Frequency Of Epidermal Growth Factor Receptor Mutations Research Articles

Frequency of Epidermal Growth Factor Receptor Mutation in Smokers with Lung Cancer Without Pulmonary Emphysema.

Chronic obstructive pulmonary disease is a smoking-related disease, and is categorized into the emphysema and airway dominant phenotypes. We examined the relationship between emphysematous changes and epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma. The medical records for 250 patients with lung adenocarcinoma were retrospectively reviewed. All patients were categorized into the emphysema or non-emphysema group. Wild-type EGFR was detected in 136 (54%) and mutant EGFR in 48 (19%). Emphysematous changes were observed in 87 (36%) patients. EGFR mutation was highly frequent in the non-emphysema group (p=0.0014). Multivariate logistic regression analysis showed that emphysema was an independent risk factor for reduced frequency of EGFR mutation (Odds Ratio=3.47, p=0.005). Our data showed a relationship between emphysematous changes and EGFR mutation status. There might be mutually exclusive genetic risk factors for carcinogenesis and development of emphysematous changes.

CT characteristics of non-small cell lung cancer with epidermal growth factor receptor mutation: a systematic review and meta-analysis

BackgroundTo systematically investigate the relationship between CT morphological features and the presence of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC).MethodsAll studies about the CT morphological features of NSCLC with EGFR mutations published between January 1, 2000 and March 15, 2015 were searched in the PubMed and EMBASE databases. Qualified studies were selected according to inclusion criteria. The frequency of EGFR mutations and CT features of ground-glass opacity (GGO) content, tumor size, cavitation, air-bronchogram, lobulation, and spiculation were extracted. The relationship between EGFR mutations and each of these CT features was tested based upon the weighted mean difference or inverse variance in the form of an odds ratio at a 95% confidence interval using Forest Plots. The publication bias was examined using Egger’s test.ResultsA total of 13 studies, consisting of 2146 NSCLC patients, were included, and 51.12% (1097/2146) of patients had EGFR mutations. The EGFR mutations were present in NSCLC with part-solid GGO in contrast to nonsolid GGO (OR = 0.49, 95% CI = 0.25–0.96, P = 0.04). Other CT features such as tumor size, cavitation, air-bronchogram, lobulation and spiculation did not demonstrate statistically significant correlation with EGFR mutations individually (P = 0.91; 0.67; 0.12; 0.45; and 0.36, respectively). No publication bias among the selected studies was noted in this meta-analysis (Egger’s tests, P > 0.05 for all).ConclusionThis meta-analysis demonstrated that NSCLC with CT morphological features of part-solid GGO tended to be EGFR mutated, which might provide an important clue for the correct selection of patients treated with molecular targeted therapies.

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.

P1.02-044 EGFR Status in a Previously Untested Population from Northeastern Brazil

There is limited Brazilian data on epidermal growth factor receptor (EGFR) gene activating mutations prevalence and their clinicopathologic associations especially in the Northeast, with no previous epidemiological reports. The current study aimed to assess the relationship between EGFR mutations and histologic subtypes according to the 2015 WHO Classification. We assessed the frequencies of EGFR mutations in consecutive pulmonary adenocarcinomas among a population-based sample in Northeastern Brazil. A sample of 351 patients diagnosed from 2014-2016 was analyzed by direct sequencing (45.5%), real time PCR (34.1%) or next generation sequencing (20.4%). The overall mutation rate was 30.5%. The ratio of exon 19 deletions to exon 21 L858R mutations was 1.2:1. Three patients had T790M mutations detected after progression in use of targeted therapy. Female sex (P = 0.002), never smoking status (P = 0.002), and nonsolid subtype of ADC (P = 0.001) were associated with EGFR mutations on univariate analyses. Acinar predominant and lepidic predominant tumors had a higher rate of mutation but with no statistical significance when evaluated solely. Papillary component did not show correlation with mutations. Tumor differentiation correlated significantly with their incidence of EGFR mutations, lower in poorly differentiated tumors (p=0.005). Follow-up will be presented. We will describe a series of consecutive adenocarciomas from a population with unknown status with a higher than expected rates (higher than Southern Brazil and similar to other Latin American countries), and correlate with the 2015 WHO classification of tumors.

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.

Analysis of the EGFR gene mutation in patients with nonsmall cell lung cancer in a Chinese population

Purpose: To investigate the epidermal growth factor receptor (EGFR) gene mutations and analyze their clinical significance in patients with non-small cell lung cancer (NSCLC) in Hubei province of China. Methods: A total of 138 paraffin embedded tissues were taken from patients with NSCLC who were treated at Hubei Hospital from January 2014 to June 2015. The tissue DNA was extracted and EGFR mutation was evaluated by polymerase chain reaction (PCR) sequencing analysis of exons 18, 19, 20, and 21. Results: The overall mutation rate of EGFR gene was 30.43 % (42/138) in 138 NSCLC patients. The mutation rates of EGFR gene at exon 18, 19, 20, 21 were 0 %（0/138), 13.8 %（19/138), 0.7 % (1/138) and 15.9 % (22/138), respectively. The mutation rate of EGFR gene was higher in female patients than that in males (62.2 % (28/45) vs 15.1 % (14/93), p 0.05). EGFR mutation frequency in adenocarcinoma was higher than that in squamous cell carcinoma: 33.9 % (41/121) vs. 5.9 % (1/17, p < 0.05). Conclusion: EGFR mutations in NSCLC patients mainly exist in exons 19 and 21, and the mutation rate of exon 21 is higher than that of exon 19, which is more commonly found in female, adenocarcinoma and non-smoking patients. Keywords: Non-small cell lung cancer, Epidermal growth factor receptor (EGFR), Targeted therapy, Sequencing

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.

Abstract 5028: Reverse translational research for identifying the correlation between EGFR mutation status and DPD protein expression in lung adenocarcinoma

Abstract [Background] Reverse translation research is often described as “From the Bedside to the Bench”, which means taking an understanding gained by observations in a patient population to create hypotheses and confirmation of the hypothesis in the laboratory. According to current chemotherapy treatment for lung adenocarcinoma, empirically, clinicians know that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) tend to be effective for radiological ground glass nodule- type lung adenocarcinomas. On the other hand, it has been shown that 5-FU sensitivity in patients with non-small cell lung cancer (NSCLC) is associated with EGFR mutation status. From such clinical hints, we identified a relationship between dihydropyrimidine dehydrogenase (DPD), a 5-FU degrading enzyme, and EGFR mutation status. [Methods] We firstly focused on clinicopathologic factors and in vitro correlations between DPD expression and EGFR mutation status. Secondly, we analyzed crosstalk between the EGFR signal cascade and DPD protein expression using EGFR mutated and not mutated cell lines. [Clinicopathological Study] EGFR mutations and messenger RNA (mRNA) levels of DPD were analyzed in 47 resected NSCLC tumors by laser-capture microdissection. EGFR mutation status and the immunohistochemical expression of DPD in 49 resected NSCLC tumors were also examined. As a result, adenocarcinoma in situ showed significantly higher DPD mRNA levels and more EGFR mutation frequency than other histological types (P &amp;lt; 0.05). DPD immunopositive cases were more frequently observed in adenocarcinoma, in females, and in nonsmokers; which were correlated with EGFR mutation status (P &amp;lt; 0.003). [Basic Study] In vitro, EGFR-mutated cell lines (PC9, HCC827; exon19 E746-A750 and H1975; exon21 L858R, T790M, gefitinib resistant) showed higher DPD mRNA and protein expression than wild types (H1437, H1299). The DPD gene (DPYD), and DPD protein expression were known to be regulated by the transcription factor Sp1. In the PC9 study, EGF treatment induced up-regulation of both Sp1 and DPD. Gefitinib, an EGFR-TKI, and mithramycin A, specific Sp-1 inhibitors, suppressed them. However, the phenomena were not observed in EGFR-wild types and EGFR-TKI resistant cell lines. These results suggest DPD is regulated mainly in EGFR signal cascade enhanced lung cancers such as EGFR mutated adenocarcinomas. 5-FU and its derivatives such as uracil-tegafur (UFT) or S-1 might be effective for EGFR wild type adenocarcinomas because of the low DPD expression. [Conclusion] Reverse translational research can provide useful information for clinical treatment. In the present study, we identified crosstalk between the EGFR signal cascade and DPD protein expression, which might affect therapeutic strategy for lung adenocarcinomas. Citation Format: Tomoshi Tsuchiya, Tetsuo Tominaga, Koji Mochinaga, Naoya Yamasaki, Keitaro Matsumoto, Takuro Miyazaki, Go Hatachi, Yuka Kitajima, Takeshi Nagayasu. Reverse translational research for identifying the correlation between EGFR mutation status and DPD protein expression in lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5028.

Abstract 2251: Intra-tumor heterogeneity in non-small-cell lung cancer (NSCLC) carrying EGFR mutations

Abstract Introduction. Driver mutations of the epidermal growth factor receptor (EGFR) are usually detected in 10% to 15% of Caucasian non-small cell lung cancer (NSCLC) patients. Evidence suggests that a fraction of EGFR mutant NSCLC might have intra-tumor heterogeneity which could potentially affect response to EGFR tyrosine kinase inhibitors (TKIs). We performed next generation sequencing (NGS)-based analysis of a large cohort of Italian EGFR mutant NSCLC to assess the level of intra-tumor heterogeneity. Materials and methods. Genomic DNA from EGFR mutant NSCLC samples as assessed with routine diagnostic methods (N. 181; 141 tissue specimens and 40 cytology samples), was retrospectively analyzed with the Ion AmpliSeq Colon and Lung Cancer Panel using Ion Torrent semiconductor sequencing. The panel assesses over 500 somatic mutations in 22 genes at a sensitivity of 2%. Variants with allelic frequency &amp;gt;2% and &amp;lt;5% were confirmed by droplet digital PCR (ddPCR), if material was available. Results. Analysis of EGFR mutant samples with NGS revealed the presence of two different hotspot EGFR mutations in 17/181 cases (9.4%). In 11 cases a EGFR sensitizing mutation and the p.T790M resistance mutation were detected; 6 tumors carried two different EGFR activating mutations at different allelic frequency. In addition, the presence of at least one variant in genes other than the EGFR was observed in 84/181 cases (46.4%), with TP53 being the most frequent mutant gene in EGFR mutant NSCLC (32/181; 17.7%). In 42 samples (23.2%) hotspot mutations were found in genes other than the EGFR, such as KRAS, NRAS, BRAF, ERBB2, PIK3CA or MET, which might cause primary resistance to EGFR targeting drugs. In 29 samples the additional mutations were at an allelic frequency &amp;gt;5%, and in 13 at a frequency &amp;gt;2% and &amp;lt;5%. All mutations at low allelic frequency for which material was available were confirmed by ddPCR (N.5). The allele frequency of the driver EGFR mutation and of the additional mutations were usually different, suggesting the sub-clonal origin of some driver mutations. In particular, in 15/42 cases the EGFR mutant allele frequency was lower as compared with the additional driver mutation. Conclusion. These preliminary data suggest that a subgroup of EGFR mutant tumors have intra-tumor heterogeneity and are likely to carry tumor clones with different molecular profile. Follow-up data are being collected to assess whether this phenomenon might affect the activity of first line EGFR TKIs. Citation Format: Anna Maria Rachiglio, Matilde Lambiase, Francesca Fenizia, Alessandro Morabito, Gaetano Rocco, Domenico Galetta, Vienna Ludovini, Bruno Vincenzi, Emiddio Barletta, Gerardo Botti, Nicola Normanno. Intra-tumor heterogeneity in non-small-cell lung cancer (NSCLC) carrying EGFR mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2251.

Comprehensive Biomarkers for Personalized Treatment in Pulmonary Large Cell Neuroendocrine Carcinoma: A Comparative Analysis With Adenocarcinoma

The prognosis for patients with large cell neuroendocrine carcinoma (LCNEC) of the lung is extremely poor, and optimal treatment strategies have not yet been established. To improve prognoses in patients with LCNEC, this study analyzed immunohistochemical expression and gene mutations of several known molecular targets in LCNECs and compared the expression levels of these targets with those in lung adenocarcinomas. Twenty-six patients with primary LCNEC and 40 patients with adenocarcinoma were analyzed. Excision repair cross-complementation group 1 (ERCC1), class III β-tubulin, topoisomerase I, topoisomerase II, epidermal growth factor receptor (EGFR)-L858R, and somatostatin receptor expression were evaluated by immunohistochemistry, and EGFR mutations were evaluated using direct DNA sequencing and the Scorpion-amplified refractory mutation system. In patients with LCNEC and adenocarcinoma, positive rates of topoisomerase I, topoisomerase II, ERCC1, class III β-tubulin, EGFR-L858R, and somatostatin were 100.0% and 100.0%, 65.4% and 15.0% (p<0.0001), 42.3% and 17.5% (p= 0.0462), 46.2% and 62.5%, 0.0% and 20.0% (p= 0.0182), and 50.0% and 5.0% (p < 0.0001), respectively. The frequencies of EGFR mutations were 0.0% and 37.5% in LCNEC and adenocarcinoma (p= 0.0002), respectively. Five-year overall survival rates were 64% in LCNEC and 91% in adenocarcinoma in stage I (p= 0.0132). Multivariate analysis showed that LCNEC histologic type was an independent prognostic factor in stage I. LCNEC showed overexpression of topoisomerase II, somatostatin, and ERCC1. These findings suggested that it was possible to have good response to treatment with etoposide and octreotide and that LCNEC may be resistant to platinum-based therapy compared with adenocarcinoma. EGFR mutations were not observed in LCNEC. These results may indicate a favorable response to adjuvant treatments that are not typically prescribed for non-small cell lung cancer.

The Frequency of EGFR Mutation in Lung Adenocarcinoma and the Efficacy of Tyrosine Kinase Inhibitor Therapy in a Hungarian Cohort of Patients.

In the last decades new therapeutic drugs have been developed for the treatment of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) significantly increase the progression free survival (PFS) of patients with NSCLC carrying epidermal growth factor receptor (EGFR) mutations. This type of lung cancer occurs mainly among non-smoking women and Asian origin. However, the new ESMO guideline recommends EGFR mutation analysis in every patient with NSCLC, because in patients with activating EGFR mutation, TKIs should be considered as first line therapy. In our recent work, we analyzed data of patients with EGFR-mutant adenocarcinoma from January 2009. The number of patients investigated was 446, among them 44 cases were positive for EGFR mutation. The ratio of positive cases was 9.86% that is lower than the average mutation rate in Europe and much lower than that found in Asia. The exon 19 deletion was detected in 61.4% of the patients, while L858R point mutation in exon 21 was observed in 34.1% of them. In one subject, both exon 19 and 21 mutations were present simultaneously. A rare mutation located in exon 21 was found in another patient. TKI therapy was conducted in 38 patients. The disease control rate by TKI therapy was 85.7%; primary resistance was documented in five subjects. Non-smoking patients with EGFR mutant adenocarcinoma had the highest benefit from TKI treatment. Our data support the recommendation that EGFR mutation status should be defined in all cases of locally advanced or metastatic lung adenocarcinoma.

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.

EGFR Mutations in Latinos From the United States and Latin America.

PurposeEpidermal growth factor receptor (EGFR) mutations confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced non–small-cell lung cancer (NSCLC). There are limited and conflicting reports on the frequency of EGFR mutations in Latinos.Patients and MethodsSamples from 642 patients with NSCLC from seven institutions in the United States and Latin America were assessed for EGFR mutations (exons 18 to 21) at Clinical Laboratory Improvement Amendments-certified central laboratories.ResultsEGFR mutation analysis was successfully performed in 480 (75%) of 642 patients; 90 (19%) were Latinos, 318 (66%) were non-Latino whites, 35 (7%) were non-Latino Asians, 30 (6%) were non-Latino blacks, and seven (2%) were of other races or ethnicities. EGFR mutations were found in 21 (23%) of 90 Latinos with varying frequencies according to the country of origin; Latinos from Peru (37%), followed by the United States (23%), Mexico (18%), Venezuela (10%), and Bolivia (8%). In never-smoker Latinos and Latinos with adenocarcinoma histology, EGFR mutation frequencies were 38% and 30%, respectively. There was a significant difference in the frequency of EGFR mutations among the different racial and ethnic subgroups analyzed (P < .001), with non-Latino Asians having the highest frequency (57%) followed by Latinos (23%), non-Latino whites (19%), and non-Latino blacks (10%). There was no difference between Latinos (23%) and non-Latinos (22%; P = .78) and Latinos and non-Latino whites (P = .37). Patients from Peru had an overall higher frequency of mutations (37%) than all other Latinos (17%), but this difference only exhibited a trend toward significance (P = .058).ConclusionThere was no significant difference between the frequency of EGFR mutations in NSCLC in Latinos and non-Latinos.

Spectrum of EGFR gene mutations in Vietnamese patients with non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) mutational status is a crucial biomarker for prediction of response to tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Although these mutations have been well characterized in other countries, little is known about the frequency or spectrum of EGFR mutations in Vietnamese NSCLC patients. Using Sanger DNA sequencing, we investigated mutations in EGFR exons 18-21 from 332 patients diagnosed with NSCLC at University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam. DNA was extracted from formalin-fixed, paraffin-embedded tissues, followed by PCR amplification and sequencing. EGFR mutations were detected in 135 samples (40.7%), of which eight samples carried double mutations. In total, 46 different types of EGFR mutations were found, including six novel mutations (p.K713E, p.K714R, p.P794S, p.R803W, p.P848S, and p.K867E). Among the four exons investigated, exon 19 was most frequently mutated (63 out of 332 patients, 19%), with the p.E746_A750del appearing in 43 samples. Exon 21 was mutated in 56 samples (16.9%), of which 47 were p.L858R. Each of exons 18 and 20 was mutated in 12 samples (3.6%). The frequency of EGFR mutations was higher in females than in males (48.9% vs 35%, P = 0.012), but not statistically different between adenocarcinomas and other histological types of NSCLC (41.3% vs 34.5%, P = 0.478). DNA sequencing detected EGFR mutations with high frequency and revealed a broad spectrum of mutation type in Vietnamese patients with NSCLC.

Concomitance of P-gp/LRP Expression with EGFR Mutations in Exons 19 and 21 in Non-Small Cell Lung Cancers.

PurposeTraditional chemotherapy is the main adjuvant therapy for the treatment of non-small cell lung cancer (NSCLC). However, the emergence of multi-drug resistance (MDR) has greatly restricted the curative effect of chemotherapy. Therefore, it is necessary to find a method to treat MDR NSCLC clinically. It is worth investigating whether NSCLCs that are resistant to traditional chemotherapy can be effectively treated with tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR).Materials and MethodsThe expression of P-glycoprotein (P-gp) and lung resistance-related protein (LRP) was detected by immunohistochemistry, and mutations in EGFR (exons 19 and 21) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (exon 2) were detected by high-resolution melting analysis (HRMA) of surgical NSCLC specimens from 127 patients who did not undergo traditional chemotherapy or radiotherapy. A Pearson chi-square test was performed to analyze the correlations between the expression of P-gp and LRP and mutations in EGFR and KRAS.ResultsThe expression frequencies of P-gp and LRP were significantly higher in adenocarcinomas from non-smoking patients; the expression frequency of LRP was significantly higher in cancer tissue from female patients. The frequency of EGFR mutations was significantly higher in well to moderately differentiated adenocarcinomas from non-smoking female patients. The frequency of EGFR mutations in the cancers that expressed P-gp, LRP, or both P-gp and LRP was significantly higher than that in cancers that did not express P-gp or LRP.ConclusionNSCLCs expressing P-gp/LRP bear the EGFR mutation in exon 19 or 21 easily.

Molecular Epidemiology of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer of Adenocarcinoma Histology - Mainland China Subset Analysis of the PIONEER study.

Epidermal growth factor receptor (EGFR) mutations are the strongest response predictors to EGFR tyrosine kinase inhibitors (TKI) therapy, but knowledge of the EGFR mutation frequency on lung adenocarcinoma is still limited to retrospective studies. The PIONEER study (NCT01185314) is a prospective molecular epidemiology study in Asian patients with newly diagnosed advanced lung adenocarcinoma, aiming to prospectively analyze EGFR mutation status in IIIB/IV treatment-naïve lung adenocarcinomas in Asia. We report the mainland China subset results. Eligible patients (≥20 yrs old, IIIB/IV adenocarcinoma and treatment-naïve) were registered in 17 hospitals in mainland China. EGFR was tested for mutations by amplification refractory mutation system using biopsy samples. Demographic and clinical characteristics were collected for subgroup analyses. A total of 747 patients were registered. Successful EGFR mutation analysis was performed in 741, with an overall mutation rate of 50.2%. The EGFR active mutation rate is 48.0% (with 1.3% of combined active and resistance mutations). Tobacco use (>30 pack-year vs. 0–10 pack-year, OR 0.27, 95%CI: 0.17–0.42) and regional lymph nodes involvement (N3 vs. N0, OR 0.47, 95%CI: 0.29–0.76) were independent predictors of EGFR mutation in multivariate analysis. However, even in regular smokers, the EGFR mutation frequency was 35.3%. The EGFR mutation frequency was similar between diverse biopsy sites and techniques. The overall EGFR mutation frequency of the mainland China subset was 50.2%, independently associated with the intensity of tobacco use and regional lymph nodes involvement. The relatively high frequency of EGFR mutations in the mainland China subset suggest that any effort to obtain tissue sample for EGFR mutation testing should be encouraged.

Correlation between EGFR Gene Mutations and Lung Cancer: a Hospital-Based Study.

Epidermal growth factor receptor (EGFR) is one of the targeted molecular markers in many cancers including lung malignancies. Gefitinib and erlotinib are two available therapeutics that act as specific inhibitors of tyrosine kinase (TK) domains. We performed a case-control study with formalin-fixed paraffin-embedded tissue blocks (FFPE) from tissue biopsies of 167 non-small cell lung carcinoma (NSCLC) patients and 167 healthy controls. The tissue biopsies were studied for mutations in exons 18-21 of the EGFR gene. This study was performed using PCR followed by DNA sequencing. We identified 63 mutations in 33 men and 30 women. Mutations were detected in exon 19 (delE746-A750, delE746-T751, delL747-E749, delL747-P753, delL747-T751) in 32 patients, exon 20 (S786I, T790M) in 16, and exon 21 (L858R) in 15. No mutations were observed in exon 18. The 63 patients with EFGR mutations were considered for upfront therapy with oral tyrosine kinase inhibitor (TKI) drugs and have responded well to therapy over the last 15 months. The control patients had no mutations in any of the exons studied. The advent of EGFR TKI therapy has provided a powerful new treatment modality for patients diagnosed with NSCLC. The study emphasizes the frequency of EGFR mutations in NSCLC patients and its role as an important predictive marker for response to oral TKI in the south Indian population.

Divergent epidermal growth factor receptor mutation patterns between smokers and non-smokers with lung adenocarcinoma.

Smoking status is an important determinant of the prevalence of epidermal growth factor receptor (EGFR) mutations in lung cancer patients. However, it is unclear whether smoking status could also influence the spectrum of EGFR mutations. We enrolled patients with lung adenocarcinoma from three medical centers in Taiwan. EGFR mutations were assessed by Sanger direct sequencing. The objective of this study was to evaluate the influence of smoking status on both the frequency and patterns of EGFR mutations. From 2001 to 2013, a total of 1175 patients with lung adenocarcinoma were enrolled for EGFR mutation analysis. The overall EGFR mutation rate was 59.6%, which was significantly higher in females than males (69.1% vs. 49.8%) and in non-smokers than current/former smokers (73.8% vs. 29.8%) (both P<0.001). Among patients harboring EGFR mutations, smokers expressed L858R mutation less frequently (35.2% vs. 50.2%, P=0.005) and exon 19 deletions more frequently (52.8% vs 38.8%, P=0.008) than non-smokers. Smokers and non-smokers also had divergent exon 19 deletions subtypes (Del E746-A750 82.5% vs. 57.6%, respectively, P<0.001). Among subgroup patients harboring the L858R mutation, smokers were associated with a higher rate of complex mutations than non-smokers (34.2% vs. 8.4%, P<0.001). Our results suggested that smoking status could influence not only the frequency but also the spectrum of EGFR mutations. These findings provide a clue for further investigation of EGFR mutagenesis.

Negative Thyroid Transcription Factor 1 Expression Defines an Unfavorable Subgroup of Lung Adenocarcinomas

Thyroid transcription factor 1 (TTF1) is a master regulator of pulmonary differentiation that is downregulated in a subset of lung adenocarcinoma, of which the clinicopathologic characteristics were not fully clarified. One thousand forty-two lung adenocarcinoma patients who underwent surgery were investigated for clinic characteristics, histologic subtyping, and spectrum of well-identified driver mutations. TTF1 expression was correlated with these clinicopathologic factors and survival. Compared with TTF1 positive (TTF1+) patients, the 133 negative individuals (12.8%, TTF1-) were more likely to be male (p = 0.006) and heavy smokers (p = 0.002) who had larger tumor size (p < 0.001) and more advanced disease stage (p < 0.001). TTF1- presented more in solid and invasive mucinous-predominant carcinomas (both p < 0.001), whereas TTF1+ was identified in 100% patients with adenocarcinoma in situ, minimally invasive and lepidic-predominant adenocarcinomas. The TTF1- tumors harbored the known driver mutations in significantly low frequency compared with TTF1+ adenocarcinomas (57.8% versus 78.1%, p < 0.001), especially in epidermal growth factor receptor (EGFR) mutations (37.6% versus 60.7%, p < 0.001). There was no significant difference in recurrence-free survival between the TTF1- and TTF1+ patients, either for the whole cohort or stratified by pathologic stage, or among the driver mutation-defined subsets. However, recurrence of multiple metastases was more likely to occur in patients with TTF1- adenocarcinomas (88.1% versus 32.4%, p < 0.001). Multivariate analysis revealed that TTF1- independently predicted both poor postrecurrence survival (hazard ratio = 1.664; 95% confidence interval , 1.097-2.524; p = 0.017) and unfavorable overall survival (hazard ratio = 1.553; 95% confidence interval , 1.013-2.381; p = 0.043). TTF1- correlated with solid and invasive mucinous subtypes of lung adenocarcinoma and lower frequency of EGFR mutations. It defines a subgroup of lung adenocarcinomas with unfavorable outcomes.