Epidermal Growth Factor Receptor Mutation Rate Research Articles

P1.13-39 Epidermal Growth Factor Receptor Mutation Among Non-Small Cell Lung Cancer Patients in Trinidad and Tobago: Frequency and Trends

Almost 70% of non-small cell lung cancer (NSCLC) patients present with unresectable disease and may benefit from chemotherapy or biologic therapy. Mutation testing now plays a vital role in their diagnostic work-up to determine which patients are more likely to receive benefit from biologic therapies. The rate of epidermal growth factor receptor (EGFR) mutations varies significantly across geographic regions and ethnicities, ranging from 13% to 64% in some areas. Several subgroups such as females, East Asians, never-smokers and those with adenocarcinoma histology have the highest reported rates of EGFR mutations. Regionally, the French West Indies reports an EGFR mutation rate of 36%. The frequency of the EGFR mutation among NSCLC patients in Trinidad and Tobago has not been previously reported in the literature. An observational, retrospective study was done using data obtained from the Lung Malignancy Unit (LMU) based at the Eric Williams Medical Sciences Complex (EWMSC). The EWMSC is the sole referral centre in Trinidad and Tobago for lung cancer and the LMU is responsible for co-ordinating clinical and educational services regarding lung cancer nationwide.The study population was limited to primary NSCLC patients presenting to the EWMSC from January 2014 to June 2017 whose biopsy samples were sent for EGFR testing and received either a positive or negative result. Patients’ clinical data was entered onto a spreadsheet and analysed using Microsoft Excel. The data for 94 patients with NSCLC were analysed. 68 of these patients were male, while 58 admitted to a history of smoking. EGFR mutations were present in 39.4% of this study population. Females demonstrated a significantly higher EGFR mutation rate than males (73.1% vs 26.5%, p < 0.0001). Smoking status was found to be significantly associated with differences in EGFR mutation status (p < 0.01). The mean age of presentation was similar despite of EGFR mutation status. Although a larger number of EGFR positive patients compared to EGFR negative patients had adenocarcinoma histology (97.3% vs. 89.5%), this was not found to be statistically significant (p = 0.29). The frequency of EGFR mutations in this study population (39.4%) was higher than most regions of the world but similar to that reported in the French Antilles. Sex and smoking status were significantly associated with differences in EGFR mutation status.

The exon 19-deleted EGFR undergoes ubiquitylation-mediated endocytic degradation via dynamin activity-dependent and -independent mechanisms

BackgroundThe epidermal growth factor receptor (EGFR) is closely implicated in cancer, and sequencing analyses have revealed a high mutation rate of EGFR in lung cancer. Recent advances have provided novel insights into the endocytic regulation of wild-type EGFR, but that of mutated EGFR remains elusive. In the present study, we aim to investigate the endocytic degradation of a frequently occurred exon 19-deleted mutant in lung cancer.MethodsThe EGF-induced endocytic degradation of EGFR was examined in a panel of lung cancer cells using immunoblotting. The subcellular distribution of internalized EGFR was investigated using immunofluorescence and confocal microscopy. The effects of dynamin were assessed using its small molecule inhibitors, while the influence of RTN3 was tested using shRNA-mediated knockdown. Finally the ubiquitylation status of EGFR mutant was studied using immunoprecipitation under steady state and tyrosine kinase inhibitor-treated conditions.ResultsEGF induced various rates of EGFR endocytic degradation in lung cancer cells. Interestingly, the exon 19 deletion mutant is constantly internalized and sorted to lysosome for degradation, and this process is independent of dynamin activity. EGF stimulation and HSP90 inhibition further enhance the endocytic degradation of the exon 19 deletion mutant, in a dynamin activity-dependent and -independent manner, respectively. Albeit with different modes of internalization, the uptake of the exon 19-deleted EGFR is mediated through receptor ubiquitylation.ConclusionsThe internalized EGFR mutant is constantly routed through endosome to lysosome for degradation. The endocytosis of EGFR mutant occurs through both dynamin activity-dependent and -independent mechanisms. Our findings gain novel insights into the endocytic regulation of mutated EGFR and may have potential clinical implications.

CtDNA assessment of EGFR mutation status in Chinese patients with advanced non-small cell lung cancer in real-world setting.

The prevalence of EGFR mutations in circulating free tumor-derived DNA (ctDNA) was still unknown in China. This large-scale study (NCT02623257) aimed to explore the prevalence of epidermal growth factor receptor (EGFR) mutations and determine the correlation of EGFR mutation status with clinical characteristics. Plasma DNA samples from 1,001 patients with stage III/IV NSCLC who received ≤1st line chemotherapy were collected from 65 hospitals. EGFR mutations were tested by amplification refractory mutation system (ARMS) method. The EGFR mutation rate was calculated and the associations between EGFR status and patients' demographic data, disease status as well as treatment pattern were explored. EGFR mutations were detected in 251 of 1,001 (25.1%) patients, 26.8% in adenocarcinoma and 11.7% in squamous carcinoma. A total of 189 harbored sensitizing mutations alone, 28 had resistance mutations alone, 3 had a combination of activating mutations, and 31 had a combination of activating and resistance mutations. Higher detection rate was observed in chemotherapy-naïve patients than those received 1st line chemotherapy (27.0% vs. 18.0%; P=0.006). Of which, the mutation rate of exon 19 deletion was 9.31% for naïve patients and 7.37% for the 1st chemotherapy patients; while the mutation rate of L858R decreased obviously from 10.20% (naïve) to 3.69% (1st line). We also noticed the mutation rate was 37.1% in patients with ≥2 organ metastases. Multivariate analysis showed female, chemotherapy-naïve, or ≥2 metastatic organs patients had higher EGFR mutation rate. ctDNA based EGFR mutation test is feasible and could be a surrogate when tissue biopsy is not available.

Abstract 5589: Detection of epidermal growth factor receptor mutations from circulating tumor DNA versus archival tissue of lung cancer

Abstract Background: Epidermal growth factor receptor (EGFR) mutations are well known predictive marker of targeted therapy. We compared the sensitivity of EGFR mutation detection techniques between matched achival lung cancer tissue and peripheral blood sample. Methods: We collected the paired samples from plasma and paraffin-embedded tumor tissue obtained before EGFR-tyrosine kinase inhibitor (EGFR-TKI). DNA extraction was performed using the QIAamp MinElute virus spin kit and EGFR mutation analysis was done by two detection methods. The current standard test is the PNAClampTM (Clamp) which is the PNA-based PCR clamping that selectively amplifies only the mutated target DNA sequence. The new technique is the PANAMutyperTM EGFR test (Mutyper), which use PNA clamping-assisted fluorescence melting curve analysis. Results: A total of 295 (188 male and 107 female) patients were analyzed in this study. The histologic types were composed of 258 adenocarcinoma, 22 squamous cell carcinoma and 15 others. Most were clinical stage IV (137, 46.4%) and the EGFR mutation rate of tissue sample by standard Clamp test was 25.7%. Plasma sensitivity was significantly higher in Mutyper than Clamp (71.2% vs. 30.0%, p&amp;lt;0.001) with tissue as reference. The overall concordance and degree of agreement between two samples were better in Mutyper (91.9%, k=0.762, p&amp;lt;0.001) than Clamp (81.7%, k=0.344, p&amp;lt;0.001). In tissue sample, the median progression-free survival (PFS) of EGFR sensitive group was significantly longer than negative group regardless of the two methods. In plasma sample, the median PFS was significantly longer only by Mutyper (9.9 vs. 2.2 months, p=0.001), not by Clamp (9.8 vs. 7.6 months, p=0.968). Conclusions: Mutyper was useful liquid biopsy technique with better sensitivity than standard Clamp test. Citation Format: In-Jae Oh, Hyeong-Won Seo, Hyun-Ju Cho, Ha-Young Park, Bo-Gun Kho, Jin-Sun Chang, Tae-Ok Kim, Hong-Jun Shin, Cheol Kyu Park, Jung-Hwan Lim, Yong-Soo Kwon, Yu-Il Kim, Sung-Chul Lim, Young-Chul Kim, Yoo-Duk Choi. Detection of epidermal growth factor receptor mutations from circulating tumor DNA versus archival tissue of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5589.

Correlation between EML4-ALK, EGFR and clinicopathological features based on IASLC/ATS/ERS classification of lung adenocarcinoma.

To investigate the correlation between echinodermmicro tubule associated protein-like 4 (EML4)-anaplasticlymphomakinase (ALK), epidermal growth factor receptor (EGFR) and clinicopathological features in patients diagnosed with lung adenocarcinoma according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) international multidisciplinary classification of lung adenocarcinoma.Ninety patients diagnosed with lung adenocarcinoma underwent surgical pathological classification. Ventana immunohistochemical staining of the EML4-ALK was performed. The mutation of EGFR and EML4-ALK was detected by real-time polymerase chain reaction (RT-PCR) using the amplification refractory mutation system.The positive rate of EML4-ALK mutation was calculated as 6.7% (6/90), dominantly occurring in patients aged < 60 years. However, it was not correlated with the gender, smoking history, maximal tumor diameter, pleural invasion, lymphatic metastasis, or clinical staging. EML4-ALK fusion gene mutation was mainly associated with the predominant subtypes of acinar and solid tumors with mucin secretion. The mutation rate of EGFR was 60% (27/45). EGFR gene mutation mainly occurred in the female, those with no smoking history and tumor size < 3 cm, whereas it had no association with age, pleural invasion, lymphatic metastasis, or clinical staging. It was histologically characterized with micropapillary, lepidic, and papillary subtypes.The mutation rate of EML4-ALK is relatively high in lung adenocarcinoma patients aged<60 years, pathologically characterized with acinar and solid subtypes with mucin secretion. Female patients with no smoking habit, tumor size<3 cm, pathologically characterized with micropapillary, lepidic, and papillary subtypes had a high mutation rate of EGFR.

Influence of Different Therapies on EGFR Mutants by Circulating Cell-free DNA of Lung Adenocarcinoma and Prognosis

背景与目的表皮生长因子受体（epidermal growth factor receptor, EGFR）基因突变与肺腺癌患者TKI靶向治疗疗效和预后密切相关，常规组织分析其突变状态有诸多局限。本研究旨在探讨非小细胞肺癌（non-small cell lung cancer, NSCLC）患者血液循环游离DNA（cell-free DNA, cfDNA）检测EGFR基因突变在治疗前、传统化疗以及靶向治疗后的表达差异。分析血液cfDNA是否能准确检测EGFR基因突变并监测耐药基因T790M的变化，以及TKI在靶向治疗患者中的预后价值。方法应用ARMS（amplification refractory mutation system）法检测107例（50例治疗前、29例传统化疗和28例靶向治疗）肺癌患者配对血液和肿瘤组织样本的EGFR基因突变并比较其表达差异；计算检测的一致性、敏感性和特异性；分析血检对靶向治疗患者的预后价值。结果血浆cfDNA检测EGFR总突变率在107例肺癌患者中为56%（60例），而配对肿瘤组织样本检出率为77.6%（83例）。一一配对比较发现两者总体一致率为68.2%。血检的敏感性是72.3%，特异性为100%。依据治疗状态分组后发现治疗前组患者血液和肿瘤组织样本的检测一致率最高（74%, 37/50），而靶向组一致率最低（57.1%, 16/28），提示靶向治疗改变血浆cfDNA中EGFR基因状态。具体分析靶向组不一致病例发现50%新检出含T790M的双突变，提示靶向治疗后耐药基因出现。生存分析证实血检含T790M双突变组的无进展生存期（progression-free survival, PFS）和总生存期（overall survival, OS）均显著低于无T790M突变组。结论应用ARMS法检测血液循环游离DNA（circulating cell-free DNA, cfDNA）的EGFR基因突变是一种特异性高、敏感性好的检测方法。适用于治疗前晚期肺癌患者的EGFR基因突变状态检测。同时，适用于靶向治疗后监测T790M耐药突变状态及预测患者预后。

Analyzing EGFR mutations and their association with clinicopathological characteristics and prognosis of patients with lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) is an important gene in the development of lung adenocarcinoma. However, there is controversy regarding the association between EGFR mutations and survival time of patients with lung adenocarcinoma. In the present study, tissue specimens and clinical data were collected from 219 patients with lung adenocarcinoma who had not undergone prior radiotherapy or chemotherapy. EGFR mutations were detected using a fluorescence polymerase chain reaction method, and the association between EGFR mutations and clinicopathological characteristics was analyzed. Overall survival (OS) curves were constructed using the Kaplan-Meier method and the influence of clinicopathological characteristics on OS was analyzed using the Cox regression model. The EGFR mutation rate was 50.7%, and the most common mutations were the L858R substitution mutation in exon 21 (L858R; 54.9%) and the deletion mutation in exon 19 (19-Del; 36%). The presence of EGFR mutations varied significantly with sex, smoking history, T stage, vascular invasion and adenocarcinoma subtypes (P<0.05). The survival time was significantly longer for female, young (<60 years-old), non-smokers or patients exhibiting EGFR mutations (G719X, 19-Del, L858R and L861Q). The survival time was also significantly longer for patients with a 19-Del mutation, early stage tumors, tyrosine kinase inhibitors targeted therapy-treated patients, for those not exhibiting nerve or vascular invasion, and for those without disease recurrence (P<0.05). Multivariate analysis revealed that tumor pathological Tumor-Node-Metastasis (pTNM) stage, nerve invasion, vascular invasion, EGFR mutation and the 19-Del mutation were independent predictors (P<0.05). Therefore, tumor pTNM stage, nerve invasion, vascular invasion and EGFR mutation status, particularly that of 19-Del, were independent prognostic factors for patients with lung adenocarcinoma.

Ground glass opacities: Imaging, pathology, and gene mutations

BackgroundLung cancer can be detected in its early stages with computed tomography (CT). Early lung adenocarcinoma often is displayed as ground glass opacity (GGO), an entity that has been well studied over the past decade. However, few studies have focused on the correlation between CT characteristics and pathologic subtype of GGO. We aimed to explore the correlation between CT characteristics, pathologic subtype, and gene mutation associated with GGO in an effort to aid in the treatment of lung adenocarcinoma. MethodsIn this retrospective study, patients with GGO who underwent surgery in our institution between 2013 and 2016 were included. Patients were divided into 2 groups on the basis of CT characteristics: group 1, diameter <20 mm and solid component <50%; and group 2, diameter ≥20 mm or solid component ≥50%. Differences in pathologic subtype and gene mutation pattern between groups were compared using the χ2 test. The correlation between pathologic subtype and epidermal growth factor receptor (EGFR) mutation was also tested using the χ2 test. ResultsA total of 1018 cases (408 in group 1, 610 in group 2) were included; of these, 544 were tested for the EGFR gene mutation. There was a significant difference in predominant subtype (P < .001) and all included subtypes (P = .044) between the groups. Of 59 cases with the pathologic subtype of micropapillary or solid, 57 were in group 2. The EGFR gene mutation rate was significantly higher in group 2 than group 1 (P < .001) and significantly correlated with pathologic subtype (P < .001); adenocarcinoma in situ was the lowest (31.4%) and papillary was the highest (85.7%). EGFR mutation subtype did not significantly differ between groups (P = .499). ConclusionsCT characteristics of GGO significantly correlated with pathologic subtype and gene mutation rate. The EGFR mutation rate differed significantly among pathologic subtypes. GGOs with a diameter of <20 mm and with a solid component <50% seldom contain subtypes with poor prognosis (micropapillary and solid) and the EGFR mutation rate was significantly lower.

EGFR mutations subset in Chinese lung squamous cell carcinoma patients.

Research has identified that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) possess large benefits for adenocarcinoma (ADC), although little benefit for squamous cell carcinoma (SCC). The aim of the present study was to investigate the percentage of patients with SCC with the EGFR mutations subset and the benefits of EGFR TKIs in SCC. In the present study, the EGFR mutations subset was detected with an amplification refractory mutation system in 1,359 clinical SCC tissues. The association of the EGFR mutations subset with clinicopathological parameters was evaluated using the Mann-Whitney U test, and Kruskal-Wallis H. Kaplan-Meier survival analysis was used to estimate the effect of the EGFR mutations subset on SCC patient survival rates. A total of 94 out of 1,359 SCC patients were identified as having EGFR mutations, an EGFR mutation rate of 6.92%. The EGFR mutations subset in the 94 cases was identified as follows: 37.2% (35/94) in exon 19; 39.4% (37/94) in L858R; 5.3% (5/94) in T790M; 4.3% (4/94) in G719X; 2.1% (2/94) in L861Q; and 11.7% (11/94) in other mutations. Kaplan-Meier survival analysis identified that the differentiation, pathological tumor, node, metastasis stage, lymph node metastasis and distant metastases were significantly associated with patients' survival (P>0.05; log-rank test), and no significant difference was observed between TKI therapy and chemotherapy in terms of patient survival rates (P>0.05). In addition, the overall discordant rate of the EGFR mutations subset in SCC patients was relatively low. Due to the non-significant difference between TKI therapy and chemotherapy in terms of patient survival and the lower discordance rate of the EGFR mutations subset in SCC patients, EGFR TKIs could be a recommended treatment for SCC.

Uncommon &lt;em&gt;EGFR&lt;/em&gt; mutations in cytological specimens of 1,874 newly diagnosed Indonesian lung cancer patients

PurposeWe aimed to evaluate the distribution of individual epidermal growth factor receptor (EGFR) mutation subtypes found in routine cytological specimens.Patients and methodsA retrospective audit was performed on EGFR testing results of 1,874 consecutive cytological samples of newly diagnosed or treatment-naïve Indonesian lung cancer patients (years 2015–2016). Testing was performed by ISO15189 accredited central laboratory.ResultsOverall test failure rate was 5.1%, with the highest failure (7.1%) observed in pleural effusion and lowest (1.6%) in needle aspiration samples. EGFR mutation frequency was 44.4%. Tyrosine kinase inhibitor (TKI)-sensitive common EGFR mutations (ins/dels exon 19, L858R) and uncommon mutations (G719X, T790M, L861Q) contributed 57.1% and 29%, respectively. Approximately 13.9% of mutation-positive patients carried a mixture of common and uncommon mutations. Women had higher EGFR mutation rate (52.9%) vs men (39.1%; p<0.05). In contrast, uncommon mutations conferring either TKI responsive (G719X, L861Q) or TKI resistance (T790M, exon 20 insertions) were consistently more frequent in men than in women (67.3% vs 32.7% or 69.4% vs 30.6%; p<0.05). Up to 10% EGFR mutation–positive patients had baseline single mutation T790M, exon 20 insertion, or in coexistence with TKI-sensitive mutations. Up to 9% patients had complex or multiple EGFR mutations, whereby 48.7% patients harbored TKI-resistant mutations. One patient presented third-generation TKI-resistant mutation L792F simultaneously with T790M.ConclusionRoutine diagnostic cytological techniques yielded similar success rate to detect EGFR mutations. Uncommon EGFR mutations were frequent events in Indonesian lung cancer patients.

Epidermal growth factor receptor mutation status and clinical characteristics of advanced lung adenocarcinoma in elderly patients

Objective To investigate the epidermal growth factor receptor(EGFR)mutation status and the corresponding clinical characteristics of advanced lung adenocarcinoma in patients over 60 years and the efficacy of first-line therapy. Methods A total of 243 cases aged 60 years and over with histologically confirmed advanced lung adenocarcinoma from January 2011 to December 2015 at Beijing Hospital were included in this retrospective study.The EGFR mutation status was detected by the amplification refractory mutation system.Clinical characteristics including gender, smoking status, and incidence of brain metastasis at initial presentation were recorded.Data for 163 cases aged below 60 years during the same period were collected as controls.The characteristics of EGFR mutation status of elderly patients were analyzed.Besides, differences between the groups in EGFR mutation status, other clinical characteristics and therapeutic efficacy of first-line treatment were compared. Results The EGFR mutation rate was 53.1%(129/243). Basic clinical features were not statistically different between the groups.For elderly patients harboring EGFR mutations, the incidences of the exon 19 deletion and the exon 21 L858R mutation accounted for 46.2%(55/119)and 53.8%(64/119), respectively, whereas for younger patients with EGFR mutations, the prevalence of the exon 19 deletion and the exon 21 L858R mutation were 66.2%(49/74)and 33.8%(25/74), respectively.The proportion with the exon 21 L858R mutation was statistically higher in elderly patients(P=0.007). Eighty-two out of 129 patients with sensitive EGFR mutations received first-line EGFR tyrosine kinase inhibitors, with an objective response rate(ORR)of 62.2%(51/82) and a progression-free survival(PFS)of 8.1 months.For the other 152 patients who received chemotherapy, the ORR was 24.3%(37 cases) and the PFS was 6.0 months.The efficacy of first-line therapy was similar between the groups. Conclusions The incidence of EGFR mutations and clinical characteristics for elderly patients with advanced lung adenocarcinoma are similar to those for younger patients, whereas the proportion of the EGFR exon and the 21 L858R mutation is higher in the elderly.Considering similar benefits from fist-line treatment between different age groups, elderly lung cancer patients should receive similar treatment. Key words: Lung neoplasms; receptor epidermal growth factor; Mutation

Comparison of EGFR mutation between supernatant and pellets of malignant pleural effusion from patients with advanced non-small cell lung cancer

Objective To compare the epidermal growth factor receptor (EGFR) mutation differences between supernatant and pellets of malignant pleural effusion (MPE) in advanced non-small cell lung cancer (NSCLC) patients and provide the evidence for clinical accurate detection. Methods A total of 386 consecutive MPE specimens were collected in the study (202 in experimental group and 184 in validation group). Specimens in experimental group were divided into 4 groups depending on tumors cell concentration in the samples: zero cell (n=77), (1-5)×104/ml cells (n=43), (6-10)×104/ml cells (n=52) and >10×104/ml cells group (n=30). Amplification refractory mutation system (ARMS) was performed to detect EGFR gene mutation in supernatant and pellets of each individual case respectively, and the EGFR mutation positive rates were compared between the two groups. EGFR mutation test was carried out using either supernatant or pellets in validation group to verify the established method. Results In the experimental group, the total EGFR mutation positive rate was 30.7% (62/202). In the zero cell group, EGFR mutation positive rate was higher in supernatant than that in pellets (37.6% vs. 33.8%). In the (1-5)×104/ml cells group and (6-10)×104/ml cells group, EGFR mutation positive rate was equal but not concordant between supernatant and pellets (25.6% and 21.1% respectively). In the >10×104/ml cells group, EGFR mutation positive rate was equal (33.3%) with 100% concordance between supernatant and pellets. In the validation group (n=184), EGFR mutation rate was 32.7% (36/110) in supernatant and 32.4% (24/74) in pellets, and there was no statistical significance (χ2=0.02, P=0.97). Conclusion Tumor cell free MPE specimens from patients with advanced NSCLC are suitable for EGFR mutation test. Heterogeneity of MPE results in difference with respect to EGFR gene mutation status between cell-free supernatant and pellet. Pathological evaluation based on the quantity and quality of tumor cells in MPE patients prior to test and optional samples selection are necessary to increase EGFR mutation positive rate. Key words: Pleural effusion, malignant; Receptor, epidermal growth factor; Mutation

Epidermal growth factor receptor somatic mutation analysis in 354 Chinese patients with non-small cell lung cancer.

Lung cancer is one of the most common types of cancer worldwide, with the highest mortality rate of all types of cancer. In the present study, epidermal growth factor receptor (EGFR) mutations of 354 primary patients with non-small cell lung cancer (NSCLC) of Chinese ethnicity were detected following formalin-fixed and paraffin-embedded specimen DNA extraction, polymerase chain reaction amplification, and sanger sequencing. The total rate of occurrence of EGFR somatic mutation in these 354 patients was 48.02%. Of these detected EGFR mutations, 27.40% were located in exon 19 and 25.99% in exon 21. The most frequent mutation in exon 19 was E746-A750del (8.47%), and in exon 21, L858R (10.17%). EGFR mutation rates were significantly associated with sex [female vs. male: 60.13 vs. 38.81%; adjusted odds ratio (OR), 1.93, 95% confidence interval (CI), 1.07–3.51, P=0.029], age (<60 vs. ≥60; 58.62 vs. 40.67%; adjusted OR, 1.87; 95% CI, 1.20–2.92; P=0.006) and histology [adenocarcinoma (ADC) vs. non-ADC; 52.76 vs. 26.56%; adjusted OR, 2.35; 95% CI, 1.28–4.50; P=0.007]. The frequency of E746_A750del, Q787Q and L858R mutations were significantly different in ADC patients compared with squamous cell carcinoma patients (P<0.001). Furthermore, a novel EGFR mutation, M793K, was detected in 7 NSCLC patients with possible gefitinib resistance. The present study analyzed the EGFR exon 18–21 mutation occurrence profile for Chinese patients with NSCLC and identified significant associations between different EGFR mutations with demographic and histological factors. These results may offer clinical benefits and potential novel treatments.

Disease-free survival improved by use of adjuvant EGFR tyrosine kinase inhibitors in resectable non-small cell lung cancer: an updated meta-analysis.

A previous meta-analysis of our research team suggested survival advantage from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) after surgery in patients with EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to follow up on the findings of the previous one and presents our latest updates through the past few years. The study advanced the previous meta-analysis and included a comprehensive range of relevant studies in PubMed. Disease-free survival (DFS) with hazard ratios (HRs) was calculated using random and/or fixed-effects models. Subgroup analysis and meta-regression analysis were also performed. A total of 2,223 patients in seven studies were eligible for the analysis. Adjuvant EGFR-TKIs administration was significantly associated with superior DFS [HR, 0.60; 95% confidence interval (CI), 0.42-0.87], corresponding to an absolute benefit of 3.4% at 3 years, yet with significant heterogeneity (I2=80.0%, P <0.001). EGFR mutation rate of included patients was found to be a source of heterogeneity by meta-regression analysis (P=0.005). In the EGFR-mutant sub-population, HR for DFS was 0.51 (95% CI, 0.39-0.65), corresponding to an absolute benefit of 7.1% at 3 years. The rate of overall grade 3 or greater adverse events (AEs) was 38.9% (95% CI, 35.9-41.9%). The updated meta-analysis provided strengthened evidence of significant DFS advantage of adjuvant EGFR-TKI treatment for patients with EGFR-mutant NSCLC after complete resection.

EGFR mutation, smoking, and gender in advanced lung adenocarcinoma.

PurposeIn the current targeted therapy era, information on the effect of smoking in epidermal growth factor receptor (EGFR)-mutant lung cancer patients is scarce.ResultsIn total, 11,678 adenocarcinoma patients were enrolled. Of these, 33.3% and 91.8% of male and female patients were non-smokers, respectively. An increased amount of smoking (P < 0.001 for trend), fewer smoke-free years (P < 0.001 for trend), and younger age of smoking initiation (P = 0.034 for trend) were all associated with significantly lower EGFR mutation rates. Smokers had a shorter median overall survival (OS) among both EGFR-mutant and EGFR-wild type patients (17.8 vs. 21.1 months, and 7.9 vs. 11.4 months respectively; both P < 0.001). Among patients with EGFR-mutant adenocarcinoma, younger smokers were associated with shorter OS (P = 0.047). In multivariate analysis, female gender was an independent prognostic factor for OS (hazard ratio: 0.86 [95% confidence interval {CI}: 0.80–0.93]; P < 0.001 in the EGFR-mutant group and 0.88 [95% CI: 0.81–0.96]; P = 0.004 in the EGFR-wild type group).Materials and MethodsWe reviewed the National Lung Cancer database (Taiwan) to assess the impact of smoking on the EGFR mutation rate and survival in advanced lung adenocarcinoma patients during 2011 and 2014 retrospectively.ConclusionsSmoking was associated with lower incidence of EGFR mutation rate and reduced OS of advanced lung adenocarcinoma patients in a dose-dependent manner. In addition to EGFR mutation and smoking, gender also plays an important role in survival among these patients.

The relationship between EGFR mutation status and clinic-pathologic features in pulmonary adenocarcinoma

To detect the relationship of the epidermal growth factor receptor (EGFR) mutation status and the clinicopathologic features. Six hundred thirty-three patients with pathologically confirmed lung adenocarcinoma who underwent lung cancer resection surgery at the Fourth Hospital of Hebei Medical University between April 2012 and April 2015 were selected for the study. The 32 types of mutations in exons 18–21 of the EGFR gene were detected. The total EGFR mutation rate among patients with lung adenocarcinoma was 56.9%. The mutation rates were 71.2% among females and 42.8% among males (P < 0.05). Among patients with TNM stage I, II, III, and IV disease, the EGFR mutation rates were significant differences (P < 0.05). Concerning different subtypes of lung adenocarcinoma, the EGFR mutation rates were differences, and these differences were statistically significant (P < 0.05). Cox multivariate regression model analysis considering EGFR mutation status revealed that differences in TNM stage (P < 0.01), smoker status, and tumor size were statistically significant predictors. Patients with minimally invasive and lepidic adenocarcinomas were categorized as low-risk group with high EGFR mutation rate; Patients with micro-papillary and solid adenocarcinomas were categorized as high-risk with lower EGFR mutation rate, so there are different mechanisms in different types of adenocarcinomas.

EGFR and KRAS Gene Mutations in 754 Patients with Resectable Stage I-IIIa Non-small Cell Lung Cancer and Its Clinical Significance

背景与目的表皮生长因子受体（epidermal growth factor receptor, EGFR）和KRAS基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）重要的分子靶点，但目前研究主要集中在晚期NSCLC组织和血浆标本的EGFR检测，早期NSCLC组织样本中EGFR和KRAS突变特征尚不清楚。本研究将探讨Ⅰ期-Ⅲa期NSCLC EGFR和KRAS基因突变与相关临床病理特征的关系。方法采用突变扩增系统（amplification refractory mutation system, ARMS）PCR方法检测北京协和医院病理科提供的754例Ⅰ期-Ⅲa期NSCLC组织样本的EGFR和KRAS基因突变状况，分析基因突变率及其与临床病理特征的关系。结果EGFR和KRAS基因热点突变的突变率分别为34.5%和13.1%，其中有3例样本具有EGFR和KRAS基因的双突变。EGFR基因在女性中的突变率高于男性（39.5% vs 29.4%, P=0.076），在腺癌中的突变率（38.7%）高于鳞癌、腺鳞癌、大细胞癌（P < 0.01），但仍明显低于其他研究报道的亚裔晚期腺癌突变率（-50%）。KRAS基因突变在男性中的突变率高于女性（16.6% vs 9%, P=0.048），且在腺癌中的突变率也高于其他类型，但差异不显著（P=0.268）。与KRAS基因突变阳性组相比，EGFR基因突变阳性组在年龄分布上有年轻化的趋势（P=0.031, 5），在性别分布上有显著性差异（P < 0.01）。结论Ⅰ期-Ⅲa期NSCLC EGFR基因突变率较晚期患者低，且EGFR和KRAS基因双突变的发生率为0.9%。

Clinicopathological, radiographic, and oncogenic features of primary pulmonary enteric adenocarcinoma in comparison with invasive adenocarcinoma in resection specimens.

Primary pulmonary enteric adenocarcinoma (PEAC) is a rare subtype of primary lung adenocarcinoma. However, it is not known whether there are any distinctive clinical or molecular features.PEACs were retrospectively identified in 28 patients from July 2014 to June 2016. We compared the clinicopathological, radiographic, and oncogenic characteristics of PEAC and primary pulmonary invasive adenocarcinoma (IAC).A total of 28 PEAC patients and 92 IAC patients were compared. PEAC occurred more frequently in males (P = .008), in older patients (P = .041), in those with larger lesions (P = .001), and in those in a more advanced stage (P = .011). Radiologically, PEAC patients had larger lesions (P = .025) and more solid (P = .006); however, there were no statistically significant differences in lobulation, spiculation, pleural indentation, pleural effusion, and lymphadenopathy between PEAC and IAC. PEAC had higher values of carcinoembryonic antigen (P = .008) and carbohydrate antigen 19-9 (P < .001) than IAC. PEAC had a higher incidence (40% vs 63%, P < .001) of Kristen rat sarcoma viral oncogene homolog (KRAS) mutations and a lower incidence (10.71% vs 3.3%, P < .001) of epidermal growth factor receptor (EGFR) mutations. Villin may be a useful marker in the differential diagnosis of PEAC. KRAS mutations occurred more frequently in PEACs, which are cytokeratin 7-negative (P = .032). EGFR mutation rates were higher in PEACs, which are cytokeratin 20- and caudal type homeobox transcription factor 2-negative (P = .041).PEAC is a rare and heterogeneous nonsmall-cell lung cancer subgroup with distinctive clinicopathological, radiographic, and molecular features. These results need to be further confirmed in future studies.

Comparison of direct sequencing and amplification refractory mutation system for detecting epidermal growth factor receptor mutation in non-small-cell lung cancer patients: a systematic review and meta-analysis.

BackgroundDirect sequencing and amplification refractory mutation system (ARMS) are commonly used to detect epidermal growth factor receptor (EGFR) mutation status in patients with non-small-cell lung cancer to inform the decision-making on tyrosine kinase inhibitors treatment. This study aimed to systematically compare the two methods in terms of the rate of detected mutations and the association of detected mutations with clinical outcomes.Material and methodsPubMed, EMBASE, China National Knowledge Infrastructure (in Chinese) and Wanfang database (in Chinese) were searched to identify relevant studies. Meta-analyses of EGFR mutation rates, rate differences, and the associations of EGFR mutations with clinical outcomes of tyrosine kinase inhibitors treatment were conducted.ResultsEight hundred and sixty-six records were retrieved and 26 studies with 3282 patients were included. The pooled rate of mutations detected by ARMS (41%, 95% confidence interval (CI) 35% to 47%) was significantly higher than that by direct sequencing (28%, 95%CI 22% to 34%), with a weighted rate difference of 11% (95%CI 8% to 13%). There was a consistent trend that the associations between ARMS-detected mutations and clinical outcomes were stronger than those between direct-sequencing-detected mutations and clinical outcomes (pooled risk ratio for objective response: 5.18 vs. 2.25; hazard ratio for progression-free survival: 0.30 vs. 0.42; hazard ratio for overall survival: 0.46 vs. 0.54).ConclusionsMore patients with EGFR mutations can be identified by ARMS than by direct sequencing, and those identified by ARMS seems to be able to benefit more from tyrosine kinase inhibitors than those identified by direct sequencing.

Preoperative serum carcinoembryonic antigen levels are associated with histologic subtype, EGFR mutations, and ALK fusion in patients with completely resected lung adenocarcinoma.

BackgroundSerum carcinoembryonic antigen (CEA) is often elevated in lung adenocarcinoma, but not in all patients. Meanwhile, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusion protein are the main driving forces in lung adenocarcinoma. However, whether CEA levels are associated with histologic subtype, EGFR mutations, and ALK fusion remain largely unclear.MethodsPreoperative serum CEA levels, postoperative histologic subtypes, and statuses of EGFR mutations and ALK fusion protein were retrospectively assessed in 442 patients with completely resected lung adenocarcinoma treated from January 2014 to December 2015 at Zhejiang Cancer Hospital, People’s Republic of China.ResultsEGFR mutations were found in 69.9% (309/442) of lung adenocarcinoma patients, and ALK fusion protein in 4.5% (20/442). EGFR mutations occurred more frequently in the lepidic subtype (P=0.001). High preoperative serum CEA levels (CEA >20 ng/mL) were independently associated with EGFR mutations (P<0.001). Moreover, in patients with CEA levels of 21–49 ng/mL, the EGFR mutation rate was 88.2%, which was higher compared to those obtained in the other subgroups. In addition, all specimens were invasive adenocarcinoma, with lepidic (18.6%), papillary (15.4%), acinar (52.7%), solid (9.7%), micropapillary (3.2%), and mucinous predominant (0.4%) subtypes; CEA levels in patients with the solid subtype were higher than those of other histologic subtypes (P=0.001).ConclusionPreoperative serum CEA levels can serve as a reference marker to identify the histologic subtype, and EGFR mutation or ALK fusion protein status, in lung adenocarcinoma patients. Moreover, histological subtypes could also predict EGFR mutations.