The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The main objective of this study was to investigate the relationship among the clinical characteristics and the frequency of T790M mutation in advanced epidermal growth factor receptor (EGFR)–mutant lung adenocarcinoma patients with acquired resistance after firstline EGFR–tyrosine kinase inhibitor (TKI) treatment. MATERIALS AND METHODS: We enrolled EGFR-mutant stage IIIB-IV lung adenocarcinoma patients, who had progressed to prior EGFR-TKI therapy, and evaluated their rebiopsy EGFR mutation status. RESULTS: A total of 205 patients were enrolled for analysis. The overall T790M mutation rate of rebiopsy was 46.3%. The T790M mutation rates among patients with exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 55.0%, 37.3%, and 27.3%, respectively. Baseline exon 19 deletion was associated with a significantly higher frequency of T790M mutation (adjusted odds ratio, 2.14; 95% confidence interval [CI], 1.20 to 3.83; p=0.010). In the exon 19 deletion subgroup, there was a greater prevalence of T790M mutation than other exon 19 deletion subtypes in patients with the Del E746-A750 mutation (61.6% vs. 40.6%; odds ratio, 2.35; 95% CI, 1.01 to 5.49; p=0.049). The progression-free survival (PFS) of first-line TKI treatment > 11 months was also associated with a higher T790M mutation rate (54.1% vs. 39.3%; adjusted odds ratio, 1.82; 95% CI, 1.02 to 3.25; p=0.044). Patients who underwent rebiopsy at metastatic sites had more chance to harbor T790M mutation (52.6% vs. 33.8%; adjusted odds ratio, 1.97; 95% CI, 1.06 to 3.67; p=0.032). CONCLUSION: PFS of first-line EGFR-TKI, rebiopsy site, EGFR exon 19 deletion and its subtype Del E746-A750 mutation are associated with the frequency of T790M mutation.

Does the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor differ according to the type of EGFR mutation in non-small cell lung cancer?

An exon 19 deletion and a L858R mutation in exon 21 of the epidermal growth factor receptor (EGFR) are the two most common mutations that predict favorable efficacy of EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Many retrospective and prospective studies, as well as meta-analyses including patients with NSCLC with various lines of EGFR TKI treatment, have demonstrated longer progression-free survival and sometimes more favorable overall survival in patients with an exon 19 deletion than those with the L858R or other mutations. In contrast, some clinical studies, including phase III trials, have demonstrated no difference in the efficacy of EGFR TKIs according to the EGFR mutation type. Therefore, the existence of clinically significant differences in sensitivity to EGFR-TKIs among different EGFR mutation subtypes remains controversial. In this review, we summarize the evidence suggesting different outcomes according to the type of EGFR mutation in patients with advanced NSCLC who were treated with EGFR-TKIs, along with their clinical significance. We also discuss possible mechanisms that can explain the different sensitivities to EGFR TKIs between cases with an exon 19 deletion and those with the L858R mutation.

Evaluation of epidermal growth factor receptor mutations based on mutation specific immunohistochemistry in non-small cell lung cancer: A preliminary study.

Background & objectives: Studies have shown that immunohistochemical (IHC) staining using epidermal growth factor receptor (EGFR) mutation specific antibodies, is an easy and cost-effective, screening method compared with molecular techniques. The purpose of present study was to assess the percentage positivity of IHC using EGFR mutation specific antibodies in lung biopsy samples from patients with primary lung adenocarcinoma (ADC). Methods: Two hundred and six biopsies of primary lung ADC were subjected to EGFR mutation specific antibodies against del E746-A750 and L858R. Detection of EGFR mutation done by high resolution melting analysis (HRM) was used as gold standard. A concordance was established between molecular and IHC results. Frequency of IHC positivity was assessed. Results: Of the 206 patients, 129 were male and 77 were female patients, with a mean age of 54.1 yr. Fifty five (26.6%) patients (36 men; 19 women) showed positivity for IHC of del E746-A750 (33) and L858R (22). HRM results were available in 14 patients which showed EGFR mutations in correspondence with del E746-750 or L858R in 64.2 per cent cases. Positive cases on HRM were further confirmed by DNA sequencing and fragment analysis. Three patients showed exon20 variation. Two cases were negative for mutation. The genotype of del E746-750 mutation was more common than L858R. A concordance was established between molecular mutation and IHC in 85.7 per cent cases. Interpretation & conclusions: In this preliminary study from India mutation specific IHC was used for assessment of mutation status of EGFR. Although the number tested was small, a good concordance was observed between molecular EGFR mutation and IHC expression. IHC methodology is a potentially useful tool to guide clinicians for personalized treatment in lung ADC, especially where facilities for molecular analysis are not readily available and for use in small biopsies where material is scant for molecular tests.

The necessity of EGFR-targeted therapy combined with synchronized whole brain radiotherapy for non-small-cell lung cancer with mutated EGFR and brain metastasis / 中华放射肿瘤学杂志

Objective To explore the necessity of EGFR?targeted therapy combined with synchronized whole brain radiotherapy ( WBRT ) for non?small?cell lung cancer ( NSCLC ) with mutated EGFR and brain metastasis by comparing the effects on prognosis between WBRT combined with tyrosine kinase inhibitor ( TKI) and TKI alone. Methods A retrospective analysis was performed in 43 patients with EGFR mutation?positive NSCLC and brain metastasis. In those patients, 24 patients received WBRT plus TKI and 19 patients TKI alone. Results The overall response rate ( RR) and 6?month intracranial disease control rate ( CR) were significantly higher in the WBRT+TKI group than in the TKI group ( 79% vs. 37%, P=0. 002;79% vs. 63%, P=0. 008). The median intracranial progression?free survival (IPFS) time was significantly longer in the WBRT+TKI group than in the TKI group ( 23. 7 vs. 8. 3 months, P=0. 025) . The multivariate analysis indicated that the control of lung cancer, WBRT+TKI, and single brain metastasis were favorable factors for substantially longer IPFS time ( P=0. 033,0. 019,0. 019) . In 23 patients with exon 19 deletion, 12 patients received WBRT+TKI and 11 patients TKI alone;compared with the TKI group, the WBRT+TKI group had significantly higher RR and 6?month CR as well as significantly longer IPFS ( 100%vs. 35%, P=0. 000;100% vs. 55%, P=0. 008;23. 7 vs. 8. 4 months, P=0. 003). In 20 patients without exon 19 deletion, however, there were no significant differences in RR or 6?month CR between the WBRT+TKI group (n=12) and the TKI group (n=8)(64% vs. 50%, P=1. 000;58% vs. 75%, P=0. 642).The median IPFS was 14. 4 and 8. 4 months ( P=0. 864) . Conclusions WBRT combined with TKI is superior to TKI alone in the treatment of NSCLC with brain metastasis. Patients with exon 19 deletion have substantially better treatment outcomes.

Research advancement on EGFR mutation detection in peripheral blood of patients with non-small cell lung cancer / 肿瘤研究与临床

The main therapies of NSCLC are surgery, chemotherapy, radiotherapy and targeted therapy. With development of targeted therapy, it was found that tyrosine kinase inhibitor(TKI) for patients with mutations in the EGFR gene was effective. Screening of such drugs before treatment is a premise of individualized treatment, and tissue samples are the current gold standard for genetic testing. However, it is hard to acquire the tumor tissues of patients with advanced NSCLC, so EGFR mutations detection of free DNA in peripheral blood had become an option. This article reviews the detections of TKIs-sensitive mutation,exon 19/21 mutation, and TKIs-acquired resistant mutation, T790M mutation at exon20, in serum or plasma of NSCLC patients.