The most common mechanism of acquired resistance to EGFR-TKIs is the EGFR T790M mutation, which occurs with an amino acid substitution at position 790 in EGFR, from a threonine (T) to a methionine (M). Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations – a review. Tony Mok and Kwok-Chi Lam, The Chinese University of Hong Kong, Sir Y.K. PIK3CA, BRAF) have been implicated in acquired resistance to EGFR-TKIs.22,23, Reduced expression of NF1 has been associated with EGFR-TKI resistance through activating RAS and the downstream RAS-ERK pathway.24, Acquired resistance to EGFR-TKIs may also be the result of histological transformation of NSCLC to SCLC, with persistence of the initial EGFR mutation in some cases.23. VPM ID: Z4-6853 | Date of preparation: September 2017 | Date of next review: September 2019, © AstraZeneca 2017 FOR HEALTHCARE PROFESSIONAL USE ONLY, https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. These include erlotinib and gefitinib and it has been demonstrated that a group of mutations centered at the ATP-binding pocket of EGFR confer sensitivity to these agents by enhancing … EGFR exon 19 insertions are a newly appreciated family of EGFR-TKI-sensitizing mutations, and patients with tumors harboring these mutations should be treated with EGFR-TKI. Abstract Background: A subset of lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutations (mEGFR) is common in non-smokers and women, suggesting that mutational stressors … 1,2 Targeted therapies can inhibit … Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. EGFR activity may be dysregulated through various mechanisms, including sensitizing mutations that affect tyrosine kinase activity and lead to constitutive activation. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. ASCO Daily News Gefitinib or. ASCO Author Services Conquer Cancer Foundation Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Cookies. A subset of lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutations (mEGFR) is common in non-smokers and women, suggesting that mutational stressors … Engelman JA, Zejnullahu K, Mitsudomi T et al. Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) are common in the therapeutic armentarium of lung cancer today. A molecular genetic abnormality indicating the presence of a sensitizing mutation in the epidermal growth factor receptor-tyrosine kinase inhibitor domain. Available at: Lee CK, Wu YL, Ding PN et al. DOI: 10.1200/JCO.2012.43.0652 Journal of Clinical Oncology - The only reason to consider EGFR … EGFR is a short name for the Epidermal Growth Factor Receptor gene. ASCO Meetings Novel D761Y and common secondary T790M mutations in epidermal growth factor. An EGFR mutation does not refer to a single gene abnormality. Reviewers Data based on an analysis of tumour specimens from 155 patients with EGFR-mutant lung cancers at the time of acquired resistance to gefitinib or erlotinib therapy. 4A). To date, there are no direct comparative data between first- and second-line EGFR TKI in patients with activating EGFR mutations. JCO Global Oncology Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI’s Lung Cancer Mutation Consortium (LCMC). Purchase. Lung cancer cells harboring EGFR mutations were 100-fold more sensitive to gefitinib than cells with wild-type receptor (Fig. EGFR-TKI Sensitizing Mutation. Contact Us TAPUR Study, Terms of Use | Privacy Policy | First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. 5 In the blood samples from those patients with the T790M mutation, the amount of T790M and EGFR‐sensitizing mutations … Cancer Discov 2014; 4: 1046–1061. HER2 or MET amplification) or phenotypic transformations (to small-cell lung cancer [SCLC] or epithelial-mesenchymal transition). Renew Your Subscription The most common EGFR mutations (around 90%) are either … Rather, there are many different types of EGFR mutations, which vary both in the type of mutation (as described above) and in the location of the mutation in a gene. NCCN Clinical Practice Guidelines in Oncology NSCLC (version 4.2017), 2017. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. T790M), alternative pathway activations (e.g. Deletion mutations result when short segments of the DNA are … Epidemiol Biomarkers Prev 2015; 24: 1254–1261. Balak MN, Gong Y, Riely GJ et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. Mendelsohn J, Baselga J. Cancer.Net, ASCO.org JCO Oncology Practice Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. In patients diagnosed with advanced NSCLC, the most common activating mutations observed are exon 19 deletions and an L858R point mutation in exon 21.4–8, Testing for ALK rearrangements and EGFR mutations at primary diagnosis of advanced NSCLC is recommended to guide treatment decisions.9,10 In patients diagnosed with advanced NSCLC and harbouring an ALK rearrangement or an activating or sensitising EGFR mutation, first-line treatment with an ALK-tyrosine kinase inhibitor (TKI) or EGFR-TKI is recommended.9,10. The diagram below outlines the known resistance mechanisms to EGFR-TKIs.12. If you have an individual subscription to this content, or if you have purchased this content through Pay Per Article within the past 24 hours, you can gain access by logging in with your username and password here: Subscribe to this Journal Lung cancer is one of the most serious threats to human where 85% of lethal death caused by non-small cell lung cancer (NSCLC) induced by epidermal growth factor receptor (EGFR) mutation. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. NCCN. Oncogene 2000; 19: Yoshida K, Yatabe Y, Park J et al. Introduction to EGFR sensitising and resistance mutations. About 45% of sensitizing mutations are what are called in frame deletions in exon 19, making them the most common EGFR mutations. 1081-1088. A number of genetic drivers of tumour growth have been identified in patients with non-small cell lung cancer (NSCLC), including mutations in the epidermal growth factor receptor (EGFR) gene.1–3 EGFR activating mutations are found in exons 18 to 21 of the EGFR gene, which is part of the gene coding for the tyrosine kinase domain of the EGFR protein. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in, Yu HA, Arcila ME, Rekhtman N et al. In other words, there are many ways in which EGFR can be changed genetically. These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division. Archive The only reason to consider EGFR TKI as second-line therapy is that none of the six comparative studies has shown improvement in overall survival, which can be explained by the high proportion of patients from the chemotherapy arm crossing over to the EGFR TKI arm on progression. February 11, 2013. The majority of patients with an EGFR sensitising mutation will progress on treatment with an EGFR-TKI.11 At disease progression, mutation testing can be used to help identify the mechanism(s) of acquired resistance. The EGFR-TKI sensitizing mutations are defined as a point mutation in the EGFR exon 21, which substitutes an arginine for a leucine (L858R), in-frame deletions (encompassing 4 amino acid residues … Bean J, Riely GJ, Balak M et al. Advertisers, Journal of Clinical Oncology However, numerous arguments, including assurance on drug exposure, improvement in quality of life, better tolerance by patients with poor performance status, and deferral of whole-brain radiation therapy for patients with brain metastasis, support the general application of first-line EGFR TKI. (March 10, 2013) Yun CH, Mengwasser KE, Toms AV et al. JCO OP DAiS, ASCO eLearning HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the. Mutations in the gene encoding EGFR that lead to overexpression of the protein have been associated with a number of different cancers. Enter words / phrases / DOI / ISBN / authors / keywords / etc. Proc Natl Acad Sci U S A 2008; 105: 2070–2075. Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) Non-small cell lung cancer (NSCLC) is the most … It is true that patients with EGFR mutations may benefit from second-line EGFR TKI therapy, but we cannot conclude that the benefit is either equal to or inferior to first-line EGFR TKI therapy. The development of resistance mutations leads to the nullification of the inhibitory activity of EGFR-TKIs. The present study showed that compared to the EGFR exon 20 insertion mutations… JCO Clinical Cancer Informatics J Clin Oncol 2011; 29(Suppl): Abstract CRA7506. In certain situations, DNA that has been shed from tumor cells in one's blood can also be tested and may be informative (liquid biopsy).The EGFR … Mutation incidence and coincidence in non. Mutations, … Proc Natl Acad Sci U S A 2012; 109: E2127–E2133. JCO Precision Oncology, ASCO Educational Book The mOS of Ex20Ins mutations was 5 months (95% CI: 0.17–9.8 months), the OS of EGFR TKI-sensitizing activating mutations was 16.1 months (95% CI: 12.8–19.5 months), and the OS of EGFR/ALK mutation-negative in patients was 10 months . 31, no. EGFR mutation status and first-line treatment in patients with stage III/IV non-small cell lung cancer in Germany: an observational study. Pau Cancer Center, State Key Laboratory of Southern China, Prince of Wales Hospital, Hong Kong; and Jin-Ji Yang, Guangdong General Hospital, Guangdong, China. The only reason to consider EGFR … Mok TS, Wu YL, Thongprasert S et al. Permissions, Authors Sequist LV, Yang JC, Yamamoto N et al. Mutations in EGFR can occur at different locations on exon 18 to 21. Science 2007; 316: Takezawa K, Pirazzoli V, Arcila ME et al. First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. Schuette W, Schirmacher P, Eberhardt WE et al. Meeting Abstracts, About Finally, EGFR p.C797S mutation … Activating mutations … Kobayashi S, Boggon TJ, Dayaram T et al. Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. (NCI Thesaurus) Certain mutations called "activating mutations" in … EGFR p.T790M mutation was found in 13 samples (45%) by digital PCR and 12 samples (41%) by NGS. Further details on EGFR mutations and subsequent testing are available throughout EGFR-mutation.com. Editorial Roster Tumor response rates to second-line EGFR TKI have been inconsistent, which could potentially be explained by the impact of first-line chemotherapy on the abundance of tumor cells with activating EGFR mutations. Non-small cell lung cancer (NSCLC) has a 5-year survival of 5–16%. Costa DB1, Halmos B, Kumar A et al. Clin Cancer Res 2008; 14: 7519–7525. EGFR Exon 19 Insertions: A New Family of Sensitizing EGFR Mutations in Lung Adenocarcinoma Mai He 1 , Marzia Capelletti 7 , Khedoudja Nafa 1 , Cai-Hong Yun 8,9 , Maria E. Arcila 1 , Vincent A. Miller 2 , ASCO Career Center Ohashi K, Sequist LV, Arcila ME et al. The most frequent EGFR mutations (Figure 2B) - commonly termed classic or sensitizing activating mutations - are in-frame deletions (around amino acid residues 747 to 750) of exon 19 (45% of EGFR … Dearden S et al. In glioblastoma a specific mutation of EGFR, called EGFRvIII, is often observed. Stewart EL, Tan SZ, Liu G et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. 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