scholarly journals The Dynamic Use of EGFR Mutation Analysis in Cell-Free DNA as a Follow-Up Biomarker during Different Treatment Lines in Non-Small-Cell Lung Cancer Patients

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Mónica Macías ◽  
Estibaliz Alegre ◽  
Gorka Alkorta-Aranburu ◽  
Ana Patiño-García ◽  
Beatriz Mateos ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Mutation Analysis ◽  
Tumor Tissue ◽  
Egfr Mutation ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Dna ◽  
Nsclc Patients ◽  
Egfr Tkis

Epidermal growth factor receptor (EGFR) mutational testing in advanced non-small-cell lung cancer (NSCLC) is usually performed in tumor tissue, although cfDNA (cell-free DNA) could be an alternative. We evaluated EGFR mutations in cfDNA as a complementary tool in patients, who had already known EGFR mutations in tumor tissue and were treated with either EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy. We obtained plasma samples from 21 advanced NSCLC patients with known EGFR tumor mutations, before and during therapy with EGFR-TKIs and/or chemotherapy. cfDNA was isolated and EGFR mutations were analyzed with the multiple targeted cobas EGFR Mutation Test v2. EGFR mutations were detected at baseline in cfDNA from 57% of patients. The semiquantitative index (SQI) significantly decreased from the baseline (median=11, IQR=9.5-13) to the best response (median=0, IQR=0-0, p<0.01), followed by a significant increase at progression (median=11, IQR=11-15, p<0.01) in patients treated with either EGFR-TKIs or chemotherapy. The SQI obtained with the cobas EGFR Mutation Test v2 did not correlate with the concentration in copies/mL determined by droplet digital PCR. Resistance mutation p.T790M was observed at progression in patients with either type of treatment. In conclusion, cfDNA multiple targeted EGFR mutation analysis is useful for treatment monitoring in tissue of EGFR-positive NSCLC patients independently of the drug received.

Role of cMET expression in non-small cell lung cancer patients treated with EGFR tyrosine kinase inhibitors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18092-e18092
Author(s):  
Hyun Chang ◽  
Xianglan Zhang ◽  
Da Rae Kim ◽  
Gun Min Kim ◽  
Se Hyun Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Small Cell Lung Cancer ◽  
Tumor Tissue ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Nsclc Patients ◽  
Egfr Tkis

e18092 Background: We performed this study to investigate whether activation of cMET is associated with sensitivity to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients. Methods: This retrospective study included 69 NSCLC patients with available tumor tissue, treatment response and survival data. cMET and hepatocyte growth factor (HGF) status was evaluated by immunohistochemistry. Results: A positive cMET, cMET[pY1003], cMET[pY1234/1235] and HGF were identified in 89%, 44%, 20% and 89% of cases, respectively. Positive cMET[pY1003] expression was associated with better objective response rate (OR) and clinical benefit rate (CBR) (OR, P = 0.033 and CBR, P = 0.039). Positive cMET[pY1234/1235] was significantly associated with a longer overall survival (OS) (P = 0.012) and time-to progression (TTP) (P = 0.031). Multivariable model confirmed that cMET[pY1234/235]-positive patients had a significant reduction in the risk of death and disease progression than cMET[pY1234/1235] –negative patients [OS; hazard ratio(HR)=0.29, P = 0.008 and TTP; HR=0.43; P=0.024] Conclusions: cMET expression in tumor tissue could be useful for predicting the clinical outcome of EGFR-TKIs treatment. Our results suggest that cMET expression in tumor tissue could be used to refine the selection of NSCLC patients expected to benefit from EGFR-TKIs treatment.

ERK Inhibitor ASN007 Effectively Overcomes Acquired Resistance to EGFR Inhibitor in Non-small Cell Lung Cancer

2021 ◽  
Author(s):  
Bo Mi Ku ◽  
Jae Yeong Heo ◽  
Jinchul Kim ◽  
Jong-Mu Sun ◽  
Se-Hoon Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Erk Signaling ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract The emergence of acquired resistance limits the long-term efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Thus, development of effective strategies to overcome resistance to EGFR-TKI is urgently needed. Multiple mechanisms to reactivate ERK signaling have been successfully demonstrated in acquired resistance models. We found that in EGFR mutant non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR-TKIs was accompanied by increased activation of ERK. Increased ERK activation was also found in in vitro models of acquired EGFR-TKI resistance. ASN007 is a potent selective ERK1/2 inhibitor with promising antitumor activity in cancers with BRAF and RAS mutations. ASN007 treatment impeded tumor cell growth and the cell cycle in EGFR-TKI-resistant cells. In addition, combination treatment with ASN007 and EGFR-TKIs synergistically decreased the survival of resistant cells, enhanced induction of apoptosis, and effectively inhibited the growth of erlotinib-resistant xenografts, providing the preclinical rationale for testing combinations of ASN007 and EGFR-TKIs in EGFR-mutated NSCLC patients. This study emphasizes the importance of targeting ERK signaling in maintaining the long-term benefits of EGFR-TKIs by overcoming acquired resistance.

scholarly journals Clinical Characteristics of Osimertinib Responder in Non-Small Cell Lung Cancer Patients with EGFR-T790M Mutation

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 365 ◽  
Author(s):  
Akihiro Yoshimura ◽  
Tadaaki Yamada ◽  
Naoko Okura ◽  
Takayuki Takeda ◽  
Kazuki Hirose ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr T790m ◽  
Egfr Tkis

Osimertinib is a mutant-selective EGFR inhibitor that is effective against non-small cell lung cancer (NSCLC) in patients with the EGFR-T790M mutation, who are resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the factors affecting response to osimertinib treatment are unknown. In this retrospective study, 27 NSCLC patients with the EGFR-T790M mutation were enrolled at five institutions in Japan. Among several parameters tested, the progression-free survival (PFS) associated with the initial EGFR-TKIs was positively correlated with the PFS after osimertinib treatment (p = 0.021). The median PFS following osimertinib treatment and the overall survival (OS) were longer in patients who responded to osimertinib than in those who did not (17.7 months versus 3.5 months, p = 0.009 and 24.2 months versus 13.5 months, p = 0.021, respectively). A multivariate analysis demonstrated that the PFS with initial EGFR-TKIs was significantly related to the PFS with osimertinib treatment (p = 0.035), whereas osimertinib response was significantly related to the PFS and OS with osimertinib treatment (p = 0.016 and p = 0.006, respectively). Our retrospective observations indicate that PFS following the initial EGFR-TKI treatment and the response rate to osimertinib might be promising predictors for effective osimertinib treatment in NSCLC patients with the EGFR-T790M mutation.

scholarly journals Next Generation Sequencing-Based Profiling of Cell Free DNA in Patients with Advanced Non-Small Cell Lung Cancer: Advantages and Pitfalls

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3804
Author(s):  
Riziero Esposito Abate ◽  
Daniela Frezzetti ◽  
Monica Rosaria Maiello ◽  
Marianna Gallo ◽  
Rosa Camerlingo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Next Generation Sequencing ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Dna ◽  
Nsclc Patients ◽  
Generation Sequencing

Lung cancer (LC) is the main cause of death for cancer worldwide and non-small cell lung cancer (NSCLC) represents the most common histology. The discovery of genomic alterations in driver genes that offer the possibility of therapeutic intervention has completely changed the approach to the diagnosis and therapy of advanced NSCLC patients, and tumor molecular profiling has become mandatory for the choice of the most appropriate therapeutic strategy. However, in approximately 30% of NSCLC patients tumor tissue is inadequate for biomarker analysis. The development of highly sensitive next generation sequencing (NGS) technologies for the analysis of circulating cell-free DNA (cfDNA) is emerging as a valuable alternative to assess tumor molecular landscape in case of tissue unavailability. Additionally, cfDNA NGS testing can better recapitulate NSCLC heterogeneity as compared with tissue testing. In this review we describe the main advantages and limits of using NGS-based cfDNA analysis to guide the therapeutic decision-making process in advanced NSCLC patients, to monitor the response to therapy and to identify mechanisms of resistance early. Therefore, we provide evidence that the implementation of cfDNA NGS testing in clinical research and in the clinical practice can significantly improve precision medicine approaches in patients with advanced NSCLC.

EGFR mutation analysis in histologic and cytologic specimens of non-small cell lung cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7176-7176 ◽  
Author(s):  
H. Sakai ◽  
K. Akagi ◽  
J. Sudoh ◽  
S. Yoneda ◽  
H. Komagata ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Mutation Analysis ◽  
Cell Lung Cancer ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Small Cell ◽  
Egfr Mutations ◽  
Polymorphism Analysis ◽  
Small Cell Lung

7176 Background: Recent studies have suggested that EGFR mutations can be used to predict tumor sensitivity to gefitinib (epidermal growth factor receptor tyrosine kinase inhibitor) in patients with non-small-cell lung cancer (NSCLC). Most previous studies of EGFR mutations have used direct sequencing to analyze surgically resected specimens. More rapid, accurate, and simple techniques for analysis of EGFR mutations in histologic or cytologic specimens (i.e., transbronchial biopsy, bronchial washing, pleural effusion, lymph node aspiration) are needed to improve outcomes. Methods: DNA was extracted from histologic or cytologic specimens of NSCLC obtained from March through October 2005. The major mutations of the EGFR gene (exons 18–21) were analyzed by our original technique for fragment analysis and polymerase-chain-reaction-restriction-fragment-length polymorphism analysis. Results: About 2 days were required for mutation analysis. Pathological analysis indicated that 64 (5 histologic and 59 cytologic specimens) of 90 specimens (11 histologic and 79 cytologic specimens) were adenocarcinomas. EGFR mutations were found in 22 of these specimens (2 histologic and 20 cytologic specimens; ex19:del 13, ex19:ins 2, ex21:L858R 7). An EGFR mutation (ex19:del) was also found in a patient with large cell carcinoma. Conclusions: Our method can efficiently detect EGFR mutations in small samples of lung cancer cells obtained from histologic or cytologic specimens. This method is useful for the identification of EGFR mutations in patients with unresectable NSCLC in whom sufficient tissue specimens are difficult to obtain. No significant financial relationships to disclose.

Clinical and analytical performance of non-small cell lung cancer biomarkers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11070-11070
Author(s):  
Steven M. Anderson ◽  
Li Cai ◽  
James H. Tepperberg ◽  
Hawazin Faruki
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Mutation Analysis ◽  
Gene Rearrangement ◽  
Egfr Mutation ◽  
Small Cell ◽  
Small Cell Lung ◽  
Chi Square ◽  
Kras Mutations ◽  
Ffpe Samples

11070 Background: A variety of biomarkers are currently used to help guide treatment decisions for patients with non-small cell lung cancer (NSCLC). These include mutation analysis for the EGFR and KRAS genes, along with gene rearrangement analysis for the ALK and ROS1 loci. In this study we have evaluated the clinical and analytical performance features of these assays in a series of formalin-fixed paraffin-embedded (FFPE) tissue samples. Methods: FFPE samples submitted for analysis of the EGFR, KRAS, ALK and ROS1 genes were evaluated using molecular and FISH assays. EGFR mutation analysis was performed using Sanger nucleic acid sequencing methods for exons 18-21. KRAS mutations were detected using allele specific PCR or pyrosequencing methods. Rearrangements involving the ALK gene were detected using break-apart FISH probes (Abbott Molecular). Genetic alterations involving the ROS1 gene were determined using FISH probes (Kreatech Diagnostics). Over 6,200 test results for these 4 markers are included in this analysis. Results: Mutations in the EGFR gene were detected in 10.1% of samples evaluated (n=3,872). A slightly higher percentage of samples from female patients (13%) had a detectable mutation compared to samples from males (7%) (chi-square p<0.0001). Deletions in exon 19 (51%) were the most common alterations detected, followed by point mutations in exon 21 (35%). KRAS mutations were detected in approximately 22% of specimens. ALK gene rearrangements were observed in 3.1% of samples (n=1,524). Specimens from individuals <50y of age were more likely to provide a positive result (11%) compared to samples from individuals >50y of age (2.5%) (chi-square p<0.0001). Gene amplification for the ALK gene was a common finding in the NSCLC samples evaluated. ROS1 alterations were detected in 2.8% of the specimens. In this cohort, no specimens were positive for both an EGFR mutation and an ALK gene rearrangement. Conclusions: Biomarker testing is well established in clinical practice for NSCLC, with results from the tests used to guide important therapy decisions. Assays for biomarkers such as EGFR, KRAS, ALK and ROS1 are robust, allowing for the analysis of multiple analytes in FFPE samples, even when the amount of tissue may be limiting.

ΔCT value of amplified refractory mutation system (ARMS) to predict efficacy of EGFR-TKIs in non-small cell lung cancer: A multicenter retrospective study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20573-e20573
Author(s):  
Laiyu Liu ◽  
Min Chen ◽  
Gong Li ◽  
Dongyong Yang ◽  
Nanjie Xiao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Retrospective Study ◽  
Small Cell Lung Cancer ◽  
Egfr Mutation ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutation System ◽  
Egfr Mutant ◽  
Egfr Mutated ◽  
Egfr Tkis

e20573 Background: This multi-center retrospective study was to determine whether the ΔCt value of Amplified Refractory Mutation System (ARMS) in EGFR mutated detection in tumors predicts the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC). Methods: A total of 108 NSCLC patients harbored an exon 19 deletion (19Del) or exon 21 L858R mutation detected by ARMS were enrolled. We identified patients with ΔCt<1(Group L) harbored a high proportion of EGFR mutation but the patients with ΔCt≥1 (Group H) harbored a low proportion of EGFR mutation in the tumor sample. The progression-free survival (PFS), objective response rates (ORRs) and overall survival (OS) between the groups were analyzed. Results: In the 108 patients we enrolled, 63 were in group L and 45 were in group H. Patients’ demographics and clinical characteristics including age, sex, smoking history, pathology, mutation sites, TNM stage, line of TKIs therapy were not significantly difference between group L and group H. The Median PFS was 331 days (95%CI: 311.8 to 350.2) in group L and 206 days (95%CI, 157.2 to 254.8) in group H and the difference showed statistically significant (P < 0.001). Moreover, the ORRs in group L was significant higher than the group H (60.0% vs 34.9%, P = 0.011). The median OS was 744 days (95%CI, 635.5 to 852.5) in group L and 596 days in group H (95%CI, 491.7 to 700.0) but showed not statistically significant ( P = 0.098). Conclusions: ΔCt value of ARMS in EGFR mutated detection could be an efficacy predictor for EGFR-TKIs treatment in advanced EGFR-mutant NSCLC.

Anti-PD-1 antibody monotherapy or anti-PD-1 antibody combination with chemotherapy treated non-small cell lung cancer (NSCLC) patients with EGFR mutation: A retrospective analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21691-e21691
Author(s):  
Shaorong Yu ◽  
Ran Hu ◽  
Meiqi Shi
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Egfr Mutation ◽  
Objective Response ◽  
Small Cell ◽  
Combined Chemotherapy ◽  
Small Cell Lung ◽  
Egfr Mutant ◽  
Nsclc Patients

e21691 Background: Anti-PD-1/PD-L1 antibody has been approved as first- or second-line therapy in non-small cell lung cancer (NSCLC) patients and modified the management of patients with locally advanced or metastatic NSCLC. However, anti-PD-1 treatment shows less effective in patients with EGFR mutation than in those without driver gene mutation. To determine the activity of anti-PD-1 antibody in EGFR mutant NSCLC, we retrospectively evaluated response patterns among EGFR mutant NSCLC patients. Methods: We identified 58 patients with EGFR mutation who were treated with anti-PD-1 monotherapy or anti-PD-1 antibody combined with chemotherapy from March 2018 to December 2019. All of patients have received more than one treatment regimen including EGFR-TKI treatment. Objective response rates (ORR) were assessed using RECIST v1.1. Results: A total of 58 patients including 53 cases of lung adenocarcinoma, 4 cases of squamous cell carcinoma and 1 case of adenosquamous carcinoma were analyzed. Among them 26 patients received nivolumab treatment, 9 patients with pembrolizumab treatment, 9 patients with sintilimab treatment, 8 patients with JS001 treatment and 6 patients with camrelizumab treatment. Seven patients received anti-PD-1 monotherapy and the other 51 patients received anti-PD-1 combined chemotherapy. The main chemotherapeutic drugs contain docetaxel, pemetrexed, paclitaxel and paclitaxel-albumin. ORR was observed in 6 out of 58 (10%) patients. The disease control rate was 50% (29/58). The median PFS was 2.82 months. All six patients who achieved PR were received anti-PD-1 combined chemotherapy. Four patients died during treatment with anti-PD-1 therapy and we can’t confirm if these were due to cancer progress or immune related tumor hyperprogression. The adverse events were immune related pneumonia (two cases with grade 2 and one case with grade 3) and immune related hepatitis (one case with grade 2). Conclusions: Anti-PD-1 antibody combined chemotherapy seems showed moderate effect on NSCLC patients with EGFR mutation who have received anti-EGFR therapy.

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