Search

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients treated with EGFR–tyrosine kinase inhibitors (TKIs) inevitably develop resistance through several biological mechanisms. However, little is known on the molecular mechanisms underlying acquired resistance to suboptimal EGFR-TKI doses, due to pharmacodynamics leading to inadequate drug exposure. To evaluate the effects of suboptimal EGFR-TKI exposure on resistance in NSCLC, we obtained HCC827 and PC9 cell lines resistant to suboptimal fixed and intermittent doses of gefitinib and compared them to cells exposed to higher doses of the drug. We analyzed the differences in terms of EGFR signaling activation and the expression of epithelial–mesenchymal transition (EMT) markers, whole transcriptomes byRNA sequencing, and cell motility. We observed that the exposure to low doses of gefitinib more frequently induced a partial EMT associated with an induced migratory ability, and an enhanced transcription of cancer stem cell markers, particularly in the HCC827 gefitinib-resistant cells. Finally, the HCC827 gefitinib-resistant cells showed increased secretion of the EMT inducer transforming growth factor (TGF)-β1, whose inhibition was able to partially restore gefitinib sensitivity. These data provide evidence that different levels of exposure to EGFR-TKIs in tumor masses might promote different mechanisms of acquired resistance. [ABSTRACT FROM AUTHOR]

The emergency of tyrosine kinase inhibitors has remarkably enhanced the clinical outcomes of cancer therapy, especially the use of EGFR inhibitors for non‐small cell lung cancer (NSCLC). However, acquired resistance is inevitable after 8–12 months treatment. New agents or treatments are urgently required to resolve this problem. In this study, we identified that compound ZYZ384 can selectively inhibit the growth of gefitinib‐resistant (G‐R) lung cancer cells, without affecting that of normal lung epithelial cells. ZYZ384 induced G2 arrest in G‐R NSCLC cells, decreasing the expression of Cyclin B1 and increasing the expression of P21. Meanwhile, ZYZ384 also induced apoptosis in NSCLC cells and correspondingly increased the expression of cleaved Caspase 3, 8, and 9 proteins. The expression of p‐JNK, p‐P38, and p‐ERK were also increased in H1975 NSCLC cells treated with ZYZ384. Finally, we observed that the JNK inhibitor effectively reversed the pro‐apoptotic effect of ZYZ384. In conclusion, ZYZ384 is a potential therapeutic agent to inhibit the growth of NSCLCs with EGFR mutations through activating JNK, which will help the development of related anticancer drugs. [ABSTRACT FROM AUTHOR]

Objectives: Despite the outstanding results achieved by osimertinib for the treatment of advanced EGFR-mutated NSCLC, the development of resistance is almost inevitable. While molecular mechanism responsible for osimertinib resistance are being mostly revealed, the definition of predictive biomarkers is crucial in order to identify patients at higher risk of progression and optimize treatment strategy., Materials and Methods: This is a prospective single-center study aimed to assess the potential role of liquid biopsy and 18F-FDG PET/CT derived metabolic parameters as noninvasive predictive biomarkers of osimertinib outcomes in advanced EGFR-mutated NSCLC patients. Patients underwent blood samples for ctDNA analysis at baseline, after 15 days and 1 month (t1) of osimertinib. 18F-FDG PET/CT was performed at baseline and after 1 month of osimertinib., Results: Seventy-two advanced EGFR-mutated NSCLC patients treated with osimertinib in first (n = 63) and in second-line (n = 9) were prospectively enrolled. Baseline positive shedding status was significantly associated with a shorter progression-free survival (PFS) (9.5 vs. 29.2 months, P = .031). Early metabolic response (MR) led to improved PFS (16.8 vs. 5.5 months, P = .038) and OS (35.2 vs. 15.3 months, P = .047). Early MR was significantly correlated with subsequent radiologic response (P = .010). All 18F-FDG PET/CT baseline parameters were significantly related to baseline EGFR activating mutation allele frequency. Both clearance and no detection of EGFR at t1 were significantly associated with MR (P = .001 and P = .004, respectively)., Conclusion: Molecular and 18F-FDG PET/CT derived metabolic parameters might represent a useful tool to predict osimertinib outcome in advanced EGFR-mutated NSCLC patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatments for advanced EGFR-mutated non–small cell lung cancer (NSCLC) patients. Osimertinib is an effective therapy for NSCLC patients with acquired resistance due to T790M mutation after first- and second-generation EGFR-TKI treatment. This study aimed to analyze the clinical outcomes of sequential therapy following first-line EGFR-TKIs and the predictive factors of an acquired T790M mutation. Methods: Between January 2014 and December 2018, data from 2190 advanced NSCLC patients with common EGFR mutations (exon 19 deletion and L858R) receiving first- and second-generation EGFR-TKIs in Linkou, Kaohsiung, Chiayi and Keelung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed. Results: Until August 2021, among 1943 patients who experienced progressive disease, 526 underwent T790M mutation tests, and their T790M-positive rate was 53.6%. Exon 19 deletion mutation and progression-free survival (PFS) of >12 months were positively associated with secondary T790M mutation. Different first-line first- and second-generation EGFR-TKI therapies did not affect the appearance of acquired T790M mutations. The median overall survival (OS) was 58.3 [95% confidence interval (CI): 49.0–67.5] months among the patients with T790M mutation who received second-line osimertinib therapy compared with 31.0 (95% CI: 27.5–34.5) months among the patients without T790M mutation who received chemotherapy alone. The multivariate analysis showed that a poor performance status (score: >2), nonadenocarcinoma histology, stage IV cancer, liver metastasis, brain metastasis, PFS while on first-line EGFR-TKIs, and subsequent chemotherapy without third-generation EGFR-TKIs were significant independent unfavorable prognostic factors for OS. Conclusion: This study demonstrated the efficacy of first-line EGFR-TKIs and sequential osimertinib therapy. The results of our study suggest that T790M mutation tests are important for the use of subsequent osimertinib, which yielded favorable survival outcomes. [ABSTRACT FROM AUTHOR]

Diarrhea is an important adverse effect of epidermal growth factor receptor-tyrosine kinase inhibitors, especially afatinib. Novel antidiarrheal agents are needed to reduce epidermal growth factor receptor-tyrosine kinase inhibitor-associated diarrhea to improve the quality of life and treatment outcome in cancer patients. This study aimed to investigate the anti-diarrheal activity of chitosan oligosaccharide against afatinib-induced barrier disruption and chloride secretion in human intestinal epithelial cells (T84 cells). Chitosan oligosaccharide (100 μg/mL) prevented afatinib-induced barrier disruption determined by changes in transepithelial electrical resistance and FITC-dextran flux in the T84 cell monolayers. In addition, chitosan oligosaccharide prevented afatinib-induced potentiation of cAMP-induced chloride secretion measured by short-circuit current analyses in the T84 cell monolayers. Chitosan oligosaccharide induced the activation of AMPK, a positive regulator of epithelial tight junction and a negative regulator of cAMP-induced chloride secretion. Moreover, chitosan oligosaccharide partially reversed afatinib-induced AKT inhibition without affecting afatinib-induced ERK inhibition via AMPK-independent mechanisms. Collectively, this study reveals that chitosan oligosaccharide prevents the afatinib-induced diarrheal activities in T84 cells via both AMPK-dependent and AMPK-independent mechanisms. Chitosan oligosaccharide represents a promising natural polymer-derived compound for further development of treatment for afatinib-associated diarrheas. [ABSTRACT FROM AUTHOR]

• The number of hemodialysis (HD) patients with malignancies continues to grow. • Evidence of chemotherapy for lung cancer patients on HD remains insufficient. • The benefits of chemotherapy are significant in patients with SCLC and EGFR-mutant NSCLC. • A commonly observed adverse event was controllable myelosuppression. • Appropriate patient selection and optimal dosage should be considered. Malignant tumors are the major cause of death in hemodialysis patients. Management of these patients remains challenging as there is no evidence that chemotherapy is beneficial, and a lack of information about actual clinical practice. This multicenter retrospective study included hemodialysis patients who were diagnosed with lung cancer from January 2002 to June 2018. We reviewed their clinical information including patient characteristics associated with lung cancer and end-stage renal disease, regimen, efficacy and safety of chemotherapy, and outcomes. A total of 162 patients from 22 institutions in Japan were registered. Of 158 eligible patients, 91 received chemotherapy (80 as palliative chemotherapy and 11 as chemoradiotherapy) and 67 received best supportive care only regardless of cancer stage. In small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients who received cytotoxic chemotherapy, the objective response rates (ORR) and median overall survival (OS) were 68.1 %, 12.3 months and 37.0 %, 8.5 months, respectively. The ORR and median OS in patients with EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKI) were 44.4 % and 38.6 months. The treatment-related adverse events (Grade 3 or higher) induced by cytotoxic chemotherapy were myelosuppression and febrile neutropenia; treatment-related death (TRD) was observed in one patient. TRD occurred in 3 of 18 patients who received EGFR-TKI. Chemotherapy should be considered for hemodialysis patients with EGFR-mutant NSCLC and SCLC. However, the survival benefits of chemotherapy for NSCLC patients with EGFR-wild type are unclear; physicians should carefully consider whether to offer chemotherapy to this patient subset. [ABSTRACT FROM AUTHOR]

Yalin Xie,1 Ning Su,1 Wei Zhou,2 An Lei,1 Xiang Li,3 Weiwei Li,4 Zhan Huang,4 Wenchang Cen,1 Jinxing Hu5 1Department of Oncology, Guangzhou Chest Hospital, Guangzhou, People’s Republic of China; 2Department of Pathology, Guangzhou Chest Hospital, Guangzhou, People’s Republic of China; 3Department of Pharmacy, Guangzhou Chest Hospital, Guangzhou, People’s Republic of China; 4Department of Medical Business, Amoy Diagnostics Co., Ltd., Xiamen, People’s Republic of China; 5Department of Tuberculosis, Guangzhou Chest Hospital, Guangzhou, People’s Republic of ChinaCorrespondence: Wenchang Cen; Jinxing Hu Email bingningbj@163.com; hujinxing2000@163.comObjective: Limited studies have clearly demonstrated the effect of EGFR-TKI in the treatment of EGFR mutant NSCLC patients with underlying pulmonary disease, like pulmonary tuberculosis (PTB). Here, we conducted the study to evaluate the impact of PTB on survival of Chinese EGFR mutant lung adenocarcinoma (LUAD) patients that underwent EGFR-TKI treatment.Methods: Clinicopathologic data of 1448 LUAD patients harboring EGFR mutations from the Guangzhou Chest Hospital between 2017 and 2019 were reviewed retrospectively. Patients receiving EGFR-TKI treatment were divided into PTB and non-PTB groups. The differences in response to EGFR-TKIs and survival between the two groups were assessed.Results: After EGFR-TKIs treatment, the objective response rate (58.14% vs 47.62%) as well as disease control rate (97.67% vs 85.71%) were higher in the non-PTB group than in the PTB group, but there was no statistical difference. In the survival analysis, both the median progression-free survival (7.47 months vs 11.77 months, p = 0.038) and the overall survival (13.00 months vs 20.00 months, p = 0.001) were significantly shorter in the PTB group than in the non-PTB group. Furthermore, for patients with 19Del mutation, or metastases sites less than 3, or using first-line EGFR-TKI, EGFR-TKIs treatment significantly prolonged the median PFS and OS in patients without PTB.Conclusion: LUAD patients with concomitant PTB have a poor response to EGFR-TKI treatment, especially in terms of survival outcome.Keywords: advanced lung adenocarcinoma, pulmonary tuberculosis, EGFR mutation, EGFR-tyrosine kinase inhibitors, prognosis

• Resistant cells showed activation and phosphorylation of AXL and MET. • CB469 and EGFR TKIs inhibited cell proliferation and colony formation rates. • The combination of CB469 and erlotinib induced apoptosis of resistant cells. • Resistant cells showed an interaction of AXL and MET. • CB469 and EGFR TKIs showed antitumor activity in xenograft models. In non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) may occur via bypass signals such as AXL or MET activation. We investigated the antitumor activity of CB469, a newly developed drug that targets both AXL and MET, in EGFR TKI-resistant NSCLC cells. We generated EGFR TKI-resistant NSCLC cell lines with acquired resistance to erlotinib, gefitinib, and osimertinib (PC9/ER, HCC827/GR and HCC827/OR, respectively). We characterized the mechanisms of CB469 action in resistant cells and investigated the antitumor efficacy of CB469 both in vitro and in vivo. Resistant cells showed activation of phosphorylated EGFR, as well as AXL and MET activation and phosphorylation. The combination of CB469 and EGFR TKIs synergistically inhibited cell proliferation and colony formation rates in resistant cell lines. The combination of CB469 and erlotinib induced apoptosis of PC9/ER cells. Mechanistically, resistant cells showed an interaction of AXL and MET. CB469 and EGFR TKI also demonstrated antitumor activity by reducing phosphorylated AXL and MET in mouse xenograft models with HCC827/GR cells. The combination of CB469 and EGFR TKI can overcome the acquired resistance to EGFR TKI mediated by AXL and MET activation. We anticipate that the dual inhibitory actions of CB469 will assist with the development of targeted therapy for EGFR -mutant NSCLC patients who fail initial EGFR TKI therapy. [ABSTRACT FROM AUTHOR]

Aim: Most epidermal growth factor receptor (EGFR) gene mutations affecting exon 19 (inframe deletions; 19 Del) and 21 (L858R), while the rest (referred as uncommon EGFR mutation) have not been fully described due to their rarity. Here we present a retrospective study that investigated clinical characteristics and outcome of patients with different EGFR mutations. Methods: We retrospectively analyzed the EGFR mutation pattern and its association with clinical‐pathological characteristics from 100 cases of nonsmall‐cell lung cancer (NSCLC) harboring EGFR mutations, and compiled the genotype response data for NSCLC patients with common and uncommon EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs). Patients with advanced EGFR‐mutated NSCLC were enrolled and treated with icotinib (oral administration, 125 mg, thrice per day). Results: Among 100 patients, 85 and 15 had common and uncommon mutations, respectively. Four patients had a single mutation in 18 or 20 exon, and 11 had a complex mutation with del‐19 or L858R. There was no significant association between the presence of different mutation type and the type of any clinical and pathological characteristics. Prolonged but not significant progression‐free survival (PFS) was noted in patients with common EGFR mutations (18.07 [14.00–26.23] vs 12.9 [8.43–23.27], P = 0.056). Patients without brain metastases had increased PFS to icotinib than those with brain metastases (18.07 [95% confidence interval, CI 14.77–27.03] vs 13.17 [95% CI 8.63–22.63], P = 0.038). Conclusion: Uncommon EGFR mutations comprised 15% of all mutated patients, in which most were complex mutations. Compared with common EGFR mutation, uncommon EGFR mutations were associated with a modest sensitivity to EGFR TKIs. Our findings will be helpful to make clinical decision and select the appropriate therapy for EGFR‐mutated NSCLC patients. [ABSTRACT FROM AUTHOR]

Approximately half of all patients with non-small cell lung cancer (NSCLC) develop central nervous system metastases during the course of their disease which indicate poor prognosis. A part of NSCLC patients demonstrates activating epidermal growth factor receptor gene (EGFR) mutations who represent effectiveness and well tolerance of EGFR-specific tyrosine kinase inhibitors (TKIs) therapy. Although the systemic efficacy of targeted agents is established, the efficacy of central nervous system (CNS) metastases is not as well characterized. In this article, we review recent data on the use of EGFR inhibitors for treatment of patients with NSCLC and CNS metastases.

Background: EGFR‐tyrosine kinase inhibitors (TKIs) combined with TS‐1 might overcome EGFR‐TKI resistance, which has been indicated by several preclinical studies. We investigated the synergistic efficacy and safety of the combination therapy of EGFR‐TKIs and TS‐1 in non‐small cell lung cancer (NSCLC) patients with acquired resistance to previous EGFR‐TKI therapy. Methods: This was a phase II, single‐arm and single‐center prospective study. Stage IIIB–IV NSCLC patients with acquired resistance to prior EGFR‐TKI treatment were enrolled. All patients were administered combination therapy of TS‐1 and continuing EGFR‐TKIs in this study. The primary endpoints were progression‐free survival (PFS), while overall survival (OS), disease control rate (DCR), and safety were secondary endpoints. Results: A total of 42 patients with acquired resistance to EGFR‐TKIs were eligible for this study. The median PFS for all patients was five months (95% confidence interval [CI] 3.6–5.4). The OS and DCR were 31.9 (95% CI 17.8–46.0) months and 69.0% (29/42), respectively. No grade 4 toxicity or grade 3 hematologic toxicity was observed in this study. One patient (2%) experienced grade 3 elevated total serum bilirubin. Conclusion: The combination treatment of TS‐1 and EGFR‐TKIs was effective and well tolerated by patients who had experienced prior EGFR‐TKI treatment failure. Our results need to be validated by larger prospective clinical trials. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the major causes of mortality worldwide and is on the rise in India. The identification of epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) has paved the way for personalized therapy in lung cancer with EGFR-tyrosine kinase inhibitors (TKIs). Despite the proven efficacy of EGFR-TKIs in patients harboring EGFR mutations, their clinical utility is limited by the development of acquired resistance mechanisms by the tumor cells. T790M mutation accounts for 60% of all resistance mechanisms to EGFR TKIs and is responsible for treatment failure with first- and second-generation TKIs. With the development of novel therapeutic agents such as osimertinib to overcome this resistance mechanism, it is essential to detect patients harboring T790M mutation. There are several limitations with the use of tissue biopsy specimens for molecular testing such as poor quality and quantity of sample, tumor heterogeneity, occurrence of complications, and issues with repeat biopsy. Liquid biopsy offers a noninvasive approach that can be used for diagnostic purposes as well as for monitoring treatment response and evaluation of resistance mechanisms. This review focuses on the methods for molecular testing of tissue and liquid biopsy specimens for EGFR mutations, particularly EGFR T790M mutation. [ABSTRACT FROM AUTHOR]

The detection of mutations in the epidermal growth factor receptor (EGFR) gene in tumor tissues has been established as the gold standard for predicting the efficacy of treatment with tyrosine-EGFR kinase inhibitors (EGFR-TKIs) in advanced non-small-cell lung cancer (NSCLC). The current study aimed to investigate whether the presence of co-existing EGFR mutations in tumor tissue and in cell-free tumor DNA (ctDNA) in the plasma predicts a more favorable outcome of EGFR-TKI treatment in advanced NSCLC. A total of 287 NSCLC patients who had undergone EGFR-TKI treatment were enrolled and stratified into four subgroups: Wild-type EGFR in plasma and tissue specimens (B-/T-); mutated EGFR in plasma and tissue specimens (B+/T+); mutated EGFR in only in plasma samples (B+/T-); or mutated EGFR in only tissue specimens (B-/T+). EGFR mutations were tested using denaturing high-performance liquid chromatography and confirmed by amplification-refractory mutation system analysis. Of the 287 patients, 101 had mutations in both tissue and plasma samples and 103 had mutation in either tissue (n=65) or plasma (n=38). The median progression-free survival (mPFS) times were 9.2 and 2.0 months in the B+/T+ and B-/T- groups, respectively. The mPFS times were 7.9 months in the B-/T+ group and 11.9 months in the B+/T-group (P=0.001). Among the 187 patients with available pre-EGFR-TKI plasma samples, 70 received first-line EGFR-TKI treatment, and the mPFS in the B+/T+ group was longer than in the B-/T+ or B+/Tgroups (18.8 vs. 9.4 vs. 6.9 months; P=0.003). In second-line setting of EGFR-TKI therapy, the groups of patients with EGFR mutation in ctDNA, regardless of the mutation status in the tissues, exhibited longer mPFS times compared with the B-/T+ group (10.0 vs. 5.8 months; P=0.044). The results suggest that co-existence of EGFR mutations in tissue and ctDNA predict longer PFS times for NSCLC patients who receive first-line EGFR-TKI therapy. In addition, real-time detection in ctDNA is an excellent predictor for the efficacy of second- or higher line EGFR-TKI therapy. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Lung Cancer is the property of Chinese Journal of Lung Cancer and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives In non-small cell lung cancer (NSCLC), the association between common EGFR mutations (Del EX19/L858R) with EGFR tyrosine kinase inhibitors (EGFR-TKIs) has been well established. However, this has not been investigated for rare EGFR mutations or their impact on treatment response and outcome to EGFR TKIs (primary objective) and chemotherapy (secondary objective). Materials and methods In an observational prospective cohort, we analyzed 188 NSCLC patients from Mexico, Colombia and Costa Rica with EGFR mutations. As a first line of treatment, 66.5% received platinum-based chemotherapy. All patients received TKIs in first-line treatment or after progression to chemotherapy. The clinical–pathological characteristics as well as the f of common and rare EGFR mutations associated with treatment response were analyzed. Results Of all patients, 79.5% had common and 20.5% had rare EGFR mutations. Lepidic and acinar adenocarcinomas were associated with common EGFR mutations ( p = 0.010). Patients with common EGFR mutations had higher response rates to EGFR-TKIs than those who had rare EGFR mutations (63.8 vs 32.4%, p < 0.001). Women had increased progression-free survival (PFS) to EGFR-TKIs than men (16.4 vs 9.5 months, p = 0.02). The median PFS and overall survival (OS) were better in patients with common EGFR mutations (15.5 vs 3.9 months, p < 0.001; and 37.3 vs 17.4 months, p < 0.001) respectively. Conclusion Our findings suggested that only patients with rare EGFR mutations could receive platinum-based chemotherapy as a first-line treatment, due to their low response rates and short PFS in response to EGFR-TKIs. Consequently, EGFR-TKIs could be reserved as a second- or third-line treatment. In patients with EGFR mutations, women have better PFS to EGFR-TKIs than men, and rare EGFR mutations are more frequent in high grade adenocarcinomas than in low grade tumors. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aim of this study is to evaluate the predictive impact of cigarette smoking on treatment outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma patients with activating EGFR mutations. Methods: We retrospectively analyzed 222 consecutive recurrent or unresectable lung adenocarcinoma patients who harbored activating EGFR mutations (exon 19 deletion or exon 21 L858R) and had received gefitinib or erlotinib. Detailed smoking histories were obtained from all patients according to a standard protocol. Results: Of 222 EGFR-mutated patients, 65.3% were never-smokers, 19.8% were smokers with <30 pack-years, and 14.9% were smokers with ≥30 pack-years smoking dosage. The disease control rate (DCR) and objective response rate (ORR) of smokers with ≥30 pack-years were significantly lower than never-smokers and smokers with <30 pack-years (DCR, 78.8% vs. 93.1%, p =0.016; ORR, 45.5% vs. 62.4%, p =0.020). Smokers with ≥30 pack-years showed significantly shorter PFS than never-smokers (6.4 vs. 11.8 months, p =0.001) and smokers with <30 pack-years (6.4 vs. 11.4 months, p =0.033), as well as shorter overall survival from the time of metastatic diagnosis than never-smokers (33.6 vs. 46.2 months, p =0.003). There was no survival difference between smokers with <30 pack-year and never smokers. In the multivariate analysis adjusted for age, sex, performance status, initial stage, and line of EGFR-TKI, the presence of smoking dosage ≥30 pack-years was an independent predictive factor for the disease progression to EGFR-TKIs (hazard ratio, 1.87; 95% confidence interval, 1.15–3.05; p =0.012). Conclusions: Cigarette smoking dosage of ≥30 pack-years is an independent negative predictive factor of EGFR-TKI treatment outcome in lung adenocarcinoma patients with activating EGFR mutations. [Copyright &y& Elsevier]

Purpose: This study was designed to determine the relationship of cigarette smoking to the frequency and qualitative differences among KRAS mutations in lung adenocarcinomas from Korean patients. Materials and Methods: Detailed smoking histories were obtained from 200 consecutively enrolled patients with lung adenocarcinoma according to a standard protocol. EGFR (exons 18 to 21) and KRAS (codons 12/13) mutations were determined via direct-sequencing. Results: The incidence of KRAS mutations was 8% (16 of 200) in patients with lung adenocarcinoma. KRAS mutations were found in 5.8% (7 of 120) of tumors from never-smokers, 15% (6 of 40) from former-smokers, and 7.5% (3 of 40) from current-smokers. The frequency of KRAS mutations did not differ significantly according to smoking history (p=0.435). Never-smokers were significantly more likely than former or current smokers to have a transition mutation (G→A or C→T) rather than a transversion mutation (G→T or G→C) that is known to be smoking-related (p=0.011). In a Cox regression model, the adjusted hazard ratios for the risk of progression with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were 0.24 (95% CI, 0.14-0.42; p<0.001) for the EGFR mutation and 1.27 (95% CI, 0.58-2.79; p=0.537) for the KRAS mutation. Conclusion: Cigarette smoking did not influence the frequency of KRAS mutations in lung adenocarcinomas in Korean patients, but influenced qualitative differences in the KRAS mutations. [ABSTRACT FROM AUTHOR]

The article examines detection of epidermal growth factor receptor (EGFR) mutations by denaturing high-performance liquid chromatography (dHPLC) in patients with nonsmall cell lung cancer. It also analyzes the impact on response to therapy with EGFR-tyrosine kinase inhibitors (EGFR-TKI). Patients included in the study were selected based on their known EGFR mutation status. Results of the study revealed that 40% of patients who received EGFR-TKI therapy during their treatment course had mutations of EGFR.

Simple Summary: In advanced non-small cell lung cancer (NSCLC) patients, tumor tissue biopsy represents the gold standard for molecular analysis procedures. However, to achieve the necessary information, both at the time of diagnosis and progressive disease, is sometimes challenging, considering the small cancer material available. Liquid biopsy consists of a non-invasive alternative approach that owns the potential to provide useful information for molecular diagnostic. We aimed to prove the worth of liquid biopsy as plasma but also as urine and exhaled breath condensate (EBC) as the best surrogate to tumor tissue as well as to explore the molecular mechanisms that underlying the resistance to second-line osimertinib in advanced EGFR mutated NSCLC. We believe that our findings, with the PLUREX study and the review of literature, may add another brick in the wall on the use of liquid biopsy in the clinical practice in the setting of EGFR-mutated NSCLC disease. In order to study alternatives at the tissue biopsy to study EGFR status in NSCLC patients, we evaluated three different liquid biopsy platforms (plasma, urine and exhaled breath condensate, EBC). We also reviewed the literature of the cfDNA biological sources other than plasma and compared our results with it about the sensitivity to EGFR mutation determination. Twenty-two EGFR T790M-mutated NSCLC patients in progression to first-line treatment were enrolled and candidate to osimertinib. Plasma, urine and EBC samples were collected at baseline and every two months until progression. Molecular analysis of cfDNA was performed by ddPCR and compared to tissue results. At progression NGS analysis was performed. The EGFR activating mutation detection reached a sensitivity of 58 and 11% and for the T790M mutation of 45 and 10%, in plasma and urine samples, respectively. Any DNA content was recovered from EBC samples. Considering the plasma monitoring study, the worst survival was associated with positive shedding status; both plasma and urine molecular progression anticipated the radiological worsening. Our results confirmed the role of plasma liquid biopsy in testing EGFR mutational status, but unfortunately, did not evidence any improvement from the combination with alternative sources, as urine and EBC. [ABSTRACT FROM AUTHOR]

Introduction: Approximately 5% of patients with EGFR-activating mutations acquire EGFR tyrosine kinase inhibitor (TKI) resistance through SCLC transformation. However, the reason for the poor outcome and the molecular basis of EGFR-mutant SCLC that has transformed from adenocarcinoma remain unclear., Methods: In this study, we established two EGFR-mutant SCLC cell lines from lung adenocarcinoma patients after failed EGFR-TKI treatment to investigate their molecular basis and potential therapeutic strategies in the hope of improving patient outcome., Results: These two EGFR-mutant SCLC cell lines displayed two different phenotypes: suspensive and adherent. Both phenotypes shared the same genomic alterations analyzed by array-based comparative genomic hybridization assay. Increased expression of EGFR and mesenchymal markers and decreased expression of neuroendocrine markers were observed in adherent cells. Principal component analysis and hierarchical clustering analysis of RNA microarray revealed that these two cell lines displayed a unique gene expression pattern that was distinctly different from that in NSCLC and classical SCLC cells. Combined treatment using an EGFR-TKI and an AKT inhibitor attenuated cell viabilities in our two cell lines. Moreover, the use of a histone deacetylase inhibitor significantly inhibited the cell viabilities of both cell lines in vitro and in vivo., Conclusion: Our findings suggest that EGFR-mutant SCLC may be a distinct subclass of SCLC that exhibits epithelial-mesenchymal transition phenotypes, and adding an AKT or histone deacetylase inhibitor to pre-existing therapies may be one of the therapeutic choices for transformed EGFR-mutant SCLC., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose The aim of this study is to evaluate the impact of weight loss at presentation on treatment outcomes of first-line EGFR-tyrosine kinase inhibitors (EGFR-TKI) in EGFR-TKI sensitive mutant NSCLC patients. Methods We retrospectively analyzed the clinical outcomes of 75 consecutive advanced NSCLC patients with EGFR-TKI sensitive mutations (exon 19 deletion or exon 21 L858R) received first-line gefitinib or erlotinib therapy according to weight loss status at presentation in our single center. Results Of 75 EGFR-TKI sensitive mutant NSCLC patients, 49 (65.3%) patients had no weight loss and 26 (34.7%) had weight loss at presentation, the objective response rate (ORR) to EGFR-TKI treatment were similar between the two groups (79.6% vs. 76.9%, p = 0.533). Patients without weight loss at presentation had significantly longer median progression free survival (PFS) (12.4 months vs. 7.6 months; hazard ratio [HR] 0.356, 95% confidence interval [CI] 0.212-0.596, p < 0.001) and overall survival (OS) (28.5 months vs. 20.7 months; HR 0.408, 95% CI 0.215-0.776, p = 0.006) than those with weight loss at presentation; moreover, the stratified analysis by EGFR-TKI sensitive mutation types also found similar trend between these two groups except for OS in EGFR exon 21 L858R mutation patients. Multivariate analysis identified weight loss at presentation and EGFR-TKI sensitive mutation types were independent predictive factors for PFS and OS. Conclusions Weight loss at presentation had a detrimental impact on PFS and OS in EGFR-TKI sensitive mutant advanced NSCLC patients treated with first-line EGFR-TKI. It should be considered as an important factor in the treatment decision or designing of EGFR-TKI clinical trials., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Introduction: The chance for elderly patients with NSCLC to receive chemotherapy decreases significantly with age. In addition, older patients are often underrepresented in clinical trials. Consequently, due to the paucity of data, evidence-based decisions with regard to chemotherapy treatment strategies in the elderly are lacking., Areas Covered: We performed a literature search to identify mainly randomized trials focusing on treatment of NSCLC in older patients with chemotherapy and targeted therapy, toxicity and quality of life. In conclusion, the efficacy of regular chemotherapy and targeted therapy seems quite similar in older patients compared to their younger counterparts, with increased toxicity, but acceptable. However, these data are mostly derived from subgroup analyses and highly selected fit patients, which may not represent the general older population., Expert Opinion: Further research is necessary to investigate the role of a comprehensive geriatric assessment in older patients, before the start of a chemotherapeutic treatment. Proteomic tests can have potential in the future, if these tests turn out to be able to separate patients with advanced NSCLC into groups with better or worse outcomes. It can be of special interest for the elderly population, to prevent unnecessary side effects of a possible inferior treatment.