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Driver mutation lung cancer

Deepali Jain, Sinchita Roy-Chowdhuri
CONTEXT: - There has been a paradigm shift in the understanding of molecular pathogenesis of lung cancer. A number of oncogenic drivers have been identified in non-small cell lung carcinoma, such as the epidermal growth factor receptor ( EGFR) mutation and anaplastic lymphoma kinase ( ALK) gene rearrangement. Because of the clinical presentation at an advanced stage of disease in non-small cell lung carcinoma patients, the use of minimally invasive techniques is preferred to obtain a tumor sample for diagnosis...
March 16, 2018: Archives of Pathology & Laboratory Medicine
Hidejiro Torigoe, Hiromasa Yamamoto, Masakiyo Sakaguchi, Chen Youyi, Kei Namba, Hiroki Sato, Kazuhiko Shien, Junichi Soh, Ken Suzawa, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka
Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations, and have been targeted for treatment in non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues...
March 13, 2018: Carcinogenesis
Xiao Sun, Tanxiao Huang, Fangsheng Cheng, Kaibing Huang, Ming Liu, Wan He, Mingwei Li, Xiaoni Zhang, Mingyan Xu, Shifu Chen, Ligang Xia
Postoperative monitoring for patients with colorectal cancer (CRC) requires sensitive biomarkers that are associated with medical response and adjuvant therapy following surgery. Conventional tumor biomarkers [including carcinoembryonic antigen (CEA), CA19-9 and CA125] are widely used, but none of the markers provide high sensitivity or specificity. Previous studies indicated that circulating tumor DNA (ctDNA) is useful for postoperative monitoring of patients with cancer. However, the majority of previous studies involved patients with lung cancer, and therefore further studies are required which investigate patients with CRC...
April 2018: Oncology Letters
Takuro Kometani, Kenji Sugio, Atsushi Osoegawa, Takashi Seto, Yukito Ichinose
BACKGROUND: The EML4-ALK fusion gene has recently been identified as a driver mutation in a subset of non-small cell lung cancers. In subsequent studies, EML4-ALK has been detected in a low percentage of patients, and was associated with a lack of EGFR or KRAS mutations, younger age, and adenocarcinoma with acinar histology. Cases with the EML4-ALK fusion gene were examined to clarify the clinicopathological characteristics of young adenocarcinoma patients. METHODS: Between December 1998 and May 2009, 85 patients aged ≤ 50 with lung adenocarcinoma were treated at our hospital...
March 8, 2018: Thoracic Cancer
Andrea Anichini, Elena Tassi, Giulia Grazia, Roberta Mortarini
Immunotherapy of non-small cell lung cancer (NSCLC), by immune checkpoint inhibitors, has profoundly improved the clinical management of advanced disease. However, only a fraction of patients respond and no effective predictive factors have been defined. Here, we discuss the prospects for identification of such predictors of response to immunotherapy, by fostering an in-depth analysis of the immune landscape of NSCLC. The emerging picture, from several recent studies, is that the immune contexture of NSCLC lesions is a complex and heterogeneous feature, as documented by analysis for frequency, phenotype and spatial distribution of innate and adaptive immune cells, and by characterization of functional status of inhibitory receptor+ T cells...
March 7, 2018: Cancer Immunology, Immunotherapy: CII
Shoko Nakasone, Sachiyo Mimaki, Tomohiro Ichikawa, Keiju Aokage, Tomohiro Miyoshi, Masato Sugano, Motohiro Kojima, Satoshi Fujii, Takeshi Kuwata, Atsushi Ochiai, Masahiro Tsuboi, Koichi Goto, Katsuya Tsuchihara, Genichiro Ishii
PURPOSE: Podoplanin-positive cancer-associated fibroblasts (CAFs) play an essential role in tumor progression. However, it is still unclear whether specific genomic alterations of cancer cells are required to recruit podoplanin-positive CAFs. The aim of this study was to investigate the relationship between the mutation status of lung adenocarcinoma cells and the presence of podoplanin-positive CAFs. METHODS: Ninety-seven lung adenocarcinomas for which whole exome sequencing data were available were enrolled...
March 6, 2018: Journal of Cancer Research and Clinical Oncology
Omer M Toor, Zaheer Ahmed, Waled Bahaj, Urooge Boda, Lee S Cummings, Megan E McNally, Kevin F Kennedy, Timothy J Pluard, Arif Hussain, Janakiraman Subramanian, Ashiq Masood
Next Generation Sequencing (NGS) of cancer tissues is increasingly being carried out to identify somatic genomic alterations that may guide physicians to make therapeutic decisions. However, a single tissue biopsy may not reflect complete genomic architecture due to the heterogeneous nature of tumors. Circulating tumor DNA (ctDNA) analysis is a robust noninvasive method to detect and monitor genomic alterations in blood in real time. We analyzed 28 matched tissue NGS and ctDNA from gastrointestinal and lung cancers for concordance of somatic genomic alterations, driver and actionable alterations...
March 2, 2018: Molecular Cancer Therapeutics
Yuzhuo Wang, Cheng Wang, Jiahui Zhang, Meng Zhu, Xu Zhang, Zhihua Li, Juncheng Dai, Hongxia Ma, Zhibin Hu, Guangfu Jin, Hongbing Shen
Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the germline-somatic interaction in lung cancer remains largely unknown. We investigated whether lung cancer driver genes (CDGs) were more likely to locate within cancer susceptibility regions. Pathway analysis was performed to identify common pathways underlying CDGs and cancer susceptibility genes (CSGs). Next, we analyzed the associations between lung cancer risk SNPs and somatic alterations, including mutations and copy number alterations, in the level of genes, pathways, and overall burden of alterations...
March 1, 2018: International Journal of Cancer. Journal International du Cancer
Kristen A Marrone, Xian Zhou, Patrick M Forde, Michael Purtell, Julie R Brahmer, Christine L Hann, Ronan J Kelly, Barbara Coleman, Edward Gabrielson, Gary L Rosner, David S Ettinger
BACKGROUND: In the absence of a targeted oncogenic driver mutation or high programmed death-ligand 1 expression, systemic therapy with platinum-based doublet chemotherapy with or without bevacizumab has been the standard treatment in advanced or metastatic non-small cell lung cancer (NSCLC). Metformin has been shown to have antitumor effects via a variety of insulin-dependent and insulin-independent mechanisms and to be potentially synergistic with chemotherapy. MATERIALS AND METHODS: This open-label single-center phase II study (NCT01578551) enrolled patients with chemotherapy-naïve advanced or metastatic nonsquamous NSCLC and randomized them (3:1) to receive carboplatin, paclitaxel, and bevacizumab with (Arm A) or without (Arm B) concurrent metformin for four to six cycles followed by maintenance therapy with bevacizumab ± metformin continued until disease progression, intolerable toxicity, or study withdrawal...
February 27, 2018: Oncologist
Bo Lan, Chengxi Ma, Chengyan Zhang, Shoujie Chai, Pingli Wang, Liren Ding, Kai Wang
Objective: To assess the association between PD-L1 expression and driver gene mutations in patients with non-small-cell lung cancer (NSCLC). Method: We performed a meta-analysis of 26 studies (7541 patients) which were published from 2015 to 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated to describe the correlation. Subgroup analysis was performed based on population characteristics, types of PD-L1 antibodies and quality of individual studies...
January 26, 2018: Oncotarget
Chiara Tomasello, Cinzia Baldessari, Martina Napolitano, Giulia Orsi, Giulia Grizzi, Federica Bertolini, Fausto Barbieri, Stefano Cascinu
In the last few years, the development of targeted therapies for non-small cell lung cancer (NSCLC) expressing oncogenic driver mutations (e.g. EGFR) has changed the clinical management and the survival outcomes of this specific minority of patients. Several phase III trials demonstrated the superiority of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) over chemotherapy in EGFR-mutant NSCLC patients. However, in the vast majority of cases EGFR TKIs lose their clinical activity within 8-12 months...
March 2018: Critical Reviews in Oncology/hematology
Wenfeng Gou, Xuejiao Zhou, Zi Liu, Lijing Wang, Jiwei Shen, Xiaobo Xu, Zengqiang Li, Xin Zhai, Daiying Zuo, Yingliang Wu
The c-ros oncogene 1 (ROS1) is a receptor tyrosine kinase, which has been identified as an oncogene driver of non-small-cell lung cancer (NSCLC). Although crizotinib has a prominent effect on ROS1, resistance is inevitable. Development of the acquired ROS1 G2032R mutation has been reported as a resistant mechanism to ROS1 inhibitors in ROS1-rearranged (ROS1+ ) NSCLC patients. To explore the mechanism of drug resistance, we constructed the crizotinib resistance cell line, A549-CD74-ROS1 G2032R mutation cells, by the methods of fusion polymerase chain reaction (PCR), plasmid construction and cell transfection in vitro...
February 22, 2018: Cancer Letters
Antonin Levy, Corinne Faivre-Finn, Baktiar Hasan, Eleonora De Maio, Anna S Berghoff, Nicolas Girard, Laurent Greillier, Sylvie Lantuéjoul, Mary O'Brien, Martin Reck, Anne-Marie C Dingemans, Silvia Novello, Thierry Berghmans, Benjamin Besse, Lizza Hendriks
BACKGROUND: Brain metastases (BM) are frequent in non-small cell lung cancer (NSCLC) patients, but there is a lack of evidence-based management of this patient group. We aimed to capture a snapshot of routine BM management in Europe to identify relevant research questions for future clinical trials. METHODS: An EORTC Lung Cancer Group (LCG) online survey containing questions on NSCLC BM screening and treatment was distributed between 16/02/17 and 15/06/17 to worldwide EORTC LCG members, and through several European scientific societies in the thoracic oncology field...
February 20, 2018: European Journal of Cancer
V Noronha, M V Chandrakanth, A P Joshi, V Patil, A Chougule, A Mahajan, A K Janu, R Chanana, K Prabhash
ROS1 rearrangement acts as a driver mutation in 1-2% of NSCLC. Crizotinib is approved in this situation both in treatment naïve and pre-treated patients. Here we report our experience with crizotinib in patients with advanced NSCLC harbouring ROS1 rearrangement. Eleven patients were included in our study. More than half of our patients had associated comorbidities and one fourth of them had a compromised performance status. Out of 11 patients, 5 of them were exposed to crizotinib .The response rates among crizotinib treated patients was 80%...
April 2017: Indian Journal of Cancer
Yang Yang, Yi Meng, Hang Zhang, Xiaoyan Shen, Rutian Li, Lixia Yu, Baorui Liu, Lifeng Wang
Epithelial growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) expressing sensitive EGFR-mutants. Other drugs target different driver mutants, including the serine/threonine-protein kinase B-raf (BRAF) inhibitor dabrafenib, which has exhibited promising efficacy for treating patients with metastatic BRAF-mutated NSCLC. Therefore, identifying patients carrying mutations that may be treated using targeted therapies is important...
March 2018: Oncology Letters
Ashley C Ly, Jacqueline L Olin, Morgan B Smith
PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosage and administration, and place in therapy of alectinib for treatment of patients with non-small-cell lung cancer (NSCLC) are reviewed. SUMMARY: In patients with NSCLC driven by mutations of ALK , the gene coding for anaplastic lymphoma kinase (ALK), treatment with the ALK inhibitor crizotinib has been found to provide median progression-free survival (PFS) of 10.9 months; however, therapeutic failures and tumor progression to brain metastases are common with crizotinib use, prompting research to find more potent and tolerable ALK inhibitors that target major oncogenic drivers of NSCLC...
February 21, 2018: American Journal of Health-system Pharmacy: AJHP
Jing Zhao, Xiaotong Chen, J Zheng, M Kong, B Wang, W Ding
BACKGROUND: ROS1 immunohistochemistry (IHC) using D4D6 antibody is a useful tool for screening patients with non-small cell lung cancer (NSCLC) slated for targeted therapy. Many studies and our data have identified cases that express the ROS1 protein strongly but are negative for ROS1 by fluorescent in situ hybridization (FISH). The present study investigated the driver mutation and clinicopathologic characteristics of 26 discordant cases (ROS1 IHC-positive but FISH-negative) to find new clues for distinguishing real ROS1-rearranged cases...
February 21, 2018: Histopathology
Marta Román, Iosune Baraibar, Inés López, Ernest Nadal, Christian Rolfo, Silvestre Vicent, Ignacio Gil-Bazo
Lung neoplasms are the leading cause of death by cancer worldwide. Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung malignancies and the majority of patients present advanced disease at onset. However, in the last decade, multiple oncogenic driver alterations have been discovered and each of them represents a potential therapeutic target. Although KRAS mutations are the most frequently oncogene aberrations in lung adenocarcinoma patients, effective therapies targeting KRAS have yet to be developed...
February 19, 2018: Molecular Cancer
Shang-Gin Wu, Jin-Yuan Shih
Recent advances in diagnosis and treatment are enabling a more targeted approach to treating lung cancers. Therapy targeting the specific oncogenic driver mutation could inhibit tumor progression and provide a favorable prognosis in clinical practice. Activating mutations of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are a favorable predictive factor for EGFR tyrosine kinase inhibitors (TKIs) treatment. For lung cancer patients with EGFR-exon 19 deletions or an exon 21 Leu858Arg mutation, the standard first-line treatment is first-generation (gefitinib, erlotinib), or second-generation (afatinib) TKIs...
February 19, 2018: Molecular Cancer
Tatjana Vlajnic, Spasenija Savic, Audrey Barascud, Betty Baschiera, Michel Bihl, Bruno Grilli, Michelle Herzog, Julien Rebetez, Lukas Bubendorf
BACKGROUND: Rearrangements of the ROS1 oncogene are found in 1% to 2% of non-small cell lung cancers (NSCLC) and are regarded as mutually exclusive oncogenic driver mutations. Since the approval of targeted therapy for ROS1-positive NSCLC, ROS1 testing has become a part of the diagnostic routine. Fluorescence in situ hybridization (FISH), optionally selected for by immunohistochemistry on histological material, is a common practice for the detection of ROS1 rearrangements. However, NSCLC often is diagnosed by cytology alone, requiring predictive marker testing on cytological specimens...
February 16, 2018: Cancer Cytopathology
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