scholarly journals Analysis of Genetic Alterations in Tunisian Patients with Lung Adenocarcinoma

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 514 ◽  
Author(s):  
Dhoha Dhieb ◽  
Imen Belguith ◽  
Laura Capelli ◽  
Elisa Chiadini ◽  
Matteo Canale ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Genetic Alterations ◽  
Small Sample ◽  
Response To Therapy ◽  
Molecular Profile ◽  
Alk Rearrangement ◽  
P53 Expression ◽  
Anaplastic Lymphoma ◽  
Tunisian Patients

The identification of the mutations that drive lung cancer have furnished new targets for the treatment of non-small cell lung cancer (NSCLC) and led to the development of targeted therapies such as tyrosine kinase inhibitors that are used to combat the molecular changes promoting cancer progression. Furthermore, biomarkers identified from gene analysis can be used to detect early lung cancer, determine patient prognosis, and monitor response to therapy. In the present study we analyzed the molecular profile of seventy-three Tunisian patients with lung adenocarcinoma (LAD). Mutational analyses for EGFR and KRAS were performed using direct sequencing, immunohistochemistry or MassARRAY. Anaplastic lymphoma kinase (ALK) rearrangement was evaluated by immunohistochemistry using the D5F3 clone, and p53 expression was also assessed. The median age of patients at diagnosis was 61 years (range 23–82 years). Using different methodologies, EGFR mutations were found in 5.47% of patients and only exon 19 deletions “E746-A750 del” were detected. KRAS mutations were present in 9.58% of cases, while only one patient was ALK-positive. Moreover, abnormal immunostaining of p53 was detected in 56.16% of patients. In conclusion, the detected rates of EGFR and KRAS mutation and ALK rearrangement were lower than those found in European and Asian countries, whereas, abnormal p53 expression was slightly more frequent. Furthermore, given the small sample size of this study, a more comprehensive analysis of this patient set is warranted.

scholarly journals The Investigation of EGFR mutation and ALK gene rearrangement rates in lung adenocarcinoma patients in Mardin

2019 ◽  
Vol 6 (11) ◽  
pp. 292-294
Author(s):  
Aydın Aytekin
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
State Hospital ◽  
Egfr Mutation ◽  
Genetic Alterations ◽  
Mutation Rates ◽  
Categorical Variables ◽  
Continuous Variables ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma

Objective: Non-Small Cell Lung Cancer (NSCLC) is a heterogeneous group of tumors comprising different histologic subtypes and genetic mutations. Important mutations are EGFR (Epidermal Growth Factor Receptor), ALK (Anaplastic Lymphoma Kinase) rearrangement and ROS 1 rearrangement. This study aimed to determine the mutation rates of lung adenocarcinoma patients admitted to Mardin State Hospital Oncology clinic and to review the literature on the term mutually exclusivity. Materials and Methods: The records of patients admitted to Mardin State Hospital Medical Oncology Clinic between 2014-2018 were retrospectively analyzed. The descriptive statistics for continuous variables mean/median; for categorical variables, frequency (n) and percentage (%) were shown. Results: There were 39 lung adenocarcinoma patients (30.2%) among 130 lung cancer patients. The median age of female patients was 49.31 (27-74), while the median age of male patients was 58.87 (43-78). There were 6 EGFR mutant (15.4%) patients and 2 (5.1%) patients with ALK rearrangement. There were no ROS-1 positive patients. Conclusion: This study indicates that EGFR mutation rates may be very low in Turkey compared to the literature and ALK rates may be close to the literature. To determine the actual mutation rates and factors affecting genetic alterations in Turkey, there are needed to further studies.

Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

2020 ◽  
Vol 16 (1) ◽  
pp. 5-10
Author(s):  
Adrien Costantini ◽  
Theodoros Katsikas ◽  
Clementine Bostantzoglou
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Standard Of Care ◽  
Genetic Alterations ◽  
Small Cell ◽  
Extensive Literature ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Mutational Status

Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

scholarly journals EML4-ALK positive lung adenocarcinoma with skeletal muscle metastasis in the right calf which was treatable with lorlatinib after resistance to treatment with alectinib

2021 ◽  
Vol 14 (4) ◽  
pp. e240295
Author(s):  
Hironari Matsuda ◽  
Munechika Hara ◽  
Shin-Ichiro Iwakami ◽  
Kazuhisa Takahashi
Keyword(s):  
Skeletal Muscle ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitor ◽  
Stable Condition ◽  
Japanese Woman ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Resistance To Treatment ◽  
Alk Positive ◽  
The Right

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

Two different patterns of lung adenocarcinoma with concomitant EGFR mutation and ALK rearrangement

2021 ◽  
pp. 030089162110055
Author(s):  
Dashi Zhao ◽  
Jun Fan ◽  
Li Peng ◽  
Bo Huang ◽  
Yili Zhu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Egfr Mutation ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Alk Rearrangement ◽  
Molecular Alterations ◽  
Anaplastic Lymphoma ◽  
Sporadic Cases ◽  
Epidermal Growth ◽  
Rare Group

Epidermal growth factor receptor ( EGFR) mutations and anaplastic lymphoma kinase ( ALK) rearrangements are considered mutually exclusive in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma (LUAC). However, sporadic cases harboring concomitant EGFR and ALK alterations have been increasingly reported. There is no consensus opinion regarding the treatment of patients positive for both molecular alterations. NSCLC with EGFR/ ALK coalterations should be separated into two subtypes: unifocal and multifocal LUAC. Here, we present an overview of the available literature regarding this rare group of patients to provide useful suggestions for therapeutic strategies.

scholarly journals Paired analysis of tumor mutation burden for lung adenocarcinoma and associated idiopathic pulmonary fibrosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yasuto Yoneshima ◽  
Eiji Iwama ◽  
Shingo Matsumoto ◽  
Taichi Matsubara ◽  
Testuzo Tagawa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Adenocarcinoma ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Somatic Variant ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
And Oxidative Stress

AbstractGenetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.

scholarly journals Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

2013 ◽  
Vol 31 (31) ◽  
pp. 3987-3996 ◽  
Author(s):  
Justin F. Gainor ◽  
Alice T. Shaw
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Genetic Alterations ◽  
Anaplastic Lymphoma ◽  
Development Of Resistance ◽  
Tki Resistance ◽  
Alk Positive ◽  
Egfr Mutant

The success of tyrosine kinase inhibitors (TKIs) in select patients with non–small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies.

scholarly journals Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma

2020 ◽  
Vol 21 (24) ◽  
pp. 9705
Author(s):  
Takahiro Tashiro ◽  
Kosuke Imamura ◽  
Yusuke Tomita ◽  
Daisuke Tamanoi ◽  
Akira Takaki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Neuroendocrine Carcinoma ◽  
Large Cell ◽  
Large Cell Neuroendocrine Carcinoma ◽  
Driver Mutations ◽  
Single Individual ◽  
Alk Rearrangement ◽  
Metastatic Tumors ◽  
Anaplastic Lymphoma ◽  
Metastatic Lesions

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions.

scholarly journals Anaplastic lymphoma tyrosine kinase oncogene in human cancer: gene aberrations, methods of detection and therapeutic potential

2017 ◽  
Vol 1 (3) ◽  
Author(s):  
Rosalaura Sabetta ◽  
Monica Gargiulo ◽  
Marina Accardo ◽  
Federica Zito Marino ◽  
Renato Franco
Keyword(s):  
Tyrosine Kinase ◽  
Therapeutic Potential ◽  
Human Cancer ◽  
Acquired Resistance ◽  
Specific Inhibitor ◽  
Genetic Alterations ◽  
Alk Rearrangement ◽  
Detection Mechanism ◽  
Targeting Therapy ◽  
Anaplastic Lymphoma

Anaplastic lymphoma tyrosine kinase (ALK) gene could be an attractive oncotarget in human cancers, since it is involved in several genetic alterations resulting in an aberrant activity of the receptor. To date, ALK-rearrangement represents a molecular target for the treatment of ALK-rearranged Non Small Cell Lung Cancer patients, who are highly sensitive to crizotinib, a specific inhibitor. ALK-rearranged patients treated with crizotinib show relevant clinical implications, however several different resistance mechanisms have been identified. Here we review various critical issues related to ALK-targeting therapy, including ALK gene aberrations, methods of detection, mechanism of acquired resistance and second-generation ALK inhibitors.

scholarly journals Later-Line Treatment with Lorlatinib in ALK- and ROS1-Rearrangement-Positive NSCLC: A Retrospective, Multicenter Analysis

2020 ◽  
Vol 13 (11) ◽  
pp. 371
Author(s):  
Maximilian J. Hochmair ◽  
Hannah Fabikan ◽  
Oliver Illini ◽  
Christoph Weinlinger ◽  
Ulrike Setinek ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Real World ◽  
Kinase Inhibitors ◽  
Resistance Mutations ◽  
Real World Data ◽  
Alk Rearrangement ◽  
World Data ◽  
Anaplastic Lymphoma ◽  
Wide Range ◽  
Alk Positive

In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement–positive non–small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced ALK- or ROS1-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the ALK- and ROS1-positive groups, respectively. In the ALK-positive group, lorlatinib proved efficacy after both brigatinib and alectinib. Lorlatinib treatment was well tolerated. Later-line lorlatinib treatment can induce sustained responses in patients with advanced ALK- and ROS1-positive lung cancer.

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