EGFR-mutant Lung Adenocarcinoma Research Articles

Alterations in the Global Proteome and Phosphoproteome in Third Generation EGFR TKI Resistance Reveal Drug Targets to Circumvent Resistance.

Lung cancer is the leading cause of cancer mortality worldwide. The treatment of patients with lung cancer harboring mutant EGFR with orally administered EGFR tyrosine kinase inhibitors (TKI) has been a paradigm shift. Osimertinib and rociletinib are third-generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard of care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here we characterized the proteome and phosphoproteome of a series of isogenic EGFR-mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs, comprising the most comprehensive proteomic dataset resource to date to investigate third generation EGFR TKI resistance in lung adenocarcinoma. Unbiased global quantitative mass spectrometry uncovered alterations in signaling pathways, revealed a proteomic signature of epithelial-mesenchymal transition, and identified kinases and phosphatases with altered expression and phosphorylation in TKI-resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition, resulting in subsequent inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Anticorrelation analyses of this phosphoproteomic dataset with published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures program predicted drugs with the potential to overcome EGFR TKI resistance. The PI3K/MTOR inhibitor dactolisib in combination with osimertinib overcame resistance both in vitro and in vivo. Taken together, this study reveals global proteomic alterations upon third generation EGFR TKI resistance and highlights potential novel approaches to overcome resistance. SIGNIFICANCE: Global quantitative proteomics reveals changes in the proteome and phosphoproteome in lung cancer cells resistant to third generation EGFR TKIs, identifying the PI3K/mTOR inhibitor dactolisib as a potential approach to overcome resistance.

Relationship between PD-L1 expression and outcome in EGFR-mutant lung cancer patients treated with EGFR tyrosine kinase inhibitors

ObjectivesPredictive biomarkers for poor response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is an area of ongoing research. This multicentre retrospective study sought to determine the impact of programmed death-ligand 1 (PD-L1) tumour proportional score (TPS) on outcome in EGFR TKI treated patients. Materials and MethodsPatients with Stage IIIB/IV lung adenocarcinoma harbouring a sensitising EGFR mutation treated with first-line TKI at five metropolitan hospitals were included. PD-L1 TPS was determined using the Ventana anti-PD-L1 (SP263) assay. High PD-L1 expression was defined as TPS ≥ 50 %. Determinants of progression and survival hazards were modelled using Cox regression. ResultsA total of 186 patients were included. Mean age was 67 years, 66 % were female and 54 % were Asian. Patients with high PD-L1 expression (n = 23; 12 %) had significantly shorter progression free survival (6.6 vs 13.0 months, hazard ratio (HR) 2.6 95 % CI 1.6–4.2, p < 0.0001) and overall survival (11.5 vs 32.9 months, HR 3.3, 95 % CI 1.9–5.7, p < 0.0001) compared to patients with PD-L1 low/negative tumours. This remained significant in multivariate analyses. High PD-L1 in post-TKI progression biopsies was not associated with poorer survival. ConclusionIn this large, real-world cohort of EGFR-mutant lung adenocarcinoma patients, high PD-L1 expression was associated with early resistance to 1st generation EGFR TKIs and shorter survival, regardless of ethnicity.

PL01.06 Molecular Epidemiology of Asian Lung Cancer

Lung adenocarcinoma (LADC), the most frequent histological type of lung cancer, develops in both ever- and never-smokers, and has two distinct characteristics in Asian populations. First, the proportion of never-smoking patients is considerably higher than that among individuals of European descent (approximately 40% vs 10%), and the rates of development and death from lung cancer in never-smokers are significantly higher in Asians than those in individuals of European descent. Second, in Asian individuals LADC frequently (in approximately 50% of cases) carries oncogenic mutations of the epidermal growth factor receptor (EGFR) gene, in contrast to lower EGFR mutation rates (approximately 10%) in European/US patients. In Asian patients, EGFR mutation frequently occurs in both never- (60%) and ever- (40%) smokers, while it occurs almost exclusively in European/US ever-smokers. Notably, EGFR-mutated LADC does not respond well to immune checkpoint blockade therapy due to its non-inflamed (immune-cold) features, including low infiltration of CD4+ and CD8+ T cells. Therefore, it is highly likely that there are specific risk factors, independent from smoking, that promote LADC development in Asians and have immunogenic effects influencing tumour characteristics. By conducting genome-wide association study, we demonstrated that HLA loci influence lung adenocarcinoma risk independently from smoking and that the association of HLA-class II, but not class I, loci is more prominent for lung adenocarcinomas with EGFR gene mutations than those without; the HLA-DPB1 Asp57 and 76Val alleles are associated with elevated risk for EGFR-mutated lung adenocarcinoma. HLA variants might influence lung adenocarcinoma risk by modulating anti-tumour immunity.

P76.70 Afatinib After Progression on Osimertinib in Patients with EGFR-Mutated Lung Adenocarcinoma

P76.70 Afatinib After Progression on Osimertinib in Patients with EGFR-Mutated Lung Adenocarcinoma

P88.02 SDC4-ROS1 Fusion as a Mechanism of Acquired Resistance in EGFR-Mutant Lung Adenocarcinoma

The enhanced understanding of the biological mechanisms underlying non-small cell lung cancer (NSCLC) development and progression has led to targeted therapies becoming an increasingly important strategy for the treatment of NSCLC. Several clinical trials have demonstrated that most NSCLC patients with specific epidermal growth factor receptor (EGFR) mutations respond significantly to EGFR tyrosine kinase inhibitors (TKIs). However, the majority of patients who initially respond to EGFR-TKI therapies eventually develop drug resistance, often within a year. The subsequent development of T790M mutations occurs in roughly half of EGFR-mutant patients who develop EGFR-TKI resistance. Herein we present a 37-year-old never-smoker Chinese female with an EGFR exon 19 deletion who was diagnosed with lung adenocarcinoma (LADC) and initially responded to first-generation EGFR-TKI treatment, later developing acquired resistance. The subsequent biopsy specimen was subjected to next generation sequencing (NGS) and a SDC4-ROS1 rearrangement was detected. The patient received crizotinib therapy and was considered to have a partial response. The progression free survival was 16.0 months. To our knowledge, SDC4-ROS1 fusion gene as a novel mechanism of acquired EGFR resistance in lung adenocarcinoma is the first reported in China. In the future, the routine use of next generation sequencing is important, more and more ROS1 fusions are identified in lung cancer by next generation sequencing.

Primary Tumor Radiotherapy During EGFR-TKI Disease Control Improves Survival of Treatment Naïve Advanced EGFR-Mutant Lung Adenocarcinoma Patients.

BackgroundWhether radiotherapy only for primary lung tumor (RTPLT) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy improves survival of treatment naïve advanced EGFR-mutant lung adenocarcinoma (LAD) patients with/without polymetastasis.Materials and MethodsThis was a retrospective, single-center, observational study. Patients with stage IIIB-IV EGFR-mutant LAD with disease control by EGFR-TKI therapy were divided into curative RTPLT, and control, without radiotherapy (WRTPLT) groups.ResultsA total of 138 patients were enrolled; 46 in the RTPLT group and 92 in the WRTPLT group. Amongst them, 37% had oligometastasis, and 26.1% brain metastasis. The RTPLT group had both significantly longer progression-free survival (PFS) (27.5 months [95% CI 18.1–36.9] vs 10.9 months [95% CI 6.3–15.5], P<0.001) and overall survivor (OS) (NR [95% CI NR-NR] vs 38.0 months [95% CI 31.2–44.8], P<0.001), respectively, when compared to the WRTPLT group. In multivariate analysis, the adjusted HR of radiotherapy on PFS was 0.30 (0.19–0.47) and on OS, 0.11 (0.04–0.30). Patients with oligometastasis had significantly longer PFS than those with polymetastasis with an HR of 0.35 (0.14–0.85), P=0.02. Patients with either oligometastasis or polymetastasis had significant longer PFS when undergoing radiotherapy than those without (both P<0.05). An EGFR-TKI to radiotherapy interval <24 weeks seemed more beneficial (P=0.097). Radiation pneumonitis comprised 32 (69.6%), 12 (26.1%), and two (4.3%) cases of common terminology criteria grade I, II, and III, respectively.ConclusionCurative RTPLT can prolong survival in patients with LAD following EGFR-TKI disease control, both involving oligometastasis and polymetastasis. RTPLT within 24 weeks after EGFR-TKI initiation appeared to be more beneficial with tolerable radiation pneumonitis.

P76.56 High PD-L1 Expression is Aassociated with Unfavorable Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy

Although programmed death-ligand 1 (PD-L1) expression is widely accepted as a predictive and prognostic biomarker in immunotherapy, its implications in lung cancer patients with driving mutations are still unclear. The objective of this study is to determine the association between PD-L1 expression and treatment outcome in epidermal growth factor receptor (EGFR)-mutated lung cancer treated with tyrosine kinase inhibitors (TKIs). We retrospectively enrolled EGFR-mutant, advanced lung adenocarcinoma patients who received first-line EGFR-TKIs and evaluated the PD-L1 tumor proportion score (TPS) using the 22C3 pharmDx assay. We investigated the distribution of patients with different PD-L1 TPS values, followed by analysis of response rate (RR), survival rate, and incidence of secondary T790M mutation according to the PD-L1 TPS group. Among the 131 patients analyzed, the proportion of patients with PD-L1 TPS ≥ 50%, 1%-49%, and < 1%, was 17.6%, 32.8%, and 49.6%, respectively. The RR was significantly lower in the group with PD-L1 TPS ≥ 50% than in the other groups (43.5% vs. 72.1% vs. 78.5%, all p = 0.001). In multivariate analysis, PD-L1 TPS ≥ 50% was independently associated with a significantly shorter PFS in the overall population (hazard ratio [HR] = 2.64, p = 0.004), and associated with shorter OS in patients with exon 19 deletion (HR = 2.55, p = 0.041) compared with PD-L1 TPS < 50%. In addition, the frequency of secondary T790M mutation after TKI failure was significantly lower in the group with PD-L1 TPS ≥ 50% than in the other groups (13.3% vs. 40.0% vs. 53.3%, all p = 0.001). PD-L1 TPS ≥ 50% was an independent predictor of a lower frequency of this mutation (HR = 0.63, p = 0.043). High PD-L1 expression was associated with unfavorable clinical outcome, and less development of secondary T790M mutation, suggesting a distinct subgroup warranting active surveillance and tailored therapeutic approach.

A rare case report: an inextricable shoulder pain as the exclusive presentation of lung adenocarcinoma with metastasis over contralateral clavicle

BackgroundLung cancer is the fourth most common form of the tumor spreading to the bone. Among all patients of lung carcinoma, the most common sites of bone metastasis are vertebrae, ribs, and pelvis. By comparison, the clavicle is an extremely rare site of metastases not only in the population of lung cancers but among all types of tumors. Enlightened by this existing fact, we would like to share our experience of management of an uncommon clavicular metastasis and illuminate the obscure mechanism of its scarcity.Case presentationA 56-year-old female without any preknown systemic disease had suffered from a sole intermittent right shoulder pain without any other discomfort for 3 months. Physical examination performed at our orthopedic department showed tenderness over the right distal third of the clavicle with limited range-of-motion of the right shoulder. EGFR-mutated lung adenocarcinoma with metastasis over the right clavicle resulting in a pathological fracture was diagnosed according to the result of the incisional biopsy. Concurrent chemoradiation therapy accompanied with target therapy was performed. Eighteen months postoperatively, the clavicle pain was found to be subsided with stationary bony lesion under appropriate medication and palliative radiotherapy during the subsequent follow-up.ConclusionsThe clavicle is an exceedingly unusual site with 2% of metastatic involvement of all type of tumors and only 1% among the population of carcinoma of lung due to its scanty red marrow and sparse vascular supply. Despite the unpleasant prognosis of clavicular metastasis from primary lung adenocarcinoma, promising quality of life is achievable under multidisciplinary management.

EGFR and PDL1: A Match (Not) Made in Heaven-A Real-World Retrospective Analysis of PDL1 Expression in EGFR-Mutated NSCLC.

EGFR (epidermal growth factor receptor) mutant NSCLC (non-small cell lung carcinoma) comprises 35-40% of cases in the Asian NSCLC cohort, compared to 15-20% in the rest of the world. Improved response rates have been observed in terms of PFS (progression-free survival) and ORR (overall response rate) when treated with EGFR TKIs (tyrosine kinase inhibitors). However, resistance eventually ensues regardless of the generation of TKI used. Preclinical studies have reported that PDL1 (programmed death ligand1) is a downstream target of EGFR and is interposed by IL-6/JAK/STAT3 (interleukin-6/Janus kinase/signal transducer and activator of transcription3), NF-κB (nuclear factor kappa beta), and p-ERK1/2/p-c-Jun pathways. Hence, it may potentially be repressed by EGFR TKIs. In this retrospective exploratory analysis, we studied whether PDL1 expression affects efficacy of EGFR TKIs and clinical outcome in patients with untreated metastatic EGFR-mutated lung adenocarcinoma. This single-center retrospective, exploratory analysis was performed between January 2015 and December 2019. Among 1350 cases of NSCLC, 470 were EGFR mutant, of which PDL1 expression testing was done in 193 patients who were included in this study. Median age was 60years (range 24-87years). A total of 116 patients (60.1%) had inframe deletion in exon19, 52 (26.9%) had L858R, and 25 (13%) had uncommon mutations. The number of patients with PDL1 tumour proportion score (TPS) < 1% was 109 (56.5%); 1-49%, 57 (29.5%); and ≥ 50%, 27 (14%). Comparing clinical characteristics among various PDL1 groups, there were no statistically significant correlations obtained. However, patients with PDL1 > 50% were smokers, and showed a trend for higher disease burden at diagnosis. Median PFS of PDL1 < 1% was 10.14months, compared to 9.4months in the PDL1 > 1% group; however, the values did not reach statistical significance. The current study was an exploratory retrospective study; however, the results add to the growing body of evidence that PDL1 expression in EGFR-mutated NSCLC does not have any prognostic significance. Also the efficacy of EGFR TKIs is not influenced by variations in PDL1 TPS.

Solid subtype predicts early bone metastases in sensitive EGFR-mutated lung adenocarcinoma patients after surgery

This study aimed to explore the prognostic significance of solid pattern for bone metastases (BM) in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma patients after surgery.A total of 237 stage I-III lung adenocarcinoma patients with EGFR mutation were analyzed after procedure. The patients were divided into four groups: the solid-present patients with BM, the solid-absent patients with BM, the solid-present patients without BM and the solid-absent patients without BM. The bone disease-free survival (bDFS), systemic disease-free survival (DFS) and overall survival (OS) were assessed.The results revealed that the patients with solid pattern had shorter DFS (15 months vs. 19 months; P < 0.001) and OS (47 months vs. 77 months; P = 0.001). Moreover, bDFS of solid-present patients was significantly shorter than solid-absent patients (27 months vs. 14 months; P < 0.001). In addition, patients with solid component had worsened bDFS, no matter with BM as first-site development (12.5 months vs. 16.5 months; P = 0.016) or non-first-site development (16.5 months vs. 45.5 months; P < 0.001).These findings suggested that solid pattern predicted worse DFS and OS and also showed shortened interval between surgery and BM.

Practical Issues in the Use of Atezolizumab for Patients with Non-Small Cell Lung Cancer: Case Reports and Literature Review.

Atezolizumab is a monoclonal antibody targeting the programmed death ligand 1 (PD-L1) that was approved in 2017 in the USA and Europe for the second-line treatment of advanced or metastatic non-small cell lung cancer (NSCLC). This review article describes the practical clinical issues associated with atezolizumab treatment in NSCLC using a combination of four illustrative cases and a narrative literature review. The first two cases highlight the importance of tumor mutational status when making treatment decisions. A 62-year-old man with epidermal growth factor receptor (EGFR)-mutated, PD-L1-positive, stage IV lung adenocarcinoma received treatment with second-line atezolizumab + bevacizumab, carboplatin, and paclitaxel (BCP) after first-line osimertinib. In the second case, a 63-year-old man with stage IVb lung adenocarcinoma with anaplastic lymphoma kinase (ALK) translocation received sixth-line treatment with atezolizumab + BCP. The two final cases both had extensive metastases. A 55-year-old woman with EGFR-mutated lung adenocarcinoma received second-line treatment with atezolizumab + BCP after development of multiple metastases, followed by atezolizumab + bevacizumab until last follow-up. A 42-year-old man with PD-L1-positive pulmonary adenocarcinoma (negative for EGFR mutations) developed liver and brain metastases after several lines of therapy. He underwent holocranial radiation and received atezolizumab + BCP, which resulted in a decrease in all measurable and evaluable tumoral lesions. These illustrative cases indicate that the type and number of mutations may influence treatment response to atezolizumab, and that atezolizumab may provide clinical benefit in patients with high disease burden.

Systemic immune-inflammation index predicts prognosis in patients with different EGFR-mutant lung adenocarcinoma.

Lung cancer is the most common type of cancer worldwide with a high mortality rate. The specific tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR) have made enormous strides in non-small-cell lung cancer (NSCLC) treatment. The novel systemic immune-inflammation index (SII), a parameter that integrates lymphocytes, neutrophils, and platelets, has been found to play the vital role of a marker for predicting survival and recrudescence in various tumors.We retrospectively examined 102 patients with different EGFR-mutant lung adenocarcinomas. Survival analysis was performed using the Kaplan-Meier method with the log-rank test. Cut-off points were identified using the receiver operating characteristic curves with the maximum log-rank values. The Cox proportional hazards regression, expressed as p value, hazards regression, and 95% confidence interval, was conducted to assess the prognostic values of variables in overall survival (OS)/ progression-free survival (PFS).Lower SII was associated with prolonged survival in patients with different EGFR mutant lung adenocarcinomas in both variable and multivariable analyses.SII before treatment was a powerful indicator for the PFS and OS of patients who received the first-generation EGFR-TKI.

Impressive response to dabrafenib, trametinib, and osimertinib in a metastatic EGFR-mutant/BRAF V600E lung adenocarcinoma patient

The survival outcomes of the FLAURA trial support osimertinib as the new standard of care for untreated patients harboring activating mutations in the epidermal growth factor receptor (EGFR). Despite the initial response, disease progression invariably occurs. Although uncommon, BRAF V600E mutation arises as a unique mechanism of resistance, and thus far, no prospective studies are available to support concurrent EGFR/BRAF blockade. We report a case of impressive radiological and ctDNA response under dabrafenib, trametinib, and osimertinib in an advanced EGFR-mutant lung adenocarcinoma patient who developed BRAF V600E as one of the acquired resistance mechanisms to second-line osimertinib. Moreover, the patient experienced remarkable clinical improvement and good tolerance to combination therapy. The present case suggests the importance of prospective studies evaluating both efficacy and safety of the combination in later line settings and points towards the potential of ctDNA to monitor resistance mechanisms and treatment benefit in clinical practice.

A clinically practical radiomics-clinical combined model based on PET/CT data and nomogram predicts EGFR mutation in lung adenocarcinoma.

This study aims to develop a clinically practical model to predict EGFR mutation in lung adenocarcinoma patients according to radiomics signatures based on PET/CT and clinical risk factors. This retrospective study included 583 lung adenocarcinoma patients, including 295 (50.60%) patients with EGFR mutation and 288 (49.40%) patients without EGFR mutation. The clinical risk factors associated with lung adenocarcinoma were collected at the same time. We developed PET/CT, CT, and PET radiomics models for the prediction of EGFR mutation using multivariate logistic regression analysis, respectively. We also constructed a combined PET/CT radiomics-clinical model by nomogram analysis. The diagnostic performance and clinical net benefit of this risk-scoring model were examined via receiver operating characteristic (ROC) curve analysis while the clinical usefulness of this model was evaluated by decision curve analysis (DCA). The ROC analysis showed predictive performance for the PET/CT radiomics model (AUC = 0.76), better than the PET model (AUC = 0.71, Delong test: Z = 3.03, p value = 0.002) and the CT model (AUC = 0.74, Delong test: Z = 1.66, p value = 0.098). Also, the PET/CT radiomics-clinical combined model has a better performance (AUC = 0.84) to predict EGFR mutation than the PET/CT radiomics model (AUC = 0.76, Delong test: D = 2.70, df = 790.81, p value < 0.001) or the clinical model (AUC = 0.81, Delong test: Z = 3.46, p value < 0.001). We demonstrated that the combined PET/CT radiomics-clinical model has an advantage to predict EGFR mutation in lung adenocarcinoma. • Radiomics from lung tumor increase the efficiency of the prediction for EGFR mutation in clinical lung adenocarcinoma on PET/CT. • A radiomic nomogram was developed to predict EGFR mutation. • Combining PET/CT radiomics-clinical model has an advantage to predict EGFR mutation.

Akt kinase LANCL2 functions as a key driver in EGFR-mutant lung adenocarcinoma tumorigenesis

Epidermal growth factor receptor (EGFR) is a key oncogene in lung adenocarcinoma (LUAD). Resistance to EGFR tyrosine kinase inhibitors is a major obstacle for EGFR-mutant LUAD patients. Our gene chip array, quantitative polymerase chain reaction validation, and shRNA-based high-content screening identified the Akt kinase lanthionine synthetase C-like protein 2 (LANCL2) as a pro-proliferative gene in the EGFR-mutant LUAD cell line PC9. Therefore, we investigated whether LANCL2 plays a role in promoting cell proliferation and drug resistance in EGFR-mutant LUAD. In silico clinical correlation analysis using the Cancer Genome Atlas Lung Adenocarcinoma dataset revealed a positive correlation between LANCL2 and EGFR expression and an inverse relationship between LANCL2 gain-of-function and survival in LUAD patients. The EGFR-mutant LUAD cell lines PC9 and HCC827 displayed higher LANCL2 expression than the non-EGFR-mutant cell line A549. In addition, LANCL2 was downregulated following gefitinib+pemetrexed combination therapy in PC9 cells. LANCL2 knockdown reduced proliferation and enhanced apoptosis in PC9, HCC827, and A549 cells in vitro and suppressed murine PC9 xenograft tumor growth in vivo. Notably, LANCL2 overexpression rescued these effects and promoted gefitinib + pemetrexed resistance in PC9 and HCC827 cells. Pathway analysis and co-immunoprecipitation followed by mass spectrometry of differentially-expressed genes in LANCL2 knockdown cells revealed enrichment of several cancer signaling pathways. In addition, Filamin A and glutathione S-transferase Mu 3 were identified as two novel protein interactors of LANCL2. In conclusion, LANCL2 promotes tumorigenic proliferation, suppresses apoptosis, and promotes gefitinib+pemetrexed resistance in EGFR-mutant LUAD cells. Based on the positive association between LANCL2, EGFR, and downstream Akt signaling, LANCL2 may be a promising new therapeutic target for EGFR-mutant LUAD.

Systemic Inflammation Response Index (SIRI) Independently Predicts Survival in Advanced Lung Adenocarcinoma Patients Treated with First-Generation EGFR-TKIs.

BackgroundSystemic inflammation response index (SIRI) has been reported to be an effective blood-based biomarker for predicting prognosis in various kinds of cancer patients. However, the prognostic role of SIRI in advanced lung adenocarcinoma patient remains unclear.MethodsThe aim of the present study is to evaluate the prognostic role of SIRI in EGFR-mutant advanced lung adenocarcinoma patients treated with first-generation EGFR-TKIs. A total of 245 patients who received gefitinib, erlotinib, or icotinib at the Second Xiangya Hospital were retrospectively evaluated. SIRI was defined as neutrophil count×monocyte/lymphocyte count. The optimal cut-off value was determined according to receiver operation characteristic curve analysis. Characteristics of patients were compared via chi-square test or Fisher’s exact test. Survivals were estimated by the Kaplan–Meier method and compared by the Log rank test. Multivariate analysis was estimated using the Cox proportional hazards model.ResultsIt is showed that high SIRI was associated with male patient, smoker, worse ECOG PS, 19-DEL mutation. Kaplan–Meier survival analysis showed that ECOG PS, brain metastasis, SIRI were significantly correlated with progression-free survival (PFS), and gender, ECOG PS, brain metastasis, NLR and SIRI were significantly correlated with overall survival (OS). Multivariate analysis showed that SIRI and ECOG PS independently predict PFS and OS.ConclusionOur findings indicate that SIRI is an effective and convenient marker for predicting prognosis in advanced EGFR-mutant lung adenocarcinoma patients treated with first-generation TKI.

A nomogram for predicting brain metastases of EGFR-mutated lung adenocarcinoma patients and estimating the efficacy of therapeutic strategies.

BackgroundTo establish a nomogram for predicting the outcome of EGFR-mutated lung adenocarcinoma patients with brain metastases (BMs) and to estimate the efficacy of different therapeutic strategies.MethodsThe data of 129 cases with BM from the period between January 1st 2011 and December 31st 2014 were collected, and all of the cases were pathologically confirmed to be lung adenocarcinoma, stages I–IV and with 19 and/or 21 exon mutations of EGFR. Cox regression analysis and log-rank test were used for data analysis. The nomogram was used to establish the progression models.ResultsIn the univariate analysis, the stage, ECOG score, interval between the diagnosis of lung cancer and BM, the number of brain metastatic lesions, and the diameter of the maximal brain metastatic lesion correlated well with overall survival (OS). In multivariate Cox proportional hazard analysis, the ECOG score, interval between the diagnosis of lung cancer and BM, and the number of brain metastatic lesions correlated well with the OS. Patients were divided into the poor prognostic group and the good prognostic group based on the nomogram prognostic model score. Subgroup analysis showed that in the poor prognostic group, the OS of patients who received radiotherapy was better than that of the patients who did not receive radiotherapy as the first-line treatment (30 vs. 19 months, P<0.05). The OS was 30 months in the TKI subgroup and 21 months in the no TKI subgroup, but no statistical difference was found (P>0.05). Patients in the good prognostic group who received radiotherapy had a better 3-y OS rate than the patients who received no radiotherapy as the first-line treatment (91.2% vs. 58.1%, P<0.05). The 3-y OS rate was 87.6% in the TKI subgroup and 67.8% in the no TKI group (P<0.05).ConclusionsWe established an effective nomogram model to predict the progression of EGFR-mutated lung adenocarcinoma patients with BM and the therapeutic effect of the individual treatments. Radiotherapy was beneficial for the patients of both the poor and good prognostic groups, but TKI may be better suited for treating the patients with good prognosis.

Targeting YAP-p62 signaling axis suppresses the EGFR-TKI-resistant lung adenocarcinoma.

BackgroundDespite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR‐TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance.MethodsWe used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR‐TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor.ResultsIn this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR‐TKI‐resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR‐TKI‐resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR‐mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP‐p62 axis, we treated EGFR‐TKI‐resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR‐TKI‐resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD‐L1. So, the cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1.ConclusionFinally, we suggest that targeting YAP‐p62 signaling axis can be useful to suppress the EGFR‐TKI‐resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD‐L1 at the same time.

A case of concomitant EGFR/ALK alteration against a mutated EGFR background in early-stage lung adenocarcinoma.

Rare cases of lung adenocarcinoma (LUAD) with concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation have been reported. However, their clonal and evolutional relationship remains unclear. We report a case of early-stage EGFR-mutated LUAD with a focal concomitant EGFR/ALK alteration. A 63-year-old male underwent lobectomy to remove a 1.9-cm-sized lung nodule, which was diagnosed with EGFR-mutated LUAD. ALK immunohistochemistry (IHC) showed focal positivity within the part of the tumor characterized by lepidic pattern, also confirmed by fluorescence in-situ hybridization (FISH). Targeted next-generation sequencing was performed separately on the ALK IHC/FISH-positive and -negative areas. EGFR L833V/L858R mutations were detected in both areas, whereas EML4 (echinoderm microtubule-associated protein-like 4)-ALK translocations was confirmed only in the ALK IHC/FISH-positive area, suggesting the divergence of an EGFR/ALK co-altered subclone from the original EGFR-mutant clone. Our study suggests that concurrent alterations of EGFR and ALK can arise via divergent tumor evolution, even in the relatively early phases of tumorigenesis.

Treatment Options of First-Line Tyrosine Kinase Inhibitors and Subsequent Systemic Chemotherapy Agents for Advanced EGFR Mutant Lung Adenocarcinoma Patients: Implications From Taiwan Cancer Registry Cohort.

ObjectivesLarge-scale, population-based real-world studies on the treatment outcomes of first-line tyrosine kinase inhibitors (TKIs) and subsequent systemic chemotherapy agents for lung adenocarcinoma (with activating epidermal growth factor receptor [EGFR] mutations) remain limited.Materials and MethodsFrom March 2014 to December 2016, patients with advanced lung adenocarcinoma, identified from the Taiwan Cancer Registry were included in this study if they received any of the three TKIs as first-line treatment. The primary outcome was overall survival (OS). The secondary outcome was time-to-treatment discontinuation (TTD).ResultsA total of 4,889 patients (median age: 67 years and two-thirds with distant metastasis) were recruited (1,778 gefitinib, 1,599 erlotinib, and 1,512 afatinib users). A 1:1 propensity score (PS)-matched cohorts of 1,228 afatinib/erlotinib and 1054 afatinib/gefitinib was created. After PS matching, it was found that afatinib was not associated with better OS (afatinib vs. erlotinib, HR: 0.96, 95% CI: 0.86–1.07; afatinib vs. gefitinib, HR: 0.91, 95% CI: 0.81–1.02). In the subgroup analysis, afatinib demonstrated a survival benefit in patients with active smoking (afatinib vs. erlotinib, HR: 0.69, 95% CI: 0.51–0.93; afatinib vs. gefitinib, HR: 0.67, 95% CI: 0.48–0.94) and ECOG > 1 (afatinib vs. erlotinib, HR: 0.79, 95% CI: 0.63–0.99; afatinib vs. gefitinib, HR: 0.78, 95% CI: 0.62–0.98). A total of 41.1% (n = 1992) of first-line TKI users received subsequent chemotherapy. Among the three TKI groups, pemetrexed usage was associated with better OS compared with other chemotherapy agents, with the exception of gemcitabine in the afatinib and gefitinib groups. Pemetrexed and gemcitabine had the longest TTD of 3–4 months.ConclusionsAmong patients with EGFR mutant lung adenocarcinoma, afatinib use may not provide longer OS compared with first-generation TKIs. Afatinib may be preferably considered among patients with active smoking and should not be withheld among those with worse performance status. With 40% of patients receiving subsequent chemotherapy, pemetrexed may be the preferred agent, while gemcitabine can be a reasonable alternative.