Positive Epidermal Growth Factor Receptor Mutation Research Articles

RELAY: A multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC).

9000 Background: Dual blockade of EGFR and VEGFR pathways in EGFRm NSCLC augments anti-tumor efficacy versus (v) EGFR inhibition alone. RELAY (NCT02411448) evaluated efficacy and safety of ERL, an EGFR TKI standard-of-care, plus RAM, a human IgG1 VEGFR2 antagonist, or PL in 1L EGFRm metastatic NSCLC. Methods: Eligibility included untreated metastatic NSCLC pts with Exon 19 deletion (del) or L858R and no CNS metastasis. Randomized (1:1) pts received ERL (150 mg/day) + RAM (10 mg/kg q2w) or ERL + PL, stratified by gender, geographic region (East Asia v other), EGFRm type (Ex19del v L858R) and EGFR testing method (Therascreen/Cobas v other). The primary endpoint was Investigator assessed progression free survival (PFS). Other objectives included ORR, DoR, PFS2, OS, safety, and plasma T790M mutation (Guardant NGS). Results: 449 pts were randomized characteristics were balanced between treatment arms: Asian 77%, Females 63%, Ex19del 54%. RAM + ERL significantly prolonged PFS, DoR, and PFS2 (Table). Grade >=3 TEAEs were greater with RAM (72%) v PL (54%), largely driven by hypertension (24 v 5%, no Gr4); with 1 treatment related on study death (hemothorax) in RAM v 0 PL. EGFR T790M+ rates at progression are forthcoming. Conclusion: RAM + ERL led to superior PFS in 1L EGFRm metastatic NSCLC. Safety was consistent with the established safety profiles of the individual compounds. Clinical trial information: NCT02411448. [Table: see text]

Early clearance of plasma EGFR mutations as a predictor of response to osimertinib and comparator EGFR-TKIs in the FLAURA trial.

9020 Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third generation EGFR-TKI, showed superior efficacy to comparator EGFR-TKIs as first line treatment for EGFR mutation-positive (EGFRm) advanced NSCLC. In an exploratory analysis, we investigated clinical outcomes associated with detection of plasma EGFRm at 3 or 6 weeks (wks) after start of treatment. Methods: Treatment-naïve patients (pts) with EGFRm (ex19del or L858R) locally advanced or metastatic NSCLC were randomized 1:1 to receive osimertinib 80 mg once daily (QD) or comparator EGFR-TKIs (gefitinib 250 mg QD or erlotinib 150 mg QD). Plasma EGFR mutation analysis was conducted at baseline (BL), wks 3 and 6 by droplet digital PCR. Clearance was defined as undetectable levels of EGFRm in ctDNA at wks 3/6, where they were detectable at BL. Progression-free survival (PFS) was investigated based on early clearance of EGFRm. Results: In total 489/556 (88%) pts (osimertinib: 244/279; comparator: 245/277) had evaluable ctDNA at BL and wks 3/6. Of these, 342/489 (70%; osimertinib: 168/244; comparator: 174/245) had detectable BL EGFRm and were included in this analysis. See table. Conclusions: Clearance of plasma EGFRm after 3/6 wks of EGFR-TKI therapy was associated with a numerical improvement in PFS. The efficacy of osimertinib was superior to comparator EGFR-TKIs regardless of clearance status. Clinical trial information: NCT02296125. [Table: see text]

Estimating long-term survival of previously untreated patients with EGFR mutation-positive (EGFRm) advanced non-small cell lung cancer (NSCLC) who received osimertinib in the FLAURA study.

e20560 Background: In the Phase III FLAURA trial (NCT02296125), osimertinib, a third-generation EGFR-TKI, provided clinically and statistically significantly longer progression-free survival versus gefitinib/erlotinib as first-line treatment for patients with EGFRm advanced NSCLC. At the time of analysis, data on overall survival (OS) were immature (25% maturity). To better understand the long-term survival potential of osimertinib beyond the observed trial follow-up period, mathematical parametric survival models were used to estimate clinically plausible survival rates up to 5 years from FLAURA. Methods: Following published best-practice guidelines, candidate parametric survival models were evaluated based on both statistical and visual goodness-of-fit to the observed FLAURA OS data. Two modeling approaches were considered: single models with treatment included as a covariate; and separate models fitted to the osimertinib and gefitinib/erlotinib arms. Point estimates of 5-year survival rates with 95% confidence intervals (CIs) are reported for the best fitting model. Results: The best fitting parametric survival model to the FLAURA OS data was the Weibull model with treatment included as a covariate. Based on this model, estimated median OS was longer with osimertinib than with gefitinib/erlotinib (41.4 months vs 30.6 months). The estimated 3- and 5-year survival rates with osimertinib were 57.3% (95% CI 46.6%, 69.2%) and 31.1% (95% CI 23.7%, 41.8%), respectively. In comparison, the estimated 3- and 5-year survival rates with gefitinib/erlotinib were 41.1% (95% CI 31.9%, 52.9%) and 15.5% (95% CI 11.6%, 22.1%), respectively. Conclusions: Based on the best fitting parametric survival model to FLAURA OS data, the estimated 5-year survival rate with osimertinib was double that with gefitinib/erlotinib (31.1% vs 15.5%) in patients with EGFRm advanced NSCLC. Long-term follow-up data from FLAURA (60% OS maturity) will further validate this finding. Clinical trial information: NCT02296125.

Gefitinib Versus Adjuvant Chemotherapy in Patients With Stage II-IIIA Non–Small-Cell Lung Cancer Harboring Positive EGFR Mutations: A Single-Center Retrospective Study

BackgroundThe superior efficacy of first-line treatment with gefitinib over that of standard chemotherapy was demonstrated in patients with advanced non–small-cell lung cancer (NSCLC) harboring sensitive mutation of epidermal growth factor receptor (EGFR). However, scarce evidence showing the superiority of gefitinib to chemotherapy exists regarding the postoperative adjuvant therapy of EGFR mutation–positive patients with stage II-IIIA NSCLC. To address this important gap, we undertook a retrospective study to assess the efficacy of adjuvant gefitinib versus adjuvant chemotherapy (AC) in patients with completely resected EGFR-mutant stage II-IIIA NSCLC. Patients and MethodsA total of 116 patients with completely resected II-IIIA NSCLC and confirmed positive EGFR mutation (exon 19 deletion or exon 21 Leu858Arg) between January 2013 and March 2017 were included in our study. Disease-free survival (DFS) was analyzed in 55 patients treated with gefitinib and 61 patients treated with a platinum-based 2-drug-combination AC. Propensity score matching allowed the generation of best matched pairs for the 2 categories (1:1 ratio). Factors affecting survival were assessed by the Kaplan-Meier method and Cox regression analysis. ResultsThe matched cohort consisted of 52 gefitinib and 52 AC patients with a median follow-up of 37.1 and 31.5 months, respectively. DFS was significantly longer in the gefitinib group than that in the AC group (34.9 months [95% confidence interval (CI), 21.1-48.7] versus 19.3 months [95% CI, 13.3-25.3]; hazard ratio = 0.36 [95% CI, 0.19-0.68], log-rank P = .001). In the gefitinib group the most common adverse events (AEs) were rash (76.9%), aminotransferase elevation (53.8%), and diarrhea (46.2%), whereas in the AC group the most common AEs were neutropenia (67.3%), nausea or vomiting (63.5%), and anemia (44.2%). Less frequent grade 3 or higher AEs were observed in the gefitinib group (15.4% vs. 38.5% in the AC group). After receiving gefitinib for 3 months, one patient was diagnosed with interstitial lung disease, which was regarded as the most severe treatment-related AE. No deaths were treatment related. ConclusionIn this retrospective study, compared to AC, gefitinib provided a statistically significant DFS benefit, reduced toxicity in EGFR mutation–positive patients with resected II-IIIA NSCLC. These results require further validation by prospective randomized trials.

Cytomorphological features as predictors of epidermal growth factor receptor mutation status in lung adenocarcinoma.

Background:Epidermal growth factor receptor mutation-positive (EGFR-p) lung adenocarcinomas are sensitive to tyrosine kinase inhibitors. Although histopathological subtype is an independent predictor of mutation status, there is a paucity of data on the cytomorphological features correlating with the EGFR mutation status. Therefore, the aim of this study was to determine whether certain cytomorphological features correlate with EGFR mutation in lung adenocarcinoma.Materials and Methods:A retrospective analysis of 48 lung adenocarcinoma cases diagnosed on fine needle aspiration cytology with known EGFR mutation status was conducted. All cytology smears with cellblock sections were reviewed. The cytomorphological features including tumor pattern, stromal features, nuclear and cytoplasmic features, and tumor grade were evaluated. Clinicoradiological features such as age, sex, smoking, tumor size, clinical stage, metastases, and presence of mass, nodule, lymphadenopathy, pleural effusion, and clinical outcome were also assessed.Results:Of 48 cases, 19 were EGFR-p and 29 were negative. EGFR-p cases showed a positive and significant correlation with flat monolayered sheets and acini, mild nuclear atypia, fine chromatin and smooth nuclear margins and these tumors were well differentiated. EGFR-negative tumors were moderate to poorly differentiated with predominance of solid clusters, moderate to marked nuclear atypia, with irregular nuclear margins and coarse chromatin. Clinically, female sex, nonsmoking status, smaller tumor size, and good clinical outcome correlated with EGFR-p status.Conclusion:Certain cytomorphological features correlate with and may suggest EGFR mutation status in advanced lung adenocarcinoma in an appropriate clinical context.

Validation of liquid biopsy: plasma cell-free DNA testing in clinical management of advanced non-small cell lung cancer.

Plasma cell-free tumor DNA, or circulating tumor DNA (ctDNA), from liquid biopsy is a potential source of tumor genetic material, in the absence of tissue biopsy, for EGFR testing. Our validation study reiterates the clinical utility of ctDNA next generation sequencing (NGS) for EGFR mutation testing in non-small cell lung cancer (NSCLC). A total of 163 NSCLC cases were included in the validation, of which 132 patients had paired tissue biopsy and ctDNA. We chose to validate ctDNA using deep sequencing with custom designed bioinformatics methods that could detect somatic mutations at allele frequencies as low as 0.01%. Benchmarking allele specific real time PCR as one of the standard methods for tissue-based EGFR mutation testing, the ctDNA NGS test was validated on all the plasma derived cell-free DNA samples. We observed a high concordance (96.96%) between tissue biopsy and ctDNA for oncogenic driver mutations in Exon 19 and Exon 21 of the EGFR gene. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the assay were 91.1%, 100% 100%, 95.6%, and 97%, respectively. A false negative rate of 3% was observed. A subset of mutations was also verified on droplet digital PCR. Sixteen percent EGFR mutation positivity was observed in patients where only liquid biopsy was available, thus creating options for targeted therapy. This is the first and largest study from India, demonstrating successful validation of circulating cell-free DNA as a clinically useful material for molecular testing in NSCLC.

Detection of epidermal growth factor receptor gene T790M mutation in cytology samples using the cobas® EGFR mutation test

ObjectiveDetection of epidermal growth factor receptor (EGFR) gene mutations is essential in deciding therapeutic strategy in non-small cell lung cancer (NSCLC) patients at initial diagnosis. Moreover, in EGFR mutation-positive (EGFRm) NSCLC patients, re-biopsy at disease progression to clarify resistance mechanisms is also important. However, collecting histology samples is often difficult because of inaccessibility and invasiveness. In some cases, only cytology samples can be collected, and studies have reported that cytology samples are appropriate for EGFR gene mutation testing. The cobas® EGFR Mutation Test (Roche Molecular Systems Inc., Branchburg, New Jersey, USA) is approved as a companion diagnostic for osimertinib, a third-generation EGFR-tyrosine kinase inhibitor approved in Japan. However, it is not clear whether the EGFR T790M mutation can be detected in cytology samples using this test. The primary objective of this study was to assess concordance of EGFR T790M gene mutation detection between histology and matched cytology samples using the cobas® EGFR Mutation Test. Materials and methodsWe conducted a multicenter, observational study in Japan. Overall, 41 EGFRm NSCLC patients who had both histology and cytology samples collected at the same time at re-biopsy and with the results of EGFR mutation test using histology samples were enrolled. The EGFR mutation status of both sample types was tested using the cobas® EGFR Mutation Test and the concordance rates were calculated. ResultsThe EGFR T790M mutation detection rate in histology and cytology samples was 42.5% and 37.5%, respectively. The overall percent agreement between the histology and cytology samples was 91.7%. ConclusionsThese data demonstrate that the cobas® EGFR Mutation Test can detect the EGFR T790M mutation in both cytology and histology samples.

Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients.

e20032 Background: Tumor tissue is currently used for EGFR testing non-small cell lung cancer (NSCLC) patients, but the detection of circulating tumor DNA (ctDNA) is being actively investigated as a new method for the detection and longitudinal monitoring of actionable mutations in plasma samples. Around 30% patients with EGFR mutation presented inconsistent status of EGFR mutation between in tissues and plasma. We compared EGFR mutation detection in circulating tumor DNA from blood to that in matched tissue. Methods: EGFR mutation status were assessed by the Human EGFR Gene Mutations Detection Kit (Beijing ACCB Biotech Ltd.) both in tissue and plasma. Retrospective analysis to evaluate the concordance of tissue and plasma EGFR determination for assessing eligibility for EGFR-TKIs therapy in NSCLC patients. 10 mL tubes of blood were collected from patients who never had been treated by EGFR TKI, and plasma circulating tumor DNA were extracted from plasma by Biomark Circulating DNA Kit. Qubit2.0 Fluorometer was used to make plasma circulating DNA tumor quantitation. The concentration of final DNA sample is ≦2ng/μl. Results: A total of 224 NSCLC patients were detected by Amplification Refractory Mutation System (ARMS), with 92 tissue positive and 49 blood positive. Results showed 53.3% sensitivity in overall samples, but 81.4% sensitivity in ⅢB~Ⅲ patients. The specificity is 100%. Conclusions: The high sensitivity and specificity between tissue and plasma EGFR determination supports the blood-based EGFR mutation testing to determinate the eligibility of NSCLC patients for EGFR-TKIs treatment, especialy in ⅢB~Ⅲ NSCLC patients. Blood, in particular plasma, is a good screening substitute when tumor tissue is absent or insufficient for testing EGFR mutations to guide EGFR TKIs treatment in patients with NSCLC. EGFR mutation positivity in blood could be used to recommend EGFR TKIs treatment, but the blood negativity should be confirmed with other sample, biopsy tissue, pleural effusion, etc..

Exploratory cohort study and meta-analysis of BIM deletion polymorphism in patients with epidermal growth factor receptor-mutant non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors.

BackgroundNon-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations might develop primary and secondary resistance to tyrosine kinase inhibitors (TKIs). The proapoptotic protein Bcl-2-like 11 (BIM) is a key modulator of apoptosis triggered by EGFR-TKIs. The recent studies have indicated that some patients with positive EGFR mutations were refractory to EGFR-TKIs if they harbored a BIM deletion polymorphism. The purpose of this study was to investigate whether BIM polymorphism predicts treatment efficacy of EGFR-TKIs in Chinese NSCLC patients.Patients and methodsA cohort of advanced NSCLC patients with EGFR mutations and treated with EGFR-TKIs (gefitinib or erlotinib) were recruited. We drew peripheral blood to determinate BIM deletion status and then compared patients’ clinical outcomes according to the BIM deletion status. Additionally, we electronically searched eligible cohort studies and conducted a meta-analysis to pool event risk.ResultsThe exploratory cohort study included 140 patients. Patients with and without the BIM deletion polymorphism had similar objective response rates (ORRs, 48.5 vs 63.0%, P=0.16), disease control rate (DCR, 93.9 vs 97.0%, P=0.60) and adverse reactions. Similar progression-free survival (PFS) and overall survival (OS) were noted in overall population (P=0.27 for PFS and P=0.61 for OS) and prespecified patient subgroups. The meta-analysis included 10 eligible cohort studies involving 1,317 NSCLC patients. It showed the positive BIM deletion was associated with shorter PFS (hazard ratio =1.45; P=0.02). Nonsignificant differences existed for ORR, DCR and OS.ConclusionThe expanded meta-analysis results demonstrated the positive BIM deletion predicts shorter PFS in NSCLC patients after treatment with EGFR-TKIs while other clinical measures do not. A large multicenter well-designed cohort study involving other concurrent genetic alterations is warranted.

A Survival Scoring System for Non-Small Cell Lung Cancer Patients with De Novo Bone Metastases.

In the pre-tyrosine kinase inhibitors (TKIs) era, non-small cell lung cancer (NSCLC) patients with de novo bone metastases had a worse prognosis than those without. However, whether epidermal growth factor receptor (EGFR)-TKIs affect the outcomes of EGFR mutant NSCLC patients with de novo bone metastases has not been well studied thus far. We retrospectively studied the effect of EGFR mutation status and first-line EGFR-TKIs on patient outcomes and created a survival scoring system for NSCLC patients with de novo bone metastases. This retrospective study evaluated 1510 NSCLC patients diagnosed between November 2010 and March 2014. Among these patients, 234 patients had de novo bone metastases. We found that 121 of these 234 patients (51.7%) had positive EGFR mutation tests, and a positive EGFR mutation test significantly affected overall survival (OS) (EGFR mutant: 15.2 months, EGFR wild type: 6.5 months; p < 0.001). Other prognostic factors significant in the multivariable analysis for NSCLC with de novo bone metastases included Eastern Cooperative Oncology Group performance status (PS) (OS; PS 0–2: 11.2 months, PS 3–4: 4.9 months; p = 0.002), presence of extraosseous metastases (OS; with extraosseous metastases: 8.8 months, without extraosseous metastases: 14.0 months; p = 0.008), blood lymphocyte-to-monocyte ratio (LMR) (OS; LMR > 3.1: 17.1months, LMR ≤ 3.1: 6.9months; p < 0.001). A positive EGFR mutation status reversed the poor outcomes of NSCLC patients with de novo bone metastases. A simple and useful survival scoring system including the above clinical parameters was thus created for NSCLC patients with de novo bone metastases.

Immunohistochemistry for EGFR Mutation Detection in Non–Small-Cell Lung Cancer

IntroductionThe sensitivity and specificity of immunohistochemistry (IHC) was compared with the standard polymerase chain reaction (PCR)-based method for detecting common activating epidermal growth factor receptor (EGFR) mutations in non–small-cell lung cancer (NSCLC). Additionally, we evaluated predictive value of IHC EGFR mutation–positive status for EGFR tyrosine kinase inhibitor (TKI) treatment outcome and estimated cost-effectiveness for the upfront IHC testing. MethodsThe trial included 79 consecutive EGFR mutation–positive and 29 EGFR mutation–negative NSCLC cases diagnosed with reflex PCR-based testing. Two mutation-specific antibodies against the most common exon 19 deletion, namely E746-A750del (clone SP111) and L858R mutation (clone SP125) were tested by using automated immunostainer. Sixty of 79 EGFR mutation–positive cases were treated with EGFR TKIs for advanced disease and included in treatment outcome analysis. A decision tree was used for the cost-effectiveness analysis. ResultsThe overall sensitivity and specificity of the IHC-based method compared with the PCR-based method were 84.8% (95% confidence interval [CI] 74.6–91.6) and 100% (95% CI 85.4–100), respectively. The median progression-free survival (PFS) and overall survival (OS) of patients with IHC-positive EGFR mutation status were highly comparable to the total cohort (PFS: 14.3 vs. 14.0 months; OS: 34.4 vs. 34.4 months). The PCR and IHC cost ratio needs to be approximately 8-to-1 and 4-to-1 in White and Asian populations, respectively, to economically justify upfront use of IHC. ConclusionThe trial confirmed an excellent specificity with fairly good sensitivity of IHC with mutation-specific antibodies for common EGFR mutations and the accuracy of IHC testing for predicting response to EGFR TKIs. The use of upfront IHC depends mainly on the population EGFR mutation positivity probability.

Quantification of epidermal growth factor receptor (EGFR) mutation may be a predictor of EGFR-tyrosine kinase inhibitor treatment response.

BackgroundEpidermal growth factor receptor (EGFR) gene mutation is a reliable predictive factor for response to EGFR‐tyrosine kinase inhibitors (TKIs). The quantified EGFR value may also predict response and survival within an EGFR mutated group.MethodsWe conducted a retrospective study of 836 lung cancer patients. The patient sample was divided into two groups based on the mean delta cycle threshold (∆Ct) value. EGFR mutation tests using peptide nucleic acid (PNA)‐mediated clamping polymerase chain reaction (PCR) were performed. The efficiency of PCR clamping was determined by measuring the Ct value and EGFR quantification was determined by the corrected ∆Ct value.Results EGFR mutation positivity was 30.1% and there were 235 single activating mutations. In this mutation group, the higher corrected ∆Ct value (≥ mean value) group showed better objective response (70.9% vs. 54.9%, P = 0.022) and clinical benefit rates (86.4% vs. 68.3%, P = 0.003) than the lower group. In addition, corrected ∆Ct values were significantly and inversely correlated with disease response (r = −0.184, P = 0.017). In multivariate analysis, both female gender (P = 0.014) and higher corrected ΔCt value (P = 0.012) were independent predictive factors for better clinical benefit rate. The higher corrected ΔCt value group had a tendency for longer progression‐free survival than the lower group (P = 0.050).ConclusionThe corrected ∆Ct value, which refers to EGFR quantification by PNA‐mediated PCR clamping, can predict better clinical response to EGFR‐TKI therapy. However, further study is warranted to determine its value as a biomarker to reflect survival.

Association between tumor heterogeneity and progression-free survival in non-small cell lung cancer patients with EGFR mutations undergoing tyrosine kinase inhibitors therapy.

For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, current staging methods do not accurately predict the risk of disease recurrence after tyrosine kinase inhibitors (TKI) therapy. Developing a noninvasive method to predict whether individual could benefit from TKI therapy has great clinical significance. In this research, a radiomics approach was proposed to determine whether the tumor heterogeneity of NSCLC, which was measured by the texture on computed tomography (CT), could make an independent prediction of progression-free survival (PFS). A primary dataset contained 80 patients (median PFS, 9.5 months) with positive EGFR mutations and a validation dataset contained 72 NSCLC (median PFS, 10.2 months) patients were used for prognosis trial. The experiment results indicated that the features: "Cluster Prominence of Gray Level Co-occurrence" (hazard ratio [HR]: 2.13, 95% confidence interval [CI]: (1.33, 3.40), P = 0.010) and "Short Run High Gray Level Emphasis of Run Length" (HR: 2.43, 95%CI: (1.46, 4.05), P = 0.005) were significantly associated with PFS in the primary dataset, and these two texture features also make a consistent performance on the validation cohort. Our study further supported that the quantitative measurement of tumor heterogeneity can be associated with prognosis of NSCLC patients with EGFR mutation.

Comparison of plasma and tissue samples in epidermal growth factor receptor mutation by ARMS in advanced non-small cell lung cancer

ObjectiveThe aim of this study was to assess the effectiveness and accuracy of blood-based circulating-free tumor DNA on testing epidermal growth factor receptor (EGFR) gene mutations. MethodsIn total, 219 non-small cell lung cancer patients in stages III-IV were enrolled into this study. All patients had tissue samples and matched plasma DNA samples. EGFR gene mutations were detected by the Amplification Refractory Mutation System (ARMS). We compared the mutations in tumor tissue samples with matched plasma samples and determined the correlation between EGFR mutation status and clinical pathologic characteristics. ResultThe overall concordance rate of EGFR mutation status between the 219 matched plasma and tissue samples was 82% (179/219). The sensitivity and specificity for the ARMS EGFR mutation test in the plasma compared with tumor tissue were 60% (54/90) and 97% (125/129), respectively. The positive predictive value was 93% (54/58) and the negative predictive value was 78% (125/161). The median overall survival was longer for those with EGFR mutations than for those without EGFR mutations both in tissue samples (23.98 vs. 12.16months; P<0.001) and in plasma (19.96 vs. 13.63months; P=0.009). For the 68 patients treated with EGFR- tyrosine kinase inhibitors (TKIs), the median progression-free survival (PFS) was significantly prolonged in the EGFR mutant group compared to the non-mutation group in tumor tissue samples (12.26months vs. 2.40months, P<0.001). In plasma samples, the PFS of the mutant group was longer than that of the non-mutant group. However, there was no significant difference between the two groups (10.88months vs. 9.89months, P=0.411). ConclusionsThe detection of EGFR mutations in plasma using ARMS is relatively sensitive and highly specific. However, EGFR mutation status tested by ARMS in plasma cannot replace a tumor tissue biopsy. Positive EGFR mutation results detected in plasma are fairly reliable, but negative results are hampered by a high rate of false negatives.

Advanced non-Small cell lung cancer patients at the extremes of age in the era of epidermal growth factor receptor tyrosine kinase inhibitors

ObjectivesThe clinical characteristics and survival of very young (≤40 years) and very old (>80years) patients with advanced non-small cell lung cancer (NSCLC) are distinct. However, the benefits of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) to patients at the extremes of age with NSCLC harboring EGFR mutation have not been well studied. We retrospectively studied the effect of extreme age on patients’ clinical characteristics and prognosis. Materials and methodsOf 1510 lung cancer patients diagnosed between November 2010 and March 2014, 555 patients who were tested for EGFR mutations were included. Patients were divided into the following groups according to age: young (≤40 years), lower medium (41–60 years), higher medium (61–80years), and very old (>80years). ResultsOf the 555 patients, 20 (3.6%) patients were aged ≤40 years and 60 (10.8%) patients were aged >80years. Young NSCLC patients had a lower BMI (p=0.003), more brain (p=0.016) and bone metastases (p=0.002) Very young lung cancer patients still have poor prognosis even they were EGFR mutant. (EGFR mutant vs. wild type patients, OS: 12 vs. 7.3 months, p=0.215) Very old NSCLC patients had a lower BMI (p=0.003) and poor ECOG PS (p=0.028). Positive EGFR mutation test reverses poor prognosis of elderly NSCLC patients. (EGFR mutant vs. wild type patients, OS: 13.2 vs. 4.9 months, p=0.003) ConclusionWe observed EGFR mutations reverse the poor prognosis of old patients with NSCLC. However, young patients with lung cancer have a poor prognosis even if they harbor EGFR mutations.

Relation entre cancer bronchique primitif et consommation tabagique. Résultats de l’étude KBP-2010-CPHG du Collège des pneumologues des hôpitaux généraux

The Collège des Pneumologues des Hôpitaux Généraux has performed a prospective multicentre epidemiological study which aims to describe the baseline characteristics of all new cases of primary lung cancer histologically or cytologically diagnosed in 2010 and followed-up in the respiratory department of general hospitals. The present publication compares the characteristics of these presentations according to their smoking history. Seven thousand and fifty-one adult patients were included from 104 respiratory departments. A standardized form was completed at diagnosis and a steering committee checked the completeness of inclusion. Only 10.9% of patients were never-smokers and 89.1% ever-smokers (i.e., current or former smokers). Respectively, 3.7%, 10.7% and 85.6% of ever-smokers consumed/had consumed 1-10, 11-20, and >20 pack-years. Mean smoking duration was 37.5 years. Former smokers had stopped smoking on average 14.8 years previously. Only 20.7% of never-smokers reported that they had been exposed to tobacco smoke passively. At diagnosis, statistically significant differences were found between never- and ever-smokers (P<0.0001) for sex (women: 60.8% vs 18.8%), age (mean: 70.7 years vs 64.9 years), stage (IV: 70.8% vs 58.7%), histology (adenocarcinoma: 68.5% vs 42.6%), EGFR mutation exploration (51.4% vs 28.0%) and positivity (37.0% vs 4.6%). Differences between never- and ever-smokers rose with increasing tobacco consumption. This study confirms that differences exist between never- and ever-smoker patients presenting with primary lung cancer and shows the impact of the level of tobacco consumption, in particular on histology.

Correlation between epidermal growth factor receptor mutations and nuclear expression of female hormone receptors in non-small cell lung cancer: a meta-analysis.

Compared with male, female non-small cell lung cancer (NSCLC) patients have better response when treated with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), suggesting a potential association between female hormones and EGFR mutation. However, the results provided by previous studies were inconclusive and controversial. We sought to examine the link between the expression of nuclear female hormone receptors and EGFR mutations in NSCLC. Electronic databases were used to search the relevant articles. The involved hormone receptors included estrogen receptor (ER) and progesterone receptor (PR). The primary endpoint was the occurrence of ER/PR expression and EGFR mutation in NSCLC patients. Five studies fulfilled the criteria and were included in our analysis. Patients with high ER-β expression had higher positive EGFR mutation than low ER-β patients (44.2% vs. 23.7%), and there was a significant difference between the two groups [odds radio (OR) 3.44, 95% confidence interval (CI): 2.40-4.93, Z=6.72, P<0.001]. However, there is no significant correlation between EGFR mutations and ER-α (when included ER-α3, OR 1.20, 95% CI: 0.62-2.33, Z=0.55, P=0.58; and when included ER-α4, OR 1.18, 95% CI: 0.62-2.25, Z=0.51, P=0.61) or PR (OR 1.29, 95% CI: 0.40-4.10, Z=0.43, P=0.67). No significant publication bias was observed. High nuclear expression of ER-β, but not ER-α or PR is correlated with EGFR mutations in NSCLC. The underlying mechanism and potential translational relevance warrant further investigation.

Early and late brain metastases in EGFR wild type and EGFR mutation positive non small cell lung cancer: Implications for survival.

e19065 Background: EGFR mutation positivity (EGFR+) is a known favorable prognostic factor in NSCLC. We sought to understand its significance in the setting of brain metastases (BM) when compared t...

Blood as a Substitute for Tumor Tissue in Detecting EGFR Mutations for Guiding EGFR TKIs Treatment of Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Tumor tissues are often absent or insufficient for testing epidermal growth factor receptor (EGFR) mutations to guide EGFR tyrosine kinase inhibitors (TKIs) treatment of patients with nonsmall cell lung cancer (NSCLC). We conducted this systematic review and meta-analysis to assess whether blood can be used as a substitute for tumor tissue in detecting EGFR mutations. MEDLINE, EMBASE, and the Cochrane Library were searched for studies that provided data to estimate the accuracy of blood testing against tissue testing in NSCLC patients and/or those directly compared the efficacy of EGFR TKIs in EGFR mutant and wild-type patients according to sources of specimens. Sensitivity, specificity, and concordance rate were used as measures of the accuracy. Risk ratio (RR) for objective response and hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) were used as measures for treatment efficacy. We combined the effects by using the fixed-effects model unless there was evidence of heterogeneity, in which case a random-effects mode was used. This systematic review included 25 studies with 2605 patients. The pooled overall sensitivity, specificity, and concordance rate were 0.61, 0.90, and 0.79, respectively. Serum showed lower sensitivity (0.56 vs 0.65) but higher specificity (0.95 vs 0.85) and higher concordance (0.86 vs 0.74) than plasma. EGFR mutations (exon 19 or 21) in blood were significantly associated with objective response (RR: 4.08; 95% confidence interval [CI] 2.48-6.70), PFS (HR: 0.72; 95% CI 0.64-0.80), and OS (HR: 0.71; 95% CI 0.50-0.99). Importantly, the association of the mutations with the 3 clinical outcomes for serum was similar to that for tumor tissue and higher than that for plasma. Blood, in particular serum, is a good substitute when tumor tissue is absent or insufficient for testing EGFR mutations to guide EGFR TKIs treatment in patients with NSCLC. EGFR mutation positivity in blood could be used to recommend EGFR TKIs treatment, but the absence of blood positivity should not necessarily be construed with confirmed negativity.

EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey.

Introduction:The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutation-positive non–small-cell lung cancer (NSCLC) patients necessitates accurate, timely testing. Although EGFR mutation testing has been adopted by many laboratories in Asia, data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods.Methods:A retrospective survey of records from NSCLC patients tested for EGFR mutations during 2011 was conducted in 11 Asian Pacific countries at 40 sites that routinely performed EGFR mutation testing during that period. Patient records were used to complete an online questionnaire at each site.Results:Of the 22,193 NSCLC patient records surveyed, 31.8% (95% confidence interval: 31.2%–32.5%) were tested for EGFR mutations. The rate of EGFR mutation positivity was 39.6% among the 10,687 cases tested. The majority of samples were biopsy and/or cytology samples (71.4%). DNA sequencing was the most commonly used testing method accounting for 40% and 32.5% of tissue and cytology samples, respectively. A pathology report was available only to 60.0% of the sites, and 47.5% were not members of a Quality Assurance Scheme.Conclusions:In 2011, EGFR mutation testing practices varied widely across Asia. These data provide a reference platform from which to improve the molecular diagnosis of NSCLC, and EGFR mutation testing in particular, in Asia.