One year experience of MET gene exon 14 skipping analysis in lung cancer: Identification of 18 cases by NGS.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20055-e20055
Author(s):  
Hendrikus J Dubbink ◽  
Willemina Geurts-Giele ◽  
Isabelle Meijssen ◽  
Cor van der Leest ◽  
Robert Peric ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Molecular Diagnostic ◽  
Molecular Characteristics ◽  
Rt Pcr ◽  
Tissue Samples ◽  
Custom Made ◽  
Routine Identification

e20055 Background: Lung adenocarcinoma (LAC) is the most common histological type of non-small-cell lung cancer and is one of the malignancies with the most evolved personalized treatments based on molecular characteristics of the tumor. Mutations in EGFR, HER2 and BRAF, specific translocations of ALK, ROS1, RET and amplification of MET all have standard diagnostic importance and lead to specific treatment options for the individual LAC patients. Recently, in 2-4% of LAC MET gene mutations leading to skipping of exon 14 were found. These mutations were described to occur more frequently in tumors with sarcomatoid histology. LAC with MET exon 14 skipping mutations showed impressive, although temporary, responses to MET tyrosine kinase inhibitors (TKI) crizotinib, cabozantinib and capmatinib. We will present our experience with routine molecular diagnostic detection of the most common MET exon 14 skipping mutations. Methods: In January 2016 we included in our standard, DNA based, molecular diagnostics custom-made NGS analyses 4 amplicons for detection of MET skipping mutations. The analyses were performed on microdissected FFPE tissue sections or routine histology or cytology stained preparations. Nine different mutations were validated for their effect on splicing by RT-PCR on RNA isolated from the same tissue samples. Results: Between January 2016 and January 2017 676 routine molecular diagnostic analyses on LAC were performed. In 18 (2.7%) cases MET mutations were detected possibly resulting in exon 14 skipping. Nine out of 16 different mutations were tested by RT-PCR and all 9 were demonstrated to result in MET exon 14 skipping. Conclusions: MET exon 14 skipping mutations can reliably be detected in routine pathology tissue samples. These analyses can easily be included in routine molecular diagnostic NGS. When necessary, confirmation of the mutational effect on RNA splicing can be implemented as well. Routine identification of MET skipping mutations (2.7% of cases) adds substantially to the personalized targeted treatment strategies for LAC patients.

scholarly journals EGFR mutation testing in lung cancer: a review of available methods and their use for analysis of tumour tissue and cytology samples

2012 ◽  
Vol 66 (2) ◽  
pp. 79-89 ◽  
Author(s):  
Gillian Ellison ◽  
Guanshan Zhu ◽  
Alexandros Moulis ◽  
Simon Dearden ◽  
Georgina Speake ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Direct Sequencing ◽  
Mutation Testing ◽  
Tumour Tissue ◽  
Clinical Samples ◽  
Screening Methods ◽  
Testing Methods ◽  
Tissue Samples ◽  
Direct Dna Sequencing

AimsActivating mutations in the gene encoding epidermal growth factor receptor (EGFR) can confer sensitivity to EGFR tyrosine kinase inhibitors such as gefitinib in patients with advanced non-small-cell lung cancer. Testing for mutations in EGFR is therefore an important step in the treatment-decision pathway. We reviewed reported methods for EGFR mutation testing in patients with lung cancer, initially focusing on studies involving standard tumour tissue samples. We also evaluated data on the use of cytology samples in order to determine their suitability for EGFR mutation analysis.MethodsWe searched the MEDLINE database for studies reporting on EGFR mutation testing methods in patients with lung cancer.ResultsVarious methods have been investigated as potential alternatives to the historical standard for EGFR mutation testing, direct DNA sequencing. Many of these are targeted methods that specifically detect the most common EGFR mutations. The development of targeted mutation testing methods and commercially available test kits has enabled sensitive, rapid and robust analysis of clinical samples. The use of screening methods, subsequent to sample micro dissection, has also ensured that identification of more rare, uncommon mutations is now feasible. Cytology samples including fine needle aspirate and pleural effusion can be used successfully to determine EGFR mutation status provided that sensitive testing methods are employed.ConclusionsSeveral different testing methods offer a more sensitive alternative to direct sequencing for the detection of common EGFR mutations. Evidence published to date suggests cytology samples are viable alternatives for mutation testing when tumour tissue samples are not available.

Screening of NSCLC samples from Chinese lung cancer patients for activating rearrangements of the ALK, RET, and ROS1 genes.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22066-e22066
Author(s):  
Li-Mou Zheng ◽  
David B. Whyte ◽  
Li Ruan ◽  
Roman Song ◽  
Luo Fei ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Real Time ◽  
Real Time Pcr ◽  
Kinase Inhibitors ◽  
Ffpe Tissue ◽  
Cancer Tissue ◽  
Fusion Genes ◽  
Tissue Samples ◽  
Lung Cancers ◽  
Pcr Assays

e22066 Background: The ALK, RET, and ROS1 genes are involved in gene rearrangements in a fraction of non-small cell lung cancers. The resulting oncogenic fusion genes define molecular sub-types of NSCLC with distinct sensitivities to treatment with various kinase inhibitors. We developed real-time reverse transcriptase PCR assays to detect rearrangements of ALK, RET, and ROS1 in FFPE lung cancer tissue. Methods: mRNA from NSCLC FFPE tissue samples was reverse transcribed to cDNA. Multiplex quantitative PCR was performed to detect 9 variants of EML4-ALK fusions, 9 variants of RET fusions and 14 variants of ROS1 fusions. A total of 409 samples were analyzed: 267 were classified as adenocarcinoma, 104 as squamous cell carcinoma and 38 had undetermined histology. EGFR and KRAS mutation status is unknown. The junctions of fusion-positive samples were sequenced by Sanger sequencing. Results: Among the 409 NSCLC specimens tested the frequency was 5.4% (22/409) for EML4-ALK fusions, 1.5% (6/409) for RET fusions, and 2.2% (9/409) for ROS1 fusions. EML4-ALK fusions were more prevalent in patients that were less than 60 years old (9.1% versus 2.0%, p= 0.004). The TNM stage was not correlated with the presence of any of the fusions. The table below lists the frequencies for specific rearrangements as determined by sequencing the real-time PCR products. Conclusions: Real-time PCR assays based on cDNA from FFPE tissue can identify patients with ALK, RET and ROS1 fusion genes. The ALK, RET and ROS1 assays will allow selection of patients most likely to respond to therapies that specifically target these cancer drivers. Further clinical testing of NSCLC patients in the Chinese population will be performed to support SFDA registration of these assays in China. [Table: see text]

scholarly journals Managing sarcoma: where have we come from and where are we going?

2017 ◽  
Vol 9 (10) ◽  
pp. 637-659 ◽  
Author(s):  
Jenna S. Bleloch ◽  
Reyna D. Ballim ◽  
Serah Kimani ◽  
Jeannette Parkes ◽  
Eugenio Panieri ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Single Agent ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Primary Treatment ◽  
Response To Treatment ◽  
Molecular Characteristics ◽  
Mortality And Morbidity ◽  
Children And Young Adults ◽  
Robust Response

Sarcomas are a heterogeneous group of neoplasms of mesenchymal origin. Approximately 80% arise from soft tissue and 20% originate from bone. To date more than 100 sarcoma subtypes have been identified and they vary in molecular characteristics, pathology, clinical presentation and response to treatment. While sarcomas represent <1% of adult cancers, they account for approximately 21% of paediatric malignancies and thus pose some of the greatest risks of mortality and morbidity in children and young adults. Metastases occur in one-third of all patients and approximately 10–20% of sarcomas recur locally. Surgery in combination with preoperative and postoperative therapies is the primary treatment for localized sarcoma tumours and is the most promising curative possibility. Metastasized sarcomas, on the other hand, are treated primarily with single-agent or combination chemotherapy, but this rarely leads to a complete and robust response and often becomes a palliative form of treatment. The heterogeneity of sarcomas results in variable responses to current generalized treatment strategies. In light of this and the lack of curative strategies for metastatic and unresectable sarcomas, there is a need for novel subtype-specific treatment strategies. With the more recent understanding of the molecular mechanisms underlying the pathogenesis of some of these tumours, the treatment of sarcoma subtypes with targeted therapies is a rapidly evolving field. This review discusses the current management of sarcomas as well as promising new therapies that are currently underway in clinical trials.

scholarly journals Endometrial Serous Carcinoma: Its Molecular Characteristics and Histology-Specific Treatment Strategies

Cancers ◽  
2012 ◽  
Vol 4 (3) ◽  
pp. 799-807 ◽  
Author(s):  
Kentaro Nakayama ◽  
Naomi Nakayama ◽  
Masako Ishikawa ◽  
Kohji Miyazaki
Keyword(s):  
Treatment Strategies ◽  
Specific Treatment ◽  
Serous Carcinoma ◽  
Molecular Characteristics

scholarly journals SYST-02. DUAL INHIBITION OF BCL-2 AND EGFR IN A PRECLINICAL MODEL OF LUNG CANCER BRAIN METASTASIS

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv8-iv8
Author(s):  
Kathryn Blethen ◽  
Samuel Sprowls ◽  
Tasneem Arsiwala ◽  
Ross Fladeland ◽  
Dhruvi Panchal ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Cell Line ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Preclinical Model ◽  
Nsclc Cell Line ◽  
The Brain

Abstract Lung cancer is the most prevalent malignancy to affect both men and women. Around 80% of all lung cancers are classified as non-small cell lung cancer (NSCLC). This subtype of lung cancer is also the most likely to metastasize to the brain. Clinically, the common treatment for NSCLC is epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), due to the high occurrence of EGFR mutations. However, the cancer cells quickly develop resistance to the EGFR TKIs. This resistance and the added difficulty of delivering drugs across the blood-tumor barrier in efficacious concentrations to treat brain lesions are important to consider when developing treatment strategies for lung cancer brain metastases. Our study utilizes a NSCLC cell line, PC-9-Br6, which was developed in our laboratory to preferentially metastasize to the brain. This cell line was demonstrated by our collaborator to express higher levels of Bcl-2 in comparison to the parental PC-9-P cell line. We hypothesized combining novel Bcl-2 inhibitors (ABT-199/ABT-263) with an EGFR inhibitor (gefitinib) would increase survival and decrease tumor burden in our clinically relevant mouse model of lung cancer brain metastases.

scholarly journals Identifying Novel Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Anaplastic Large Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5060-5060
Author(s):  
Elif Atabay ◽  
Qi Wang ◽  
Ambrogio Chiara ◽  
Taek-Chin Cheong ◽  
Silvia Peola ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Candidate Genes ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Specific Treatment ◽  
Large Cell ◽  
Anaplastic Lymphoma

INTRODUCTION: Anaplastic large cell lymphomas (ALCL) frequently carry oncogenic fusion proteins as a consequence of chromosomal translocations of the anaplastic lymphoma kinase (ALK) gene. The fusion protein resulting from the translocation between dimerization domain of nucleophosmin (NPM) and intracellular tyrosine kinase domain of ALK activates several signaling pathways, promoting cell growth, transformation, migration, and survival of the cells. Chemotherapy has been used as a standard treatment approach for ALCL patients, yet about 30% of patients relapse. A more specific treatment method is based on targeting ALK tyrosine kinase using tyrosine kinase inhibitors (TKIs). Crizotinib is an ALK TKI that is approved for the treatment of ALK-rearranged lung cancer and has received Breakthrough Therapy designation for lymphoma because of its high activity in chemo refractory ALCL. However, as for lung cancer, also ALCL patient develop crizotinib resistance due to ALK mutations or unknown mechanisms. In this study, we aimed at elucidating unknown by-pass mechanisms of crizotinib resistance in ALCL. METHODS: We used Genome-wide CRISPR-Cas9 Knockout Screening (GeCKO) to identify candidate genes that contribute to resistance to crizotinib. Four different ALCL cell lines were infected with Lenti-GeCKO libraries. After treatment with crizotinib for 14 days, DNA isolation and next generation sequencing was performed on crizotinib resistant cells to identify candidate genes depleted by the GeCKO screening. Top candidates were selected for validation assays and further analyses. RESULTS: We identified two phosphatases, PTPN1 and PTPN2, in different ALCL cell lines as consistent top hits. Functional validation of these candidate genes showed that single loss of either PTPN1 or PTPN2 generate immediate resistance to crizotinib in ALCL cell lines. Analysis of downstream pathways showed that while loss of PTPN1 activates primarily the MAPK pathway, loss of PTPN2 promotes persistent STAT3 and MAPK activation in ALK inhibited cells. Remarkably, in PTPN1 knockout cells we observed hyperactivation of SHP2, an oncogenic phosphatase that positively regulates the RAS-MAPK pathway. On the other hand, over-expression of PTPN1 and PTPN2 partially inhibited SHP2 phosphorylation. A treatment that combined crizotinib and the recently developed SHP2 inhibitor completely blocked the sustained ERK phosphorylation and reverted the crizotinib resistance observed in PTPN1 and PTPN2 deficient lymphoma cells. CONCLUSIONS: GeCKO library screen identified PTPN1 and PTPN2 as specific genes that mediate crizotinib resistance in ALCL cell lines. Loss of PTPN1 and PTPN2 drives resistance by activating MAPK and/or JAK-STAT pathway. Combined inhibition of SHP2 is a potent therapeutic approach to overcome resistance to crizotinib in ALCL cells. Disclosures Gambacorti-Passerini: Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.

scholarly journals Co-Occurring Potentially Actionable Oncogenic Drivers in Non-Small Cell Lung Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yiming Zhao ◽  
Shuyuan Wang ◽  
Zhengyu Yang ◽  
Yu Dong ◽  
Yanan Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
First Generation ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Treatment Strategies ◽  
Small Cell ◽  
Small Cell Lung ◽  
Nsclc Patients

BackgroundSeveral oncogenic drivers in non-small cell lung cancer (NSCLC) are considered actionable with available or promising targeted therapies. Although targetable drivers rarely overlap with each other, there were a minority of patients harboring co-occurring actionable oncogenic targets, whose clinical characteristics and prognosis are not yet clear.MethodsA total of 3,077 patients with NSCLC who underwent molecular analysis by NGS were included, and their demographic and clinical data were retrospectively collected.ResultsOur study found that the frequency of NSCLC patients harboring co-occurring potentially actionable alterations was approximately 1.5% (46/3077); after excluding patients with EGFR-undetermined mutations, the incidence was 1.3% (40/3077); 80% (37/46) harbored both EGFR mutations and other potentially actionable drivers such as MET amplification (21.6%; 8/37) and alterations in ERBB2 including mutations (27%; 10/37) and amplification (21.6%; 8/37); other combinations of potentially actionable drivers including alterations in ERBB2, KRAS, MET, ALK, and RET were also identified. Additionally, de novo MET/ERBB2 amplification in patients harboring EGFR-mutant NSCLC treated with first-generation EGFR tyrosine kinase inhibitors (TKIs) was associated with shorter PFS (p &lt; 0.05). The efficacy of TKIs in NSCLC patients harboring other co-occurring potentially actionable drivers varied across different molecular subtypes.ConclusionsApproximately 1.5% of NSCLCs harbored co-occurring potentially actionable oncogenic drivers, commonly involving EGFR mutations. Co-occurring actionable targets may impact the efficacy of TKIs; therefore, future clinical trials in these patients should be anticipated to tailor the combination or sequential treatment strategies.

Patterns of Care and Survival in Non Small Cell Lung Cancer: 15 Years’ Experience in a General Hospital

1994 ◽  
Vol 80 (2) ◽  
pp. 106-112 ◽  
Author(s):  
Maurizia Clerici ◽  
Daniela Panvini ◽  
Valter Torri ◽  
Fulvia Colombo ◽  
Gino Luporini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Research ◽  
Small Cell Lung Cancer ◽  
General Hospital ◽  
Cell Lung Cancer ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Small Cell ◽  
Small Cell Lung ◽  
Over Time

Background Transferring results derived from clinical research into practice is particularly difficult in lung cancer where clear indications for treatment are defined only for selected subgroups of patients. Studies on hospital-based lung cancer population could provide data for quantifying this issue. Patients and methods This was a follow-up study of consecutive, first-diagnosis cases referred to the in-and outpatient cancer clinics of a large italian general hospital between January 1975 and December 1990. Data were collected from medical records and recorded on ad hoc standardized forms. Analysis focused on changes in distribution over time of patient-related characteristics, prevalence of specific treatment strategies and survival of the study population. Results 1345 primary non small cell lung cancer cases were reviewed and 1125 were fully evaluable. In early stages (510/1125, 45%) only 237 patients actually underwent surgery. In this group surgery increased from 36 to 69% whereas chemotherapy decreased from 58 to 15%. In the advanced group (615/1125, 55%) chemotherapy was the preferred treatment but combined modalities tripled over time (from 4 to 12%). No significant changes in survival were observed within each group over time. Conclusion Despite changes in the therapeutic approaches, mortality from lung cancer does not seem reduced over time. Since the proportion of cases that could potentially benefit from “active” treatments is small, for the large majority of patients a switch in clinical research from a cure to a careoriented strategy should be considered.

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