Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer

Lopes, Gabriel Lima; Vattimo, Edoardo Filippo de Queiroz; Castro, Gilberto de

doi:10.1590/s1806-37132015000004531

Cited by 37 publications

(26 citation statements)

References 72 publications

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“…Approximately 13% of the NSCLC patients have EGFR mutations such as L858R and these patients initially respond to the TKI such as erlotinib or gefitinib [25, 32]. Subsequently NSCLC patients become resistant to erlotinib or gefitinib due to secondary EGFR mutations such as T790M [24]. It is important to increase the sensitivity of TKI in NSCLC patients with wild type EGFR or secondary T790M mutations.…”

Section: Discussionmentioning

confidence: 99%

Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells

et al. 2017

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Endothelin (ET)-1 is an important peptide in cancer progression stimulating cellular proliferation, tumor angiogenesis and metastasis. ET-1 binds with high affinity to the ETA receptor (R) and ETBR on cancer cells. High levels of tumor ET-1 and ETAR are associated with poor survival of lung cancer patients. Here the effects of ET-1 on epidermal growth factor (EGF)R and HER2 transactivation were investigated using non-small cell lung cancer (NSCLC) cells. ETAR mRNA was present in all 10 NSCLC cell lines examined. Addition of ET-1 to NCI-H838 or H1975 cells increased EGFR, HER2 and ERK tyrosine phosphorylation within 2 min. The increase in EGFR and HER2 transactivation caused by ET-1 addition to NSCLC cells was inhibited by lapatinib (EGFR and HER2 tyrosine kinase inhibitor (TKI)), gefitinib (EGFR TKI), ZD4054 or BQ-123 (ETAR antagonist), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor) or Tiron (superoxide scavenger). ET-1 addition to NSCLC cells increased cytosolic Ca2+ and reactive oxygen species. ET-1 increased NSCLC clonal growth, whereas BQ123, ZD4054, lapatinib or gefitinib inhibited proliferation. The results indicate that ET-1 may regulate NSCLC cellular proliferation in an EGFR-and HER2-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells

et al. 2017

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“…Indeed, cancer invasiveness is stimulated by numerous mechanisms, including activating EGFR mutations [33]. Furthermore, a recent meta-analysis by Wang and Wang [34] exploring the correlation of EGFR status between primary tumors and metastases revealed that EGFR mutations should occur before metastasis, suggesting that EGFR mutations play a role in this process.…”

Section: Discussionmentioning

confidence: 99%

EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer

Tomasini

Serdjebi

Khobta

et al. 2016

IJMS

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Background: Lung cancer is the leading cause of brain metastases (BM). The identification of driver oncogenes and matched targeted therapies has improved outcome in non-small cell lung cancer (NSCLC) patients; however, a better understanding of BM molecular biology is needed to further drive the process in this field. Methods: In this observational study, stage IV NSCLC patients tested for EGFR and KRAS mutations were selected, and BM incidence, recurrence and patients’ outcome were assessed. Results: A total of 144 patients (142 Caucasian and two Asian) were selected, including 11.27% with EGFR-mutant and 33.10% with KRAS-mutant tumors, and 57.04% patients had developed BM. BM incidence was more frequent in patients with EGFR mutation according to multivariate analyses (MVA) (Odds ratio OR = 8.745 [1.743–43.881], p = 0.008). Among patients with treated BM, recurrence after local treatment was less frequent in patients with KRAS mutation (OR = 0.234 [0.078–0.699], p = 0.009). Among patients with untreated BM, overall survival (OS) was shorter for patients with KRAS mutation according to univariate analysis (OR = 7.130 [1.240–41.012], p = 0.028), but not MVA. Conclusions: EGFR and KRAS mutations have a predictive role on BM incidence, recurrence and outcome in Caucasian NSCLC patients. These results may impact the routine management of disease in these patients. Further studies are required to assess the influence of other biomarkers on NSCLC BM.

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“…They postulated that the differences might be explained by different ethnic makeup of these countries. Argentina, for example, has a predominantly white population, with lower reported rates than Peru, where there have traditionally been higher rates of Asian migration .…”

Section: Introductionmentioning

confidence: 99%

EGFR Mutation Testing: Changing Patterns of Molecular Testing in Brazil

et al. 2018

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Background. In Brazil, cancer is the second most common cause of death. Most patients in resource-limited countries are diagnosed in advanced stages. Current guidelines advocate for EGFR mutation testing in all patients with metastatic adenocarcinoma. Tyrosine kinase inhibitors are recommended in patients with advanced or metastatic disease harboring sensitizing mutations. In Brazil, there are limited data regarding the frequency of EGFR testing and the changes in patterns of testing overtime. Materials and Methods. This was an observational, retrospective study. We obtained deidentified data from a commercial database, which included 11,684 patients with non-small cell lung cancer treated between 2011 and 2016 in both public and private settings. We analyzed the frequency of EGFR mutation testing over time. We also directly studied 3,664 tumor samples, which were analyzed between 2011 and 2013. These samples were tested for EGFR mutations through an access program to tyrosine kinase inhibitors in Brazil.Results. Overall, 38% of patients were tested for EGFR mutations; 76% of them were seen in the private sector, and 24% were seen in the public center. The frequency of testing for EGFR mutations increased significantly over time: 13% (287/2,228 patients) in 2011, 34% (738/2,142) in 2012, 39% (822/2,092) in 2013, 44% (866/1,972) in 2014, 53% (1,165/2,184) in 2015, and 42% (1,359/3,226) in 2016. EGFR mutations were detected in 25.5% of analyzed samples (857/3,364). Deletions in Exon 19 were the most frequent mutations, detected in 54% of patients (463/857). Conclusion. Our findings suggest that the frequency of EGFR mutation in this cohort was lower than that found in Asia but higher than in North American and Western European populations. The most commonly found mutations were in Exon 19 and Exon 21. Our study shows that fewer than half of patients are being tested and that the disparity is greater in the public sector. The Oncologist 2019;24:e137-e141 Implications for Practice: These data not only indicate the shortage of testing but also show that the rates of positivity in those tested seem to be higher than in other cohorts for which data have been published. This study further supports the idea that awareness and access to testing should be improved in order to improve survival rates in lung cancer in Brazil.

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Identifying activating mutations in the EGFR gene: prognostic and therapeutic implications in non-small cell lung cancer

Cited by 37 publications

References 72 publications

Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells

Endothelin causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells

EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer

EGFR Mutation Testing: Changing Patterns of Molecular Testing in Brazil

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