Growth Factor Receptor Sensitive Mutations Research Articles

Icotinib: efficacy in different solid tumors and gene mutations.

Icotinib is a first-generation inhibitor of epidermal growth factor receptor, which has been approved by the Chinese National Medical Products Administration, for the treatment of non-small cell lung cancer with epidermal growth factor receptor sensitive mutations. In addition, icotinib also shows moderate activity in other solid tumors driven by epidermal growth factor receptor, including non-small cell lung cancer with epidermal growth factor receptor rare non-resistant mutations, and esophageal cancer with epidermal growth factor receptor amplification or overexpression. This article reviews the efficacy of icotinib in different solid tumors with different epidermal growth factor receptor alterations.

Long non-coding RNA H19 confers resistance to gefitinib via miR-148b-3p/DDAH1 axis in lung adenocarcinoma.

Epidermal growth factor receptor tyrosine kinase inhibitors therapy, such as gefitinib, have proven to be effective for lung adenocarcinoma with epidermal growth factor receptor-sensitive mutations. However, drug resistance remains inevitable and the underlying mechanisms are still elusive and poorly understood. In order to explore the mechanisms underlying tyrosine kinase inhibitors resistance, we used long non-coding RNA microarray analysis and found that long non-coding RNA H19 was highly expressed in gefitinib-resistant cell lines. In addition, knockdown of long non-coding RNA H19 was found to be able to decrease cell proliferation, half maximal inhibitory concentration (IC50) of gefitinib, migration and invasion. Mechanistically, we demonstrated that long non-coding RNA H19 positively regulated dimethylarginine dimethylaminohydrolase-1 expression via sponging miR-148b-3p. Furthermore, overexpression or inactivation of miR-148b-3p could enhance or reverse the inhibitory effect of long non-coding RNA H19 inhibition in lung adenocarcinoma cells, respectively. High expression of either long non-coding RNA H19 or dimethylarginine dimethylaminohydrolase-1 was associated with poorer overall survival in patients with lung adenocarcinoma, while high expression of miR-148b was associated with better overall survival. Overall, our data revealed that long non-coding RNA H19 confers resistance to gefitinib via miR-148b/dimethylarginine dimethylaminohydrolase-1 axis in lung adenocarcinoma, which offers a new insight into the epidermal growth factor receptor tyrosine kinase inhibitors therapy resistance.

The concomitant gene alterations impact the therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small cell lung cancer patients with epidermal growth factor receptor sensitive mutation

Objective: To investigate if concomitant gene alterations impact the therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation. Methods: From November 2016 to December 2017, 51 patients (19 males and 32 females, age 37-85 years) with histology or cytology diagnosed,locally advanced or metastatic NSCLC from Zhongshan Hospital Fudan University were prospectively recruited in the study. All patients harboring EGFR sensitive mutation detected by a 123 lung cancer specific gene panel of next-generation sequencing(NGS) analysis were under treatment of EGFR-TKIs. Multi-factors analysis of the correlation between EGFR-TKIs efficacy and concomitant gene alterations were analyzed by multivariate Cox regression model. Results: 82% of the NSCLC patients with EGFR mutation presented concomitant gene alterations with an average number of 2.1. Patients not harboring concomitant gene alterations had a longer median progression free survival (mPFS: not reached vs 8.8 m, P=0.008). Those who had less than 2 concomitant genes had a higher objective response rate[ORR: 52% (17/33) vs 33% (6/18) , P=0.251]and better mPFS (13.8 vs 8.0 m, P=0.003). The top 3 concomitant gene alterations were TP53 gene mutation(55%, 28/51), EGFR gene amplification (26%, 13/51) and RB1 gene mutation (18%,9/51) respectively. The mPFS of EGFR-TKI treatment in patients with either one of these 3 concomitant genes was 8.0, 8.0, and 6.0 months respectively, significantly shorter than those without one of the 3 gene alterations (13.8, 13.1, and 10.8 months respectively). Multivariate Cox regression revealed that concomitant gene abnormalities (P=0.036) and accompanied by RB1 gene mutation (P=0.025) were independent risk factors for the survival benefit of EGFR-TKI in the treatment of advanced NSCLC with EGFR-sensitive mutation. Conclusions: The efficacy of EGFR-TKI decreased significantly in advanced NSCLC with EGFR-sensitive mutation who had concomitant gene abnormalities, especially accompanied by more than 2 of the 3 gene alterations (TP53 gene mutation, EGFR gene amplification or RB1 gene mutation). This study suggested that the concomitant gene alterations should be an important issue for consideration when applying a personalized combination therapy for advanced NSCLC harboring EGFR sensitive mutation.

Prognostic and predictive value of serum carcinoembryonic antigen levels in advanced non-small cell lung cancer patients with epidermal growth factor receptor sensitive mutations and receiving tyrosine kinase inhibitors.

BackgroundDespite the widespread use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced or recurrent non-small cell lung cancer (NSCLC), no biomarkers for predicting the efficacy of EGFR-TKIs in patients with EGFR-sensitive mutations have yet been identified. The purpose of our study was to explore the effect of baseline serum tumor markers in stage IIIB/IV NSCLC patients treated with EGFR-TKIs.MethodsOne hundred and seventy-seven patients with stage IIIB/IV NSCLC who harbored EGFR-sensitive mutations and were treated with EGFR-TKIs were retrospectively reviewed. Their levels of CEA, CYFRA 21-1, NSE and CA199 were measured before treatment with EGFR-TKIs.ResultsThe response rate for all patients was 54.8%, with a median progression-free survival of 6.6 months and overall survival of 14.8 months. In univariate analyses, patients with CEA levels below the cutoff point (10 ng/ml) had higher RR, better PFS, and better OS than those with CEA levels above 10 ng/mL (RR: 69.2% vs. 43.4%, p= 0.001; mPFS: 7.8 months vs. 5.3 months, p=0.029; mOS: 18.8 months vs. 11.8 months, p=0.000). The baseline serum CEA level was an independent factor for RR (odds ratio [OR] =0.322, p=0.001), PFS (hazard ratio [HR] =1.45, p=0.025), and OS (HR=2.133, p=0.000).ConclusionOur study suggests that baseline serum CEA levels may play a role in predicting the efficacy of EGFR-TKIs in stage IIIB/IV NSCLC patients with EGFR-sensitive mutations who are treated with EGFR-TKIs.

Factors associated with efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.

The finding of epidermal growth factor receptor tyrosine kinase inhibitors, which reflects a classical process of translational research, is a critical milestone for non-small-cell lung cancer treatment. Currently, epidermal growth factor receptor tyrosine kinase inhibitors are recommended as first-line therapy for non-small-cell lung cancer patients harboring epidermal growth factor receptor-sensitive mutations. The status of epidermal growth factor receptor mutation is widely acknowledged as superior to other clinical factors, such as smoking, gender, and histological types for predicting the response to epidermal growth factor receptor tyrosine kinase inhibitors. However, recent studies have shown that the efficacy might differ in patients with the same epidermal growth factor receptor-sensitive mutations, highlighting the need to investigate the putative factors related to the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors. This article reviews the factors associated with clinical efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib and erlotinib, and analyzes their potential implications with respect to clinical application. In addition, new findings related to clinical practice with respect to epidermal growth factor receptor tyrosine kinase inhibitors efficacy were summarized in this article.

Comparison of clinical outcomes of patients with non-small cell lung cancer harboring different types of epidermal growth factor receptor sensitive mutations after first-line EGFR-TKI treatment

To analyze whether there are differences in the efficacy and clinical outcomes to first-line tyrosine kinase inhibitors (TKI) therapy in Chinese patients with metastatic non-small-cell lung cancer (NSCLC) harboring different subtypes of epidermal growth factor receptor (EGFR) mutations. A retrospective analysis was made on the clinical data of stage ⅢB or Ⅳ NSCLC patients who were diagnosed by histology and received EGFR mutation test, in order to confirm if there is any difference between the therapeutic effects of TKIs as first-line therapy and the prognosis. A total of 165 patients harboring EGFR exon 19 deletion (19del, n=71), exon 21 L858R mutation (L858R, n=80) or uncommon sensitive mutation (n=14) were treated with EGFR-TKIs for first-line treatment. The comparison among different groups of common types of sensitive mutations revealed that the objective response rate (ORR) of group 19del and group L858R were 57.8% and 45.0%, respectively (P=0.113). The disease control rate (DCR) was 93.0% and 93.8%, respectively (P=0.158). However, the ORR and DCR of uncommon sensitive mutation were 35.7% and 78.6%, which were significantly lower than that of the group 19del (P=0.035) and group L858R (P=0.020). The median progression-free survival (PFS) of group 19del, group L858R and uncommon sensitive mutation were 14.0 months, 7.8 months and 5.1 months, respectively (P=0.001). The median PFS of the group 19del was significantly longer than that of the group L858R (P=0.009). The median overall survival (OS) of these three groups had significant difference (22.8, 15.2 and 10.0 months) (P=0.048). But those of group 19del and group L858R were similar (P=0.152). The multivariate analysis indicated that ECOG-PS (P=0.030), cigarette smoking (P=0.013) and EGFR mutation types (P=0.034) are independent prognostic factors of OS. For Chinese NSCLC patients with different types of sensitive mutation, there are differences between their efficacy and prognosis of EGFR-TKIs as first-line treatment. The PFS of group 19del is obviously longer than that of other types of sensitive mutations, but have no significant differences in OS. The PFS and OS of patients with common types of sensitive mutation are better than those with uncommon sensitive mutation.

Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation.

This study aimed to investigate the potential use of icotinib as first-line treatment to prevent brain metastasis from advanced lung adenocarcinoma. This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first-line treatment. The therapeutic efficacy was compared among patients with advanced. (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)-sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas, the secondary endpoint was overall survival(OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan-Meier method and statistical significance was determined using the log-rank test. The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR-sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups. Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR.sensitive mutation.

Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation.

This study aimed to investigate the potential use of icotinib as first-line treatment to prevent brain metastasis from advanced lung adenocarcinoma. This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first-line treatment. The therapeutic efficacy was compared among patients with advanced (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)-sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas the secondary endpoint was overall survival (OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan-Meier method and statistical significance were determined using the log-rank test. The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR-sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups. Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR-sensitive mutation.