Mutant Epidermal Growth Factor Research Articles

Binding of single-mutant epidermal growth factor (EGF) ligands alters the stability of the EGF receptor dimer and promotes growth signaling

The epidermal growth factor receptor (EGFR) is a membrane-anchored tyrosine kinase that is able to selectively respond to multiple extracellular stimuli. Previous studies have indicated that the modularity of this system may be caused by ligand-induced differences in the stability of the receptor dimer. However, this hypothesis has not been explored using single-mutant ligands thus far. Herein, we developed a new approach to identify residues responsible for functional divergence by selecting residues in the epidermal growth factor (EGF) ligand that are conserved among orthologs yet divergent between paralogs. Then, we mutated these residues and assessed the mutants' effects on the receptor using a combination of molecular dynamics (MD) and biochemical techniques. Although the EGF mutants had binding affinities for the EGFR comparable with the WT ligand, the EGF mutants showed differential patterns of receptor phosphorylation and cell growth in multiple cell lines. The MD simulations of the EGF mutants indicated that mutations had long-range effects on the receptor dimer interface. This study shows for the first time that a single mutation in the EGF is sufficient to alter the activation of the EGFR signaling pathway at the cellular level. These results also support that biased ligand–receptor signaling in the tyrosine kinase receptor system can lead to differential downstream outcomes and demonstrate a promising new method to study ligand–receptor interactions.

Analysis of the Efficacy of Immunotherapy on the Posterior Lines of Advanced EGFR Mutant Patients with Non-small cell Lung Cancer

背景与目的免疫检查点抑制剂单药治疗在驱动基因阳性的晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者中疗效甚微。研究表明，部分驱动基因阳性患者靶向治疗耐药后对免疫联合治疗仍有效。国内研究甚少。本研究旨在分析人表皮生长因子（epidermal growth factor receptor, EGFR）敏感突变NSCLC患者后线接受免疫治疗的疗效，评价真实世界免疫联合化疗在EGFR突变晚期患者后线治疗中的价值。方法收集2018年6月-2020年11月在首都医科大学附属北京胸科医院确诊的EGFR突变的初治晚期肺腺癌患者共27例，均在靶向治疗进展后接受了程序性死亡受体1（programmed cell death protein 1, PD-1）检查点抑制剂联合化疗以及抗血管生成药物治疗。结果27例晚期NSCLC患者中，未合并T790M突变的有19例（70.4%），合并T790M点突变的有8例（29.6%）。总客观缓解率为40.7%。Kaplan-Meier生存分析显示，不同EGFR突变类型之间接受含PD-1单抗治疗的无进展生存期（progression-free survival, PFS）均无统计学差异（χ2=4.15, P=0.23）。未合并T790M突变的患者PFS较合并T790M突变的患者显著延长（9.2个月vs 3.3个月，χ2=2.81，P=0.041），两者总生存时间未见统计学差异（12.2个月vs 7.3个月，χ2=3.22，P=0.062）。未合并T790M的客观缓解率明显优于合并T790M的患者（52.63% vs 12.5%, P=0.045）。结论EGFR突变患者人群能从后线免疫联合治疗中获益，但合并T790M突变的患者后线接受免疫联合治疗疗效差。因此，这部分患者的后续治疗和全程化管理需要探索更优的治疗策略来提高获益。

Mycoplasma hyorhinis infection promotes tyrosine kinase inhibitor (TKI) resistance in lung adenocarcinoma patients.

To explore the relationship between Mycoplasma hyorhinis infection and tyrosine kinase inhibitor (TKI) resistance in lung adenocarcinoma patients. Mycoplasma hyorhinis infection can be verified with the monoclonal antibody PD4, which specifically recognizes a distinct protein of M. hyorhinis. Immunohistochemistry (IHC), using PD4 to detect M. hyorhinis, was performed on paraffin-embedded lung adenocarcinoma tissues of patients who had epidermal growth factor (EGFR) mutations and had received oral TKI. The number of patients enrolled in our study was 101. Assessments following TKI treatment were performed until objective disease progression or stable disease at the cutoff date was reached. In all of the patients, the primary endpoint was investigator-assessed progression-free survival (PFS). Immunohistochemistry revealed that 61 of 101 cases (60.4%) of lung adenocarcinoma were positive for M. hyorhinis, which comprised of 31 low-positive cases and 30 high-positive cases; the remaining 40 cases (39.6%) were negative. The median PFS was significantly longer in the negative group [18months (95% CI 14.15-21.85)] than in the low-positive group [10months (95% CI 7.70-12.30); hazard ratio (HR) 4.095, 95% CI 2.254-7.438; p < 0.001] and in the high-positive group [4months (95% CI 2.85-5.15); HR 31.703, 95% CI 14.425-69.678; p < 0.001]. The results of the subgroup analysis were satisfactory. The PFS benefit with negative M. hyorhinis infection was consistent across subgroups. In this retrospective, exploratory analysis, M. hyorhinis infection significantly reduced PFS. With increased levels of M. hyorhinis infection, the progression of the disease was more advanced, likely due to the hydrolysis of TKI by M. hyorhinis. A strong correlation was found between M. hyorhinis infection and TKI resistance in lung adenocarcinoma. This study provides potent evidence that M. hyorhinis hydrolyses TKI and will assist in the research of related mechanisms in the future. It provides an option to improve the efficacy of TKI, including strategies to decrease M. hyorhinis infection, thereby reducing long-term distress in TKI resistance patients with EGFR mutations.

IMMUNOHISTOCHEMICAL EXPRESSION OF P53 AND CYCLIN D1 IN SQUAMOUS CELL CARCINOMAAND EPITHELIAL HYPERPLASIA OF ORAL MUCOSA.

Oral cancer is among the top three types of cancers in India. Most invasive oral carcinomas are preceded by a pre-invasive stage, that may last for many years. . Understanding the molecular mechanisms involved in the initiation and progression to malignancy of oral cancer will help to improve its prognosis and in the elaboration of new forms of treatment. The most common genetic alterations, include gene amplication and overexpression of oncogenes such as myc, erbB-2, Epidermal Growth Factor Receptor (EGFR), Cyclin D1 and mutations, deletions and hypermethylation leading to p16 and p53 tumor suppressor gene inactivation. There still remains the problem of differentiating epitheliomatous hyperplasia from squamous cell carcinoma (SCC) especially on biopsies. AIMS: 1. To study and evaluate the expression of p53 and Cyclin D1 in oral SCC and epithelial hyperplasia. 2. To correlate the expression of p53 and Cyclin D1 in different grades of oral SCC. SETTINGS AND DESIGN:Cross-sectional study conducted over a period of 18 months. METHODS AND MATERIAL: 30 cases (n=30) of oral squamous cell carcinoma &amp; 30 cases (n=30) of epithelial hyperplasia diagnosed on H &amp; E were included in this study. All these cases of oral SCC were further classied into different histological grades according to BRODERS' HISTOLOGICALGRADE. STATISTICAL ANALYSIS: The data was collected and the association between different groups was analysed by using Chi square test and quantitative variables were compared using Independent Ttest/Mann-Whitney Test (when the data sets were not normally distributed) between the two groups and ANOVA/Kruskal Wallis test between three groups. Ap value of ≤0.05 was considered statistically signicant. RESULTS: There was a signicant increase in the expression of p53 in oral SCC compared to epithelial hyperplasia. The results were statistically signicant (p value &lt;0.0001). Similarly , Cyclin D1 also showed an increased expression in cases of SCC in contrast to epithelial hyperplasia (p value &lt;0.0001). The expression of p53 signicantly increased with increase in grade of the tumor. The results being statistically signicant, p value=0.004. Similarly, poorly and moderately differentiated SCC also showed an increased expression of Cyclin D1 compared to well differentiated SCC (p value=0.03, statistically signicant). CONCLUSION: Thus the author concludes that the expression of both p53 and Cyclin D1 is increased in oral SCC compared to epithelial hyperplasia of oral mucosa and these markers can be used to differentiate between these two lesion especially on biopsy cases.

Molecular Mechanisms of Resistance to Osimertinib from Liquid Biopsies of Plasma and Pleura Effusion in EGFR Mutant NSCLC Patients

In the past decade, tyrosine kinase inhibitors (TKI) have been developed and widely-approved by countries to treat advanced lung cancer patients with sensitizing epidermal growth factor (EGFR) mutations, and substantially improved patients’ prognosis compared to traditional chemotherapies. However, a large proportion of patients who initially experienced ostensibly remarkable therapeutic outcomes still developed inevitable drug resistance eventually, including those received newly developed third-generation TKIs. Previous studies have demonstrated the value of plasma cell-free DNA (cfDNA) in monitoring patients’ response to therapies in lung cancer. However due to several physiological reasons and DNA degradation, DNA released from tumor cell apoptosis in lung was hard to maintain at a high concentration and good quality before being collected from venous blood, leading to the loss of pivotal mutational information. Pleural effusion is a potential substitute to overcome these problems. However, limited studies have been reported to characterize the consistency of genetic alterations found in these two sample types, and due to the modest sample sizes, the mechanisms underlying third-generation TKI resistance remains elusive. Herein we drew 8ml venous blood and collected 20ml pleural effusion by pleural effusion drainage from 8 lung cancer patients, and performed hybrid-capture based next generation sequencing assays on 18 matched plasma cfDNA, pleural effusion cells genomic DNA and pleural effusion supernatant cfDNA samples, we have shown that only sequencing either plasma or pleural effusion sample resulted in the missing of mutations in key cancer drivers. Sequencing both pleural effusion and plasma yielded a more concrete genetic landscape for monitoring tumor response. We have also exhibited that somatic mutations and copy number changes in PI3K/AKT pathway, NOTCH signaling pathway, hedgehog signaling pathway and pathways involved in DNA damage repair might be potential mechanisms underlying TKI resistance, and might serve as candidate targets for developing novel therapies to circumvent patients’ resistance.

Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor via the PI3K/AKT pathway in non-small cell lung cancer cells in vitro.

Patients with lung cancer harboring activating epidermal growth factor (EGFR) mutations and pre-existing diabetes have been demonstrated to exhibit poor responses to first-line EGFR-tyrosine kinase inhibitor (TKI) therapy. Strategies for the management of acquired resistance to EGFR-TKIs in patients with advanced non-small cell lung cancer (NSCLC) are urgently required. Only a limited number of studies have been published to date on the effects of insulin on EGFR-TKI resistance in NSCLC. Hence, the aim of the present study was to investigate the roles of hyperinsulinemia and hyperglycemia in mediating gefitinib resistance in NSCLC cells with activating EGFR mutations. In the present study, the HCC4006 cell line, which harbors EGFR mutations, was co-treated with gefitinib and long-acting insulin glargine. Whether hyperinsulinemia is able to mediate EGFR-TKI resistance in the NSCLC cell line harboring activating EGFR mutations was also investigated, and the possible underlying mechanisms responsible for these actions were explored. The inhibition of cell proliferation, and the potential mechanism of gefitinib resistance, were examined using an MTS proliferation assay and western blot analysis, and through the transfection of siRNAs. Whether the inhibition of AKT is able to overcome EGFR-TKI resistance induced by long-acting insulin was also investigated. The results obtained suggested that hyperinsulinemia induced by glargine upregulated NSCLC cell proliferation and survival, and induced gefitinib resistance. By contrast, the morphology and proliferation of the cells in a medium containing a 2-fold concentration of glucose were not significantly affected. Gefitinib resistance induced by hyperinsulinemia may have been mediated via the phosphoinositide 3-kinase (PI3K)/AKT pathway rather than the mitogen-activated protein kinase extracellular signal regulated kinase (MAPK/ERK) pathway. AKT serine/threonine kinase 1 knockdown by siRNA rescued the gefitinib resistance that was induced by hyperinsulinemia. In conclusion, hyperinsulinemia, but not hyperglycemia, was identified to cause the development of gefitinib resistance in NSCLC cells with activating EGFR mutations. However, additional studies are required to investigate strategies, such as co targeting hyperinsulinemia and the PI3K/AKT pathway, for overcoming EGFR-TKI resistance in patients with NSCLC.

Abstract 5900: ERBB2 alteration with or without co-existent EGFR mutation in metastatic non-small cell lung cancer

Abstract Background: For epidermal growth factor (EGFR) mutated non-small cell lung carcinoma (NSCLC) multiple EGFR tyrosine kinase inhibitors (TKIs) are approved. ERBB2 alteration (mutation and/or amplification) has been commonly reported as a resistance mechanism to EGFR TKIs. Here we report the prevalence of ERBB2 alteration with or without EGFR mutation in NSCLC. Methods: We retrospectively analyzed ERBB2 alterations and EGFR mutations in NSCLC patients who underwent next-generation sequencing (NSG) with Caris Life Sciences. We obtained de-identified clinical information and molecular testing results from the Caris database. The objectives were to determine the prevalence and types of ERBB2 alterations with and without EGFR as a co-mutation. Results: A total of 12946 NSCLC tumors having EGFR and/or ERBB2 NGS were available, of which 50.1% were male. Among them, 12491 patients had copy number alteration (CNA) data available for ERBB2. 1551 (12%) patients had EGFR mutation, of whom 68% were female, the median age was 68 years and 89% of patients had adenocarcinoma. 186 patients had 2 or more EGFR mutations. The most common EGFR mutation was exon 19 in 47% of patients, followed by exon 21 in 33% of patients. 321 patients (2.5%) had ERBB2 alteration (mutation and/or amplification). Among them ERBB2 was mutated in 197 patients (1.5%) and amplified in 134 (1.1%) patients. The median age of ERBB2 mutated patients was 65 years. Sixty two percent were female and 84% had adenocarcinoma. None of the patients had multiple ERBB2 mutations. 70.5% of ERBB2 mutations were in exon 20, while 10.1% in exon 8. 24 patients had concurrent EGFR mutation and ERBB2 alteration (8 had ERBB2 mutation and 16 had ERBB2 amplification). Among 8 patients who had both EGFR and ERBB2 mutations, 3 had EGFR mutation in exon 19 (E746-A750del) and exon 8 ERBB2 mutation (S310F). For the remaining 5 patients, EGFR mutation was in exon 21 (L858R), while ERBB2 mutations included exon 8 (S310F) in 3 patients, exon 8 (S310Y) in 1 patient, and exon 17 (G660D) in 1 patient. Conclusion: A minority of EGFR mutated NSCLC patients had ERBB2 alterations. In ERBB2 and EGFR co-mutated patients, exon 21 mutations for EGFR and exon 8 mutations for ERBB2 were common. Forty percent of patients who had exon 8 ERBB2 mutation had EGFR as a co-mutation. Citation Format: Vijendra Singh, Yasmine Baca, Seongho Kim, Yanis Boumber, Hirva Mamdani, Edward S. Kim, Ammar Sukari, Chul Kim, Gerold Bepler, Stephen V. Liu, Alexander I. Spira, Hossein Borghai, Mikaso Nagasaka. ERBB2 alteration with or without co-existent EGFR mutation in metastatic non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5900.

Influence of Biopsy Technique on Molecular Genetic Tumor Characterization in Non-Small Cell Lung Cancer-The Prospective, Randomized, Single-Blinded, Multicenter PROFILER Study Protocol.

The detection of molecular alterations is crucial for the individualized treatment of advanced non-small cell lung cancer (NSCLC). Missing targetable alterations may have a major impact on patient’s progression free and overall survival. Although laboratory testing for molecular alterations has continued to improve; little is known about how biopsy technique affects the detection rate of different mutations. In the retrospective study detection rate of epidermal growth factor (EGFR) mutations in tissue extracted by bronchoscopic cryobiopsy (CB was significantly higher compared to other standard biopsy techniques. This prospective, randomized, multicenter, single blinded study evaluates the accuracy of molecular genetic characterization of NSCLC for different cell sampling techniques. Key inclusion criteria are suspected lung cancer or the suspected relapse of known NSCLC that is bronchoscopically visible. Patients will be randomized, either to have a CB or a bronchoscopic forceps biopsy (FB). If indicated, a transbronchial needle aspiration (TBNA) of suspect lymph nodes will be performed. Blood liquid biopsy will be taken before tissue biopsy. The primary endpoint is the detection rate of molecular genetic alterations in NSCLC, using CB and FB. Secondary endpoints are differences in the combined detection of molecular genetic alterations between FB and CB, TBNA and liquid biopsy. This trial plans to recruit 540 patients, with 178 evaluable patients per study cohort. A histopathological and molecular genetic evaluation will be performed by the affiliated pathology departments of the national network for genomic medicine in lung cancer (nNGM), Germany. We will compare the diagnostic value of solid tumor tissue, lymph node cells and liquid biopsy for the molecular genetic characterization of NSCLC. This reflects a real world clinical setting, with potential direct impact on both treatment and survival.

Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion.

The identification of driver mutations in epidermal growth factor receptor, anaplastic lymphoma kinase, the BRAF and ROS1 genes and subsequent successful clinical development of kinase inhibitors not only significantly improves clinical outcomes but also facilitates the discovery of other novel driver mutations in non-small cell lung cancer. These driver mutations can be categorized into mutations in or near the kinase domain, gene amplification or fusion. In this review, BRAF V600E, EGFR and HER-2 exon 20 mutation, FGFR1–4, K-RAS, MET, neuregulin-1, NRTK, PI3K/AKT/mTOR, RET and ROS1 gene aberration and their therapeutics will be discussed.

501P - Oncogenic mutations at the dimer interface of EGFR lead to formation of covalent homo-dimers and allosteric activation of the kinase domain: A mechanism which alters the selectivity profile of oncogenic EGFR

BackgroundMutation of either the intracellular catalytic domain or the extracellular domain of the receptor for epidermal growth factor (EGFR) drives oncogenicity. Extracellular domain EGFR mutations are highly expressed in patients with glioblastoma. Despite clinical success with targeting EGFR catalytic site mutants, no drugs have proven effective in glioblastoma patients expressing extracellular EGFR mutations. MethodsHerein, we define the molecular mechanism for oncogenic activation of families of extracellular EGFR mutations and reveal how this mechanism renders current generation small molecule ATP-site inhibitors ineffective. We define these types of lesions as allosteric oncogenic mutations. ResultsWe demonstrate that a group of the most commonly expressed extracellular domain EGFR mutants expressed in glioblastomas is activated by disulfide-bond mediated covalent homodimerization, collectively referred to as locked dimerization (LoDi-EGFR oncogenes). Strikingly, current generation small molecules binding to the active kinase conformation potently inhibit catalytic site mutants, but induce covalent dimerization and activate LoDi-EGFR receptors, manifesting in paradoxical acceleration of proliferation. Herein we describe the discovery of novel ATP competitive small molecules that potently (<50nM) inhibit the family of LoDi-EGFR oncogenes expressed in GBM, and importantly, achieve selectivity versus WT-EGFR of greater than 10-fold. ConclusionsThese data demonstrate how the locked-dimer mechanism of EGFR oncogenesis has profound impact on the activity of small molecules acting at the distal catalytic site, providing further evidence for “inside-out” allosteric signaling in EGFR. This provides a mechanistic understanding for the failure of current generation EGFR inhibitors to effectively treat LoDi-EGFR mutants in GBM and sets guidelines for the discovery and development of novel selective LoDi-EGFR inhibitors. Legal entity responsible for the studyBlack Diamond Therapeutics. FundingBlack Diamond Therapeutics. DisclosureE. Buck: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Black Diamond Therapeutics. M. O’Connor: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Black Diamond Therapeutics. A. Flohr: Leadership role, Shareholder / Stockholder / Stock options: Black Diamond Therapeutics. R. Iacone: Leadership role, Shareholder / Stockholder / Stock options: Black Diamond Therapeutics. A.V. Mayweg: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Black Diamond Therapeutics. D.M. Epstein: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Black Diamond Therapeutics. All other authors have declared no conflicts of interest.

Non-invasive detection of EGFR and TP53 mutations through the combination of plasma, urine and sputum in advanced non-small cell lung cancer.

The sensitivity and utility of liquid biopsy in clinical practice requires some improvement. The aim of the present study was to improve the detection of epidermal growth factor (EGFR) and cellular tumor antigen p53 (TP53) mutations in liquid biopsies from patients with advanced non-small cell lung cancer (NSCLC) by combining plasma, sputum and urine samples under the same sequencing platform. Plasma, sputum and urine samples, and tumor tissues were obtained from 50 patients with NSCLC and were analyzed using next-generation sequencing. The sensitivity of EGFR-sensitive mutation detection was 84% in plasma, 63% in sputum, 28% in urine, and 91% when combining the three liquid samples (P<0.001). The sensitivity of TP53 mutation detection increased from 87% in plasma to 94% when the three samples were combined (P<0.001). The sensitivity of EGFR or TP53 mutations detection was higher in patients with multiple metastatic sites compared with patients ≤1 metastatic site. In addition, the progression free survival (PFS) rates obtained following analysis of the three samples independently in patients with EGFR sensitizing mutations were similar, and were 9.0 months in the tissue sample, 7.5 months in plasma, 7.9 months in the sputum and 7.3 months in urine (P=0.721). The PFS of patients with TP53 mutations was shorter compared with patients without TP53 mutations and was as follows: Tissue, 8.2 months compared with 10.2 months (P=0.412); plasma, 8.4 months compared with 10.2 months (P=0.466); sputum, 8.3 months compared with 9.1 months (P=0.904); and when combined, 8.8 months compared with 10.3 months (P=0.599). The combination of plasma, sputum and urine increased the detection of EGFR or TP53 mutation with higher sensitivity, and may improve the predictive value of personalized treatment.

Abstract LB-111: Epidermal growth factor receptor oncogenes expressed in glioblastoma are activated as covalent dimers and exhibit unique pharmacology

Abstract Mutation of either the intracellular catalytic domain or the extracellular domain of the receptor for epidermal growth factor (EGFR) drives oncogenicity. Extracellular domain EGFR mutations are highly expressed in patients with glioblastoma. Despite clinical success with targeting EGFR catalytic site mutants, no drugs have proven effective in glioblastoma patients expressing extracellular EGFR mutations. Herein, we define the molecular mechanism for oncogenic activation of families of extracellular EGFR mutations and reveal how this mechanism renders current generation small molecule ATP-site inhibitors ineffective. We demonstrate that a group of the most commonly expressed extracellular domain EGFR mutants expressed in glioblastomas is activated by disulfide-bond mediated covalent homodimerization, collectively referred to as locked dimerization (LoDi-EGFR oncogenes). Strikingly, current generation small molecules binding to the active kinase conformation potently inhibit catalytic site mutants, but induce covalent dimerization and activate LoDi-EGFR receptors, manifesting in paradoxical acceleration of proliferation. These data demonstrate how the locked-dimer mechanism of EGFR oncogenesis has profound impact on the activity of small molecules acting at the distal catalytic site, providing further evidence for “inside-out” allosteric signaling in EGFR. This provides a mechanistic understanding for the failure of current generation EGFR inhibitors to effectively treat LoDi-EGFR mutants in GBM and sets guidelines for discovery of selective LoDi-EGFR inhibitors. Citation Format: Matthew O'Connor, Theodore Nicolaides, Jie Zhang, Alexander Flohr, Roberto Iacone, Alexander V. Mayweg, David M. Epstein, Elizabeth Buck. Epidermal growth factor receptor oncogenes expressed in glioblastoma are activated as covalent dimers and exhibit unique pharmacology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-111.

PCN79 COST EFFECTIVENESS OF OSIMERTINIB VERSUS CHEMOTHERAPY IN SECOND LINE TREATMENT OF NON SMALL CELL LUNG CANCER WITH EPIDERMAL GROWTH FACTOR AND 790M MUTATION IN CHILEAN HEALTH SYSTEM

The aim of this analysis is to estimate the cost effectiveness of Osimertinib versus standard chemotherapy for patients with non-small cell lung cancer (NSCLC) with epidermal growth factor and 790m mutation who have failed to first line tirosin-kinase inhibitor treatment. A partitioned cohort model with 3 health states (Pre progression, progression and death) was adapted in order to represent the natural evolution of the disease. Estimates of resource usage and costs were performed from the perspective of public payer. Expected costs were measured in Chilean pesos (1 USD = 650 CLP) and benefits in quality adjusted life years (QALYs). Health related quality of life was estimated from AURA-3 trial study. A lifetime time horizon was used, and a 3% discount rate was considered for costs and outcomes. A probabilistic sensitivity analyses was performed to account for uncertainty. The total expected costs of treating NSCLC with Osimertinib are higher than standard chemotherapy (USD122,500 and USD13,000 respectively). Similarly, the expected incremental health benefit is higher in Osimertinib group (1.07 incremental QALYs). The base case scenario (current market prices for all treatments) shows an average ICER of Osimertinib versus standard chemotherapy of USD 101,777/QALY. The ICER is reduced to USD 78,206/QALY when the base price of Osimertinib is reduced a 25%. Both ICERs are above the cost effectiveness threshold range suggested by WHO of 1 to 3 GDPs per capita (USD15,000 to USD45,000). Deterministic sensitivity analysis shows a high impact of the price of treatment as a driver for incremental cost-effectiveness ratio. Osimertinib delivers high gains in life years and quality adjusted life years in comparison with standard chemotherapy. Higher costs driven by the price of the intervention under analysis should be a matter of negotiation in order to provide financial coverage to Chilean population.

Factors Associated With Distant Metastasis in EGFR-mutated Non-small Cell Lung Cancer Patients: Logistic Analysis.

The aim of this retrospective study was to identify, using logistic analysis, the factors associated with distant metastasis in non-small cell lung cancer patients carrying mutations in epidermal growth factor receptor. Patients who were diagnosed with distant metastasis at the time of diagnosis up to their death and during the period from April 2009 to March 2019, were included in this study. Clinical charts and imaging studies were reviewed. A total of 64 patients during the research period. The factors associated with pleural metastasis were "female" and "no bone metastasis". The factor associated with brain metastasis was "lung metastasis". The factors associated with liver metastasis were "age under 70" and "Exon 19 deletion". Knowing the factors associated with distant metastasis will provide useful information to conduct targeted and efficient imaging studies.

Analysis of cytomorphology in NSCLC with specific epidermal growth factor (EGFR) mutations

Analysis of cytomorphology in NSCLC with specific epidermal growth factor (EGFR) mutations

Radiopathologic correlation of collision lung cancer with ground-glass opacity

Pulmonary collision tumors have been described as a special entity of synchronous multiple lung cancer. There have been no reports detailing the chronological changes in primary collision lung cancers on chest computed tomography. We report a case of ground-glass lung nodules gradually colliding with each other. The collision tumors of the lung were composed of minimally invasive adenocarcinoma and adenocarcinoma in situ with epidermal growth factor mutations. Immunohistochemically, the Ki-67 labeling indices were different in the 2 components. Ki-67 staining was useful to distinguish the 2 components. The 2 dominant ground-glass tumors grew slowly with radiologic and pathologic heterogeneity.

Therapeutic bronchoscopy in the era of genotype directed lung cancer management.

Lung cancer is the leading cause of cancer related deaths. Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers. Our understanding of driver mutations and genotype directed therapy has revolutionized the management of advanced NSCLC. Commonly described mutations include mutations in epidermal growth factor (EGFR) & BRAF and translocations in anaplastic lymphoma kinase (ALK) & rat osteosarcoma (ROS1). Drugs directed against these translocations have significantly improved progression free survival individually and have shown a survival benefit when studied in the Lung Cancer Mutation Consortium (median survival 3.5 vs. 2.4 years compared to standard therapy). In a related yet parallel universe, the number of bronchoscopic ablative modalities available for management of cancer related airway obstruction have increased exponentially over the past decade. A wealth of literature has given us a better understanding of the technical aspects, benefits and risks associated with these procedures. While they all show benefits in terms of relieving airway obstruction, symptom control, quality of life and lung function testing, their complication rates vary based on the modality. The overall complication rate was ~4% in the AQuIRE registry. Bronchoscopic therapeutic modalities include rigid bronchoscopy with mechanical debulking, laser, thermo-coagulation [electrocautery & argon plasma coagulation (APC)], cryotherapy, endobronchial brachytherapy (EBT), photodynamic therapy (PDT), intratumoral chemotherapy (ITC) and transbronchial needle injection (TBNI) of chemotherapy. Intuitively, one would assume that the science of driver mutations would crisscross with the science of bronchoscopic ablation as they overlap in the same patient population. Sadly, this is not the case and there is a paucity of literature looking at these fields together. This results in several unanswered questions about the interplay between these two therapies.

A review of existing and new methods of bronchoscopic diagnosis of lung cancer.

Bronchoscopy is one of the main techniques used for sampling lung tumor biopsies. In recent years, a large number of tumor specimens have been required to determine the best chemotherapy regimen for each patient; this personalized approach is known as precision medicine. In this review, radial endobronchial ultrasound; bronchoscopic navigation systems, including virtual bronchoscopic navigation and electromagnetic navigation; ultrathin bronchoscope,; and endobronchial ultrasound-guided transbronchial needle aspiration are highlighted as techniques used to increase the diagnostic yield. Personalized therapy includes tests for analysis of epidermal growth factor mutations, anaplastic lymphoma kinase or ROS proto-oncogene 1 fusion gene, and programmed death ligand 1 expression. In cryobiopsy, a relatively large amount of tissue is collected from endobronchial lung cancer and peripheral pulmonary lesions, and it is a promising technique for analyzing these tissues using molecular tests.

Abstract 2414: Interrogating cellular metabolism reveals mTORC2 as a new biomarker to stratify epidermal growth factor receptor-mutant non-small cell lung cancer

Abstract Most non-small cell lung cancer (NSCLC) patients with epidermal growth factor (EGFR) mutations initially respond to EGFR tyrosine-kinase inhibitors (TKIs), but these inhibitors are only effective for approximately one year, thus limiting the benefits to patients' survival. Stratification of patients with EGFR-mutant NSCLC would help physicians personalize and optimize patient treatment plans. To this end, we hypothesized that factors residing in the tumor microenvironment play a pivotal role in the evolutionary dynamics of therapeutic response to anti-EGFR therapies. We used the Operetta® High Content Imaging System to track cell dynamics over time under different microenvironmental stresses, and we found that the growth of TKI-resistant cells is more sensitive to glucose starvation than TKI-sensitive cells. To further interrogate cellular metabolism in TKI-sensitive and resistant cells, we utilized both seahorse metabolic assays and fluorescence lifetime imaging microscopy to monitor the changes in glycolysis and oxidative phosphorylation of living cells. We found TKI-resistant cells have higher glycolysis and lower oxidative phosphorylation rates compared to TKI-sensitive cells. Such metabolic reprogramming rendered TKI-resistant cells with lower metabolic plasticity to cope with metabolic stress. Using both genetic and pharmacologic approaches, we then demonstrated that mTORC2 activation contributes to the different metabolic phenotypes between TKI-sensitive and resistant cells. Furthermore, gene set enrichment analysis showed that the oxidative phosphorylation gene set is significantly enriched in patients with low mTORC2 activation, and the glycolysis gene set is upregulated in patients with high mTORC2 activation, which is correlated with shorter progression-free and overall survival time in patients. Overall, these data suggest that TKI-resistant cells use and require distinct metabolic programs that can be employed to stratify EGFR-mutant NSCLC patients for treatment with EGFR-TKIs. Citation Format: Chun-Te Chiang, Nolan Ung, Alexandra N. Demetriou, Chi-Li Chiu, Niha Choudhury, Cosimo Arnesano, Scott E. Fraser, David B. Agus, Naim Matasci, Dan L. Ruderman, Shannon M. Mumenthaler. Interrogating cellular metabolism reveals mTORC2 as a new biomarker to stratify epidermal growth factor receptor-mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2414.

Evolving concepts in lung cancer pathology and its impact on thoracic oncology practice

Lung cancer is the commonest cause of death worldwide but unfortunately, most patients present in an advanced stage of the disease. The classification of lung cancer has evolved since the first WHO publication in 1981, and the present edition was published in March 2015. A major change in 2015 was the introduction of the new terms adenocarcinoma in situ and minimally invasive adenocarcinoma to describe early adenocarcinoma of lung and abolition of the previous term bronchioloalveolar carcinoma. Tumors with micropapillary pattern and those showing spread through alveolar spaces have significant clinical implications with an increased propensity for recurrence. Tissue specimens require proper fixation in 10% buffered formalin which is an essential but an often neglected basic step; proper fixation is a prerequisite for good immunohistochemistry (IHC) and molecular test outcomes. Needle core biopsies should be handled judiciously to ensure that sufficient material is prioritized for molecular studies which are needed to guide personalized treatment. The WHO 2015 classification recommends the use of a single squamous cell marker (p40, or CK5/6) and a single adenocarcinoma marker (TTF1, or napsin) to distinguish squamous cell carcinoma and adenocarcinoma in difficult biopsies. The non-committal designation of non-small cell lung carcinoma (NSCLC) is discouraged. The exciting ongoing research findings on molecular biology of lung cancer necessitate constant expansion of laboratory test menu. Testing and treating lung cancer patients with epidermal growth factor (EGFR) mutation and anaplastic lymphoma kinase (ALK) gene fusion is now a standard of care, and ROS1 has been approved recently. The updated guidelines from the College of American Pathologists (CAP) and approval notifications from the Federal Drug Authority (FDA) are invaluable to justify initiation of new tests by pathology laboratories. Recently, FDA has approved testing for programmed death ligand (PDL1) with 22C3 antibody by IHC and EGFR testing on plasma by a non-invasive liquid biopsy test approach. To conclude, a comprehensive pathology report is vital for staging, comparing outcomes, and developing better strategies for patient care in the future.