EGFR Mutation Rate Research Articles

Regional distribution of genetic mutation in lung cancer in Turkey (REDIGMA).

The results of standard chemotherapy in lung cancer are not very satisfactory, so it is important to identify genetic mutations that provide targeted therapies. Recent reports have suggested influences of racial difference on the frequency of mutation in lung cancer. We aimed to determine the frequency and regional distribution of genetic mutations of non-small cell lung cancer (NSCLC) in Turkey. Regional distribution of genetic mutations in lung cancer in Turkey (REDIGMA) study was carried out as a prospective, cross-sectional, observational study in a large number of centers in which lung cancer patients were followed and could perform genetic mutation analysis on patients' biopsy materials. The 703 patients (77.7% male, mean age 63.3 ± 12.5 years) who were diagnosed as NSCLC from 25 different centers were included in the study. Tumor samples from patients were reported as 87.1% adenocarcinoma, 6.4% squamous cell carcinoma and 6.5% other. Mutation tests were found to be positive in 18.9% of these patients. The mutations were 69.9% EGFR, 26.3% ALK, 1.6% ROS and 2.2% PDL. Mutations were higher in women and non-smokers (p<0.000, p<0.001). Again, the frequency of mutations in adenocarcinoma was higher in metastatic disease. There was no difference between the patient's age, area of residence, comorbidity and clinical stage and mutation frequency. Our study revealed that the EGFR mutation rate in Turkey with NSCLC was similar to East European, African-American and Caucasian patients, and was lower than in East Asia.

Carcinoembryonic antigen in pleural effusion of patients with lung adenocarcinoma: a predictive marker for EGFR mutation.

BackgroundCarcinoembryonic antigen (CEA) can reflect tumor growth, recurrence and metastasis, and also predict the clinical efficacy of the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). In the present study, we investigated the association between CEA in serum and pleural effusion (PE) and EGFR mutations in patients with lung adenocarcinoma.MethodsWe retrospectively investigated 114 lung adenocarcinoma patients with malignant pleural effusion (MPE). CEA levels in serum and MPE were measured by immunoradiometric assay, we analysed the correlation between CEA and EGFR mutation status.ResultsFifty-three cases had EGFR mutation (46.5%). EGFR mutations were more common in females, patients with high levels of PE (≥107.2 ng/mL) and serum CEA (≥87 ng/mL). There was no significant difference in EGFR mutation rate between in tumor tissue and PE samples (49.3% vs. 41.9%, P=0.440). The result of receiver operating characteristic (ROC) indicated that the cut off value of CEA in MPE was 107.2 ng/mL, which had the highest sensitivity (SEN) and specificity (SPE) for predicting EGFR mutation [SEN 66%, and SPE 62.3%, AUC =0.668, 95% confidence interval (CI): 0.569–0.767, P=0.025]. The combination of gender, smoking history, serum and MPE CEA level had a higher calculated AUC (0.718, 95% CI: 0.622–0.813, P=0.000). Moreover, multivariate analysis showed that CEA level in MPE but not in serum was confirmed as the only independent factor associated with EGFR gene mutation status (P=0.026) with an odds ratio of 2.885 (95% CI: 1.137–7.317).ConclusionsMPE CEA can probably serve as a predictive marker for EGFR mutation in advanced lung adenocarcinoma. Combining gender, smoking history, and CEA has a relatively better predictive value. However, detecting EGFR mutations in lung adenocarcinomas is necessary for determining EGFR-TKI treatment in clinic.

Deep targeted sequencing analysis of hot spot mutations in non-small cell lung cancer patients from the Middle Eastern population.

The overall 5-year survival of lung cancer remains dismal despite the current treatment regimens. Testing for driver mutations has become routine practice for oncologists due to the presence of targeted therapy readily available for patients. Deep targeted sequencing through next generation sequencing (NGS) is an adequate methodology to detect mutations at multi-genetic levels. The molecular pathology of non-small cell lung cancer (NSCLC) is poorly understood in the Middle East and, to date, no other reports have been published on deep targeted sequencing of lung adenocarcinoma (LUAD) tissues. Deep targeted sequencing using TruSeq Amplicon Cancer panel of 48 genes was performed on 85 formalin-fixed paraffin-embedded tissues from patients with LUAD who were treatment-naive at the time of the collection. Variants with an allele frequency higher than 10% were retained. Variant calling identified a total of 2,455 variants of which missense mutations were the most frequent (75.6%). All of our samples showed at least one mutation in one of the 10 most commonly mutated genes with FLT3 being the gene with the highest mutation rate (67%). TP53, KRAS and STK11 were the second, third and fourth most commonly mutated genes, respectively while EGFR mutation rate reached 22.4%. To the best of our knowledge, this is the first hot spot profiling study on patients from this area. The frequencies of mutated genes presented in our study showed similarity to other reported outcomes. At least one mutation was detected in our cohort of LUAD.

Afatinib in the treatment of advanced NSCLC with EGFR mutation: An observational real-world study.

e20518 Background: Compared with the first generation of EGFR-TKI, Afatinib has a broader spectrum of activity and can better inhibit tumor growth. At present, the therapeutic effects of Afatinib varies on patients with different EGFR mutations and studies on the mechanism of acquired Afatinib resistance are limited. The aim of this study was to evaluate the efficacy and safety of Afatinib in the treatment of EGFR-mutation NSCLC who hadn’t received EGFR-TKI in the past. Methods: 88 patients with advanced NSCLC who had EGFR mutations were enrolled and given oral 40 mg Afatinib daily until disease progression or adverse events that could not be handled by dosage reduction. Efficacy and safety in different subgroups were analyzed. Results: Among 88 patients, the common mutation rate of EGFR was 79.5%, and the rare mutation rate was 20.5%. The objective remission rate (ORR) was 54.5%, and the disease control rate (DCR) was 92.0%. The median progression-free survival (PFS) was 14.2 months (95% CI 11.4-18.5), 27 patients (30.7%) continued Afatinib treatment after tumor progression, and the median time to progression of clinical symptoms (TTSP) was 16.3 months (95% CI 12.7-19.3). A total of 13 patients (14.8%) reduced Afatinib dosage of due to adverse events. Subgroup analysis showed that Afatinib had better effect on patients harboring common EGFR mutation but not exon 20 mutation, and was not affected by brain metastasis, dosage and lines of therapy. Among patients who progressed on Afatinib, 65.4% harbored T790M mutation. Most T790M patients received the third generation EGFR-TKI including AZD9291 and oxetinib treatment. The most common adverse reactions were diarrhea, rash, paronychia and stomatitis. Conclusions: Afatinib showed good efficacy and tolerance in advanced NSCLC patients with EGFR mutations. Continuation of Afatinib treatment after cancer progression could delay the progression of disease symptoms. The third generation EGFR-TKI could become a treatment option after Afatinib resistance. These findings reflected the real-world clinical practice of Afatinib.

Single center, open and prospective evaluation of genomic sequencing on cerebro-spinal fluid, brain metastatic lesions and plasma from patients in non-small cell lung cancer with brain metastasis.

e13578 Background: Leptomeningeal metastases are observed in 9.4% non–small Cell Lung Cancer (NSCLC) patients with EGFR mutations. Depending on patient specific gene mutations, tumor cells may also have different proliferative activity, leading to differential metastatic potential. However, the clinical significance of observed gene mutation differences between CSF, plasma, primary pulmonary tumor and metastatic brain tumor samples remains unclear and should be further explored. Methods: From Apr. 2018 to Jan. 2019, plasma and CSF paired samples were drawn from consented NSCLC patients with diagnosed brain metastasis. Of these 21, brain lesion samples were obtained from 5 patients. All the samples were tested by next-generation sequencing. Patients were treated based on the detection results. Results: For this cohort, the detection rate of EGFR mutations in CSF cfDNA versus plasma cfDNA/CTC was 57.1% and 23.8% respectively (p &lt; 0.05). For patients who had not received tyrosine kinase inhibitor (TKI) therapy, the CSF cfDNA EGFR mutation results were consistent with results for plasma, brain lesion and primary tumor samples. Conversely, for patients who had received TKI therapy, EGFR mutations detected in CSF were consistent with those from brain samples, but different from those observed in plasma or primary tumor samples. A high response rate (ORR, 70%; DCR, 90%) was observed in patients with EGFR positive detected in CSF after treatment with second orthird-generation TKI. Among the EGFR mutations detected in CSF, the EGFR uncommon mutation frequency was 58.3%(7/12), including G7I9A/L861Q/L703P/R776H/G575R/T790M 85.7% (6/7) of these occurred in LM patients. One patient who progressed from BM to LM had an uncommon mutation in the CSF sample. Among these five patients with EGFR G719A or L861Q positive and T790M negative, 4 patients had PR and 1 patient had SD after the second-generation TKI therapy. Conclusions: Differences in EGFR gene mutations were observed between CSF, plasma, primary pulmonary lesion and brain tissue samples in NSCLC patients with diagnosed brain metastasis after TKI therapy. The reasons for this discrepancy remain to be understood. Nevertheless, CSF may be a useful prognostic tool for patient monitoring and metastasis risk evaluation. The detection of uncommon EGFR mutations may increase the risk of LM in NSCLC patients. Clinical trial information: ChiCTR1800017499.

Comparative study of EGFR mutations detected in malignant pleural effusion, plasma and tumor tissue in patients with adenocarcinoma of the lung

ObjectivesThe utility of malignant pleural effusion (MPE) as a source for determining EGFR mutations to guide EGFR TKI therapy in advanced adenocarcinoma of the lung remains unclear. This study compared MPE, plasma and tumor tissues as sources of biological samples for EFGR mutational analysis of lung adenocarcinoma patients. Materials and methodsTotal 295 MPE samples were retrospectively collected from lung adenocarcinoma patients. Matched tissue and plasma samples were available for 92 patients, and 248 patients had plasma samples. EGFR exon-19-deletion and exon 21-L858R mutation were detected with Denaturing high performance liquid chromatography (DHPLC). The concordance of EGFR mutation status in MPE, tissue, and plasma were evaluated, and the value of EGFR mutations in MPE with respect to efficacy of EGFR-TKI was investigated. ResultsThe EGFR mutation rate in MPE samples was 39.3% (116/295). The concordance between MPEs and tissues was 87.1% (Kappa = 0.71); the sensitivity and specificity of EGFR mutation in MPEs according to tissues was 71.4% and 96.5%, respectively. And 219 patients received EGFR-TKI, and the objective response rate was similar for patients with EGFR mutation either in MPE, tissues or plasma (57.6% vs 56.0% vs 47.4%, p = 0.51). Similar results were found in progression free survival (8.9 months vs 9.0 months vs 7.7 months, p = 0.077 and overall survival (29.8 months vs 25.9 months vs 25.3 months, p = 0.33). ConclusionMPE is a reliable surrogate for tumor tissue for identifyingEGFR mutations. MPE could offer reference of EGFR mutation to EGFR-TKIs treatment decision for advanced lung adenocarcinoma patients even when tissue and plasma were available.

PCN208 REAL WORLD TREATMENT PATTERNS ANALYSIS FOR PATIENTS WITH ADVANCED OR METASTATIC LUNG CANCER IN THEIR INITIAL TREATMENT: A NATIONWIDE, MULTI-CENTER, RETROSPECTIVE MEDICAL CHART REVIEW IN CHINA (PASSION STUDY)

Up-to-date data on lung cancer treatments used in real-world clinical practice in China is limited. This national first large-scale investigation aims to examine the treatment modalities, outcomes and costs of patients with advanced lung cancer. This study is a chart review of patients diagnosed with advanced (stage IIIb/IV) non small cell lung cancer (NSCLC) or extensive stage small cell lung cancer (SCLC) between 1-Dec-2013 and 30-Nov-2014 from 33 hospitals. Patients were retrospectively observed for up to three years. We present interim data on baseline characteristics and initial treatment modalities of 1,002 patients from 27 hospitals. Within the study cohort of 1,002 patients, a total of 990 patients (98.80%) were recorded within three histological sub-groups: 16.5% had a diagnosis of SCLC, 21.8% squamous-NSCLC and 60.6% non-squamous-NSCLC. Mean age at diagnosis was 59.10±10.10 years, 66.37% were male (91.28%, 56.01% and 72.12% for squamous-NSCLC, non-squamous-NSCLC and SCLC) and 47.90% were current/ex-smokers (72.48%, 36.74% and 57.58% or squamous-NSCLC, non-squamous-NSCLC and SCLC). Among 990 analyzed patients, 86.67% were initially treated with systemic therapy (89.09%, 88.99% and 85.17% for SCLC, squamous-NSCLC and non-squamous-NSCLC, respectively) and the majority received chemotherapy only (88.96%, 87.16% and 76.49% for SCLC, squamous-NSCLC and non-squamous-NSCLC, respectively). Of patients who received systemic treatment, platinum doublet-based chemotherapy was most common (94.56%, 85.57% and 80.08% for SCLS, squamous-NSCLC and non-squamous-NSCLC, respectively). Among 517 non-squamous patients who received systemic treatment, 177 had EGFR mutations data available, 102 were EGFR negative and 75(42.4%) were EGFR positive. Among EGFR positive patients, 25 patients (33.33%) received TKI treatment. The use of biologics was considerably low in initial treatment, even though EGFR mutation rates were high among tested patients. These data on real world practice will be useful to clinicians and health policy makers in improving care strategies for this increasingly incident and devastating cancer.

Differential effects of adjuvant EGFR tyrosine kinase inhibitors in patients with different stages of non-small-cell lung cancer after radical resection: an updated meta-analysis.

PurposeA survival improvement was achieved with adjuvant chemotherapy in non-small-cell lung cancer (NSCLC) patients, but its differential effects among patients with different stages remained controversial. This study aimed to compare the beneficial effects of adjuvant tyrosine kinase inhibitor (TKI) therapy with those of traditional therapy on NSCLC patients, specifically on EGFR-mutant and stage II–IIIA patients, who might benefit most from such treatment.MethodsMEDLINE, Embase, and the Cochrane Library were searched, and the results were screened independently according to certain criteria by two authors. Disease-free survival (DFS) and overall survival (OS) with HRs were used as the summary statistics.ResultsA total of 2,915 publications were identified and screened. Six randomized control trials and three retrospective cohort studies of 2,467 patients with acceptable quality were included. The overall EGFR mutation rate was 48.62%. DFS was significantly improved in all the patients (HR, 0.77; 95% CI, 0.68–0.88) and in the subgroup of EGFR-mutant patients (HR, 0.49; 95% CI, 0.40–0.61). The difference of 5-year OS in the subgroup of EGFR-mutant patients (HR, 0.48; 95% CI, 0.31–0.72) was statistically significant, while in all the patients (HR, 1.01; 95% CI, 0.85–1.19), the difference was not significant. In the subgroups of studies in which <50% of patients were in stage I (HR, 0.46; 95% CI, 0.35–0.60) and >30% of patients were in stage IIIA (HR, 0.46; 95% CI, 0.35–0.60), DFS was significantly improved, while in the subgroups of studies in which <30% of patients were in stage IIIA (HR, 0.90; 95% CI, 0.77–1.04) and >50% of patients were in stage I (HR, 0.90; 95% CI, 0.77–1.04), DFS was not significantly improved.ConclusionStage IIIA NSCLC patients might benefit more from adjuvant TKIs than stage I NSCLC patients after radical resection.

Primary tumor location is an important predictor of survival in pulmonary adenocarcinoma.

PurposeThe prognostic value of tumor location in pulmonary adenocarcinoma (ADC) is controversial. We compared the prognosis and relevant data between central-type ADC (CT-ADC) and peripheral-type ADC (PT-ADC) in order to identify the reasons for the different outcomes between them and to improve the treatment strategy and prognosis of these two types.Patients and methodsData of 256 patients with pathologically diagnosed ADC were retrospectively reviewed. The prognostic factors for disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) were analyzed using univariate and multivariate analyses.ResultsA total of 124 and 132 patients had CT-ADC and PT-ADC, respectively. CT-ADC was associated with an earlier age, poorer Karnofsky Performance Status (KPS), higher rates of advanced stage, bone metastasis, contralateral pulmonary metastasis, and pleural effusion. Besides, CT-ADC showed a trend toward lower rate of EGFR mutation. Patients with CT-ADC had a significantly shorter PFS/DFS and OS than did those with PT-ADC. Multivariate analysis revealed that advanced stage, central-type location, EGFR wild-type, no surgery, presence of COPD, and interstitial lung disease (ILD) were independent poor prognostic factors for OS. The rate of surgery was significantly lower in patients with CT-ADC. Among patients with ILD or COPD, OS is shorter in patients with central- than peripheral-type tumors.ConclusionCT-ADC is associated with poorer survival than PT-ADC and the lower rate of surgery in patients with CT-ADC is an important reason for this. Tumor location of pulmonary ADC plays a critical role in predicting prognosis and choosing therapeutic strategies.

Analysis of the frequency of oncogenic driver mutations and correlation with clinicopathological characteristics in patients with lung adenocarcinoma from Northeastern Switzerland

BackgroundMolecular testing of lung adenocarcinoma for oncogenic driver mutations has become standard in pathology practice. The aim of the study was to analyze the EGFR, KRAS, ALK, RET, ROS1, BRAF, ERBB2, MET and PIK3CA mutational status in a representative cohort of Swiss patients with lung adenocarcinoma and to correlate the mutational status with clinicopathological patient characteristics.MethodsAll patients who underwent molecular testing of newly diagnosed lung adenocarcinoma during a 4-year period (2014–2018) were included. Molecular analyses were performed with Sanger sequencing (n = 158) and next generation sequencing (n = 311). ALK, ROS1 and RET fusion gene analyses were also performed with fluorescence in situ hybridization and immunohistochemistry/immunocytochemistry. Demographic and clinical data were obtained from the medical records.ResultsOf 469 patients with informative EGFR mutation analyses, 90 (19.2%) had EGFR mutations. KRAS mutations were present in 33.9% of the patients, while 6.0% of patients showed ALK rearrangement. BRAF, ERBB2, MET and PIK3CA mutations and ROS1 and RET rearrangements were found in 2.6%, 1.9%, 1.9%, 1.5%, 1.7% and 0.8% of the patients, respectively. EGFR mutation was significantly associated with female gender and never smoking status. ALK translocations were more frequent in never smokers, while KRAS mutations were more commonly found in ever smokers. The association between KRAS mutational status and female gender was statistically significant only on multivariate analysis after adjusting for smoking.ConclusionThe EGFR mutation rate in the current study is among the higher previously reported mutation rates, while the frequencies of KRAS, BRAF, ERBB2 and PIK3CA mutations and ALK, ROS1 and RET rearrangements are similar to the results of previous reports. EGFR and KRAS mutations were significantly associated with gender and smoking. ALK rearrangements showed a significant association with smoking status alone.

The clinical and pathological features, biomarker characteristics and prognosis analysis of lung adenosquamous carcinoma

Objective: Adenosquamous carcinoma of lung is an uncommon subtype with more aggressive behavior and poor prognosis than adenocarcinoma and squamous cell carcinoma. This study was aimed to investigate the clinicopathological characteristics and prognostic factors of lung adenosquamous carcinoma. Methods: The pathological features and follow-up data of 133 patients were collected and the prognostic factors of these patients were retrospectively analyzed. Results: Among the 133 patients, 81 cases (60.9%) smoked. Among the 62 patients whose percentage of histological components were identified, 45 cases had >50% adenocarcinoma components, and 17 cases had >50% squamous cell carcinoma components. 55 patients had lymph node metastasis at the first visit. All patients accepted at least one test of tumor driven gene mutation, and the results showed that the mutation rate of EGFR was 50.8% (67/132), the mutation rate of K-ras was 8.6% (11/128), the ALK-positive rate was 4.2% (2/48). The gender, smoking status, and the proportion of pathological components were the main influence factors of EGFR mutation status. The median overall survival was 28 months, the rates of 1-year, 3-year, and 5-year survival were 72.9%, 23.3%, and 9.0%, respectively. EGFR tyrosine kinase inhibitors (TKIs) treatment was an independent risk factor for prognose of these patients (P=0.024). Conclusions: Lung adenosquamous carcinoma is a rare subtype with high malignancy and poor prognosis. Early diagnosis and driven-mutation-based individualized therapy may improve the survival of patients with lung adenosquamous carcinoma.

Detection of Plasma EGFR Mutations in NSCLC Patients with a Validated ddPCR Lung cfDNA Assay.

Purpose: The clinical utility of cell-free DNA (cfDNA) to assess EGFR mutations is increasing. However, there are limited studies determining their clinical validity and utility. The value of cfDNA assays in cancer management remains controversial.Methods: In this study, we first evaluated the analytical performance of the ddPCR Lung cfDNA Assay. We next analyzed the concordance of the results with tissue amplification refractory mutation system PCR (ARMS-PCR) and plasma next-generation sequencing (NGS) genotyping. Finally, we assessed its clinical utility by exploring the association of cfDNA EGFR mutations with metastatic sites and the efficacy of EGFR-TKIs treatment.Results: The ddPCR Lung cfDNA Assay demonstrated a limit of blank of 1 droplet per reaction, an analytical specificity of 100%, and detection limit of 0.05%, 0.05%, and 0.1% for E746_A750del, L858R, and T790M, respectively. With tissue ARMS-PCR as a standard for comparison, the clinical sensitivity and specificity of ddPCR were 62.5% (15/24) and 100% (82/82) for E746_A750del, and 75.0% (15/20) and 94.2% (81/86) for L858R, respectively. The ddPCR showed high concordance with NGS in determining cfDNA EGFR mutations. Patients with bone and/or brain metastasis showed a higher detection rate and mutant abundance of cfDNA EGFR mutations compared to those with other sites of metastasis. Moreover, EGFR-TKIs treatment was effective in patients with sensitive EGFR mutations in either plasma cfDNA or tumor tissue-derived DNA.Conclusions: We validated in this study that the ddPCR Lung cfDNA Assay is reliable for detection of EGFR mutations in lung cancers, in terms of analytical performance, clinical validity and utility.

P3.01-78 The Cytology Samples and Plasma Specimens were Feasible for the EGFR Molecular Testing.

EGFR mutation detection with real-time PCR is standard method to identify eligible patients for EGFR-TKI treatments in daily routine practice. Surgically resected tissues or biopsy specimens are mainly used as the sample materials for testing. However, the biopsy samples sometimes have a certain limitation in their volume and so the cytology specimens are chosen for EGFR testing instead. Plasma has also become an option especially in EGFR-TKI resistant cases in which often have difficulties to obtain the adequate tumor yield. In this study, we evaluated the feasibilities of using cytology samples and plasma specimens for the EGFR molecular testing. Patients provided written informed consent for use of the samples were participated in this prospective research. Cytology samples were obtained from biopsy and cells were suspended into liquid-based cytology (LBC) media. Tumor contents in the samples were confirmed with Papanicolaou stained slides. Plasma samples were also collected from patients shortly before the tissue biopsy. EGFR mutations in these samples were analyzed by cobas EGFR Mutation Test v2. Also, EGFR testing result of tissue specimens of the patients corresponded were collected from the medical records measured by cobas EGFR Mutation Test v2 as reference. The feasibilities of both cytology and plasma specimen were evaluated comparing with the tissue samples. One-hundred fifty-eight patients were registered to this study. Among those patients, 77 patients with matched set of samples were enrolled to this study. EGFR mutation rates in tissue, cytology, and plasma were 37.7, 29.9 and 16.9 %, respectively. Overall agreement rate of the cytology specimens and the plasma specimens against the tissue samples were 87.0 and 75.3%, respectively. All eightT790M mutation positive cases were perfectly matched between tissue and cytology specimens. The results suggested that tissue specimen is the most suitable sample for detecting mutations. Since high specificities were confirmed in both cytology and plasma specimens, the results are reliable as long as the call is positive. Choosing cytology or plasma specimens for EGFR testing can be the considerations for the patients who have difficulties in collecting tissue samples in the real world setting.

P2.13-17 Non-Small Lung Cancer in the Very Young: More EGFR/ALK Mutation Rate Than the Elder.

Lung cancer was the leading cause of cancer in worldwise1. Although it remains a disease of older patients, there is a subset of patients who are diagnosed at younger age, such as blow 40 year old. Several studies had shown that the younger group had more females, more non-smokers, more advanced stages of disease, and better survive rate. However, most of these studies didn’t include tumor EGFR/ALK mutation data, especially for the younger group. We retrospectively studied the clinical difference between the younger and the older in patients, including pathologic type, treatment characteristics, and EGFR/ALK mutation status. We retrospective reviewed data of NSCLC patients diagnosed during Jun. 2007 to Dec. 2014, and whose age was less than 90 year-old. at Taipei Veterans General Hospital(TPEVGH). There were 5,051 cases of NSCLC, including 168 patients who were <40 years old (younger group) and 4,883 patients aged 40 years or older (older group). It was found younger group had significantly higher EGFR mutation rate than older group (22.6% VS 16.2%, p=0.026), and ALK mutation (4.2% VS 0.5%, p<0.001). Although the younger group had more stage IV patients (60.1% VS 49.6%, p=0.002), they had better (one year:73.7% VS 66.2%, five year:44.4% VS 33.7%) overall survival rate(OS) ( median survival time: 55 VS 26 months ,p=0.002). Regarding histologic subtype, younger group had less squamous cell carcinoma (4.2% VS 16.1% , p<0.001), while adenocarcinoma subtype was similar between two groups (76.8% VS 76.5%, p=0.924). Overall survival rate in younger NSCLC patients were better than the older ones. This survival benefit most likely due to higher EGFR mutation and ALK mutation rate and corresponding TKI treatment. Although more advanced-stage NSCLC patients were seen in the younger group at the same time.

Real-world EGFR testing in patients with stage IIIB/IV non-small-cell lung cancer in North China: A multicenter, non-interventional study.

BackgroundBefore tyrosine kinase inhibitor (TKI) therapy can be administered in patients with advanced non‐small cell lung cancer (NSCLC), EGFR mutation testing is required. However, few studies have evaluated the extent of EGFR testing in real‐world practice in China.MethodsA multicenter, observational study of EGFR testing in NSCLC patients in North China was conducted. Treatment‐naïve patients or those with postoperative recurrent stage IIIB/IV NSCLC were enrolled. The primary objective was EGFR testing rate. Secondary objectives included EGFR mutation status, EGFR testing methods and specimens, factors associated with EGFR testing, and overall survival with or without EGFR testing.ResultsOverall, 2809 patients with stage IIIB/IV NSCLC were enrolled; 90.78% had adenocarcinoma. The EGFR screening rate was 42.54%. EGFR testing rates were higher in tumor samples obtained by lymph node puncture, and in patients with urban medical insurance, adenocarcinoma, non‐smokers, or those located in developed cities (all P < 0.001). The EGFR mutation rate was 46.44%. The most commonly used specimens for EGFR testing were biopsy tumor samples (67.53%). PCR‐based methods (72.05%), Sanger sequencing (5.36%), and Luminex liquid chip (5.10%) were the most frequently used testing platforms. Similar positive EGFR mutation rates were achieved with different platforms. TKI therapy was the first‐line treatment administered to most EGFR‐positive patients (56.22%), and chemotherapy in EGFR‐negative patients (84.88%). Overall survival was higher in EGFR‐tested than in untested patients (27.50 vs. 19.73 months; P = 0.007).ConclusionReal‐world EGFR testing rates for NSCLC in North China were relatively low because of clinical and social factors, including medical insurance coverage.

Large-Scale EGFR Mutation Testing in Clinical Practice: Analysis of a Series of 18,920 Non-Small Cell Lung Cancer Cases.

We make use of a very large dataset of non-small cell lung cancer specimens to examine the molecular epidemiology of EGFR mutations, particularly with respect to rare and compound mutations, and to non-adenocarcinoma histological subtypes. We also demonstrate the feasibility of large-scale EGFR mutation screening using the full range of specimens encountered in routine practice. We retrospectively reviewed 18,920 unselected EGFR mutation results from our centre between July 2009 and October 2016, using Qiagen's therascreen EGFR RGQ PCR Kit. Mutation rates were correlated with patient demographics and tumour histology. Our testing success rate was 93.9%, with similar success rates using histological and cytological specimens. Rare, potentially-targetable mutations accounted for 9.5% of all mutations detected. We identified a 2.5% mutation rate in tumours diagnosed as squamous cell carcinomas. There was a trend towards increasing EGFR mutation rates with increasing age, and while Del19 was the commonest mutation in the young, L858R predominated in the elderly. We found that EGFR mutation heterogeneity is rare within tumours and between primary and metastatic deposits. Our data demonstrate that large-scale, reflex EGFR mutation testing is feasible and affordable in the context of a publicly-funded health system. Furthermore, we have shown that the use of techniques sensitive only to classical mutations and selection of patients on the grounds of age, sex and histology denies patients access to potentially beneficial TKI therapy.

Common cancer-driver mutations and their association with abnormally methylated genes in lung adenocarcinoma from never-smokers

ObjectivesLung adenocarcinoma in never-smokers accounts for 15–20% of all lung cancer. Although targetable mutations are more prevalent in these tumors, the biological and clinical importance of coexisting and/or mutually exclusive abnormalities is just emerging. This study evaluates the relationships between common genetic and epigenetic aberrations in these tumors. Materials and methodsNext-generation sequencing was employed to screen 20 commonly mutated cancer-driver genes in 112 lung adenocarcinomas from never-smokers. The relationship of these mutations with cancer-related methylation of 59 genes, and geographical/ethnic differences in the prevalence for mutations compared to multiple East Asian never-smoker lung adenocarcinoma cohorts was studied. ResultsThe most common driver mutation detected in 40% (45/112) of the tumors was EGFR, followed by TP53 (18%), SETD2 (11%), and SMARCA4 (11%). Over 72% (81/112) of the cases have mutation of at least one driver gene. While 30% (34/112) of the tumors have co-mutations of two or more genes, 42% (47/112) have only one driver gene mutation. Differences in the prevalence for some of these mutations were seen between adenocarcinomas in East Asian versus US (mainly Caucasian) never-smokers including a significantly lower rate of EGFR mutation among the US patients. Interestingly, aberrant methylation of multiple cancer-related genes was significantly associated with EGFR wildtype tumors. Among 15 differentially methylated genes by EGFR mutation, 14 were more commonly methylated in EGFR wildtype compared to mutant tumors. These findings were independently validated using publicly available data. ConclusionMost lung adenocarcinomas from never-smokers harbor targetable mutation/co-mutations. In the absence of EGFR mutation that drives 40% of these tumors, EGFR wildtype tumors appear to develop by acquiring aberrant promoter methylation that silences tumor-suppressor genes.

Abstract 5375: Whole-genome sequencing reveals genomic signatures associated with the immunologic microenvironments in Chinese NSCLC patients

Abstract Over the past decades, next-generation sequencing has accelerated the systematic characterization of genomic events, including single base substitutions and small insertions/deletions (indels), and has yielded substantial insights into the unique and shared genomic features of the two NSCLC subtypes. Genomic studies of lung cancer have mainly been conducted in patients from Western countries; however, Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms in addition to smoking. To reveal the underlying mechanisms, we presented a comprehensive genomic landscape of 149 Non-Small Cell Lung Cancer (NSCLC) cases. We identified 15 potential driver genes and three mutational signatures, two of which have been connected with APOBEC enzymes and smoking. In addition, we revealed that Chinese patients are specially characterized by not only highly clustered and functional EGFR mutations but also a mutational signature, that is associated with inflammatory tumor-infiltrating lymphocytes (P = 0.001). The EGFR mutation rate is significantly increased with the proportion of the MS3 signature (P&amp;lt;0.001). As a classic tumor-enabling hallmark, inflammatory infiltration may contribute to the accumulation of EGFR mutations, especially in never-smokers. Additionally, patients with a higher proportion of the MS3 signature carried a higher contribution of characterized chromosomal rearrangements (P&amp;lt;0.001). The results revealed specific genomic features in the inflammatory microenvironments in Chinese patients with potential implications for understanding the etiology, prevention and therapy of NSCLC. Citation Format: Cheng Wang, Juncheng Dai, Yayun Gu, Zhibin Hu, Hongbing Shen. Whole-genome sequencing reveals genomic signatures associated with the immunologic microenvironments in Chinese NSCLC patients [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 5375.

Abstract PR03: Somatic mutations and ancestry markers in Hispanic lung cancer patients

Abstract Introduction: Hispanics are projected to constitute 23% of the U.S. population by 2050. However, large-scale sequencing projects, such as The Cancer Genome Atlas (TCGA), provide little information on this ethnic population. In fact, only seven out of over 500 lung adenocarcinoma tumors sequenced in the TCGA database are reported to be Hispanic. To address the lack of genomic data from Hispanic/Latino patients with lung cancer, the Latino Lung Cancer Registry was established to collect patient data and biospecimens from these patients. Methods: This retrospective observational study examined lung cancer tumor samples from 163 Hispanic/Latino patients, and tumor-derived DNA was subjected to targeted-exome sequencing (&amp;gt;1000 genes, including EGFR, KRAS, STK11, and TP53) and ancestry analysis. Mutation frequencies in this Hispanic/Latino cohort were compared with those in a similar cohort of non-Hispanic white (NHW) patients. Novel mutations in EGFR were functionally characterized, and mutation rates were correlated with ancestry, patient sex, smoking status, and tumor histology. Results: Among adenocarcinomas (n=120) in the Hispanic/Latino cohort, 31% had EGFR mutations versus 17% in the NHW control group (p &amp;lt; 0.001). The EGFR mutations in Hispanic/Latino patients included well-characterized activating mutations, such as L858R, and uncharacterized EGFR variants. A rare exon 19 mutation, W731R, was identified that conferred resistance to both erlotinib and AZD9291. KRAS (20% vs. 38%; p=0.002) and STK11 (8% vs. 16%; p=0.065) mutations occurred at lower frequency, and mutations in TP53 occurred at similar frequency (46% vs. 40%; p=0.355) in Hispanic/Latino and NHW patients, respectively. Within the Hispanic cohort, ancestry influenced the rate of TP53 mutations (p=0.009) and may influence the rate of EGFR, KRAS, and STK11 mutations. Conclusions: Driver mutations in Hispanic/Latino lung adenocarcinoma patients differ in frequency from those in NHWs associated with their Indigenous American ancestry. The spectrum of driver mutations needs to be further assessed in the Hispanic/Latino population. Citation Format: William D. Cress, Nicholas T. Gimbrone, Bhaswati Sarcar, Edna Gordian, Jason I. Rivera, Christian Lopez, Jamie K. Teer, Eric A. Welsh, Alberto A. Chiappori, Matthew B. Schabath, Gary W. Reuther, Pedro G. Santiago-Cardona. Somatic mutations and ancestry markers in Hispanic lung cancer patients [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr PR03.

PO-062 Circulating tumour cells in patients with non-small cell lung cancer exhibit notable heterogeneity

IntroductionOncogenic EGFR is the most common driver mutations by which targeted therapies in NSCLC through their ability to induce dramatic and durable responses. However, almost all patients will eventually have disease progression resulting from drug resistance. Therefore, understanding the resistance mechanism remains essential to prevent or delay the emergence of resistance by EGFR mutations. TKIs resistance generally were considered to be acquired as for that occurred or more easily to be detected of a secondary mutation in the targeting process that interferes with inhibition.The present study set out to investigate the EGFR mutation status in circulating tumour cells and pathological specimens from patients with untreated lung cancer.Material and methodsPeripheral blood samples (4.5 mL) were collected from 91 patients with lung cancer (lung cancer group), 10 patients with benign lung diseases and 10 healthy volunteers (control group). Circulating tumour cells (CTCs) were then enriched by positive immunomagnetic separation with an anti-CD326 antibody, detected by immunocytochemistry with anti-cytokeratin/anti-EpCAM/anti-CD45 antibody and Hoechst staining, and processed by an MMI CellEctor for single-cell selection. Subsequently, CTC DNA was amplified, and the EGFR gene was analysed by the amplification refractory mutation system (ARMS) and NGS.Results and discussionsThe CTC capture rate in lung cancer patients was 61.5% (56/91), whereas no CTCs were detected in patients with benign lung disease or healthy volunteers. The positive CTC detection rate in patients at TNM stage III and IV was 69.3% (52/75) and 25.0% (4/16), respectively. The number of CTCs captured from patients with small cell lung cancer was significantly higher than that from patients with other pathological types of cancer. In patients positive for EGFR mutations, the detection rate of EGFR mutations in a single CTC was very low (6.25%, 1/16). Other inconsistent EGFR mutations were observed among CTCs derived from the same patient with lung adenocarcinoma. There was notable heterogeneity among EGFR and driver gene mutations in different samples from the same patient.ConclusionA simplified technique for isolating CTCs from blood was established. Based on pure CTC DNA amplification and analysis, our data clearly show significant gene heterogeneity in NSCLC patients before treatment.