect cell apoptosis after 48-hour treatment. Semiquantitative RT-PCR was conducted to determine the mRNA expression of Bcl-2 and Bax, and Western blot analysis to determine the expression of apoptosis-related proteins cleaved caspase-3, cleaved caspase-9, Bcl-2, Bax, cell proliferation-related proteins phosphorylated mammalian target of rapamycin (p-mTOR) , phosphorylated protein kinase B (p-AKT) , phosphorylated 70-kDa ribosomal protein S6 kinase (p-P70S6k) , and cyclin D1. Comparisons among groups were carried out by using one-way analysis of variance, and multiple comparisons between 2 groups by using Student-Newman-Keuls q test. Results:MTT assay showed that the proliferative activity of Colo-16 cells was significantly lower in the sirolimus group, EGFR shRNA group and combined group during 24 - 96 hours than in the normal cell group (all P < 0.05) , and higher in the combined group than in the sirolimus group and EGFR shRNA group at 24-96 hours (all P < 0.001) , and there was no significant difference in the cellular proliferative activity at any time points between the normal cell group and negative control group (all P > 0.05) . Flow cytometry showed that the apoptosis rate was significantly higher in the sirolimus group, EGFR shRNA group and combined group (9.52% ± 0.25%, 12.65% ± 0.23%, 19.81% ± 0.31%, respectively) than in the normal cell group (3.33% ± 0.18%, q = 60.07, 78.08, 122.81, respectively, all P < 0.001) and negative control group (3.42% ± 0.19%, q = 59.90, 77.91, 122.64, respectively, all P < 0.001) , and was highest in the combined group. As RT-PCR and Western blot analysis revealed, the sirolimus group, EGFR shRNA group and combined group showed significantly decreased mRNA expression of Bcl-2 and protein expression of cyclin D1, p-AKT, p-mTOR, p-P70S6K and Bcl-2, but significantly increased mRNA expression of Bax and protein expression of cleaved caspase-3, cleaved caspase-9 and Bax compared with the normal cell group (all P < 0.05) . Compared with the sirolimus group and EGFR shRNA group, the combined group showed significantly decreased mRNA expression of Bcl-2 and protein expression of cyclin D1, p-AKT, p-mTOR, p-P70S6K and Bcl-2 (all P < 0.05) , but significantly increased mRNA expression of Bax and protein expression of cleaved caspase-3, cleaved caspase-9 and Bax (all P < 0.01) . Conclusion:EGFR shRNA and sirolimus exerted a synergistic effect in inhibiting the proliferation and promoting the apoptosis of Colo-16 cells, which may be related to the inhibition of the phosphoinositide 3-kinase (PI3K) /AKT/mTOR pathway.
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Objective:To evaluate the effect of propofol on proliferation of neural stem cells (NSCs) in mice and the role of specificity protein-1 (Sp-1)-epidermal growth factor receptor (EGFR)-protein kinase B (Akt) signaling pathway.Methods:Primary NSCs harvested from both the cortices and hippocampus of C57BL/6 mouse embryos were identified by immunofluorescent staining of Nestin.NSCs at passages 3-6 were divided into 3 groups ( n=21 each) using a random number table method: normal saline control group (C group), propofol group (P group) and propofol plus Sp1 inhibitor plicamycin group (PP group). Propofol at a final concentration of 10 μmol/L was added in group P. Propofol at a final concentration of 10 μmol/L and plicamycin at a final concentration of 100 nmol/L were added in group PP.The equal volume of normal saline was added in group C. The medium was replaced after 6 h of incubation and the cells were continuously incubated.The proliferation of NSCs was assessed by direct cell counting at 24, 36, 48, 60 and 72 h after the end of treatment with drugs.At 6 h after the end of treatment with drugs, the expression of Sp1 and EGFR mRNA was detected by real-time fluorescent quantitative polymerase chain reaction, and the expression of Sp1, Akt and phosphorylated Akt (p-Akt) by Western blot. Results:Compared with group C, the count of NSCs was significantly increased at 48, 60 and 72 h after treatment with drugs, and the expression of EGFR mRNA, Sp1 protein and mRNA and p-Akt was up-regulated in group P ( P<0.05 or 0.01), and no significant change was found in each parameter in group PP ( P>0.05). Compared with group P, the count of NSCs was significantly decreased at 48 and 60 h after treatment with drugs, and the expression of EGFR protein and mRNA and p-Akt was down-regulated in group PP ( P<0.05 or 0.01). Conclusions:Propofol can promote the proliferation of NSCs, and the mechanism may be related to activation of Sp1-EGFR-Akt signaling pathway in mice.
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Objective:To explore the feasibility of pretargeting technique for immunoPET with epidermal growth factor receptor (EGFR) monoclonal antibody in EGFR positive/negative tumor bearing mice.Methods:Cetuximab- Trans-cyclooctene (TCO)was obtained by modifying Cetuximab with TCO- N-hydroxysuccinimide (NHS). 2, 2′-((6-amino-1-(4, 7-bis-(carboxymethyl)-1, 4, 7-triazonan-1-yl)hexan-2-yl)azanediyl)-diacetic acid (L-NETA)was used as a chelating agent to prepare the radioligand 68Ga-L-NETA-tetrazine (Tz), then the labeling rate and in vitro stability of the product were determined. Human basal breast cancer cells MDA-MB-468 (EGFR+ ) and MDA-MB-231 (EGFR-) were cultured in vitro. In vitro experiments were performed to explore the specificity of the probe and the feasibility of pretargeting technique. Nude mice (Balb/c-nu) bearing xenografts of the above two cell lines were established. Cetuximab-TCO (50 μg) was injected into the tumor-bearing mice in advance, then 68Ga-L-NETA-Tz was injected at different time points (48, 36, 24 and 12 h), and pretargeting was realized through " click chemistry" . Small-animal PET imaging and biodistribution were performed to evaluate pharmacokinetic properties and specificity of the probe. The one-way analysis of variance was used to compare the data. Results:The 68Ga-L-NETA-Tz molecular probe was successfully prepared with the labeling yield >95%, and the radiochemical purity was >95% after 2 h. Cetuximab-TCO and 68Ga-L-NETA-Tz were added to MDA-MB-468 cells successively, and the cell uptake rate reached (0.69±0.04)% at 1 h, which demonstrated the feasibility of the pretargeting technique. PET imaging and biodistribution results showed that the best imaging results were obtained in 36 h pre-injection group, in which the tumor uptake was the highest ((0.77±0.05) percentage activity of injection dose per gram of tissue (%ID/g), 1 h) and the tumor/muscle ratio was optimal (4.67±0.46); the tumor uptake in the blocking group, the group without injecting Cetuximab-TCO, and the MDA-MB-231 group were significantly lower ((0.35±0.01), (0.39±0.05), (0.45±0.10) %ID/g; F=15.50, P=0.002). Conclusions:EGFR targeted immunoPET imaging is successfully performed in mouse models of breast cancer by injecting Cetuximab-TCO and 68Ga-L-NETA-Tz successively. It provides an effective method for immunoPET imaging of monoclonal antibodies.
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Objective:To study the effect and mechanism of Rab4A knockout expression on proliferation, migration and invasion of gastric cancer cells. Methods:The expression of Rab4A in four human gastric cancer cell lines MGC-803, SGC-790, MKN45 and AGS was detected by Western blot. Rab4A was knocked out in AGS cells with the highest expression level, and untransfected gastric cancer cells were used as control group. Cell proliferation, migration and invasion were detected by CCK8 and Transwell assay, respectively. Western blot analysis was used to investigate the expression changes of epidermal growth factor receptor (EGFR), downstream pathway proteins AKT and β-catenin induced by Rab4A knockout. The interaction between Rab4A and MiR- 496 was detected by dual luciferase reporter gene, and the effect of MiR- 496 transfection on Rab4A expression was detected by qPCR and Western blot. GraphPad Prism 9 software was used for data analysis, t-test was used for comparison between the two groups, and normal distribution measurement data were expressed as mean ± standard deviation ( ± s). Results:The expression of Rab4A was the highest in AGS cells, and the knockdown of Rab4A inhibited the proliferation, migration and invasion of AGS cells ( P<0.05). In Rab4A knockout gastric cancer cells, the surface expression of epidermal growth factor receptor (EGFR) was significantly decreased, and the expression of downstream pathway proteins p-AKT and β-catenin was also inhibited ( P<0.05). The luciferase reporter showed that MiR- 496 could bind the 3′UTR of Rab4A. In addition, MiR- 496 down-regulated the expression of Rab4A in AGS cells( P<0.05). Conclusion:The expression of Rab4A is inhibited by MiR- 496, and the proliferation, migration and invasion of gastric cancer cells can be inhibited by down-regulating the surface expression of EGFR after inhibiting Rab4A expression.
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Cell epidermal growth factor receptor (EGFR) mutation is one of the causes of non-small cell lung cancer (NSCLC). The emergence of targeted drugs for EGFR gene mutation provides a new direction for NSCLC treatment. The common EGFR-targeted drugs like the first-generation gefitinib and erlotinib, the second-generation afatinib and the third-generation osimertinib have shown their good efficacies in a number of large international clinical trials. EGFR gene mutation in Chinese NSCLC patients is different from that in European and American NSCLC patients. This paper briefly reviews the characteristics of EGFR gene mutation and the current status and progress of EGFR-targeted drugs in Chinese NSCLC patients to investigate the mutation characteristics of EGFR in Chinese NSCLC patients and the response as well as prognosis of Chinese patients to EGFR-TKI therapy.
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Epidermal growth factor receptor (EGFR) plays an important role in the development and occurrence of a variety of malignant tumors. Molecular targeted therapy for EGFR is in the ascendant. Molecular imaging can reveal the expression of EGFR and its mutations in vivo. The molecular probes labeled with 89Zr, 11C and 18F are used for imaging and the main research is about tyrosine kinase inhibitors labeled with 11C. PET is used to visualize EGFR expression and mutations in vivo, which can noninvasively screen patients suitable for targeting treatment and evaluate efficacy. This paper reviews the clinical researches and trials of these probes, and summarizes the clinical value of imaging methods, hoping to provide the evidence for clinical translation and application in the future.
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As an important tumor driver gene, epidermal growth factor receptor (EGFR) gene plays an important role in the development and progression of non-small cell lung cancer (NSCLC). As the latest generation of EGFR-tyrosine kinase inhibitor (TKI) drugs, osimertinib has brought significant therapeutic efficacies and encouraging results both in patients with sensitive EGFR mutations and patients with rare EGFR mutations. Compared with previous EGFR-TKI drugs, osimertinib has strong blood-brain barrier penetration, which can effectively prevent the occurrence of lung cancer brain metastasis. After the resistance of first and second generation of targeted drugs, osimertinib is still effective in the follow-up treatment process. This article reviews the characteristics of EGFR mutation, the action mechanism of osimertinib, and the latest progress of osimertinib in treatment of EGFR mutations in NSCLC.
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Objective:To investigate the epidermal growth factor receptor (EGFR) gene mutation status in patients with non-small cell lung cancer (NSCLC) in Shiyan, Hubei and its relationship with the clinicopathological characteristics of patients.Methods:The data of 173 NSCLC patients who were admitted to Affiliated Dongfeng Hospital of Hubei University of Medicine from November 2017 to January 2020 were retrospectively analyzed. EGFR gene mutations in NSCLC tissues were detected by amplification refractory mutation system (ARMS)-TaqMan probe method, and clinicopathological data of patients were also collected to analyze the relationship between EGFR gene mutation status and clinicopathological characteristics of patients.Results:EGFR gene mutations were found in 76 of 173 patients, and the total mutation rate was 44.5%. The mutation rate of exon 18 was 6.6% (5/76), all of which were G719X mutation; the mutation rate of exon 19 was 46.1% (35/76), all of which were Del mutation; the mutation rate of exon 20 was 1.3% (1/76), which were EGFR gene 20ins mutation; the mutation rate of exon 21 was 44.7% (34/76), of which 33 cases were EGFR gene L858R mutation, and 1 case was EGFR gene L861Q mutation; 1 case was a double mutation of exon 19 Del combined with exon 20 T790M. The differences in EGFR mutation rates were statistically significant among patients with different gender, smoking history and pathological staging (all P < 0.05), and EGFR mutation rate in female patients was higher than that in male patients [59.7% (46/77) vs. 31.3% (30/96), χ2 = 14.08, P < 0.001], it was lower in patients with smoking history than that in patients without smoking history [27.1% (13/48) vs. 52.9% (63/119), χ2 = 9.22, P < 0.001], and it was higher in patients with adenocarcinoma than that in patients with non-adenocarcinoma [50.7% (75/148) vs. 4.0% (1/25), χ2 = 18.92, P < 0.001]. EGFR mutation status had no relevance with patients' age. Conclusions:The main types of EGFR mutations are exon 19 Del and exon 21 L858R in NSCLC patients in Shiyan, Hubei. EGFR mutations are more likely to occur in adenocarcinoma, female and no-smoking patients.
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With the development of biomolecular diagnostic technology and genetic analysis, it has been gradually discovered that some gene abnormalities can drive the occurrence and development of lung cancer. Among them, epidermal growth factor receptor (EGFR) is the most common mutant gene in non-small cell lung cancer (NSCLC). However, most of the current researches focus on the common mutations of EGFR, such as exon 19 deletion (19del) and exon 21 point mutation (L858R). There are few studies on rare EGFR mutations. This article reviews the progress of rare EGFR mutations in NSCLC.
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Objective:To explore the treatment effect of gefitinib on epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC).Methods:Sixty patients with EGFR-positive advanced NSCLC who were admitted to the 904th Hospital of Joint Logistics Support Force of Chinese PLA from March 2016 to January 2020 were selected. They were divided into gefitinib treatment group (30 cases, treated with gefitinib) and combined treatment group (30 cases, treated with pemetrexed combined with cisplatin) by random number table. The anti-tumor efficacy, levels of tumor markers [serum carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen (CYFRA21-1) and neuron-specific enolase (NSE)] before and after treatment, adverse reactions and 6-month overall survival (OS) rate were compared between the two groups.Results:The clinical control rate of gefitinib treatment group was higher than that of combined treatment group [76.7% (23/30) vs. 50.0% (15/30), χ2 = 4.593, P = 0.032]. There was no significant difference in the levels of CEA, CYFRA21-1 and NSE between the two groups before treatment (all P > 0.05). The levels of CEA, CYFRA21-1 and NSE after treatment in gefitinib treatment group were (902±41) μg/L, (3.1±0.4) ng/ml and (17.7±2.3) ng/ml. The levels of CEA, CYFRA21-1 and NSE after treatment in combined treatment group were (999±51) μg/L, (4.0±0.5) ng/ml and (19.4±3.1) ng/ml. The levels of CEA, CYFRA21-1 and NSE after treatment in gefitinib treatment group were lower than those in combined treatment group ( t = 7.441, P < 0.01; t = 7.459, P < 0.01; t = 2.486, P = 0.016).The levels of CEA, CYFRA21-1 and NSE after treatment in the two groups were all lower than those before treatment, and the differences were statistically significant (all P < 0.05). There was no significant difference in the incidence of rash, thrombocytopenia, digestive tract reaction, and proteinuria between the two groups [26.7% (8/30) vs. 23.3% (7/30), χ2 = 0.089, P = 0.766; 16.7% (5/30) vs. 13.3% (4/30), χ2 = 0.131, P = 0.718); 30.0% (9/30) vs. 26.7% (8/30), χ2 = 0.082, P = 0.774; 10.0% (3/30) vs. 13.3% (4/30), χ2 = 0.162, P = 0.688]. After 6 months of treatment, the OS rate in gefitinib treatment group was 93.3%, and that in combined treatment group was 83.3%, and there was no statistical difference between the two groups ( χ2 = 1.456, χ2 = 0.228). Conclusion:Gefitinib treatment for EGFR-positive advanced NSCLC patients can enhance the anti-tumor efficacy, reduce the content of tumor markers, and has good safety.
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Objective:To investigate the epidermal growth factor receptor (EGFR) mutation rate, mutation characteristics and distribution characteristics of different mutation types in patients with non-small cell lung cancer (NSCLC) in Fuyang of Yunnan province, to provide the clinical individualized targeted therapy of NSCLC in this region.Methods:A total of 328 NSCLC patients whose native place were Fuyuan and who underwent EGFR test in Fuyuan County People's Hospital in Yunnan Province from January 2018 to August 2020 were selected, and their clinical data such as gender, age, ethnicity, pathological type and the results of EGFR test were collected for statistical analysis.Results:The EGFR mutation rate of NSCLC patients was 40.55% (133/328). The EGFR mutation rate of female patients was higher than that of males ( P < 0.01). The EGFR mutation rate showed a downward trend with age, the EGFR mutation rate of patients ≤ 60 years old was higher than that of patients > 60 years old ( P = 0.014). The EGFR mutation rate in ethnic minority was not statistically different from Han nationality ( P = 0.789). The EGFR mutation rate of patients without smoking history was higher than that of patients with smoking history ( P<0.01). Patients with adenocarcinoma had a higher EGFR mutation rate than squamous cell carcinoma ( P = 0.002). The EGFR mutation rate in patients with stage Ⅰ-Ⅱwere higher than that in patents with stage Ⅲ-Ⅳ ( P = 0.013). The EGFR mutation rate in tissue samples were higher than that in peripheral blood samples ( P = 0.009). In 328 patients the EGFR single-point mutation rate was 24.70% (81/328), and the compound mutation rate was 15.85% (52/328); the common mutation rate was 17.07% (56/328), and the rare mutation rate was 23.48% (77/328). The top 5 mutation types were L858R (10.06%), G719X+S768I (7.32%), 19-Del (7.01%), G719X+L861Q (6.40%), and G719X (4.21%). In 133 patients with EGFR mutation, the proportion of patients with rare mutation [57.89% (77/133)] was higher than the proportion of patients with common mutation [42.11% (56/133)]. Conclusion:The EGFR mutation rates of female, adenocarcinoma, non-smoking and young NSCLC patients in Fuyuan area are high, and the rare mutation rate is high.
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Objective:To screen 89Zr-labeled anti-epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) monoclonal antibody molecular probes suitable for monitoring the gastric mucinous adenocarcinoma bearing mouse models with low glucose metabolism. Methods:The expression of EGFR and HER2 in the MGC803 gastric cancer cell line was verified by analyzing cell slides and xenograft tumor sections. 89Zr-Deferoxamine (DFO)-Cetuximab and 89Zr-DFO-Pertuzumab were prepared and the radiochemical purity was detected. Cell binding experiments and blocking experiments were performed to verify the binding ability and specificity of the probes. Twelve gastric mucinous adenocarcinoma bearing mouse models were divided into 3 groups ( n=4 in each group): 89Zr-DFO-Cetuximab group (7.4 MBq/mouse, 74 μg/mouse), 89Zr-DFO-Pertuzumab group (7.4 MBq/mouse, 70 μg/mouse) and 18F-fluorodeoxyglucose (FDG) group (7.4 MBq/mouse). MicroPET imaging was performed at 4, 24 and 48 h ( 18F-FDG group underwent imaging at 1 h only) post-injection. The biodistribution study of 89Zr-DFO-Cetuximab and 89Zr-DFO-Pertuzumab was conducted in 2 groups ( n=4 in each group) 48 h after the injection. The independent sample t test was used for data analysis. Results:The immunofluorescent staining demonstrated EGFR expression was significantly higher than HER2 expression in MGC803 gastric cancer cell line. The radiochemical purity of 89Zr-DFO-Cetuximab and 89Zr-DFO-Pertuzumab were both more than 95%, and the specific activities were 100 and 95 MBq/mg, respectively. The two probes had good stability in normal saline and fetal bovine serum, with the radiochemical purity higher than 80% at 72 h. MicroPET imaging showed that the uptake of 89Zr-DFO-Cetuximab in the MGC803 tumor was significantly higher than that of 18F-FDG and 89Zr-DFO-Pertuzumab. The biodistribution study demonstrated the 89Zr-DFO-Cetuximab uptake (percentage activity of injection dose per gram of tissue, %ID/g) of tumors at 48 h was significantly higher than that of 89Zr-DFO-Pertuzumab (56.3±12.0 vs 22.0±3.6; t=4.31, P<0.05). Conclusion:Compared with 89Zr-DFO-Pertuzumab, 89Zr-DFO-Cetuximab has a better potential for non-invasive monitoring of gastric mucinous adenocarcinoma with low glucose metabolism.
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Objective:To explore the predictive values for mutation subtypes of epidermal growth factor receptor (EGFR) in patients with lung adenocarcinoma (LUAD) based on machine learning and 18F-fluorodeoxyglucose (FDG) PET/CT images. Methods:18F-FDG PET/CT images and pathological data of 238 patients with LUAD (126 patients (54 males, 72 females, median age 62 years) with EGFR mutation; 112 patients (68 males, 44 females, median age 61 years) with wild-type EGFR)) were retrospectively collected at Tianjin Medical University Cancer Institute and Hospital between April 2016 and May 2020. Volumes of interest (VOI) of PET and CT images were delineated respectively and three-dimensional-based and two-dimensional-based radiomics features were extracted from VOIs. Three machine learning classifiers of K-nearest neighbor (KNN), support vector machine (SVM) and Adaboost were trained in training set with CT, PET and fusion PET/CT radiomics features respectively. Well trained classifiers were tested in test set. Each predictive model was evaluated by using the receiver operating characteristic (ROC) curve. Results:A total of 126 patients were EGFR mutation including 3 patients with 18 exon mutation, 6 patients with 20 exon mutation, 42 patients with 19 exon mutation, and 75 patients with 21 exon mutation. Finally, patients with 18 exon mutation and 20 exon mutation were removed due to the scale was too small to be trained adequately by machine learning classifiers. Predictive performance of mean PET/CT feature-based model (Adaboost: area under curve (AUC)=0.87, 95% CI: 0.75-0.99) in EGFR mutation subtypes was better than PET feature-based model (Adaboost: AUC=0.64, 95% CI: 0.46-0.83; z=2.04, P<0.05) and CT feature-based model (Adaboost: AUC=0.64, 95% CI: 0.45-0.83; z=2.06, P<0.05). There was no statistical difference between predictive performance of mean PET/CT feature-based model (SVM: AUC=0.76, 95% CI: 0.56-0.96) and PET/CT concatenation feature-based model (SVM: AUC=0.75, 95% CI: 0.59-0.92; z=1.14, P>0.05). Conclusion:Machine learning and 18F-FDG PET/CT radiomics features can provide predictive value for EGFR mutation subtypes in patients with LUAD.
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Objective:To investigate the efficacy of osettinib in the treatment of first-line tyrosine kinase inhibitor-resistant advanced lung adenocarcinoma and its effects on carcinoembryonic antigen (CEA) and vascular endothelial growth factor (VEGF) levels.Methods:Seventy-two patients with first-line tyrosine kinase inhibitor-resistant advanced lung adenocarcinoma (T790M test negative or rejected) who received treatment in Jinhua Guangfu Cancer Hospital from June 2017 to June 2019 were included in this study. They were randomly assigned to undergo either conventional pemetrexed plus cisplatin (control group, n = 36) or osimertinib mesylate (observation group, n = 36) for 4 successive weeks. Before and after 4 weeks of treatment, serum CEA and VEGF levels were measured. Curative effects were evaluated. Adverse reactions and 6-month, 1-year and 2-year survival rate were recorded. Results:Effective rate and disease-control rate in the observation group were 80.6% (29/36) and 94.4% (34/36) respectively, which were significantly higher than 58.3% (21/36) and 75.0% (27/ 36) in the control group ( χ2 = 4.193, 5.261, both P < 0.05). Before treatment, there were no significant differences in serum CEA and VEGF levels between the two groups (both P > 0.05). Compared with before treatment, serum CEA and VEGF levels were significantly increased after treatment (both P < 0.05). After treatment, serum CEA and VEGF levels in the observation group were (5.36 ± 0.33) U/mL and (121.56 ± 11.57) ng/L respectively, which were significantly lower than those in the control group [(8.25 ± 0.54) U/mL, (163.68 ± 14.59) ng/L, t = 27.399, 13.572, both P < 0.001]. The incidence of adverse reactions in the observation group was significantly lower than that in the control group [19.4% (7/36) vs. 44.4% (16/36), χ2 = 5.173, P = 0.011]. 6-month, 1-year and 2-year survival rate were 94.29%, 77.14% and 60.00% respectively, in the observation group and 91.43%, 54.29% and 34.29% respectively in the control group. There was no significant difference in 6-month overall survival rate between the two groups ( χ2 = 0.352, P = 0.251). 1-year and 2-year survival rate in the observation group were significantly higher than those in the control group ( χ2 = 4.058, P = 0.044; χ2 = 4.644, P = 0.031). Conclusion:Ositinib is effective in the targeted treatment of first-line tyrosine kinase inhibitor-resistant advanced lung adenocarcinoma. It can effectively decrease serum CEA and VEGF levels and prolong the survival of patients, thereby exhibiting a clinical application value.
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Objective@#The aim of the study was to investigate association of response depth and prognosis in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC)patients treated with first-line tyrosine kinase inhibitors (TKIs).@*Methods@#The clinicopathological data and prognosis information of patients with locally advanced or metastatic (ⅢB or Ⅳ) lung adenocarcinoma with EGFR classical (19del or 21L858R) mutation who were treated in our hospital from 2015 to 2016 were collected. The tumor remission depth [stable disease (SD), partial response (PR), complete response (CR)] was measured by recist 1.1 standard. The survival curve was drawn by Kaplan-Meier method and log rank test was performed.@*Results@#During the study period, 204 advanced lung adenocarcinoma patients with 19del or 21L858R mutation were treated with TKI drugs of the first generation. Among them, 24 patients were lost or unable to evaluate the efficacy, 20 patients were evaluated as progression disease (PD), 62 patients as SD, 98 patients as CR or PR. Disease control rate (DCR) and objective remission rate (ORR) were 88.9% and 54.4%, respectively. The median progression free survival time (PFS) was 12.6 months (95% CI: 10.9-14.4 months) and 13.1 months (95% CI: 11.6-14.7) for patients assessed as SD (group A) and CR or PR (group B), respectively, with no significant difference (P=0.27). Subgroup analysis showed that the median overall survival of patients with EGFR 19del and 21L858R mutations was 12.5 months (95% CI: 9.9-15.4) and 12.7 months (95% CI: 9.4-16.1), respectively, with no significant difference (P=0.66); Similar result was also observed in Group B with a median PFS of 13.9 months (95% CI: 12.3-15.5 months) and 12.3 months (95% CI: 9.5-15.1 months) in patients who had EGFR 19del or 21L858R mutations (P=0.41).@*Conclusions@#Response depth was not a positive predictor for prognosis in EGFR-mutant NSCLC patients treated with first-line TKIs.