Epidermal Growth Factor Receptor Mutation Rate Research Articles

Relationship between EGFR Mutations and Pathological Classification and Specimen of Lung Adenocarcinoma

背景与目的随着基因突变技术及靶向药物治疗如火如荼的开展，对肺腺癌的精准治疗越来越受到关注，目前肺腺癌中研究最多的是表皮生长因子受体（epidermal growth factor receptor, EGFR）。对于EGFR突变和病理分型的关系在不同标本中是否一致，目前不甚明了。本研究比较肺腺癌活检标本和手术切除标本中EGFR基因突变与病理分型的关系是否一致，探讨EGFR基因突变与肺腺癌病理分型的关系以及标本类型对EGFR基因检测的影响。方法收集肺腺癌手术切除标本（楔形肺切除、肺叶切除标本）163例，肺腺癌活检[粘膜活检、肺穿刺、支气管内超声引导针吸活检术（endobronchial ultrasound-guided transbronchial needle aspiration, EBUS-TBNA）标本]173例，按照2015年世界卫生组织（World Health Organization, WHO）肺腺癌分型标准对其主要组织学分型确认（贴壁型、腺泡型、乳头型、微乳头型、实体型），行EGFR基因检测[基因测序法及突变扩增阻滞系统（amplification refractory mutation system, ARMS）]。分别对活检标本和手术切除标本进行统计。结果163例的肺腺癌手术切除标本中，102例EGFR基因突变，突变率为62.58%，173例的活检标本中，114例EGFR基因突变，突变率为65.9%。两组标本中EGFR突变率没有统计学差异（P > 0.05）。两组标本中女性的EGFR突变率均明显高于男性（P < 0.05）。手术切除标本中60岁以上患者的EGFR突变率明显低于60岁以下（P < 0.05），而活检标本中EGFR突变与年龄无关（P > 0.05）。在EGFR突变的两组标本中病理分型构成比不同（χ2=8.040, P < 0.05）。手术切除标本肺腺癌中EGFR突变的102例中，腺泡型占54.9%（56例），贴壁型占23.53%（24例），乳头型占17.65%（18例），实体型占3.9%（4例），其中腺泡型所占比例最高，其次是贴壁型和乳头型，实体型则比例最少。19、21外显子单独突变最多，21外显子突变在贴壁型较其他两型高（P < 0.05），19外显子突变在乳头型较贴壁型高（P < 0.05）。腺泡型和乳头型比较，19、21外显子突变无统计学意义。活检标本肺腺癌中EGFR突变的114例中腺泡型占48.25%（55例），贴壁型占26.32%（30例），乳头型占11.4%（13例），微乳头型占4.39%（5例），实体型占9.65%（11例）。腺泡型所占比例最高，其次是贴壁型，乳头状、微乳头状和实体型最少。同样是19、21外显子单独突变最多，但不同病理分型中，19、21外显子突变均无显著差异（P > 0.05）。结论肺腺癌中手术切除标本和活检标本EGFR突变率没有差异，且突变与性别有关，均为女性突变率高于男性。手术切除标本中EGFR突变与年龄有关，年龄越大突变率越低，而在活检标本中则与年龄无关。两组标本的病理分型构成比不同。19、21外显子单独突变最多。手术切除标本中EGFR突变类型与主要病理分型有关，21外显子单独突变中贴壁型最多，19外显子单独突变中乳头型最多。EGFR突变活检标本中，19、21外显子单独突变与主要病理分型无明显相关。

Clinical efficacy evaluation of tyrosine kinase inhibitors for non-adenocarcinoma lung cancer patients harboring EGFR-sensitizing mutations.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as a standard therapy have been used in EGFR-mutated adenocarcinoma of non-small-cell lung cancer (NSCLC) patients in recent years. But in current randomized prospective clinical trials, due to few cases of non-adenocarcinoma patients having been found, the efficacy of TKIs for EGFR-mutated non-adenocarcinoma and the relationship with clinicopathological characteristics remained debatable. The results of retrospective studies showed that the frequency of EGFR mutation was significantly associated with nationality, gender, smoking history, and histology type. Being female, never-smoker and adenocarcinoma had a higher mutation rate. Furthermore, the EGFR mutation rate and efficacies of TKIs in adenocarcinoma were higher than those in non-adenocarcinoma. And in non-adenocarcinoma, the EGFR mutation rate and efficacies of TKIs in adenosquamous cell carcinoma were higher than those in squamous cell carcinoma or in large-cell lung carcinoma. In conclusion, it may be necessary to conduct a large sample prospective study to understand the clinicopathological characteristics of non-adenocarcinomas and to evaluate the efficacy of EGFR TKI and/or chemotherapy for EGFR-mutated non-adenocarcinoma NSCLC. So we searched relevant articles between the year 2010 and 2016 through the major indexed literature database PubMed by searching the keywords such as EGFR mutation, Tyrosine kinase inhibitors, and Non-adenocarcinoma.

Analytic and Clinical Validation of an Ultrasensitive, Quantitative Polymerase Chain Reaction Assay for EGFR Mutation Analysis With Circulating Tumor DNA.

- The mutation analysis of epidermal growth factor receptor (EGFR) has become a common test to guide therapeutic decision making for lung cancer. Molecular testing with circulating tumor DNA in plasma allows diagnosis of mutations when tumor tissue is not available as well as monitoring treatment response with repeat biopsies. - To develop a timely and cost-effective assay that can accurately detect EGFR mutations in circulating tumor DNA and to evaluate the analytic and clinical performance of the assay. - Analytic assessment was conducted with a set of reference materials carrying classic EGFR mutations. A recently developed Poisson distribution-based approach was employed to understand the assay sensitivity. Clinical evaluation was performed with 224 pairs of plasma and matched tissues from patients with stage I to IV disease. EGFR mutation rates of 390 consecutive plasma samples processed in the central service laboratory were compared with previously reported prevalence in an Asian population. - Our results suggested that limit of detection for the EGFR quantitative polymerase chain reaction assay was 10 mutation copies, and the lowest detectable copy numbers could be extended to a single-digit level. The clinical sensitivity was 53.3% for all stages combined and 81.4% for late stages, with a high specificity of 100%. Clinical observations showed an overall positive finding rate of 32.5% and 41.4% for stage IV disease, which is consistent with previously reported EGFR mutation prevalence in an Asian population. - Our results supported the clinical utility of the ultrasensitive, quantitative polymerase chain reaction assay for EGFR mutation analysis with circulating tumor DNA.

Dynamic monitoring of EGFR mutations in circulating cell-free DNA for EGFR-mutant metastatic patients with lung cancer: Early detection of drug resistance and prognostic significance.

Detecting genetic mutations in circulating cell-free DNA (cfDNA) is a promising approach of liquid biopsy. Between June 2014 and May 2015, 168 plasma samples were collected monthly from 20 patients with metastatic lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation receiving gefitinib therapy. Clinically relevant EGFR mutations, including exon 19 deletion, L858R and T790M, were quantified using droplet digital polymerase chain reaction. In baseline samples, 19 (95.0%) patients had the same mutation with the matched tumors, and pretreatment T790M mutations were also detected in 3 (15.0%) patients. The dynamics of EGFR mutations were generally associated with treatment response for patients with or without measurable disease. For patients with immeasurable tumor deposits, monitoring disease evolution using cfDNA-based mutation quantification appeared to be more reliable compared with measuring the diameters of target tumor lesions. In addition, molecular progressive disease, defined as a ≥20% increase of EGFR mutation concentration compared with the lowest concentration recorded during treatment, was tracked up to 8 months prior to objective progression. In survival analysis, sex (P=0.005), pretreatment T790M mutation status (P=0.006), T790M mutation status at the disease progression (P=0.043) and growth rate of EGFR mutations (P=0.023), had a significant impact on median progression-free survival. In conclusion, dynamic monitoring of EGFR mutations in cfDNA is feasible and appears to be useful in early prediction of drug resistance for patients with lung cancer receiving EGFR tyrosine kinase inhibitors.

Relationship between EGFR gene mutation and local metastasis of resectable lung adenocarcinoma

BackgroundResectable lung adenocarcinoma is dominated by peripheral distribution, and surgical resection is the main treatment protocol. However, high recurrence rate remains after surgery. Lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation has strong invasion ability, but the effects of this mutation on local invasion in early lung adenocarcinoma have been rarely studied. This study aimed to assess the effects of EGFR mutation on local invasion in resectable lung adenocarcinoma.MethodsA retrospective analysis of 103 patients clinically diagnosed with peripheral lung adenocarcinoma was included. They underwent preoperative bronchoscopy, which indicated grades 2 or 3 bronchial involvement (lumen of the lobe or segment). The associations of EGFR mutation with pleural invasion, endobronchial metastasis, and lymph node metastasis were analyzed according to pathologies of pleural invasion and lymph node metastasis, as well as EGFR gene mutation detected by postoperative pathological specimens. Statistical analyses were performed by unpaired Chi-square test using the SPSS16.0 software.ResultsIn patients with EGFR mutation, pleural invasion, endobronchial metastasis, and lymph node metastasis rates were 62.5, 39.1, and 34.4%, respectively, indicating statistically significant differences (p = 0.003). Meanwhile, the pleural invasion rate in patients with wild-type EGFR was 43.6%, significantly reduced compared with patients with mutated EGFR (62.5%; p = 0.018). In addition, the endobronchial metastasis rate in patients with wild-type EGFR was 17.9%, significantly lower than in patients with EGFR mutation (39.1%; p = 0.005). However, lymph node metastasis rates were similar between EGFR mutated and wild-type patients (34.4 vs 25.6%, respectively, p > 0.05).ConclusionsEarly resectable lung adenocarcinoma patients with EGFR mutation showed a higher rate of local invasion compared with those harboring wild-type EGFR. This finding provides a basis for improved therapy.Trial registrationThis study was supported by Project of Medical and Health Science Technology in Shandong Province (2015WS0376)

Clinical value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of lung adenocarcinoma.

BackgroundWe explored correlations between the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, epidermal growth factor receptor (EGFR) mutation status, and prognosis.MethodsData from 293 patients with lung adenocarcinoma were classified according to the new classification. Fisher’s exact, χ2, and log‐rank tests and Cox regression analysis were used to analyze correlations between EGFR mutation status, lung cancer prognosis, and the new histologic subtype. Disease‐free survival and progression‐free survival (PFS) were estimated using the Kaplan–Meier method.Results Lepidic and non‐solid adenocarcinomas showed significantly elevated EGFR mutation rates (79.0% and 65.8%, respectively; P < 0.05). EGFR mutation status was only associated with gender (P < 0.001). EGFR mutation‐positive patients who received targeted therapy had better median PFS than those who received chemotherapy as first‐line treatment (P < 0.001). The median PFS of patients with exon 19 and exon 21 mutations who received first‐line targeted therapy were 12.5 and 9.5 months, respectively (P = 0.970). Patients with micropapillary predominant adenocarcinomas had the shortest disease‐free survival (<18 months) and PFS. Histologic subtype (P = 0.036), treatment type (P = 0.031), and EGFR mutation status (P = 0.019) might be good prognostic factors for lung adenocarcinoma.ConclusionPatients with exon 19 mutations obtained greater benefits from targeted therapy. In the new classification, EGFR mutation rates are higher in lepidic cases and in cases without the solid subtype. The micropapillary subtype of adenocarcinoma has the worst prognosis, while the lepidic subtype has the best.

A regional analysis of epidermal growth factor receptor (EGFR) mutated lung cancer for HSE South.

EGFR mutated lung cancer represents a subgroup with distinct clinical presentations, prognosis, and management requirements. We investigated the survival, prognostic factors, and real-world treatment of NSCLC patients with EGFR mutation in clinical practice. A retrospective review of all specimens sent for EGFR analysis from December 2009 to September 2015 was performed. Patient demographics, specimen type, EGFR mutation status/type, stage at diagnosis, treatment, response rate, and survival data were recorded. 27/334 (8%) patient specimens sent for EGFR testing tested positive for a sensitising EGFR mutation. The median age was 65years (40-85years). Exon 19 deletion represented the most commonly detected alteration, accounting for 39% (n=11). First-line treatment for those with Exon 18, 19, or 21 alterations (n=24) was with an EGFR tyrosine kinase inhibitor (TKI) in 79% (n=19). Objective response rate among these patients was 74% and median duration of response was 13months (range 7-35months). The incidence of EGFR mutation in our cohort of NSCLC is 9% which is consistent with mutation incidence reported in other countries. The rate of EGFR mutation in our population is slightly below that reported internationally, but treatment outcomes are consistent with published data. Real-world patient data have important contributions to make with regard to quality measurement, incorporating patient experience into guidelines and identifying safety signals.

Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) of Yunnan in southwestern China.

To investigate the Epidermal Growth Factor Receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC) in Yunnan province in southwestern China, we detected EGFR mutation by Amplification Refractory Mutation System (ARMS) polymerase chain reaction (PCR) using DNA samples from 447 pathologically confirmed NSCLC specimens (175 tissue, 256 plasma and 16 cytologic samples). The relationship between EGFR mutations and demographic and clinical factors were further explored. Subgroup analyses according to sample type (tissue and plasma) and histological type (adenocarcinoma) were done. We found the mutation rate was 34.9% in overall patients (42.3%, 29.7%, and 37.5% for tissue, plasma, and cytologic samples respectively). We found female (p < 0.0001), no smoking (p = 0.001), adenocarcinoma (p < 0.0001), and tissue specimen (p = 0.026) were associated with higher EGFR mutation rate. The most common mutations were exon 19 deletions (40%) and L858R point (30%) mutation. Interestingly, NSCLC patients from Xuanwei harbored a strikingly divergent mutational pattern for EGFR when compared with non-Xuanwei patients (higher G719X, G719X+S768I mutations, but lower 19 deletion and L858R mutations). Generally, EGFR mutation rate and pattern in Yunnan province was in accord with other Asian populations. However, Xuanwei subgroup showed strikingly divergent EGFR mutation spectrum from other general population. Our analysis also indicated that cftDNA analysis for EGFR mutations detection was feasibility for the patients lacking sufficient tissue for molecular analyses.

P1.02-032 Diagnosis and Treatment of EGFR Mutated NSCLC among Arabic Patients

About 15% of western patient population with advanced NSCLC harbor the epidermal growth factor receptor (EGFR) mutation compared tossssssss about 50% in the Asian population. These mutations are more frequently found in NSCLC with adenocarcinoma histology, in women, East Asians and never smokers. EGFR tyrosine kinase inhibitors (TKIs) are the first-line treatment of choice for NSCLC patients harboring EGFR mutation. Nowadays there is only a scarce information regarding EGFR epidemiology and response to EGFR TKI among other ethnicities, although there has been limited reports regarding increased rate of EGFR mutation among arabic patients. Single institution retrospective analysis of serial advanced NSCLC patients tested for EGFR mutation in 2011-2015. Information was obtained using the medical records. Of 616 patients with advanced NSCLC tested for EGFR in our institutions in 2011-2015, there were a total of 134 Arabic patients, 38 of them harboring EGFR mutation (28%), as opposed to 64 (13%) among the non-arabic population. Twenty patients had exon 19 deletion, 9 patients had L858R and 1 patient had exon 21 mutation. The median age at diagnosis was 58 (39-80), 22 patients were males and 16 females, of them- 13 were never smokers, 5 are previous smokers, and 20 are active smokers. Thirty-six patients had adenocarcinoma histology while 2 patients had carcinosarcoma and squamous cell carcinoma. The median survival was longer than 9 months. Thirty patients were treated with EGFR TKI, 27 of them as 1ST line treatment, and 3 as 2ND line treatment. Of the 30 patients treated with EGFR TKI, 69% had partial response, 16% had stable disease. Among Arabic patients with NSCLC, the frequency of EGFR mutation is higher than in western population, and is more frequent among males and smokers. The response to EGFR TKI matches the reported literature.

P3.02b-018 Detection of Epidermal Growth Factor Receptor Mutations in Circulating Cell-Free DNA versus Tumor Biopsy: Topic: EGFR Biomarkers

Epidermal growth factor receptor (EGFR) mutations are predictive marker of EGFR-tyrosine kinase inhibitor (TKI) therapy. We compared the sensitivity of EGFR mutation detection techniques between matched tumor tissue and peripheral blood sample in patients with lung adenocarcinoma. We collected the paired samples from plasma and paraffin-embedded tumor tissue in 202 patients before EGFR-TKIs. DNA extraction was performed using the QIAamp MinElute virus spin kit and EGFR mutation analysis was done by two detection methods. One is the PNAClampTM which is the PNA-based PCR clamping that selectively amplifies only the mutated target DNA sequence as minor portion in mixture with the major wild type DNA sequences. The other is the PANAMutyperTM EGFR kit, which use PNA clamping-assisted fluorescence melting curve analysis to perform mutation detection and genotyping. The degree of agreement was evaluated by Cohen's kappa value. The EGFR mutation rates by PANAMutyperTMR and PNAClampTM were 51.0% vs. 47.0% in tissue, and 22.2% vs. 11.4% in plasma sample, respectively. Overall concordance rates and the degree of agreement between tissue and plasma samples was better in PANAMutyperTMR (69.3%, k=0.393, p<0.001) than PNAClampTM (62.3%, k=0.211, p<0.001). Sensitivity of plasma EGFR mutations was higher (41.7% vs. 22.1%, p<0.001) and false negative rate was lower in PANAMutyperTMR test (58.3% vs. 77.9%, p<0.001). Response to EGFR-TKI was correlated with plasma EGFR mutation by PANAMutyperTMR (p=0.025) unlike PNAClampTM (p=0.829). The sensitivity and concordance rate of PANAMutyperTMR test were better than standard PNAClampTM test. So this technique can be useful to detect EGFR mutation in circulating cell-free DNA sample.

P2.06-044 Frequency of Mutations and Related Factors in Lung Adenocarcinoma Cases in Turkey: Topic: LAB, Other

Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 receptor tyrosine kinase (ROS1) gene mutations in lung adenocarcinoma (LA) cases give an opportunity to use some of targeted therapy agents. The aim of this study is to obtain EGFR, ALK and ROS1 gene mutation frequencies in Turkey and to examine the factors affecting these frequencies. EGFR, ALK, ROS1 mutation analyses were examined in a total of 971 LA cases; 745 men (76.7%), and 226 women (23.3%) diagnosed in 12 hospitals from different districts of Turkey were enrolled in the study. The demographic characteristics, smoking status, asbestos exposure history, radiological findings associated with asbestos exposure (AE) were investigated with relation to the frequencies of EGFR, ALK and ROS1 gene mutations. In the univariate analysis of the study data chi-square and t-tests were used. To determine the independent factors associated with gene mutations, multivariate logistic regression model was created with the variables that give p <0.10 level of significance in univariate analysis. The mean age of 971 patients was 60.8±9.8 years (range: 23-91). Smoking rate was 92.6% in men, 42.5% in women (p<0.001). The number of patients with AE history was 279 (28.7%) and the number of patients with radiologic findings associated with AE was 114 (11.7%). The frequencies of EGFR, ALK and ROS1 mutations were 15.9% (152/956), 3.3% (26/768) and 1.6% (6/379), respectively. Female patients were more likely to have EGFR mutations compared with male patients (37.8% versus 9.3%; p<0,001). Never-smokers had higher incidence of EGFR mutations than smokers (39.6% versus 10.3%; p<0.001). The patients with radiological findings of AE had a 24.6% rate of EGFR mutations compared with a 14.7% rate of patients with no radiological findings (p=0.007). ALK rearrengement was detected in patients with younger age, having history of AE or radiological findings associated with AE (11.1%; p<0.001, 5.9%; p=0.014, 6.7%; p=0.044, respectively). No associated factor was found with ROS1 fusion frequency. To have a relationship between radiographic findings associated with AE or AE history and EGFR and ALK mutation frequencies is an original finding. The obtained results will be useful in the discussion of standards of treatment with the new agents and pathogenesis. *This study was carried out through the project named as “Network cooperation for the management of environmental and occupational exposure to mineral fibers induced pulmonary pathologies” which was supported by General Directorate of Health Researches, Republic of Turkey, Ministry of Health.

PD1.03 (also presented as P1.12): EGFR Mutation Testing Patterns and Results in Brazil and the Need for Greater Public Health Awareness of Molecular Testing

Epidermal growth factor receptor (EGFR) mutation testing allows for optimal selection of therapy with tyrosine kinase inhibitors in patients with non-small-cell lung cancer (NSCLC). Previous studies have shown a variation in EGRF genotype according to ethnic background, with scarce data about EGFR mutation status and testing patterns among Brazilian patients with NSCLC. Between 2011 and 2013, as part of a program sponsored by a pharmaceutical company in Brazil, tumor samples of patients with stage IIIb/IV NSCLC were submitted, at the discretion of the attending physicians, for EGFR mutation testing. All analyses were performed at 02 reference laboratories, as follows: after microdissection, DNA was isolated from serial sections of formalin-fixed, paraffin-embedded tumor tissue to obtain at least 70% tumor cells. Exons 18, 19, 20 and 21 of the EGFR gene were analysed using Sanger sequencing. EGFR mutation rate was calculated and its frequency compared between clinical subgroups using chi-square test. Data about smoking status was incomplete and thus not included in this analysis. Furthermore, a commercial database with 3,296 patients treated in Brazil in 2014 was evaluated for mutation testing patterns. 3,364 tests out of 3,771 samples analyzed (1,799 male; 1,942 female) yielded informative results. EGFR mutation was present in 25.5% (857/3364) of informative samples. Deletions in exon 19 were the most frequent alteration detected (54%), followed by point mutations in exon 21 (28%) and exon 20 (9.7%). The most important predictors for the presence of EGFR mutations were adenocarcinoma histology (p<0.001), 89% of positive tests occurred in this histology; and female gender (p<0.001), for which 30.2% of the patients tested were positive. No differences in EGFR mutation frequency were found between age groups or regions within the country. In the commercial database of patients with NSCLC treated in the country in 2014, 1,792 patients had adenocarcinomas, 930 had squamous cancer, 71 had large cell cancer and 99 had other histologies. Overall, 34% of patients were tested for mutations (47% in the private sector and 20% in public centers); the corresponding number was 50% for patients with adenocarcinoma (62% of cases in the private and 33% in the public settings, respectively) and 10% for patients with squamous cancer. Of note fewer than 5% of patients overall were tested for ALK alterations. To the best of our knowledge, this is the largest study to assess EGFR mutation status in Latin America and in Brazil. Our findings suggest that the frequency of EGFR mutation in this cohort was lower than that found in Asia, but higher than in Caucasian populations, confirming findings seen in other Latin American countries. Despite this high prevalence, a significant number of patients, especially in the public sector, are not currently tested for mutations in the country, and further advocacy efforts are necessary to improve this situation.

Comparison of Epidermal Growth Factor Receptor Mutations between Metastatic Lymph Node Diagnosed by EBUS-TBNA and Primary Tumor in Non-Small Cell Lung Cancer.

IntroductionAlthough the use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasing for epidermal growth factor receptor (EGFR) testing in lung cancer, the discordance rate in EGFR mutations between lymph node (LN) samples obtained by EBUS-TBNA and primary tumor (PT) is not well known. Thus, we compared the EGFR mutation status of LN samples obtained by EBUS-TBNA and PTs to estimate the efficacy of using EBUS-TBNA specimens for EGFR testing in advanced, non-squamous, non-small cell lung cancer (NSCLC).Materials and MethodsUsing data of patients from the EBUS-TBNA database (N = 1914) obtained between January 2009 and January 2013, we identified 100 treatment-naïve, advanced, non-squamous NSCLC patients (stage 3 and 4) with matched LN specimens obtained by EBUS-TBNA and PT specimens. Of these, 74 patients with paired specimens were feasible for EGFR mutation analysis, which we performed using a direct sequencing method.ResultsOf the 74 cases, at least one major [exon 19 deleted (19del) and L858R] or minor (T790M, exon 20 insertion, and other point mutations) EGFR mutation was detected in 31 cases (41.9%), which included PT (n = 31, 41.9%) and LN (n = 28, 37.8%) specimens. Major mutations were detected in 25 PT (33.8%, 19del = 13, L858R = 12) and 22 LN (29.8%, 19del = 11, L858R = 11) specimens. The discordance rate in major mutations between matched PT and LN specimens was 4.1% (3/74). Among minor mutations, T790M was detected in LN specimen only in 2 cases with L858R in PT and LN. The discordance rate major and minor EGFR mutations combined between matched PT and LN specimens was 12% (9/74).ConclusionsWe observed a high concordance rate of major EGFR mutations between matched LN specimens sampled by EBUS-TBNA and PTs, suggesting that LN samples obtained by EBUS-TBNA from advanced non-squamous NSCLC patients are effective for use in EGFR mutation testing.

Higher frequency but random distribution of EGFR mutation subtypes in familial lung cancer patients.

Despite the advancement of epidermal growth factor receptor (EGFR) inhibitors in lung cancer therapy, it remains unclear whether EGFR mutation status in familial lung cancers is different from that of sporadic cases. In this multicenter retrospective study, we compared both the EGFR mutation frequency and patterns between familial and sporadic cases. The results explored that family history of lung cancer is an independent predictor for higher EGFR mutation rate in 1713 lung adenocarcinoma patients (Odd ratio 1.68, 95% CI 1.06–2.67, P = 0.028). However, the distribution of EGFR mutation subtypes was similar to that of sporadic cases. Part of our study involved 40 lung cancer families with at least 2 tumor tissues available within each single family (n = 88) and there was no familial aggregation pattern in EGFR mutation subtypes. There were two families harboring the YAP1 R331W germline risk allele and EGFR mutation statuses among YAP1 family members also varied. These phenomena may hint at the direction of future research into lung carcinogenesis and EGFR mutagenesis.

EGFR mutation testing using archival-stained smears in non-small cell lung carcinoma.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown benefits regarding progression-free and overall survival in patients whose tumours show EGFR mutations. Most patients' lung cancer is metastatic when detected. Small tissue samples and cytological materials are widely used in diagnosis. The aim of the present study was to compare the EGFR mutation analysis results between cytology, small biopsies and resections. Archival material for EGFR testing was reviewed. Cell blocks and/or stained smears and tissue blocks were used where appropriate. The tumour cell count and percentage were recorded as well as the DNA content. The influence of TTF-1 immunoreactivity on EGFR testing was also investigated. The study cohort included 300 unpaired specimens of 84 resections, 83 small biopsies and 133 cytological materials. EGFR mutation rates did not differ significantly for cytology, small biopsy and resections (P > 0.05). The higher tumour cell percentage in FNAs than in exfoliative cytology did not affect the EGFR mutation status. EGFR mutation rates were similar when either slides or cell blocks were used. Cytology slides revealed a higher tumour cell content and DNA concentration than the cell blocks. May-Grünwald-Giemsa (MGG)-stained smears had higher rates of the EGFR mutation than the Papanicolaou (Pap)-stained slides (P < 0.05). Tumours with negative immunoreactivity for TTF-1 are less likely to have an EGFR mutation (P < 0.05). Cytological materials can be used successfully for mutation analysis in lung cancer.

Characteristics of young lung cancer: Analysis of Taiwan's nationwide lung cancer registry focusing on epidermal growth factor receptor mutation and smoking status.

Lung cancer is relatively rare in young patients as the median age at diagnosis is 65–70 years. The main objective of this nationwide study was to investigate the characteristics of young lung cancer in Taiwan, especially the relationships among smoking behavior, epidermal growth factor receptor (EGFR) mutation, and age. The National Taiwan Lung Cancer Registry, a database contain detailed cancer statistics, was analyzed in this study for the period 2011–2012. Young lung cancer was defined as age ≦ 45 years. There were 21,536 lung cancer patients (13,187 men and 8349 women). Among these patients, 1074 (5.0%) were in the younger group, and 20,462 patients (95.0%) were in the older group. Female gender (48.8% versus 38.2%, P < 0.001), never-smokers (47.3% versus 43.8%, P = 0.015), and adenocarcinoma (70.4% versus 58.1%, P < 0.001) were more frequent in the younger group. While the EGFR mutation rate was lower in the younger group (52.5% versus 60.6%, P = 0.001), the primary site of lung cancer and stage distribution were not significantly different. If only adenocarcinoma patients were included in the analysis, female gender, older age, and never-smokers were more likely to have EGFR mutation. In conclusion, lung cancer in young patients (≦ 45 year-old) was associated with unique characteristics, with greater percentages of female patients, adenocarcinoma, and never-smokers and a lower EGFR mutation rate compared with older patients.

Prevalence and Clinical Profile of EGFR Mutation In Non- Small-Cell Lung Carcinoma Patients in Southwest China.

To investigate the distribution of epidermal growth factor receptor (EGFR) mutations, and explore any relationships with clinical characteristics in non-small-cell lung carcinoma (NSCLC) patients. EGFR mutations were assessed by ADx-ARMS in 261 NSCLC patients from West China Hospital of Sichuan University. Relationships between EGFR mutation and clinical characteristics were analyzed by SPSS. The EGFR mutation rate was 48.7% (127/261), 19-del and L858R mutations occurred predominantly, accounting for 33.1% and 40.9%, respectively, in mutated cases. Moreover, 10.2% patients were found to carry double mutations. EGFR mutations occurred more frequently in women (57.5%) than in men (41.8%) (P=0.01), and were more frequent in non-smokers (61.2%) than in former or current smokers (31.2%) (P<0.00). In addition, they were more common in adenocarcinomas (52.8%) and adenosquamous carcinomas (42.8%) than in squamous cell carcinomas (14.8%) (p<0.00). However, only smoking history and pathological types, rather than gender, proved to be associated with EGFR mutations on multivariate logistic regression analysis. No significant differences in pathological stage and metastasis status were found between EGFR wild-type and mutated cases, although EGFR mutation type was related to pathological type (p=0.00) - 19-del, L858R and other mutation types respectively occurred in 34.2%, 42.5% and 23.3% of adenocarcinomas, but in 14.3%, 0% and 85.7% of non-adenocarcinomas. The EGFR mutation rate was 48.7% in NSCLCs in Southwest China, so that nearly 40% patients might benefit from targeted therapies. Smoking status and pathological types were independent predictors of EGFR mutation, while EGFR mutation type was related to only pathological type, rather than smoking status.

Discrepancy of epidermal growth factor receptor mutation in lung adenocarcinoma presenting as multiple ground-glass opacities.

To identify epidermal growth factor receptor (EGFR) mutation status between different lesions in lung adenocarcinoma presenting as multiple ground-glass opacity (GGO) lesions and analyse its association with clinical characteristics. Seventy-eight patients with lung adenocarcinoma presenting as multiple GGO lesions were identified to investigate EGFR mutation in exon 18-21. Lesions with the largest size in diameter were defined as the primary lesions; the others were defined as the secondary lesions. One hundred and fifty-nine lesions of these patients were classified into pure GGO and mixed GGO by computed tomography scan images. The EGFR mutation rate in the patients was 48.7% (38 of 78). Patients with high frequency of EGFR mutation were females and non-smokers. The EGFR mutation rate of invasive adenocarcinoma was higher than that of atypical adenomatous hyperplasia/adenocarcinoma in situ and minimally invasive adenocarcinoma (P = 0.001). Although 19-deletion and L858R were the most common EGFR mutations, there was no difference of EGFR mutation in pathological subtypes of adenocarcinoma. Of the 38 paired lesions in patients harbouring EGFR mutation, the discordance rate of EGFR mutation was 92.1%. The study showed different EGFR mutational profiles in multiple GGO lesions, suggesting that lesions seem to arise as independent events. It would offer useful information for determining the appropriate treatment strategy for lung adenocarcinoma presenting as multiple GGO lesions.

Comparison of EGFR mutation rates in lung adenocarcinoma tissue and pleural effusion samples.

The goal of the current study was to investigate the differences in epidermal growth factor receptor (EGFR) mutation rates in tumor tissue and pleural effusion specimens from patients with lung adenocarcinoma. PCR amplification and gene sequencing were used to detect EGFR mutations in exons 18, 19, 20, and 21 in tumor tissue and pleural effusion samples from 50 patients with advanced lung adenocarcinoma. The EGFR mutation rate was 34.0% in tissue samples from patients with advanced lung adenocarcinoma. There were 11 cases with exon 19 mutations and 6 cases with exon 21 mutations. The EGFR mutation rate was 30.0% in pleural effusion specimens, including 10 cases with exon 19 mutation and 5 cases with exon 21 mutations. Although the tissue samples had a slightly higher mutation rate compared to the pleural effusion samples, the difference was not statistically significant. These results indicate that the EGFR mutation rate detected in pleural effusion specimens from patients with advanced lung adenocarcinoma is similar to that detected in tumor tissue samples. Therefore, pleural effusion specimens can potentially be used for EGFR mutation detection in advanced lung adenocarcinoma.

Monitoring of high-density lipoprotein cholesterol level is predictive of EGFR mutation and efficacy of EGFR-TKI in patients with advanced lung adenocarcinoma.

High-density lipoprotein cholesterol (HDL-C) has an inverse association with the incidence of lung cancer. However, whether it can be used as a predictive factor in advanced lung adenocarcinoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) still remains undefined. This research aimed at studying the relationship of serum HDL-C baseline level and HDL-C kinetics to EGFR mutation, the efficacy of EGFR-TKI, and the predictive value of PFS. The presence of mutation rate in the 192 patients with lung adenocarcinoma was compared within stratified groups. Levels of baseline HDL-C and kinetics of HDL-C were analyzed retrospectively in patients treated with EGFR-TKI harboring EGFR mutation. Univariate and multivariate analyses were performed to investigate the prognostic value of HDL-C. EGFR mutation rate of HDL-C high-level group was significantly higher than that of low-level group (59.0% vs 35.6%, P=0.001). Multivariate logistic analysis showed that high-level HDL-C was an independent predictive factor for EGFR gene mutation (P=0.005; odds ratio =0.417; 95% confidence interval [CI], 0.227–0.768). Patients with a low level of HDL-C before therapy showed a progression of disease in most cases (P<0.001). According to HDL-C kinetics, patients who received EGFR-TKI treatment harboring EGFR mutation were divided into four groups. Univariate analysis showed that patients in nondecreased group had longer progression-free survival (P<0.001; hazard ratio =0.003; 95% CI, 0.001–0.018). Multivariate Cox proportional hazards model analyses showed the same result (P<0.001; hazard ratio =0.003; 95% CI, 0.001–0.018). Current results suggest that HDL-C seems to be a good independent predictive biomarker for advanced lung adenocarcinoma patients treated with the first-line EGFR-TKI. Roles of this biomarker include indicating EGFR mutation, assessing the efficacy of EGFR-TKI, and predicting the progression-free survival.