Management of acquired resistance to egfr tkitargeted. Management of egfr mutation positive metastatic nonsmall cell lung cancer leora horn, md, msc vanderbiltingram cancer center rogerio lilenbaum, md yale cancer centersmilow cancer hospital egfr mutation in advanced nsclc. Purpose approximately 10% of patients with epidermal growth factor receptor egfr mutation positive nonsmallcell lung cancer nsclc harbor uncommon mutations. Molecular dynamics simulationguided drug sensitivity. Pdf receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer nsclc and matched normal tissue. If you receive a lung cancer diagnosis, the very first thing you should do is make sure your doctors have ordered comprehensive biomarker testing done on your lung cancer tumor. In this study, we prospectively explored the role of ctdna in detecting egfr mutations in patients plasma and determined the efficacy of egfr tyrosine kinase inhibitors tkis in patients with suspected advanced lung cancer, in the absence of pathologic diagnosis. Egfr mutations prevalence in chilean lung cancer patients. In this study, we report the effects of the egfr tki gefitinib on expression of the antiapoptotic protein survivin that have. Nonsmall cell lung cancer targeted therapy lung cancer. Epidermal growth factor receptor egfr mutant nonsmall cell lung cancers nsclc are commonly adenocarcinomas in never smokers. Advanced nonsmallcell lung cancer nsclc is the leading cause of cancer related deaths in the world.
Aug 22, 2019 as such, incremental gains in knowledge for this subset of lung cancer are relevant and timely, given the emergence of a proliferation of ici therapies to the therapeutic armamentarium for lung cancer, and the question arises of treatment sequencing and best combinations. The egfr mutations of 70 nsclc patients were determined by. Unlike somatic egfr mutations, reported more often in asians, females and nonsmokers, few data for patients harbouring egfr germline mutations are available. Nonsmallcell lung cancer nsclc, the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and. What you need to know about lung cancer and egfr mutations. Mutational activation of the epidermal growth factor receptor egfr gene is implicated in lung cancer. Tyrosine kinase inhibitors for the treatment of egfr. Epidermal growth factor receptor mutations in lung cancer. Inframe deletions around the lrea motif of exon 19 and exon 21 l858r point mutation, which are classic hotspot egfr mutations, ac. The impact of rare egfr mutations on the treatment. Comprehensive biomarker testing can determine whether an egfr lung cancer mutation or another lung cancer mutation is present. Nccn, florida 2016 rogerio lilenbaum, md professor of medicine yale cancer center chief medical officer smilow cancer hospital.
The molecular mechanism by which epidermal growth factor receptortyrosine kinase inhibitors egfr tki induce apoptosis in nonsmall cell lung cancer nsclc cells that are positive for activating mutations of the egfr remains unclear. It is important that lung cancer patients are tested for oncogenic drivers of cancer and receive matched targeted therapy 4. Mutations of the epidermal growth factor receptor egfr gene have been identified in specimens from patients with nonsmallcell lung cancer who have a response to anilinoquinazoline egfr. These results suggest that egfr mutations may predict sensitivity to gefitinib. Egfr mutant lung cancer patients whose tumors had tmb in the upper tertile had. We investigated the clinical characteristics and epidermal growth factor receptor egfr mutation rate of nsclc patients with mipc at initial diagnosis. Egfr mutations in patients with brain metastases from lung. A the t790m mutation affects the binding pocket of atp to the egfr, causing a steric hindrance that reduces the capability of egfr tyrosine kinase inhibitors tkis to. Identification of egfr mutations in cytological specimens of non. Egfr mutation and resistance of nonsmallcell lung cancer. The discovery of driver mutations in lung cancer allows the creation of personalized targeted treatment.
Somatic epidermal growth factor receptor egfr mutations are now routinely integrated in the molecular diagnosis of nonsmall cell lung cancers nsclc 1, 2. Epidermal growth factor receptor tyrosine kinase inhibitors egfr. Unlike one of our cases, the germline v843i mutation has been reported in a family with lung cancer 10 and in a family with other cancer susceptibility 9. This recommendation is not intended to affect treatment with osimertinib that was started in the nhs before this guidance was published. Role of survivin in egfr inhibitorinduced apoptosis in. Gefitinib or erlotinib vs chemotherapy for egfr mutation positive lung cancer. Recently, the study of the egfr mutations in lung cancer has become mandatory due to their usefulness in target therapy. Prevalence of egfr mutations in lung cancer in uruguayan. Egfr mutations in patients with brain metastases from lung cancer. In preclinical studies, bevacizumab as a single drug or in combination with erlotinib inhibited tumour growth of h1975 xenografts bearing egfr l858r and t790m mutations. The tissue samples of the lung cancer patients were collected bronchoscopically. Here, we report the efficacy and safety of osimertinib in patients with nsclc harboring uncommon egfr mutations.
Incorporation of molecular analysis of the epidermal growth factor receptor egfr gene into routine clinical practice represents a milestone for. Rare epidermal growth factor receptor egfr mutations in nonsmall cell lung cancer article pdf available in seminars in cancer biology september 2019 with. Lung cancer is a type of cancer that starts in the lungs. Both the aforementioned mutations result in changes. Egfr mutations are usually observed in lung cancer as more than 60% of the nonsmall lung carcinoma cells overexpress egfrs da cunha santos et al. Treatment of uncommon egfr mutations in nonsmall cell. Lung cancer is the leading cause of cancer related deaths.
Potential genetic modifiers for somatic egfr mutation in lung cancer. E746a750 comprise up to 86% of all egfr mutations in some studies 25. Thatcher n, hirsch fr, luft av, szczesna a, ciuleanu te, dediu m, et al. Approximately 1015% of patients with nonsmall cell lung cancer in the united states and 35% in asia have an egfr positive mutation. The most common mutations are dele746a750 in exon 19 and l858r in exon 21, accounting for. Nonsmall cell lung cancer nsclc presenting with miliary intrapulmonary carcinomatosis mipc is rare. Pretreatment egfr t790m resistance mutation occurs in a proportion of patients with nonsmallcell lung cancer nsclc and activating egfr mutations. Germline exon 21 egfr mutations, v843i and p848l, in nonsmall cell lung cancer patients to the editor. Lung cancer patients with mutations in the egfr gene represent a significant amount of patients diagnosed with nonsmall cell lung cancer. Erlotinib and bevacizumab in patients with advanced non. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as firstline therapy in patients with stage iv squamous nonsmallcell lung cancer squire.
Sensitizing mutations in epidermal growth factor receptor egfr are associated with positive responses to antiegfrtargeted therapy, leading to a new era of treatment for nonsmall cell lung cancer nsclc. Summary mutations of the epidermal growth factor receptor egfr gene have been identified in specimens from patients with nonsmallcell lung cancer who have a response to anilinoquinazoline. The aim of this study was to find a correlation between morphological changes and egfr mutational status using both immunohistochemistry and molecular techniques. Germline exon 21 egfr mutations, v843i and p848l, in. Egfr mutated lung cancer means theres been a change mutation to the egfr protein and this mutation makes cancer cells grow. Dna mutations in egfr as detected by polymerase chain reaction pcr can occur in regions corresponding to the extracellular or intracellular portions of the protein. Epidermal growth factor receptor egfr mutations in lung cancer. Given that more than 60% of nonsmall cell lung carcinomas nsclcs express egfr, egfr has become an important therapeutic target for the treatment of these tumors. Egfr mutation analysis in sputum of lung cancer patients. Targeted therapy using egfr inhibitors has become the standard of care for nonsmall cell lung cancers that contain activating egfr mutations 3, even though not all patients with egfr mutations.
Familial lung cancers more likely have concurrent egfr mutations along with mutations in their germline cancer predisposition genes including. Comutations in egfr driven nonsmall cell lung cancer the lancet. Activating mutations in the epidermal growth factor receptor egfr gene have been identified in 1040% of the patients with nonsmallcell lung cancer nsclc, and egfr inhibition leads to suppression of downstream signalling pathways such as mitogenactivated protein kinase mapk and akt protein kinase pathways. Lung adenocarcinomas with mutated epidermal growth factor receptor have significant responses to tyrosine kinase inhibitors, although for unselected patients it does not appear to have a survival benefit. Molecular diagnosis of activating egfr mutations in non. Gefitinib or erlotinib vs chemotherapy for egfr mutation. Targeting specific cancers in the lungs in the past, doctors thought that all lung cancers were pretty much the same.
Lately, the use of specific antibodies to study the most prevalent of these. Somatically acquired mutations in the epidermal growth factor receptor egfr gene in lung cancer are associated with significant clinical responses to gefitinib. Therapeutic responses of nonsmall cell lung carcinoma nsclc to epidermal growth factor receptor egfr targeted drugs, such as gefitinib and erlotinib, are closely associated with activating egfr mutations. Feb 04, 2010 mutations in epidermal growth factor receptor have been discovered in association with some lung cancers. In nonsmall cell lung cancer, overexpression of egfr or mutations in intracellular egfr have been observed in 4389% of cases 5.
Some, but not all, lung cancers carrying such mutations are responsive to treatment with smallmolecule egfr inhibitors, including the two fdaapproved drugs erlotinib and gefitinib. Clinical correlation and outcome to egfr targeted therapy. Osimertinib for patients with nonsmallcell lung cancer. Management of egfrmutation positive metastatic non. Epidermal growth factor receptor egfr is a transmembrane protein with cytoplasmic kinase activity that transduces important growth factor signaling from the. Egfr mutation testing usually focuses on common mutations like the exon 19 deletion and exon 21 point mutation l858r. Mutations in the tyrosine kinase domain of egfr encoded by exons 1824 have mostly been found in lung cancers. The availability of 3 generations of epidermal growth factor receptor egfr tyrosine kinase inhibitors tkis with different pharmacologic characteristics and clinical profiles has provided oncologists with a potentially confusing choice for the treatment of egfr mutation positive nonsmallcell lung cancer. Egfr mutations as a prognostic and predictive marker in. Pdf egfr mutation analysis in sputum of lung cancer. Epidermal growth factor receptor egfr in lung cancer.
Although recent headtohead clinical trials have demonstrated. Detection of plasma egfr mutations for personalized. Epidermal growth factor receptor in nonsmall cell lung cancer ncbi. Frequent egfr mutations in nonsmall cell lung cancer. Egfr, nsclc, cytological samples, mutation test, arms. Epidermal growth factor receptor egfr is a transmembrane protein with cytoplasmic kinase activity that transduces important growth factor signaling from the extracellular milieu to the cell. From june 2004 to december 2008, we screened newly diagnosed nsclc patients for.
Mutations within the tyrosine kinase domain of egfr gene. Egfr mutations were found in additional lung cancer samples from u. The study of epidermal growth factor receptor mutations has become essential for the treatment of lung cancer. Outcome of uncommon egfr mutation positive newly diagnosed. Tumor mutation burden and efficacy of egfrtyrosine kinase. Patient and methods this was a multicenter, singlearm. Main mechanisms of acquired resistance to egf receptor tyrosine kinase inhibitors. Growth factor receptor egfr gene mutations in a chilean cancer center. Nsclc patients with activating epidermal growth factor receptor egfr mutations, such as exon 19 deletion and exon 21 point mutation l858r, respond signi.
Nonsmallcell lung cancer nsclc has entered the age of individual treatment, and increasing point mutations of specific oncogenes and rearrangement of some chromosomes are biomarkers used to predict the therapeutic effect of targeted therapy. Lung cancer with epidermal growth factor receptor gene egfr mutations accounts for 1020% and 4050% of nsclc cases in caucasians and east asians, respectively 5. Epidermal growth factor receptor egfr is expressed in 50% of nsclcs, and its expression is. Individual patient data metaanalysis of overall survival article in journal of the national cancer institute 1096. Osimertinib for untreated egfr mutationpositive nonsmall. Nonsmall cell lung cancer nsclc represents approximately 85 % of lung cancer cases and about 75 % of them are diagnosed in advanced nsclc ansclc i.
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