Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 55-year-old Caucasian woman with lung adenocarcinoma stage IV presented with repeated relapse after treatment with cytotoxic chemotherapy (carboplatin, gemcitabine, docetaxel, pemetrexed) and targeted agents (erlotinib, cetuximab, sunitinib). Comprehensive molecular diagnostics (EGFR-, ALK-, RAS-, BRAF-, PIK3CA-, HER2- and DDR2-aberrations) were performed and failed initially to detect any driver mutation. While the patient suffered from rapid deterioration of her general condition, in particular from progressive dyspnea due to lung metastases, we implemented screening for RET- and ROS1 translocations into our molecular diagnostic program based on recent reports of these new molecular subgroups in lung adenocarcinoma. On retesting the patient's tumor sample was found to harbor a ROS1-translocation. The patient was subsequently treated with crizotinib and experienced a pronounced clinical improvement corresponding to a complete metabolic response in (18)F-FDG-PET and a good and confirmed partial response in CT (RECIST 1.1). Our case exemplifies the need for rapid implementation of newly discovered rare genetic lung cancer subtypes in routine molecular diagnostics.
Lung Cancer 2013 Jul
PMID:Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib. 2355 10

BRAF V600E is an emerging drug target in lung cancer, but the clinical significance of non-V600 BRAF mutations in lung cancer and other malignancies is less clear. Here, we report the case of a patient with metastatic lung adenocarcinoma with BRAF G469L mutation refractory to vemurafenib. We calculated a structure model of this very rare type of mutated BRAF kinase to explain the molecular mechanism of drug resistance. This information may help to develop effective targeted therapies for cancers with non-V600 BRAF mutations.
Lung Cancer 2013 Nov
PMID:Lung adenocarcinoma with BRAF G469L mutation refractory to vemurafenib. 2403 31

BRAF mutation is seen in a variety of human neoplasms including cutaneous malignant melanoma, papillary thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, pleomorphic xanthoastrocytoma, and others. Currently, there are 2 commercially available monoclonal antibodies for the detection of BRAF V600E mutation; however, a full and practical comparison of their performance in various tumor types on an automated staining platform has not been done. We investigated their sensitivity and specificity in detecting the BRAF V600E mutation in a series of 152 tumors including 31 malignant melanomas, 25 lung carcinomas, 32 gastrointestinal carcinomas, 23 thyroid carcinomas, 35 gliomas, and 6 other malignancies. In this series, the concordance rate between immunohistochemistry (IHC) and mutational analyses was 97% (148/152) for VE1 and 88% (131/149) for anti-B-Raf. The sensitivity and specificity were 98% (60/61) and 97% (88/91) for monoclonal VE1 and 95% (58/61) and 83% (73/88) for anti-B-Raf, respectively. There were 4 cases with discordant IHC and mutational results for monoclonal VE1 in contrast to 18 cases for anti-B-Raf. Our studies showed that IHC with monoclonal VE1 has a better performance compared with anti-B-Raf in an automated staining platform and confirmed that clone VE1 provides excellent sensitivity and specificity for detecting the BRAF V600E mutation in a variety of tumor types in a clinical setting.
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PMID:Comparison of 2 monoclonal antibodies for immunohistochemical detection of BRAF V600E mutation in malignant melanoma, pulmonary carcinoma, gastrointestinal carcinoma, thyroid carcinoma, and gliomas. 2407 Oct 17

Non-small cell lung carcinoma (NSCLC) is the most common subtype of lung cancer. The oncogenic potential of receptor tyrosine kinases (RTKs) is widely known and they are potential targets for tailored therapy. Ephrin receptors (Ephs) form the largest group of RTKs. Nevertheless, Ephs are not widely studied in NSCLC so far. The aim of our study was to investigate novel mutations of Eph genes (EPHA1-8, EPHB1-4, EPHB6) and their association with clinically relevant mutations in BRAF, EML4-ALK, EGFR, INSR, KDR, KRAS, MET, PDGFRA, PDGFRB, PIK3, PTEN, RET, and TP53 in NSCLC patients. Targeted resequencing was conducted on 81 formalin-fixed, paraffin-embedded NSCLC tumor specimens. We analyzed missense and nonsense mutations harbored in the coding regions of the selected genes. We found 18 novel mutations of Ephs in 20% (16 of 81) of the patients. Nearly half of these mutations occurred in the protein kinase domain. The mutations were not mutually exclusive with other clinically relevant mutations. Our study shows that Ephs are frequently mutated in NSCLC patients, and occur together with other known mutations relevant to the pathogenicity of NSCLC.
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PMID:Mutated ephrin receptor genes in non-small cell lung carcinoma and their occurrence with driver mutations-targeted resequencing study on formalin-fixed, paraffin-embedded tumor material of 81 patients. 2412 10

Somatic BRAF mutations have been reported in 1-4% of non-small cell lung cancer (NSCLC), primarily in adenocarcinomas with the BRAF (V600E) mutation in about 50% of the cases. The role of BRAF mutation in NSCLC and the treatment for tumors with such mutations is still evolving. Our patient had metastatic NSCLC with metastases to her brain. Due to the BRAF (V600E) mutation in her tumor and her poor functional status, we offered her off-label treatment with vemurafenib, a BRAF inhibitor approved for use in metastatic melanoma. Our patient's visceral disease improved supporting vemurafenib's efficacy in the treatment of metastatic BRAF-mutated NSCLC. The regression of intracranial disease indicated vemurafenib was able to cross the blood-brain barrier and was efficacious in treating brain metastases in this patient with lung cancer.
Lung Cancer 2014 Aug
PMID:BRAF V600E-mutated lung adenocarcinoma with metastases to the brain responding to treatment with vemurafenib. 2488 29

Tumor tissue biomarkers are the basis for targeted therapy in non-small cell lung cancer (NSCLC). These biomarkers either reflect the target of the specific drug or some factor that might abrogate the effect of the drug. These targeted drugs are small-molecule inhibitors of a specific tyrosine kinase or a monoclonal antibody against a specific receptor. In this review, tissue biomarkers in NSCLC and companion diagnostics will be described, followed by an overview of targeted therapy to EGF/EGFR, HER2, VEGF/VEGFR, ALK, KRAS, BRAF, MEK and MET and some of the newer potential targets. Recent initiatives include the Lung Cancer Matrix Network, the BATTLE trials and the Lung Cancer Mutation Consortium. There are a number of key clinical trials in targeted therapy in NSCLC which will be reporting during the next year.
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PMID:Current status of targeted therapy in non-small cell lung cancer. 2510 32

Lung adenocarcinomas have diverse genetic and morphological backgrounds and are usually classified according to their distinct oncogenic mutations (or so-called driver mutations) and histological subtypes (the de novo classification proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society [IASLC/ATS/ERS]). Although both these classifications are essential for personalized treatment, their integrated clinical effect remains unclear. Therefore, we analyzed 981 lung adenocarcinomas to detect the potential correlation and combined effect of oncogenic mutations and histological subtype on prognosis. Analysis for oncogenic mutations included the direct sequencing of EGFR, KRAS, HER2, BRAF, PIK3CA, ALK, and RET for oncogenic mutations/rearrangements, and a rereview of the IASLC/ATS/ERS classification was undertaken. Eligible tumors included 13 atypical adenomatous hyperplasia/adenocarcinoma in situ, 20 minimally invasive adenocarcinomas, 901 invasive adenocarcinomas, 44 invasive mucinous adenocarcinomas, and three other variants. The invasive mucinous adenocarcinomas had a lower prevalence of EGFR mutations but a higher prevalence of KRAS, ALK, and HER2 mutations than invasive adenocarcinomas. Smoking, a solid predominant pattern, and a mucinous component were independently associated with fewer EGFR mutations. The ALK rearrangements were more frequently observed in tumors with a minor mucinous component, while the KRAS mutations were more prevalent in smokers. In addition, 503 patients with stage I-IIIA tumors were analyzed for overall survival (OS) and relapse-free survival. The stage and histological pattern were independent predictors of relapse-free survival, and the pathological stage was the only independent predictor for the OS. Although patients with the EGFR mutations had better OS than those without the mutations, no oncogenic mutation was an independent predictor of survival. Oncogenic mutations were associated with the novel IASLC/ATS/ERS classification, which facilitates a morphology-based mutational analysis strategy. The combination of these two classifications might not increase the prognostic ability, but it provides essential information for personalized treatment.
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PMID:Oncogenic mutations are associated with histological subtypes but do not have an independent prognostic value in lung adenocarcinoma. 2515 23

Discoidin death receptor 2 (DDR2) receptor belongs to a DDR family that shows a tyrosine kinase activity. The somatic mutations in DDR2 gene, reported in non-small cell lung cancer (NSCLC), are involved in up-regulation of cells' migration, proliferation and survival. A S768R substitution in DDR2 gene was commonly reported in squamous cell lung carcinoma. Clinical data of patients carrying the DDR2 gene mutation suggest that its presence can be independent of gender and age. The effectiveness of an oral dual-specific (Src and Abl) multikinase inhibitors-dasatinib-was observed in different cell lines and in some NSCLC patients with identified DDR2 mutation. In the present study, we have used three molecular methods (ASP-real-time PCR, ASP-DNA-FLA PCR and direct sequencing) to detect the DDR2 gene mutation in 143 patients with NSCLC metastases to the central nervous system (CNS). The prevalence of the DDR2 gene mutation was correlated with the occurrence of mutations in the EGFR, KRAS, HER2 and BRAF genes. We identified three patients (2.1% of studied group) with DDR2 mutation. The mutation was observed in two patients with low differentiated squamous cell lung cancer and in one patient with adeno-squamous cell carcinoma (ADSCC). In ADSCC patients, DDR2 mutation coexisted with G12C substitution in KRAS gene. According to the current knowledge, examination of the presence of the DDR2 gene mutation in metastatic lesion is the first such report worldwide. The information, that these driver mutations are present in CNS metastases of NSCLC, could broaden therapeutic choices in such group of patients.
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PMID:Sensitive methods for detection of the S768R substitution in exon 18 of the DDR2 gene in patients with central nervous system metastases of non-small cell lung cancer. 2517 30

We present the case of a patient with rapidly accelerated fibrosarcoma gene F (BRAF) mutated adenocarcinoma of the lung, responding to BRAF inhibitor dabrafenib after progressing on vemurafenib followed by docetaxel. The present case illustrates the potential benefit of successful rechallenge with a BRAF inhibitor, a well known phenomenon observed in other oncogenic driven molecular subtypes of non-small cell lung cancer (NSCLC) such as epidermal growth factor receptor mutation. Rechallenge with a BRAF inhibitor in BRAF mutated NSCLC should be considered, particularly in the absence of alternative therpateutic options.
Lung Cancer 2015 Jan
PMID:Response to dabrafenib after progression on vemurafenib in a patient with advanced BRAF V600E-mutant bronchial adenocarcinoma. 2546 51

It is widely acknowledged that there is a need for molecular profiling in non-small-cell lung cancer. For example, treatment based on EGFR mutation status has attained successful results. However, in spite of excellent initial response to oral EGFR tyrosine kinase inhibitors (TKIs), progression-free survival is still limited. Current research has focused mostly on acquired resistance mechanisms, such as overexpression of AXL and loss of the Mediator MED12. In this review, in contrast, we discuss adaptive, rather than acquired, resistance. Adaptive resistance can occur almost immediately after starting targeted therapy through a rapid rewiring of cancer cell signaling. By losing ERK negative feedback on receptor tyrosine kinase (RTK) expression, cancer cells are exposed to the stimuli of several ligands, and the ensuing activation of several RTKs reprograms all the canonical signaling pathways. The overexpression of several RTKs was observed in breast cancer cell lines treated with a MEK inhibitor and in BRAF(V600E) melanoma cell lines treated with BRAF inhibitors. This rebound effect of overexpression of several RTKs, including ERBB3, also occurs in lung cancers driven by Kras or EGFR mutations when treated with MEK, PI3K or dual PI3K/mTOR inhibitors. Synthetic lethality can be effectively induced by co-targeting these overexpressed RTKs. We speculate that in patients with EGFR mutations, adaptive resistance occurs in a significant proportion of patients. Rebiopsies performed hours after starting treatment with EGFR TKIs can identify which RTKs are overexpressed after treatment. Efficient co-targeting of these RTKs can induce synthetic lethality and help overcome the limited effect of EGFR TKI monotherapy.
Transl Lung Cancer Res 2013 Jun
PMID:Adaptive resistance to targeted therapies in cancer. 2580 28


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