Growth Factor Receptor Gene Mutations Research Articles

Predictive value of multiple metabolic and heterogeneity parameters of 18F-FDG PET/CT for EGFR mutations in non-small cell lung cancer

To explore the value of multiple metabolic and heterogeneity parameters of 2-deoxy-2-[fluorine-18] fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in predicting epidermal growth factor receptor gene (EGFR) mutations in non-small cell lung cancer (NSCLC). A retrospective analysis was performed by reviewing 98 patients with NSCLC who underwent EGFR mutation testing and 18F-FDG PET/CT examination in our hospital between March 2016 and March 2021. Patients were divided into an EGFR-mutant group and a wild-type group. A multivariate logistic regression analysis was performed to screen and construct a prediction model. The diagnostic performance of the model was evaluated using a receiver-operating characteristic (ROC) curve. The study found that EGFR mutations were more likely to occur in women, non-smokers, and patients with peripheral lesions, shorter maximum tumor diameter, adenocarcinoma, and T1 stage cancer. Low maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume, total lesion glycolysis, and high coefficient of variation (COV) were significantly correlated with EGFR mutations, and the area under the ROC curve (AUC) was 0.622, 0.638, 0.679, 0.687, and 0.672, respectively. Multivariate logistic regression analysis indicated that non-smokers (odds ratio (OR) = 0.109, P = 0.014), peripheral lesions (OR = 6.917, P = 0.022), low SUVmax (≤ 7.85, OR = 5.471, P = 0.001), SUVmean (≤ 5.34, OR = 0.044, P = 0.000), and high COV (≥ 106.08, OR = 0.996, P = 0.045) were independent predictors of EGFR mutations. The AUC of the prediction model established by combining the above factors was 0.926; the diagnostic efficiency was significantly higher than that of a single parameter. Among the metabolic and heterogeneity parameters of 18F-FDG PET/CT, low SUVmax, SUVmean, and high COV were significantly associated with EGFR mutations, and the predictive value of EGFR mutations could be enhanced when combined with clinicopathological features.

Improved BYOL method for predicting epidermal growth factor receptor gene mutations in non-small cell lung cancer

Improved BYOL method for predicting epidermal growth factor receptor gene mutations in non-small cell lung cancer

Comparison of Gefitinib in the treatment of patients with non-small cell lung cancer and clinical effects of Osimertinib and EGFR Gene mutation.

Objectives:To compare the clinical effects of Osimertinib and Gefitinib in the treatment of non-small cell lung (NSCLC) complicated with epidermal growth factor receptor (EGFR) gene mutation.Methods:We retrospectively analyzed the clinical data of 102 patients with advanced NSCLC and EGFR gene mutations treated in the Chest Disease Diagnosis and Treatment Center of our hospital from January 2018 to January 2020. We divided the data based on the administered treatments into Osimertinib and Gefitinib groups. The disease control rate (DCR), progression free survival (PFS) and the incidence of adverse events in both groups were analyzed.Results:In the Osimertinib group, there was one patients with complete response (CR), 38 with partial response (PR), eight with stable disease (SD), and two with progressive disease (PD)/ The overall response rate (ORR) was 79.59% (39/49), and the disease control rate (DCR) was 95.92% (47/49). In the Gefitinib group, we found zero patients with CR, 37 patients with PR, 11 with SD, and five with PD. The ORR in the Gefitinib group was 69.80% (37/53) and DCR was 90.57% (48/53). There was no statistical significance between the two groups, ORR was Χ2=0.927 (P=0.336) and the DCR Χ2=0.221 (P=0.638). The median PFS of and Gefitinib groups was significantly higher in the oxitinib group, compared to the Gefitinib group (18.1 months (95% CI 15.4-20.7) and 10.7 months (95% CI 9.9-11.4), respectively, P<0.001). The incidence of adverse reactions in the Osimertinib group was 12.24% (6/49), which was significantly lower than 28.30% (15/53) in the Gefitinib group (P < 0.05).Conclusions:The clinical effect of oxitinib in the treatment of non-small cell lung cancer complicated with EGFR gene mutation is similar to that of Gefitinib. In patients with advanced NSCLC and EGFR gene mutations, oxitinib treatment is associated with significantly longer PFS and lower adverse reaction rate compared with Gefitinib treatment.

Clinical significance of epidermal growth factor receptor mutations in resected stage IA non-small cell lung cancer

Background: Epidermal growth factor receptor (EGFR) gene mutation is a known predictor of the response to EGFR tyrosine kinase inhibitors. However, detecting EGFR mutations is a potential challenge because of the ground-glass opacity component, and its prognostic value for stage IA lung adenocarcinoma remains controversial. This study aimed to investigate the associations between EGFR mutation status, clinicopathological characteristics, and prognosis in surgically resected stage IA non-small cell lung cancer (NSCLC). Materials and Methods: We retrospectively examined the data of patients who underwent surgical resection for lung cancer between 2004 and 2014. The clinical data, imaging characteristics of nodules, surgical approaches, and outcomes were analyzed. Results: A total of 429 patients (female, n = 303; male, n = 126) with surgically resected stage IA NSCLC were analyzed and 343 were nonsmokers. The EGFR mutation rate was 48.3% (n = 207). Of the patients, 192 (44.8%) had stage IA1, 165 (38.5%) had stage IA2, and 72 (16.8%) had stage IA3 NSCLC. In the analysis of the correlations between clinicopathological features and EGFR status, older age (P = 0.032), nonsmoking history (P = 0.039), and pathological stage (P < 0.05) were related to EGFR mutation. Patients with stage IA2 NSCLC had a higher positive expression of EGFR than patients with stages IA1 and IA3. The 5-year overall survival rates and disease-free survival rates were better in the EGFR mutation group; however, the difference was not statistically significant. Conclusion: EGFR mutations are common in older and nonsmoking patients with stage IA NSCLC. Further separate analyses of EGFR gene mutations and pathological stage could improve the diagnostic performance and predict patients with unavailable EGFR gene testing who may benefit from targeted drug treatment.

Clinicopathologic Features and Molecular Biomarkers as Predictors of Epidermal Growth Factor Receptor Gene Mutation in Non-Small Cell Lung Cancer Patients.

Lung cancer ranks first in the incidence and mortality of cancer in the world, of which more than 80% are non-small cell lung cancer (NSCLC). The majority of NSCLC patients are in stage IIIB~IV when they are admitted to hospital and have no opportunity for surgery. Compared with traditional chemotherapy, specific targeted therapy has a higher selectivity and fewer adverse reactions, providing a new treatment direction for advanced NSCLC patients. Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) are the widely used targeted therapy for NSCLC patients. Their efficacy and prognosis are closely related to the mutation status of the EGFR gene. Clinically, detecting EGFR gene mutation is often limited by difficulty obtaining tissue specimens, limited detecting technology, and economic conditions, so it is of great clinical significance to find indicators to predict EGFR gene mutation status. Clinicopathological characteristics, tumor markers, liquid biopsy, and other predictors are less invasive, economical, and easier to obtain. They can be monitored in real-time, which is supposed to predict EGFR mutation status and provide guidance for the accurate, individualized diagnosis and therapy of NSCLC patients. This article reviewed the correlation between the clinical indicators and EGFR gene mutation status in NSCLC patients.

Female infant with apert syndrome and high imperforate anus without fistula

Apert syndrome (AS) is a rare type of congenital craniofacial dysmorphic and severe syndactyly of the hands and feet. Fibroblast growth factor receptor (FGFR) gene mutations are suspect to be involved in this anomaly. The distinct features are craniosynostosis-a condition of premature closure of skull's sutures-, midface hypoplasia-an incomplete development of the middle of the face-, and syndactyly-webbed fingers or toes-. The anorectal malformations (ARMs) associations with AS is rare, and the genetic link is highly complex. Only 12.7% of ARMs cases were associated with a syndrome that has a well-known impact on intellectual development, including AS. To our knowledge, this is the first reported case of AS with a high imperforate anus without fistula. • The association of anorectal malformations (ARMs) with AS is rare, and the genetic link is highly complex. • High imperforate anus can be associated with apert syndrome. This is the first reported case of apert syndrome and high imperforate anus.

Worldwide Prevalence of Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer: A Meta-Analysis.

BackgroundIdentification of variable epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC) is important for the selection of appropriate targeted therapies. This meta-analysis was conducted to provide a worldwide overview of EGFR mutation and submutation (specifically exon 19 deletions, exon 21 L858R substitutions, and others) prevalence, and identify important covariates that influence EGFR mutation status in patients with advanced NSCLC to address this clinical data gap.MethodsEmbase® and MEDLINE® in Ovid were searched for studies published between 2004 and 2019 with cohorts of ≥ 50 adults with EGFR mutations, focusing on stage III/IV NSCLC (≤ 20% of patients with stage I/II NSCLC). Linear mixed-effects models were fitted to EGFR mutation endpoints using logistic transformation (logit), assuming a binomial distribution. The model included terms for an intercept reflecting European studies and further additive terms for other continents. EGFR submutations examined were exon 19 deletions, exon 21 L858R substitutions, and others.ResultsOf 3969 abstracts screened, 57 studies were included in the overall EGFR mutation analysis and 74 were included in the submutation analysis relative to the overall EGFR mutation population (Europe, n = 12; Asia, n = 51; North America, n = 5; Central America, n = 1; South America, n = 1; Oceania, n = 1; Global, n = 3). The final overall EGFR mutations model estimated Asian and European prevalence of 49.1% and 12.8%, respectively, and included an additive covariate for the proportion of male patients in a study. There were no significant covariates in the submutation analyses. Most submutations were actionable: exon 19 deletions (49.2% [Asia]; 48.4% [Europe]); exon 21 L858R substitutions (41.1% [Asia]; 29.9% [Europe]).ConclusionsAlthough EGFR mutation prevalence was higher in Asian than Western countries, data support worldwide testing for EGFR overall and submutations to inform appropriate targeted treatment decisions.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40291-021-00563-1.

High-resolution computed tomography findings independently predict epidermal growth factor receptor mutation status in ground-glass nodular lung adenocarcinoma.

BACKGROUNDFor lung adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutation, small molecule tyrosine kinase inhibitors are more effective. Some patients could not obtain enough histological specimens for EGFR gene mutation detection. Specific imaging features can predict EGFR mutation status to a certain extent.AIMTo assess the associations of EGFR mutations with high-resolution computerized tomography (HRCT) features in ground-glass nodular lung adenocarcinoma.METHODSThis study retrospectively assessed patients with ground-glass nodular lung adenocarcinoma diagnosed between January 2011 and March 2017. EGFR gene mutations in exons 18-21 were detected. The patients were classified into mutant EGFR and wild-type groups, and general data and HRCT image characteristics were assessed.RESULTSAmong 98 patients, 31 (31.6%) and 67 (68.4%) had mutated and wild-type EGFR in exons 18-21, respectively. Gender, age, smoking history, location of lesions, morphology, edges, borders, pleural indentations, and associations of nodules with bronchus and blood vessels were comparable in both groups (all P > 0.05). Patients with mutant EGFR had larger nodules than those with the wild-type (17.19 ± 6.79 and 14.37 ± 6.30 mm, respectively; P = 0.047). Meanwhile, the vacuole/honeycomb sign was more frequent in the mutant EGFR group (P = 0.011). The logistic regression prediction model included the combination of nodule size and vacuole/honeycomb sign (OR = 1.120, 95%CI: 1.023-1.227, P = 0.014) revealed a sensitivity of 83.9%, a specificity of 52.2% and an AUC of 0.698 (95%CI: 0.589-0.806; P = 0.002).CONCLUSIONNodule size and vacuole/honeycomb features could independently predict EGFR mutation status in ground-glass nodular lung adenocarcinoma.

Effect of epidermal growth factor receptor gene mutation on the prognosis of pathological stage II–IIIA (8th edition TNM classification) primary lung cancer after curative surgery

ObjectivesThis retrospective study aimed to elucidate the effect of epidermal growth factor receptor (EGFR) gene mutations on the prognosis of patients with pathological stage II–IIIA primary lung cancer after curative surgery. Materials and methodsWe enrolled 539 patients with p-stage II–IIIA (8th edition tumor–node–metastasis [TNM] classification) lung cancer who underwent curative resection at Kanagawa Cancer Center between January 2010 and December 2020 and whose tumors were tested for EGFR mutations. Relapse-free survival (RFS) and overall survival (OS) of patients with EGFR-mutant lung cancer (Mt, n = 126) including EGFR exon 21 L858R point mutation and EGFR exon 19 deletion mutation and EGFR mutation-wild lung cancer (Wt, n = 413) were analyzed using Kaplan–Meier curves and compared using a log-rank test. Cox regression analysis was performed to evaluate the effects of EGFR gene mutations on RFS and OS at each stage. ResultsThere were 56/256 patients with p-stage II EGFR-Mt/Wt and 70/157 patients with p-stage IIIA EGFR-Mt/Wt. The 5-year RFS rate of patients with EGFR-Mt/Wt was 46.6%/52.0% (p = 0.787) for p-stage II and 17.4%/29.7% (p = 0.929) for p-stage IIIA. The 5-year OS rate was 92.0%/65.7% (p = 0.001) for p-stage II and 56.0%/39.3% (p = 0.016) for p-stage IIIA. EGFR-Mt was not an independent prognostic factor for OS of patients with p-stage IIIA lung cancer (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.51–1.76; p = 0.872); however, EGFR-Mt was an independent favorable prognostic factor for OS of patients with p-stage II lung cancer (HR, 0.59; 95% CI, 0.36–0.96; p = 0.034). ConclusionThe OS of lung cancer patients with p-stage II or IIIA, classified according to the 8th edition TNM classification, was remarkably favorable. Incorporating EGFR mutations to the anatomical TNM classification may lead to a more accurate prognosis prediction.

A Quarter-split Domain-adaptive Network for EGFR Gene Mutation Prediction in Lung Cancer by Standardizing Heterogeneous CT image.

Epidermal growth factor receptor (EGFR) gene mutation status is crucial for the treatment planning of lung cancer. The gold standard for detecting EGFR mutation status relies on invasive tumor biopsy and expensive gene sequencing. Recently, computed tomography (CT) images and deep learning have shown promising results in non-invasively predicting EGFR mutation in lung cancer. However, CT scanning parameters such as slice thickness vary largely between different scanners and centers, making the deep learning models very sensitive to noise and therefore not robust in clinical practice. In this study, we propose a novel QuarterNetadaptive model to predict EGFR mutation in lung cancer, which is robust to CT images of different thicknesses. We propose two components: 1) a quarter-split network to sequentially learn local lung features from different lung lobes and global lung features; 2) a domain adaptive strategy to learn CT thickness-invariant features. Furthermore, we collected a large dataset including 1413 patients with both EGFR gene sequencing and CT images of various thicknesses to evaluate the performance of the proposed model. Finally, the QuarterNetadaptive model achieved AUC over 0.88 regarding CT images of different thicknesses, which improves largely than state-of-the-art methods.Clinical relevance-We proposed a non-invasive model to detect EGFR gene mutation in lung cancer, which is robust to CT images of different thicknesses and can assist lung cancer treatment planning.

P27.06 Multiscale NSCLC Tumor Growth Knowledge-Based Model Reproduces Tumor-Non-Progression under Gefitinib

Non-small cell lung cancer (NSCLC) is the leading form of lung cancer and adenocarcinoma (LUAD) its most common histotype. Tumor size, part of the TNM-staging, is important for prognosis and treatment guidance. Response to Tyrosine Kinase Inhibitors, e.g. Gefitinib, is altered with certain epidermal growth factor receptor (EGFR+) gene mutations making time-to-progression (TTP) predictions difficult. We therefore developed an in silico EGFR+LUAD model to characterize tumor size and TTP in advanced-stage adenocarcinoma patients (IIIb or higher) with EGFR mutations (exon19-deletion (E19+) or exon21-L858R-substitution (E21+)). The model is a mechanistic representation of tumor evolution upon Gefitinib administration, including tumor heterogeneity, age, gender, initial clinical stage and smoking status as covariates. Three-step in silico model development: 1. Model Building using a Knowledge and a Computational Model (CM): Pathophysiology of EGFR+LUAD was characterized with seven sub-models: mutational burden, EGFR downstream pathways, tumor growth and heterogeneity, Gefitinib PK/PD, treatment-induced resistance and clinical outcome. For each sub-model, relevant biological entities and their functional relationships were extracted from scientific papers and translated into ordinary differential equations (ODEs). The CM has 43 variables, 170 parameters and 18 to 83 ODEs reflecting intra-tumor heterogeneity. 2. Calibration with information from scientific literature: Spheroids, xenografts and clinical results were used for stepwise calibration. 3. Validation against published data: Patients[1] (n=159) had E19+ or E21+ mutations and were treated with Gefitinib (250mg/day orally). A Virtual Population with equivalent baseline characteristics was simulated using the calibrated CM. Kaplan-Meier curves show tumor non-progression over time. Validation metrics: (1) “Raw-Data-Coverage” expressing the fit with the 95% prediction interval (PI) of the simulated curve (computed by bootstrapping), (2) Comparison of bootstrapped simulated survival curves (n=159) with log-rank tests (LR) for statistical significance (α=0.05). Coverage of the model simulations with raw data was 95.92%. Proportion of non-significant bootstrapped LR tests comparing the observed curve with simulated curves was 88.43% (Figure 1). We reproduced a clinical trial of advanced-stage EGFR+LUAD patients treated with Gefitinib. We created a modular, reusable, multiscale Knowledge-Based model adaptable to also test the efficacy of other treatments and drug combinations on tumor-non-progression. This enables us to identify best responders and to optimize trial designs in silico.

Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring.

Simple SummaryNon-small cell lung cancer (NSCLC) is the most common cancer in the world. For common EGFR mutations, treatment is based on different inhibitors. Despite the excellent disease control with inhibitors, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and some possible drug targets. Resistance mechanisms could be involved as gene mutations, amplifications or fusions, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of inhibitors and could be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.

Palindromic-assisted self-annealing transcription amplification for reliable genotyping of epidermal growth factor receptor exon mutations

Reliable discrimination of specific epidermal growth factor receptor (EGFR) gene mutations plays a critical role in guiding lung cancer therapeutics. Until now, convenient and accurate recognition of the specific deletion of EGFR exons has remained particularly challenging. Herein, we propose a palindromic-assisted self-annealing transcription amplification (PASTA) strategy for the reliable detection of circulating EGFR exon mutations. We designed a palindromic DNA hairpin nanorobot consisting of a palindromic tail, a T7 promoter, a target recognition region, and a transcription template. The nanorobot enabled prompt self-assembly into a target-hairpin/hairpin-target dimer in the presence of single-stranded DNA target and further triggered in vitro transcription. In a proof-of-concept experiment for detecting circulating 15n-del EGFR mutation, a detection limit of 0.8 fM and a linear detection range of 1 fM to 100 pM was achieved, and an accuracy of 100% was reached in clinical validation by analyzing 20 samples from clinical lung cancer patients. Empowered by the intrinsic sensitivity and selectivity, the proposed PASTA approach will lead to the development of a universal platform for reliable molecular subtyping.

Development of Brain Metastases in Patients With Non-Small Cell Lung Cancer and No Brain Metastases at Initial Staging Evaluation: Cumulative Incidence and Risk Factor Analysis.

BACKGROUND. Although established guidelines give indications for performing staging brain MRI at initial diagnosis of non-small cell lung cancer (NSCLC), guidelines are lacking for performing surveillance brain MRI for patients without brain metastases at presentation. OBJECTIVE. The purpose of this study is to estimate the cumulative incidence of and risk factors for brain metastasis development in patients with NSCLC without brain metastases at initial presentation. METHODS. This retrospective study included 1495 patients with NSCLC (mean [± SD] age, 65 ± 10 years; 920 men and 575 women) without brain metastases at initial evaluation that included brain MRI. Follow-up brain MRI was ordered at the discretion of the referring physicians. MRI examinations were reviewed in combination with clinical records for brain metastasis development; patients not undergoing MRI were deemed to have not had metastases develop through last clinical follow-up. The cumulative incidence of brain metastases was determined, with death considered a competing risk, and was stratified by clinical stage group, cell type, and epidermal growth factor receptor (EGFR) gene mutation status. Univariable and multivariable Cox proportional hazards regression analyses were performed. RESULTS. A total of 258 of 1495 patients (17.3%) underwent follow-up brain MRI, and 72 (4.8%) had brain metastases develop at a median of 12.3 months after initial diagnosis of NSCLC. Of the 72 patients who had metastases develop, 44.4% had no neurologic symptoms, and 58.3% had stable primary thoracic disease. The cumulative incidence of brain metastases at 6, 12, 18, and 24 months after initial evaluation was 0.6%, 2.1%, 4.2%, and 6.8%, respectively. Cumulative incidence at 6, 12, 18, and 24 months was higher (p < .001) in patients with clinical stage III-IV disease (1.3%, 3.9%, 7.7%, and 10.9%, respectively) than in those with clinical stage I-II disease (0.0%, 0.8%, 1.2%, and 2.6%, respectively), and it was higher (p < .001) in patients with EGFR mutation-positive adenocarcinoma (0.7%, 2.5%, 6.3%, and 12.3%, respectively) than in those with EGFR mutation-negative adenocarcinoma (0.4%, 1.8%, 2.9%, and 4.4%, respectively). Among 1109 patients with adenocarcinoma, independent risk factors for the development of brain metastasis were clinical stage III-IV (hazard ratio [HR], 9.39; p < .001) and EGFR mutation-positive status (HR, 1.78; p = .04). The incidence of brain metastasis over the study interval was 8.7% among patients with clinical stage III-IV disease and 17.4% among those with EGFR mutation-positive adenocarcinoma. CONCLUSION. Clinical stage III-IV and EGFR mutation-positive adenocarcinoma are independent risk factors for brain metastasis development. CLINICAL IMPACT. For patients with clinical stage III-IV disease or EGFR mutation-positive adenocarcinoma, surveillance brain MRI performed 12 months after initial evaluation may be warranted.

Identification of predictors for brain metastasis in newly diagnosed non-small cell lung cancer: a single-center cohort study.

To identify clinical and staging chest CT characteristics predictive of brain metastasis in patients with newly diagnosed NSCLC dichotomized according to resectability. Patients newly diagnosed with NSCLC of clinical stages II-IV between November 2017 and October 2018 were enrolled and classified into resectable (stage II+IIIA) and unresectable stages (stage IIIB/C+IV) according to chest CT. Associations of clinicopathological characteristics and CT findings with brain metastasis were analyzed using logistic regression. Predictive models were evaluated using receiver operating characteristics curve analysis. A subgroup analysis for unresectable-stage patients with known epidermal growth factor receptor gene (EGFR) mutation status was performed. This study included 911 NSCLC patients (mean age, 65 ± 11 years; 620 men), 194 of whom were diagnosed with brain metastasis. For resectable stages, independent predictors for brain metastasis were N2-stage (13 of 25 patients), absence of air-bronchogram/bubble lucency (23 of 25 patients), and presence of spiculation (15 of 25 patients), with a model combining the two imaging features showing an AUC of 0.723. In unresectable stages, independent predictors of brain metastasis were younger age, female sex, extrathoracic metastasis, and adenocarcinoma, with models combining these showing AUCs of 0.675-0.766. In the subgroup with known EGFR-mutation status, extrathoracic metastasis and positive EGFR mutation were independent predictors of brain metastasis, with the model showing AUCs of 0.641-0.732. CT-derived imaging features, clinical stages, lung cancer subtype, and EGFR mutation were associated with brain metastasis in patients with newly diagnosed NSCLC. The predictors were completely different between resectable and unresectable stages. • In resectable stages of NSCLC, two imaging features (absence of air-bronchogram/bubble lucency and presence of spiculation) and N2 stage were independent predictors of brain metastasis. • In unresectable stages of NSCLC, younger age, female sex, extrathoracic metastasis, and adenocarcinoma were associated with brain metastasis. • In the subgroup of NSCLC with known EGFR-mutation status, extrathoracic metastasis and positive EGFR mutation were independent predictors of brain metastasis.

A randomized phase II study comparing nivolumab (NIVO) with carboplatin-pemetrexed (CbPEM) for patients (pts) with EGFR mutation-positive non-small cell lung cancer (NSCLC) who acquire resistance to tyrosine kinase inhibitors (TKIs) not due to a secondary T790M mutation (WJOG8515L).

9037 Background: Although the efficacy of antibodies to programmed cell death–1 (PD-1) appears to be less pronounced in patients with NSCLC harboring epidermal growth factor receptor gene ( EGFR) mutations, patients who develop disease progression (PD) to TKIs due to mechanisms other than secondary T790M mutation of EGFR might be more likely to benefit from NIVO. Here, we report the results of first randomized phase II trial to compare NIVO with the CbPEM in those population. Methods: Pts with advanced EGFR mt NSCLC who experienced PD after EGFR-TKIs were randomized 1:1 to NIVO or CbPEM. Eligibility criteria included the treatment history with TKIs as follow; no evidence of T790M after PD on 1st/2nd generation (gen) TKIs (A) after PD on 3rd gen TKIs as a 2nd line for T790M positive tumor (B) or 3rd gen TKIs as a front-line (C). The primary end point is progression-free survival (PFS) and biomarker analysis were included for exploratory analysis. Results: A total of 102 patients was randomized. Median PFS and overall survival (OS) were 1.7 and 20.7 months (mo), respectively, for NIVO arm (n = 52) versus 5.6 and 19.9 months for CbPEM (n = 50) (Hazard ratio [HR] = 1.92 and 0.88, respectively). Overall response rate and duration of response were 9.6% and 5.3 months for NIVO and 36.0% and 5.5 months for CbPEM. PD-L1 expression on tumor cells and tumor mutation burden (TMB) were evaluated in 77 (TPS 0%. 1-49%, &gt; 50%, n = 46, 20, and 11) and 50 (Median TMB 6.2mt/mb). Immune-related gene expression profiling was under evaluation and the results will be demonstrated in the meeting. The efficacy of NIVO in PD-L1 strong positive (&gt;50%, n = 8) and no evidence of T790M after PD on 1st/2nd gen TKIs (n = 29) was tended to be better than their counterparts. There was no significant correlation between TMB and the efficacy of NIVO. Pneumonitis was observed in one patient (1.0%) for NIVO arm and no new safety signals were noted. Conclusions: NIVO was not associated with longer PFS than CbPEM in selected pts with advanced EGFR mt NSCLC. OS was similar between groups. Baseline PD-L1 status and genetic alteration features may be relevant predictive markers to select pts who would benefit from NIVO. Clinical trial information: jRCTs051180133. [Table: see text]

Utilizing Publicly Available Cancer Clinicogenomic Data on CBioPortal to Compare Epidermal Growth Factor Receptor Mutant and Wildtype Non-Small Cell Lung Cancer.

Publicly available clinicogenomic data on platforms such as the cancer BioPortal (cBioPortal.org) allow for efficient analyses by researchers with little or no experience working with Big Data. cBioPortal.org also allows for appropriate statistical testing and downloadable images for easy dissemination of findings. In this study, the cBioPortal.org platform was tested and its utility demonstrated by comparing cases of non-small cell lung cancer (NSCLC) with and without epidermal growth factor receptor gene (EGFR) mutations. Patients with EGFR mutations were more likely to be female, of Asian ethnicity, never-smokers, and be diagnosed with lung adenocarcinoma. Metastasis to the pleura, pleural fluid, and liver was common in patients with EGFR mutant NSCLC. On the other hand, lymph node, brain, and adrenal gland metastases were more common in patients with other mutations. While the median overall survival was about the same in the two groups, progression-free survival was significantly shorter in the EGFR mutant group. The mutational landscape was significantly different in the two groups with EGFR mutant NSCLCs having a lower mutational burden. Differences in copy number alterations between the two groups were also noted. The descriptive data generated from this study such as age, gender, smoking history, and histological subtype recapitulate findings of other studies on EGFR mutant NSCLCs. Further prospective and/or preclinical studies are needed to confirm differences noted in this study. cBioPortal.com queries may be used to supplement clinical/pre-clinical studies or to generate novel hypotheses.

Activity of tarloxotinib-E in cells with EGFR exon-20 insertion mutations and mechanisms of acquired resistance.

BackgroundApproximately 10% of non‐small cell lung cancers (NSCLCs) that harbor epidermal growth factor receptor (EGFR) gene mutations have in‐frame insertions in exon 20 of the EGFR gene. These tumors do not usually respond to currently available EGFR‐tyrosine kinase inhibitors (TKIs). Tarloxotinib is a novel hypoxia‐activated prodrug that releases a potent, irreversible pan‐ERBB TKI (tarloxotinib‐E) under solid tumor hypoxia.MethodsWe examined the efficacy of tarloxotinib‐E against several types of Ba/F3 cells with introduced EGFR exon 20 mutations (EGFR A763insFQEA, V769insASV, D770insSVD, H773insH and H773insNPH mutations). We assayed growth inhibition for tarloxotinib (prodrug), tarloxotinib‐E (active form), poziotinib, afatinib, and osimertinib in Ba/F3 cells with each EGFR exon 20 mutation. We also explored acquired resistance mechanisms to tarloxotinib‐E by establishing cells with resistance to tarloxotinib‐E via chronic drug exposure after N‐ethyl‐N‐nitrosourea mutagenesis treatment.ResultsAmong all tested Ba/F3 cell lines, IC50 was ≥72.1 times higher for tarloxotinib than for tarloxotinib‐E, which implies a wide therapeutic window with this prodrug strategy. Tarloxotinib‐E was efficacious against all tested Ba/F3 cells except for H773insH, which was less sensitive to all tested EGFR‐TKIs. As acquired resistance mechanisms to tarloxotinib‐E, we identified either T790M or C797S secondary mutations, depending on the original EGFR exon 20 mutation.ConclusionsThese findings indicate that tarloxotinib‐E could be effective for NSCLC with EGFR exon 20 mutations. Our results also show that T790M or C797S mutations can confer acquired resistance to tarloxotinib‐E; and suggest that resistance mechanisms are influenced by the baseline EGFR exon 20 mutations.

EGFR mutation-guided use of afatinib, erlotinib and gefitinib for advanced non-small-cell lung cancer in Hong Kong - A cost-effectiveness analysis.

IntroductionTyrosine kinase inhibitors (TKIs) therapy targets at epidermal growth factor receptor (EGFR) gene mutations in non-small-cell lung cancer (NSCLC). We aimed to compare the EGFR mutation-guided target therapy versus empirical chemotherapy for first-line treatment of advanced NSCLC in the public healthcare setting of Hong Kong.MethodsA Markov model was designed to simulate outcomes of a hypothetical cohort of advanced (stage IIIB/IV) NSCLC adult patients with un-tested EGFR-sensitizing mutation status. Four treatment strategies were evaluated: Empirical first-line chemotherapy with cisplatin-pemetrexed (empirical chemotherapy group), and EGFR mutation-guided use of a TKI (afatinib, erlotinib, and gefitinib). Model outcome measures were direct medical cost, progression-free survival, overall survival, and quality-adjusted life-years (QALYs). Incremental cost per QALY gained (ICER) was estimated. Sensitivity analyses were performed to examine robustness of model results.ResultsEmpirical chemotherapy and EGFR mutation-guided gefitinib gained lower QALYs at higher costs than the erlotinib group. Comparing with EGFR mutation-guided erlotinib, the afatinib strategy gained additional QALYs with ICER (540,633 USD/QALY). In 10,000 Monte Carlo simulations for probabilistic sensitivity analysis, EGFR mutation-guided afatinib, erlotinib, gefitinib and empirical chemotherapy were preferred strategy in 0%, 98%, 0% and 2% of time at willingness-to-pay (WTP) 47,812 USD/QALY (1x gross domestic product (GDP) per capita), and in 30%, 68%, 2% and 0% of time at WTP 143,436 USD/QALY (3x GDP per capita), respectively.ConclusionsEGFR mutation-guided erlotinib appears to be the cost-effective strategy from the perspective of Hong Kong public healthcare provider over a broad range of WTP.

P76.45 Evolution of Epidermal Growth Factor Receptor (EGFR) Gene Mutations in EGFR-TKIs Treated Chinese NSCLC

Mutations in epidermal growth factor receptor (EGFR) gene such as ex19del, L858R and T790M are leading oncogenic alternatives in NSCLC and more common in Chinese. Patients carried targeted EGFR mutations are routinely treated with EGFR-TKIs. How the EGFR driver mutations change after TKI treatment remains a controversial issue. In this real world study, we employed longitudinal analysis in a EGFR-TKI treated cohort and clarify the dynamic changes of EGFR alternatives. 483 NSCLCs were diagnosed between Jan 2017 and Dec 2019. The median follow-up time is 206 days. Each patient underwent EGFR-TKI treatment and accepted at least two follow-up molecular evaluations, via NGS and ddPCR methods applied on tumor samples including tissue, plasma DNA and pleural effusion. 473 cases were EGFR-mut positive at the time of first detection. Ex19del (n=242) and L858R (n=215) were dominant and mutually exclusive in majority, with only 1 (0.21%) exception. T790M preferred to co-exist with ex19del than L858R (18.2% vs 10.7%). 182 cases kept harboring the same EGFR driver mutations with a median follow-up time of 97 days (28 cases with more than 1 year), 176 of which carried either ex19del or L858R exclusively and only 7 accompanied with T790M. In the other 288 cases we observed EGFR driver mutations changed. 28 cases become EGFR-naïve with a median time of 388 days, while 5 of them relapsed in following time. 260 cases kept EGFR-mut positive with EGFR evolutions and among them, disappearance of ex19del and L858R occurred in 4 cases and 8 cases, respectively. The newly emerged EGFR mutations, including T790M (n=3 for ex19del group, n=6 for L858R group), S229C (n=1 for ex19del group), E602K (n=1 for L858R group) and V60M (n=1 for L858R group) had no co-current mutation. Among 26 cases detected C797X, 18 cases were initially T790M-accompanied and emerged to carry C797X within a relatively short time (median 12 days), while 8 cases initially with single driver mutation (6 of ex19del, 2 of L858R) evolved to harbor C797X after relatively long treatment time (median 449 days). 10 cases were EGFR-naïve at the time of first detection yet turned to be positive with a median time of 203 days. Ex19del and L858R are dominant oncogenic alternatives and tend to maintain in NSCLC even during TKI treatment. The probability of their disappearance is quite small, often happened after 1-year TKI treatment and mainly replaced by T790M. C797X only emerges in patients harboring T790M subsequently soon.