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Driver mutation lung cancer

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https://www.readbyqxmd.com/read/28919011/dabrafenib-plus-trametinib-in-patients-with-previously-untreated-braf-v600e-mutant-metastatic-non-small-cell-lung-cancer-an-open-label-phase-2-trial
#1
David Planchard, Egbert F Smit, Harry J M Groen, Julien Mazieres, Benjamin Besse, Åslaug Helland, Vanessa Giannone, Anthony M D'Amelio, Pingkuan Zhang, Bijoyesh Mookerjee, Bruce E Johnson
BACKGROUND: BRAF(V600E) mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver. Dabrafenib, alone or combined with trametinib, has shown substantial antitumour activity in patients with previously treated BRAF(V600E)-mutant metastatic non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of dabrafenib plus trametinib treatment in previously untreated patients with BRAF(V600E)-mutant metastatic NSCLC. METHODS: In this phase 2, sequentially enrolled, multicohort, multicentre, non-randomised, open-label study, adults (≥18 years of age) with previously untreated metastatic BRAF(V600E)-mutant NSCLC were enrolled into cohort C from 19 centres in eight countries within North America, Europe, and Asia...
September 8, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28915716/implementation-and-utilization-of-the-molecular-tumor-board-to-guide-precision-medicine
#2
REVIEW
Shuko Harada, Rebecca Arend, Qian Dai, Jessica A Levesque, Thomas S Winokur, Rongjun Guo, Martin J Heslin, Lisle Nabell, L Burt Nabors, Nita A Limdi, Kevin A Roth, Edward E Partridge, Gene P Siegal, Eddy S Yang
BACKGROUND: With rapid advances in genomic medicine, the complexity of delivering precision medicine to oncology patients across a university health system demanded the creation of a Molecular Tumor Board (MTB) for patient selection and assessment of treatment options. The objective of this report is to analyze our progress to date and discuss the importance of the MTB in the implementation of personalized medicine. MATERIALS AND METHODS: Patients were reviewed in the MTB for appropriateness for comprehensive next generation sequencing (NGS) cancer gene set testing based on set criteria that were in place...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28911955/brief-report-somatic-mutations-and-ancestry-markers-in-hispanic-lung-cancer-patients
#3
Nicholas T Gimbrone, Bhaswati Sarcar, Edna R Gordian, Jason I Rivera, Christian Lopez, Sean J Yoder, Jamie K Teer, Eric A Welsh, Alberto A Chiaporri, Matthew B Schabath, Gary W Reuther, Julie Dutil, Miosotis Garcia, Ronald Ventosilla-Villanueva, Luis Vera-Valdivia, Alejandro Yabar-Berrocal, Rodrigo Motta-Guerrero, Pedro G Santiago-Cardona, Teresita Muñoz-Antonia, W Douglas Cress
INTRODUCTION: To address the lack of genomic data from Hispanic/Latino (H/L) patients with lung cancer, the Latino Lung Cancer Registry was established to collect patient data and biospecimens from these patients. METHODS: This retrospective observational study examined lung cancer tumor samples from 163 H/L patients, and tumor-derived DNA was subjected to targeted-exome sequencing (>1000 genes, including EGFR, KRAS, STK11, and TP53) and ancestry analysis. Mutation frequencies in this H/L cohort were compared with those in a similar cohort of non-Hispanic white (NHW) patients and were correlated with ancestry, sex, smoking status, and tumor histology...
September 11, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28901268/nrg1-erbb-lost-in-translation-a-new-paradigm-for-lung-cancer
#4
Domenico Trombetta, Antonio Rossi, Federico Pio Fabrizio, A Sparaneo, Paolo Graziano, Vito Michele Fazio, Lucia Anna Muscarella
The ErbB network of receptor tyrosine kinases represents one of the best examples of how the understanding of molecular basis of tumor pathogenesis can give a significant improvement for patients treatment, suggesting new therapeutic options to overcome acquired treatment resistance. This amazing bridge between growth factor receptors and cancer has been consolidated during the last decades through the identification of many driver mutations in the gene key of the RTKs network. Unexpected molecular lesions of the NRG1 gene followed by an aberrant ErbB signaling were recently described as a new molecular features of non-small cell lung cancer, but it has been also sporadically reported in other tumors...
September 11, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28900044/regulation-of-autophagy-nf-%C3%AE%C2%BAb-signaling-and-cell-viability-by-mir-124-in-kras-mutant-mesenchymal-like-nsclc-cells
#5
Anita K Mehta, Kevin Hua, William Whipple, Minh-Thuy Nguyen, Ching-Ti Liu, Johannes Haybaeck, Joanne Weidhaas, Jeff Settleman, Anurag Singh
KRAS mutant non-small cell lung cancer (NSCLC) may be classified into epithelial or mesenchymal subtypes. Despite having the same "driver" mutation, mesenchymal NSCLCs are less responsive than are epithelial NSCLCs to inhibition of the RAS pathway. Identifying alternative networks that promote survival specifically in mesenchymal NSCLC may lead to more effective treatments for this subtype. Through their numerous targets in cellular signaling pathways, noncoding microRNAs (miRNAs) often function as tumor suppressors or oncogenes...
September 12, 2017: Science Signaling
https://www.readbyqxmd.com/read/28898697/chronic-cigarette-smoke-induced-epigenomic-changes-precede-sensitization-of-bronchial-epithelial-cells-to-single-step-transformation-by-kras-mutations
#6
Michelle Vaz, Stephen Y Hwang, Ioannis Kagiampakis, Jillian Phallen, Ashwini Patil, Heather M O'Hagan, Lauren Murphy, Cynthia A Zahnow, Edward Gabrielson, Victor E Velculescu, Hariharan P Easwaran, Stephen B Baylin
We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer...
September 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28881856/strategies-targeting-angiogenesis-in-advanced-non-small-cell-lung-cancer
#7
REVIEW
Jun Wang, Jianpeng Chen, Yan Guo, Baocheng Wang, Huili Chu
Tumor angiogenesis is a frequent event in the development and progression of non-small cell lung cancer (NSCLC) and has been identified as a promising therapeutic target. The vascular endothelial growth factor (VEGF) family and other angiogenic factors, including fibroblast growth factor and platelet-derived growth factor, promote the growth of newly formed vessels from preexisting vessels and change the tumor microenvironment. To date, two antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab, which target VEGF-A and its receptor VEGF receptor-2, respectively, have been approved for the treatment of locally advanced or metastatic NSCLC when added to first-line standard chemotherapy...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881820/brain-metastases-in-patients-with-non-small-cell-lung-cancer-the-role-of-mutated-egfrs-with-an-exon-19-deletion-or-l858r-point-mutation-in-cancer-cell-dissemination
#8
Shih-Hsin Hsiao, Yu-Ting Chou, Sey-En Lin, Ru-Chun Hsu, Chi-Li Chung, Yu-Rung Kao, H Eugene Liu, Cheng-Wen Wu
Non-small cell lung cancer (NSCLC) patients tend to develop brain metastases (BM), but the link between BM occurrence and driver mutations in NSCLC is not very clear. We explored whether activating mutations of epidermal growth factor receptors (EGFRs) in exon 19 deletion or L858R predict BM in NSCLC. A retrospective multivariable logistic regression analysis of 384 patients demonstrated that the presence of mutated-EGFRs was associated with overall BM (OR=2.24, P=0.001) compared to that of wild-type EGFR (WT-EGFR)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28874890/patterns-of-spread-and-prognostic-implications-of-lung-cancer-metastasis-in-an-era-of-driver-mutations
#9
F Hsu, A De Caluwe, D Anderson, A Nichol, T Toriumi, C Ho
BACKGROUND: In the present study, we examined the pattern of metastatic spread in patients with advanced non-small-cell lung cancer (nsclc) and the effect of EGFR mutations. METHODS: Patients were identified from a provincial cancer registry, and individual medical records were reviewed. Patients were included if they had stage iv nsclc and underwent diagnostic EGFR mutation testing. Patients were divided into EGFR mutation-positive (EGFR+) and EGFR wild type (wt) cohorts...
August 2017: Current Oncology
https://www.readbyqxmd.com/read/28866070/next-generation-sequencing-a-novel-approach-to-distinguish-multifocal-primary-lung-adenocarcinomas-from-intrapulmonary-metastases
#10
Snehal B Patel, Wendy Kadi, Ann E Walts, Alberto M Marchevsky, Andy Pao, Angela Aguiluz, Tudor Mudalige, Zhenqui Liu, Nan Deng, Jean Lopategui
Distinguishing between multiple lung primaries and intrapulmonary metastases is imperative for accurate staging. The American Joint Committee on Cancer (AJCC) criteria are routinely used for this purpose but can yield equivocal conclusions. We evaluated whether next generation sequencing (NGS) using the 50 gene AmpliSeq Cancer Hotspot Panel v2 can be used to facilitate this distinction. NGS was performed on known primary-metastatic pairs (8 patients) and multiple lung adenocarcinomas (11 patients). Primary-metastatic pairs showed high mutational concordance: Seven pairs shared mutations, and 1 was concordant for having no mutations...
August 30, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28864950/correlation-of-early-pet-findings-with-tumor-response-to-molecular-targeted-agents-in-patients-with-advanced-driver-mutated-non-small-cell-lung-cancer
#11
Tomonobu Koizumi, Toshirou Fukushima, Daisuke Gomi, Takashi Kobayashi, Nodoka Sekiguchi, Keiko Mamiya, Kazunari Tateishi, Akane Katou, Kazuhiro Oguchi
Recent advances in positron emission tomography with fluorine-18-fluorodeoxyglucose (FDG-PET) have facilitated not only the diagnosis and staging of lung cancer, but also the prediction of treatment outcome. The present study was designed to assess the usefulness of early FDG-PET examination for predicting subsequent tumor size reduction in response to molecular targeted agents in metastatic non-small cell lung cancer (NSCLC) with sensitive gene anomalies. I. In 29 targeted lesions of 10 NSCLC patients, changes in FDG uptake before and on day 7 after the initiation of molecular targeted therapy (gefitinib, n = 7; crizotinib, n = 3) were compared with subsequent radiographic tumor size reduction by RECIST...
September 1, 2017: Medical Oncology
https://www.readbyqxmd.com/read/28860576/pd-l1-expression-in-lung-cancer-and-its-correlation-with-driver-mutations-a-meta-analysis
#12
Minghui Zhang, Guoliang Li, Yanbo Wang, Yan Wang, Shu Zhao, Pu Haihong, Hongli Zhao, Yan Wang
Although many studies have addressed the prognostic value of programmed cell death-ligand 1 (PD-L1) expression in lung cancer, the results remain controversial. A systematic search of the PubMed, EMBASE, and Cochrane Library databases was performed to identify the correlation between PD-L1 expression and driver mutations and overall survival (OS). This meta-analysis enrolled a total of 11,444 patients for 47 studies, and the pooled results showed that increased PD-L1 expression was associated with poor prognosis (HR = 1...
August 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28856564/the-current-landscape-of-anaplastic-lymphoma-kinase-alk-in-non-small-cell-lung-cancer-emerging-treatment-paradigms-and-future-directions
#13
Angel Qin, Shirish Gadgeel
Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3-7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors...
August 31, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28843992/tracking-met-de-addiction-in-lung-cancer-a-road-towards-the-oncogenic-target
#14
REVIEW
S Pilotto, L Carbognin, N Karachaliou, P C Ma, R Rosell, G Tortora, E Bria
The discovery of druggable oncogenic drivers (i.e. EGFR and ALK), along with the introduction of comprehensive tumor genotyping techniques into the daily clinical practice define non-small-cell lung cancer (NSCLC) asa group of heterogeneous diseases, requiring a context-personalized clinico-therapeutical approach. Among the most investigated biomarkers, the MET proto-oncogene has been extensively demonstrated to play a crucial role throughout the lung oncogenesis, unbalancing the proliferation/apoptosis signaling and influencing the epithelial-mesenchymal transition and the invasive phenotype...
August 20, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28843359/combination-osimertinib-and-gefitinib-in-c797s-and-t790m-egfr-mutated-non-small-cell-lung-cancer
#15
Surein Arulananda, Hongdo Do, Ashan Musafer, Paul Mitchell, Alexander Dobrovic, Thomas John
INTRODUCTION: Osimertinib, a third generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) has demonstrated efficacy in tumours harbouring the EGFR T790M resistance mutation. Inevitably, resistance to 3(rd) generation inhibitors result in disease progression, with the EGFR C797S mutation being one of several resistance pathways identified to date. Based on preclinical data, we report the first known case of a patient harbouring the T790M and C797S mutations in trans treated with combination gefitinib and osimertinib...
August 23, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28839001/t790m-selective-egfr-tki-combined-with-dasatinib-as-an-optimal-strategy-for-overcoming-egfr-tki-resistance-in-t790m-positive-non-small-cell-lung-cancer
#16
Satomi Watanabe, Takeshi Yoshida, Hisato Kawakami, Naoki Takegawa, Junko Tanizaki, Hidetoshi Hayashi, Masayuki Takeda, Kimio Yonesaka, Junji Tsurutani, Kazuhiko Nakagawa
T790M mutation-selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated clinical benefits in non-small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as co-oncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced anti-tumor activity in T790M-positive cells...
August 24, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28838405/emergence-of-egfr-g724s-mutation-in-egfr-mutant-lung-adenocarcinoma-post-progression-on-osimertinib
#17
A Oztan, S Fischer, A B Schrock, R L Erlich, C M Lovly, P J Stephens, J S Ross, V Miller, S M Ali, S-H I Ou, L E Raez
Mutations in the epidermal growth factor receptor (EGFR) are drivers for a subset of lung cancers. Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) recently approved for the treatment of T790M-positive non-small cell lung cancer (NSCLC); however, acquired resistance to osimertinib is evident and resistance mechanisms remain incompletely defined. The EGFR G724S mutation was detected using hybrid-capture based comprehensive genomic profiling (CGP) and a hybrid-capture based circulating tumor DNA (ctDNA) assays in two cases of EGFR-driven lung adenocarcinoma in patients who had progressed on osimertinib treatment...
September 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28821559/synergy-of-wee1-and-mtor-inhibition-in-mutant-kras-driven-lung-cancers
#18
Josephine Hai, Shengwu Liu, Lauren Bufe, Khanh Do, Ting Chen, Xiaoen Wang, Christine Ng, Shuai Li, Ming-Sound Tsao, Geoffrey I Shapiro, Kwok-Kin Wong
PURPOSE: KRAS-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multi-targeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations. EXPERIMENTAL DESIGN: We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines...
August 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28814544/direct-detection-of-early-stage-cancers-using-circulating-tumor-dna
#19
Jillian Phallen, Mark Sausen, Vilmos Adleff, Alessandro Leal, Carolyn Hruban, James White, Valsamo Anagnostou, Jacob Fiksel, Stephen Cristiano, Eniko Papp, Savannah Speir, Thomas Reinert, Mai-Britt Worm Orntoft, Brian D Woodward, Derek Murphy, Sonya Parpart-Li, David Riley, Monica Nesselbush, Naomi Sengamalay, Andrew Georgiadis, Qing Kay Li, Mogens Rørbæk Madsen, Frank Viborg Mortensen, Joost Huiskens, Cornelis Punt, Nicole van Grieken, Remond Fijneman, Gerrit Meijer, Hatim Husain, Robert B Scharpf, Luis A Diaz, Siân Jones, Sam Angiuoli, Torben Ørntoft, Hans Jørgen Nielsen, Claus Lindbjerg Andersen, Victor E Velculescu
Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb...
August 16, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28806950/precision-medicine-approaches-to-lung-adenocarcinoma-with-concomitant-met-and-her2-amplification
#20
Doo-Yi Oh, Kyungsoo Jung, Ji-Young Song, Seokhwi Kim, Sang Shin, Yong-Jun Kwon, Ensel Oh, Woong-Yang Park, Sang Yong Song, Yoon-La Choi
BACKGROUND: Patient-derived xenograft (PDX) models are important tools in precision medicine and for the development of targeted therapies to treat cancer patients. This study aimed to evaluate our precision medicine strategy that integrates genomic profiling and preclinical drug-screening platforms, in order to personalize cancer treatments using PDX models. METHODS: We performed array-comparative genomic hybridization, microarray, and targeted next-generation sequencing analyses, in order to determine the oncogenic driver mutations...
August 10, 2017: BMC Cancer
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