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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factor receptors (GFRs) are amenable to therapeutic intervention in cancer and it is important to select patients appropriately. One of the mechanisms for activation of GFRs is gene amplification (GA) but discrepancies arising from the difficulties associated with data interpretation and the lack of agreed parameters confound the comparison of results from different laboratories. Here, we attempt to establish appropriate conditions for standardization of the determination of GA in a panel of GFRs. A NSCLC tissue microarray panel containing 302 samples was screened for alterations at ALK, FGFR1, FGFR2, FGFR3, ERBB2, IGF1R, KIT, MET and PDGFRA by FISH, immunostaining and/or real-time quantitative RT-PCR. Strong amplification was found for FGFR1, ERBB2, KIT/PDFGRA and MET, with frequencies ranging from 1 to 6%. Thresholds for overexpression and GA were established. Strong immunostaining was found in most tumors with ERBB2, MET and KIT amplification, although some tumors underwent strong immunostaining in the absence of GA. KIT and PDFGRA were always coamplified, but only one tumor showed PDGFRA overexpression, indicating that KIT is the main target. Amplification of FGFR1 predominated in squamous cell carcinomas, although the association with overexpression was inconclusive. Interestingly, alterations at ALK, MET, EGFR, ERBB2 and KRAS correlated with augmented levels of phospho-S6 protein, suggesting activation of the mTOR pathway, which may prove useful to pre-select tumors for testing. Overall, here, we provide with parameters for the determination of GA at ERBB2, MET, KIT and PDGFRA which could be implemented in the clinic to stratify lung cancer patients for specific treatments.
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PMID:Determining the profiles and parameters for gene amplification testing of growth factor receptors in lung cancer. 2340 Jun 71

We summarize significant changes in pathologic classification of lung cancer resulting from the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification. The classification was developed by an international core panel of experts representing IASLC, ATS, and ERS with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. Because 70% of patients with lung cancer present with advanced stages, a new approach to small biopsies and cytology with specific terminology and criteria focused on the need for distinguishing squamous cell carcinoma from adenocarcinoma and on molecular testing for EGFR mutations and ALK rearrangement. Tumors previously classified as non-small-cell carcinoma, not otherwise specified, because of the lack of clear squamous or adenocarcinoma morphology should be classified further by using a limited immunohistochemical workup to preserve tissue for molecular testing. The terms "bronchioloalveolar carcinoma" and "mixed subtype adenocarcinoma" have been discontinued. For resected adenocarcinomas, new concepts of adenocarcinoma in situ and minimally invasive adenocarcinoma define patients who, if they undergo complete resection, will have 100% disease-free survival. Invasive adenocarcinomas are now classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype with poor prognosis. Former mucinous bronchioloalveolar carcinomas are now called "invasive mucinous adenocarcinoma." Because the lung cancer field is now rapidly evolving with new advances occurring on a frequent basis, particularly in the molecular arena, this classification provides a much needed standard for pathologic diagnosis not only for patient care but also for clinical trials and TNM classification.
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PMID:New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. 2340 43

Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC). However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22-q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer.
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PMID:Mouse model for ROS1-rearranged lung cancer. 2341 94

Lung cancer continues to be the leading cause of cancer death worldwide, and non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Molecular targeted therapy is the most promising development part in the treatment of NSCLC. In recent years, more and more attention has been focused on some new molecular targets in NSCLC, such as echinodem microtubule-associated protein-like4/anaplastic lymphoma kinase (EML4-ALK) fusion gene. This review will focus on the basic structure, clinicopathologic features, detection method, ALK inhibitor and therapeutic meaning of EML4-ALK in NSCLC.
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PMID:[Clinical meaning of EML4-ALK fusion gene in non-small cell lung cancer]. 2342 2

The discovery in 2004 of activating mutations in the EGFR gene opened the era of personalized medicine in thoracic oncology. Treatment with drugs that target EGFR typically results in dramatic tumour response compared with conventional chemotherapy in patients with non-small-cell lung cancer. Subsequently, newer driver oncogenes such as ALK, ROS1 and RET have been discovered. Nevertheless, surgery has become safer and less invasive in the past 10-15 years. In the era of personalized medicine, thoracic surgeons have to think about their evolving roles. In this article, we discuss four topics relevant to this issue. Firstly, the value of surgical specimens as opposed to biopsy specimens for further understanding tumour biology is discussed. Secondly, extended indication of surgery in the era of targeted therapy is considered. Thirdly, in clinical trials that examine neoadjuvant therapy in patients selected by appropriate biomarkers, the important role of surgeons is highlighted. Finally, the possibility of personalizing the surgical procedure itself according to lung cancer subtypes defined by biomarkers is reviewed.
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PMID:Surgery for NSCLC in the era of personalized medicine. 2343 59

Squamous cell carcinoma (SQCC) of the lung is the second-largest subtype of non-small cell lung cancer (NSCLC), causing an estimated 400,000 deaths per year worldwide. Recent developments in cancer genome sequencing technology expanded our knowledge of driver mutations, which were identified as novel candidates for targeted therapy in various cancers. Successful targeted treatments for lung adenocarcinoma, NSCLC's primary subtype, with EGFR mutation or ALK fusion are clinically available, and a clinical trial of personalized targeted therapy in patients with lung adenocarcinoma is underway by the Lung Cancer Mutation Consortium. Although there are targeted treatments for lung adenocarcinoma, no personalized therapies currently exist for SQCC. Recently, comprehensive genomic characterization of lung SQCC using massively parallel sequencing has enabled us to identify several potential driver mutations/signaling pathways. These are FGFR1 amplifications, PI3KCA mutations, PTEN mutations/deletions, PDGFRA amplifications/mutations, and DDR2 mutations. The march toward personalized therapy may have taken a step forward with the discovery of these potential biomarkers for the treatment of SQCC of the lung. This article reviewed the current knowledge of genomic landscape of lung SQCC and summarized ongoing clinical trials of targeted agents for lung SQCC. Also, we will suggest several other actionable mutations with matching drugs that should be investigated in future clinical trials for the personalized treatment of lung SQCC.
Lung Cancer 2013 Jun
PMID:Personalized therapy on the horizon for squamous cell carcinoma of the lung. 2348 60

The management of non-small cell lung cancer has significantly changed over the past few years through greater understanding of tumour biology. The identification of activating mutations has led to the development of targeted agents. Coexisting mutations in non-small cell lung cancer is uncommon, particularly in squamous cell carcinoma. Our case represents a late gentleman with squamous cell carcinoma of the lung with both a BRAF mutation and ALK rearrangement prior to treatment.
Lung Cancer 2013 Jun
PMID:A rare case of squamous cell carcinoma of the lung harbouring ALK and BRAF activating mutations. 2349 98

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

An article in a recent edition of Current Oncology explored the validation of progression-free survival (pfs) as an endpoint in clinical trials of antineoplastic agents for metastatic colorectal cancer, metastatic renal cell carcinoma, and ovarian cancer. The support for pfs as a surrogate endpoint for overall survival (os) was elucidated. As with the aforementioned tumour types, advanced non-small-cell lung cancer (nsclc) has seen a rise in active agents since the year 2000. Those agents range from improved cytotoxics such as pemetrexed, to targeted therapies such as tyrosine kinase inhibitors of the epidermal growth factor receptor and agents that target the EML4-ALK gene mutation. More recently, it has also become apparent that histology plays an important role in the response to and outcomes of treatment. With the therapeutic options for patients with advanced nsclc increasing, concerns are being raised that the efficacy of drugs measured by os may be diluted in clinical trials, thereby underestimating their true clinical benefit. That possibility, together with the need to have efficacious drugs available to patients earlier, has resulted in the search for a surrogate to the os endpoint in advanced nsclc. The present article follows up the recent article on pfs as a surrogate. Although advances in identifying pfs as a valid surrogate endpoint for os have been made in other tumour types, in advanced nsclc, such surrogacy has not been formally validated. Until it has, os should remain the primary endpoint of clinical trials in advanced nsclc.
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PMID:Overall survival should be the primary endpoint in clinical trials for advanced non-small-cell lung cancer. 2355 82

In non-small cell lung cancer (NSCLC), receptor tyrosine kinases (RTKs) stand out among causal dominant oncogenes, and the ablation of RTK signaling has emerged as a novel tailored therapeutic strategy. Nonetheless, long-term RTK inhibition leads invariably to acquired resistance, tumor recurrence and metastatic dissemination. In ALK+ cell lines, inhibition of ALK signaling was associated with coactivation of several RTKs, whose pharmacological suppression reverted the partial resistance to ALK blockade. Remarkably, ERBB2 signaling synergized with ALK and contributed to the neoplastic phenotype. Moreover, the engagement of wild-type epidermal growth factor receptor or MET receptors could sustain cell viability through early growth response 1 (EGR1) and/or Erk1/2; Akt activation and EGR1 overexpression prevented cell death induced by combined ALK/RTK inhibition. Membrane expression of ERBB2 in a subset of primary naive ALK+ NSCLC could be relevant in the clinical arena. Our data demonstrate that the neoplastic phenotype of ALK-driven NSCLC relays 'ab initio' on the concomitant activation of multiple RTK signals via autocrine/paracrine regulatory loops. These findings suggest that molecular and functional signatures are required in de novo lung cancer patients for the design of efficacious and multi-targeted 'patient-specific' therapies.
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PMID:The EGFR family members sustain the neoplastic phenotype of ALK+ lung adenocarcinoma via EGR1. 2356 20


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