Gene:
EGFR
epidermal growth factor receptor

PharmGKB contains no dosing guidelines for this . To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.



last updated 12/16/2013

FDA Label for afatinib and EGFR

This label is on the FDA Biomarker List
Genetic testing required

Summary

Afatinib (GILOTRIF) is indicated for patients with metastatic non-small cell lung cancer (NSCLC) who have tumors with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test.

There's more of this label. Read more.


last updated 10/25/2013

FDA Label for cetuximab and EGFR, KRAS

This label is on the FDA Biomarker List
Genetic testing required

Summary

Cetuximab is used in alone or in combination therapy to treat advanced squamous cell carcinoma of the head and neck and to treat K-Ras mutation-negative, EGFR expressing metastatic colorectal cancer. In cases of colorectal cancer, the label states "Determine K-Ras mutation and EGFR-expression status using FDA-approved tests prior to initiating treatment."

There's more of this label. Read more.


last updated 10/25/2013

FDA Label for erlotinib and EGFR

This label is on the FDA Biomarker List
Genetic testing required

Summary

TARCEVA (erlotinib) is a kinase inhibitor indicated for First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Information on FDA-approved tests for the detection of EGFR mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

There's more of this label. Read more.


last updated 10/25/2013

FDA Label for gefitinib and EGFR

This label is on the FDA Biomarker List
Informative PGx

Summary

The FDA-approved drug label for gefinitib contains information that no clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to gefitinib.

There's more of this label. Read more.


last updated 10/25/2013

FDA Label for panitumumab and EGFR, KRAS

This label is on the FDA Biomarker List
Genetic testing required

Summary

The panitumumab drug label contains information about EGFR-expressing metastatic colorectal carcinoma with disease progression on or following certain chemotherapy regimens. Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy. The label was updated to include information about treatment of patients with KRAS mutations. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations.

There's more of this label. Read more.


last updated 01/14/2014

FDA Label for regorafenib and EGFR, KRAS, VEGFA

Informative PGx

Summary

The FDA-approved drug label for regorafenib (Stivarga) states that it is intended for patients with metastatic colorectal cancer who were previously given fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if they were KRAS wild type, an anti-EGFR therapy. The label does not specifically mention any form of genetic testing. This drug-biomarker pair was previously in the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" but has subsequently been removed.

There's more of this label. Read more.


last updated 05/02/2014

European Medicines Agency (EMA) Label for afatinib and EGFR

Genetic testing required

Summary

Afatinib (GIOTRIF) is indicated in adult patients with non-small cell lung cancer with activating EGFR mutations. The EMA European Public Assessment Report (EPAR) for afatinib (GIOTRIF) states that EGFR mutation status should be established before initiation of afatinib therapy using a well-validated and robust methodology.

There's more of this label. Read more.


last updated 10/25/2013

European Medicines Agency (EMA) Label for cetuximab and EGFR, KRAS

Genetic testing required

Summary

The EMA European Public Assessment Report (EPAR) highlights information regarding the contraindication of Cetuximab (Erbitux) in colorectal cancer patients with tumors with KRAS mutations or if tumor status is not known.

There's more of this label. Read more.


last updated 10/25/2013

European Medicines Agency (EMA) Label for erlotinib and EGFR, UGT1A1

Genetic testing required

Summary

The EMA European Public Assessment Report (EPAR) requires testing tumours for EGFR mutations in patients with non-small cell lung cancer prior to treatment with erlotinib and recommends using a well-validated method of testing. The drug should be used with caution in patients with low expression of UGT1A1 or Gilbert's disease (caused by genetic variants in UGT1A1 gene), due to the inhibitory effects of erlotinib on glucuronidation by UGT1A1 (UGT1A1 genetic testing is not required).

There's more of this label. Read more.



Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below. Please follow the link in the "Position" column for more information about a particular variant. Each link in the "Position" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the table.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Related Drugs?
EGFR PCR Kit EGFR EGFR: 19 deletions in exon 19 , EGFR L858R , EGFR L861Q , EGFR G719X (detects the presence of G719S , EGFR G719A or G719C but does not distinguish between them) , EGFR S768I , EGFR 3 insertions in exon 20 (detects the presence of any of 3 insertions, but does not distinguish between them)

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page on the appropriate tab.

Links in the "Drugs" column lead to PharmGKB Drug Pages.

Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available CA VA
rs11568315 55020563_55020564CA[9][14][15][16][17][18][19][20][21][22][23]
CACACACACACACACACACACACACACACA > 15
CACACACACACACACACACACACACACACA > 16
CACACACACACACACACACACACACACACA > 17
CACACACACACACACACACACACACACACA > 18
CACACACACACACACACACACACACACACA > 22
CACACACACACACACACACACACACACACA > 23
CACACACACACACACACACACACACACACA > (CA)9
CACACACACACACACACACACACACACACA > 14
CACACACACACACACACACACACACACACA > 20
CACACACACACACACACACACACACACACA > 21
CACACACACACACACACACACACACACACA > 19
Not Available
rs121434568 177791T>G, 2573T>G, 55181822T>G, 55191822T>G, Leu858Arg
T > G
Not Available
Leu858Arg
rs121434569 1193G>A, 167347C>T, 2369C>T, 55171378C>T, 55181378C>T, Thr790Met
C > T
Not Available
Thr790Met
rs2227983 147531G>A, 147531G>C, 147531G>T, 1562G>A, 1562G>C, 1562G>T, 4818624G>A, 4818624G>C, 4818624G>T, 55229255G>A, 55229255G>C, 55229255G>T, Arg521Lys, Arg521Met, Arg521Thr, EGFR: 497G/A, EGFR:1562G>A, EGFR:R497K, R497K, R521K
G > A
G > T
G > C
Missense
Arg521Thr
Arg521Lys
Arg521Met
No VIP available No Clinical Annotations available VA
rs2293347 187192C>T, 2982C>T, 4858285C>T, 55268916C>T, Asp994=
C > T
Synonymous
Asp994Asp
VIP No Clinical Annotations available No Variant Annotations available
rs28929495 159983G>A, 159983G>T, 2155G>A, 2155G>T, 4831076G>A, 4831076G>T, 55241707G>A, 55241707G>T, Gly719Cys, Gly719Ser
G > A
G > T
Missense
Gly719Cys
Gly719Ser
rs712829 -216G>T, 216G>T, 4676124G>T, 5031G>T, 55086755G>T, EGFR:-216G>T
G > T
5' UTR
No VIP available No Clinical Annotations available VA
rs712830 -191A>C, 191C>A, 4676149A>C, 5056A>C, 55086780A>C, EGFR:
A > C
5' UTR
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138

Overview

Alternate Names:  erythroblastic leukemia viral (v-erb-b) oncogene homolog (avian)
Alternate Symbols:  ERBB1
PharmGKB Accession Id: PA7360

Details

Cytogenetic Location: chr7 : p11.2 - p11.2
GP mRNA Boundary: chr7 : 55086725 - 55275031
GP Gene Boundary: chr7 : 55076725 - 55278031
Strand: plus
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for potential regulatory regions.

Introduction

Epidermal growth factor receptor (EGFR) encodes a transmembrane glycoprotein. This protein is a member of the protein kinase superfamily, which consists of EGFR (ErbB1/HER1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). All family members contain an extracellular ligand-binding domain, a single membrane-spanning region, a juxtamembrane nuclear localization signal, and a cytoplasmic tyrosine kinase domain. They are collectively called as HER receptors and are ubiquitously expressed in various cell types, but primarily in those of epithelial, mesenchymal and neuronal origin. Under homeostatic conditions, receptor activation is tightly regulated by the availability of ligands, which together form the epidermal growth factor (EGF) family [Article:11252954]. From those ligands, EGF, transforming growth factor alpha and amphiregulin bind specifically to EGFR [Article:15864276]. Binding of the EGFR or other family members to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. The EGFR involvement in carcinogenesis has been well established and mutations in EGFR can be utilized as predictive markers in the treatment of cancer.

EGFR Gene, Molecular Structure and Function

EGFR maps on chromosome 7p11.2, it covers 188.3 kb, from 55,086,725 to 55,275,031, on the positive strand. EGFR is composed of 28 exons and encodes a protein of 1210 amino acids (ENST00000275493, Ensembl v69) [Article:11752248]. Multiple alternatively spliced transcript variants that encode different protein isoforms have been found [Article:16925834].

EGRF activation by binding of growth factor leads to the autophosphorylation of the intracellular tyrosine kinase domain and results in the formation of receptor homodimers or heterodimers with other HER family members, and the tyrosine phosphorylated residues act as a docking site for various adapter molecules, and resulting in the activation of the downstream signaling pathways [Articles:18375904, 12648464], driving different biological processes including cell cycle progression and differentiation, increased cell invasiveness, apoptosis and angiogenesis [Articles:16014887, 11129168]. Thus, overexpression of EGFR is believed to have a critical role in tumor progression [Articles:16014887, 11129168, 16377102].

The principal cause of cancer-related mortality is lung cancer, and non-small cell lung cancer (NSCLC) constitutes almost 80% of all lung cases. NSCLC is arisen from lung epithelial cells, and comprises diverse histological subtypes including adenocarcinoma, bronchioloalveolar, squamous, anaplastic and large-cell carcinomas, about half of the NSCLC patients manifest advance disease at the time of diagnosis thus making the treatment difficult [Article:18287387]. Various oncogenic mechanisms, including EGFR gene mutations, increased EGFR copy number and EGFR protein overexpression may impair the regulation of tyrosine kinase activity of EGFR in tumor cells [Articles:18337605, 20388064] and may result in increased malignant cell survival, proliferation, invasion and metastasis [Article:19138950]. The current approach is that patients with specific types and stages of cancer should be treated according to standardized, predetermined protocols [Article:22594511]. However, understanding the molecular genesis of NSCLC and advances in the field of pharmacogenomics can lead to a rational use of targeted therapies.

EGFR as cancer drug target

EGFR has been linked to the growth of many human epithelial malignancies, including NSCLC, metastatic colorectal cancer (CRC), head and neck squamous-cell carcinoma (HNSCC), and pancreatic cancer [Articles:16377102, 20551942, 18681783]. Intensive laboratory and clinical research have facilitated development of EGFR inhibitors. There are two main types of EGFR inhibitors; tyrosine kinase inhibitors and monoclonal antibodies against EGFR (http://pharmgkb.org/pathway/PA162356267).

Tyrosine Kinase Inhibitors (TKIs): TKIs are synthetic molecules that block ligand-induced receptor autophosphorylation by binding to the ATP-binding pocket of the intracellular tyrosine kinase domain and disrupting tyrosine kinase activity, thus eliminating intracellular downstream signaling [Articles:18375904, 12648464].

Gefitinib and erlotinib are specific for EGFR, whereas afatinib, lapatinib and neratinib inhibits EGFR (HER1) and HER2; pelitinib inhibits EGFR, HER2 and HER4; and vandetanib inhibits EGFR, vascular endothelial growth factor receptor (VEGFR) and the RET-tyrosine kinases [Article:20551942].

The FDA approved gefitinib through an accelerated process in May 2003 as monotherapy for the treatment advanced NSCLC patients after failure of both platinum-based and docetaxel chemotherapies. As a condition of accelerated approval, the FDA required demonstration of a survival benefit in a subsequent clinical trial. Three large, prospective studies showed no improvement in overall survival [Articles:14990632, 14990633, 16257339], therefore the original FDA approval for gefitinib was modified. Currently gefitinib is indicated as monotherapy for the continued treatment of advanced NSCLC patients after failure of both platinum-based and docetaxel chemotherapies who are benefiting or have benefited from gefitinib (http://dailymed.nlm.nih.gov/dailymed/).

Erlotinib monotherapy is indicated for the treatment of advanced NSCLC patients after failure of prior chemotherapy regimen. FDA also approved erlotinib in combination with gemcitabine for advanced pancreatic cancer patients who have not received previous chemotherapy (http://dailymed.nlm.nih.gov/dailymed/).

Previously, treatment outcomes of erlotinib or gefitinib were studied in unselected patients presenting conflicting results depending on the type of patient population enrolled in each study. However, the discovery that response to erlotinib or gefitinib is associated with the presence of activating somatic EGFR mutations in NSCLC has led to the design of clinical trials in which patients were selected on the basis of the EGFR mutational status [Articles:22594511, 23022519]. This pharmacogenetic approach and its results will be discussed in detail below.

Other TKIs (lapatinib, neratinib, pelitinib and vandetanib) were either approved or in clinical trial phases for cancers other than NSCLC (http://dailymed.nlm.nih.gov/dailymed/). Several clinical trials are continuing for afatinib and preliminary result of one of these trials will be discussed in the context of treatment of advanced NSCLC harboring activating somatic EGFR mutations.

Monoclonal antibodies: Cetuximab and panitumumab are monoclonal antibodies that specifically target the extracellular domain of EGFR. Cetuximab functions by blocking endogenous ligand binding to the extracellular domain of EGFR and enhances receptor internalization and degradation [Articles:6298788, 11255078]. Cetuximab and panitumumab were approved for the treatment of patients, other than NSCLC, with EGFR-expressing metastatic CRC refractory to chemotherapy [Articles:18316547, 19339720, 18003960]. Cetuximab was also approved for the treatment of advanced HNSCC in combination with radiation therapy [Articles:18784101, 16467544]. Since cetuximab and panitumumab block extracellular domain of EGFR, not TK domain, activating mutations might not affect treatment outcome.

Genetic variation of EGFR: Somatic mutations & germline SNPs

Somatic Mutations:

COSMIC database, designed to store somatic mutation information and related details of human cancers was used to explore EGFR somatic mutations (release v62, date of access: 12/03/2012, http://www.sanger.ac.uk/cosmic) [Article:20952405].

Out of 68,986 unique samples deposited in the COSMIC database for EGFR (partial or full sequence and genotype data) including all cancers examined, 13,201 (19.1%) samples had somatic mutations and about 1.3% of all samples has more than one mutation. There are 842 unique location entries for somatic EGFR mutations. Among the mutation bearing patients, six of the mutations have a frequency >= 1% and five has 0.1%-1% frequency, remaining somatic mutations were spread out along EGFR, mostly missense substitutions but there are insertions and deletions as well. All six common somatic mutations (>= 1%) constitutes ~93% of all mutations and are in the tyrosine kinase domain (between 712 and 968 amino acids, exon 18-24) of EGFR (Table 1). The most common one is exon 19 (codon 729-761) mutations, essentially it is not a simple mutation, rather collection of different deletions and a few missense substitutions concentrated on codons 744-753 of exon 19, the most frequent one of this group is E746_A750del mutation. Exon 19 mutations comprise 48.3% of all mutations.

The second common mutation is L858R (rs121434568, T-to-G change at middle base of the codon) and comprises 36.2% of all mutations. Other missense mutations were also observed on this codon in different base(s) as monoallelic or biallelic mutation combinations (L858K, L858M, L858Q, L858R and L858L) in one or few subjects. The third common mutation, T790M (rs121434569) is detected in 3.8% of all mutations. The forth common is exon 20 mutations, a group of different insertions were concentrated at codons 763-774 and this group comprises 2.3% of all mutations. The fifth common one is observed at codon 719; mutation at the first base of codon 719 is in dbSNP as rs28929495 (G719S/G719C) and second base mutations give rise to G719A or G719D; all 719 codon mutations comprises 1.6% of all mutations. The last common mutation, L861Q (rs121913444) comprises ~1% of all mutations. L861R and L861V mutations were also observed on this codon in one or few subjects. The five rare mutations (0.1%-1% frequency) are A289V, G598V, E709K, S768I and L833V; and totaling ~1% of all mutations (Table 1).

Table 1: Incidence of the Common (1%) and Rare (0.1%-1% ) Specific Somatic Mutations of EGFR.

MutationIncidence*
Exon 19 mutations: Collection of different deletions and a few missense substitutions, the most frequent one is E746_A750del48.3%
L858R (rs121434568). Other missense mutations were also observed on this codon in extremely low frequency36.2%
T790M (rs121434569)3.8%
Exon 20 mutations: A group of different insertions concentrated at codons 763-7742.3%
Codon 719 mutation: Mutation at the first base of codon G719S or G719C (rs28929495), 0.82%; Mutation at the second base of codon G719A or G719D, 0.77% 1.6%
L861Q (rs121913444). L861R and L861V mutations were also observed on this codon in extremely low frequency ~1.0%
A289V, G598V, E709K, S768I and L833V: combined incidence ~1.0%
*Incidences are derived from COSMIC database. 68,986 unique samples are deposited for EGFR of which 69% of are from lung cancer tissues.

TK domain of EGFR (exon 18-21) was sequenced or assayed by TaqMan probes for known mutations in other than lung cancers. Although EGFR somatic mutations were not observed in many cancer tissues [Articles:15741570, 16199108, 16353180, 22252115, 22426987], when systematic approaches with more samples were collected as in COSMIC database [Article:20952405], mutations were observed in other cancers tissues. For the EGFR mutations in COSMIC database, the majority of the samples (69% of 68,986 unique samples) are derived from lung cancer tissues and remaining samples are derived from 38 different cancer tissues. EGFR mutations are observed at 7.4% of the lung cancer samples and 1-2% of salivary gland, eye, peritoneum, upper aerodigestive tract, adrenal gland, and thyroid cancer tissues. Of the 39 cancer tissue results deposited, 22 of them have EGFR mutations ranging from 0.1% (pancreas, hematopoietic and stomach tissues) to 7.4% (lung) of their respective tissues.

In a recent study, whole exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs were analyzed and EGFR mutations were observed at 17.5% of patients with a few of them having more than one mutation. The L858R (rs121434568) and exon 19 deletions constituted half of the EGFR mutations [Article:22980975]. In contrast, whole exome sequencing of 31 NSCLC revealed a L858R mutation in only one patient (3.2%) [Article:22510280]. Several somatic mutations were also observed in genes other than EGFR [Articles:22980975, 22510280].

L858R (rs121434568) and exon 19 deletions: EGFR mutations that lead to increased response to epidermal growth factors are called activating mutations, thus having these mutations produce a more significant and persistent activation of intracellular signaling pathways, resulting in increased cell proliferation. On the other hand, lower concentrations of TKIs are required to inhibit TK phosphorylation, because the mutant receptor has reduced ATP affinity that accounts for increased sensitive to drugs as compared with wild type EGFR [Articles:16014887, 15118073, 19147750]. EGFR kinase domain mutations that are clustered around the ATP-binding pocket of the enzyme exon 19 mutations, L858R, G719X (G719C, G719S and G719A) and L861Q increase the kinase activity of EGFR therefore they are activating mutations [Articles:15118073, 19147750]. There are many rare mutations in this region that their functionalities have not been determined. The L858R and exon 19 mutations constitutes ~84.5% of COSMIC, 86.7% [Article:18670300] and 90.9% [Article:17888036] of all mutations, therefore many studies utilize these two mutations in their analysis.

Although prospective studies did not demonstrate increased overall survival [Articles:14990632, 14990633, 16257339] as first-line treatment for NSCLC, several trials have confirmed their clinical usefulness as second- or third-line therapy in advanced NSCLC based on longer progression free survival (PFS) and lower toxicity obtained with TKIs as compared to standard therapy [Articles:16014882, 19027483]. However, clinical responses to both erlotinib and gefitinib differ among NSCLC patients, approximately 10% of patients had clinical responses when treated with TKIs [Articles:14990632, 14990633, 16257339, 16014882, 19027483]. Sequencing of the EGFR in tumor samples from these responders showed somatic gain-of-function (e.g. activating) mutations and this guide to the new clinical trials or retrospective analysis in which patients were chosen depending on the activating EGFR mutational status [Articles:22594511, 23022519].

Clinical responses for NSCLC patients harboring EGFR mutations were evaluated who are treated with TKIs in retrospective or prospective studies. Patients with an activating somatic EGFR mutation had significantly increased response rate (RR)[Articles:22740981, 22370314, 18349398, 17387341, 16956694, 20038723, 16204011, 17047654, 17473659, 17106442, 15897572, 15897572, 16203769, 17317677, 16865253, 16115929, 17285735, 15118073, 22982650, 17285735] and longer progression-free survival (PFS) [Articles:22370314, 18349398, 17387341, 16956694, 22982650, 21969500, 17429313, 17192902, 15897572, 16043828, 17047654, 20038723, 22215752, 22760226] time compared to patients who have no somatic mutation when treated with erlotinib or gefitinib. Although none of the prospective studies reported a statistical overall survival (OS) advantages, in a few relatively small studies analyzed mutational status retrospectively and suggested that OS was increased in mutation harboring East Asian NSCLC patients when treated with gefitinib [Articles:16956694, 17429313, 17192902, 16043828, 16865253, 17106442, 22370314, 22982650]. EGFR mutations were present in most cases of NSCLC patients who responded well to TKIs, yet approximately 10-20% of patients who do show a partial response to gefitinib do not have identifiable EGFR mutations, indicating that EGFR mutations are not the sole determinants of TKI response [Article:17318210]. Most studies presented their results according to activating somatic EGFR mutation status, regardless of the mutation type, but all or majority of the mutations were either rs121434568 (L858R) or exon 19 deletion(s).

Having better clinical output with TKIs in patients with activating EGFR mutations led to new clinical trial design. In prospective phase III randomized trials comparing TKIs and chemotherapy as first-line therapy in patients with advanced NSCLC harbouring activating EGFR mutations, erlotinib [Article:21783417] gefitinib [Articles:20022809, 20573926] and afatinib treatment arms had significantly increased RR and longer PFS time, whereas OS did not show any clinical benefits when compared to standard chemotherapy [Articles:21783417, 20022809, 20573926]. Similarly, in a phase III trial where previously untreated East Asian NSCLC patients who were nonsmoker/former light smokers and treated with gefinitib or carboplatin/paclitaxel (IPASS trial), activating mutation harboring patients treated with gefitinib had significantly longer PFS time compared to carboplatin/paclitaxel group; on the contrary, EGFR mutation negative group had significantly shorter PFS time when treated with gefinitib [Articles:19692680, 21670455]. OS did not differ between two treatments arm (gefitinb vs. carboplatin/paclitaxel)[Article:21670455].

Few studies compared the clinical benefits of common L858R (rs121434568) and exon 19 mutations and failed to show any differential benefits [Articles:21670455, 17106442, 17610986, 16785471] between two types of mutations, except one small study suggested exon 19 deletions group had longer PFS compared to L858R in TKIs treated NSCLC patients [Article:21725039].

Demographic differences of the incidence of EGFR mutations in NSCLC patients were observed. Activating mutations in EGFR are more frequent in women (38% vs. 10% in man), nonsmokers (47% vs. 7% in smokers), adenocarcinomas (30% vs. 2% in non-adenocarcinoma) and Asian populations (26-36% vs. 7-12% in Whites) [Articles:20952405, 19147750, 17888036, 16850125]. EGFR mutations in all NSCLC patients (whether smokers or not) will be important, as inhibition of this receptor has considerable clinical benefits [Article:16850125]. This observation was particularly clear in Asian patients with EGFR mutations treated with gefitinib in the IPASS trial [Article:19692680].

T790M (rs121434569): Acquired resistance to TKIs: The majority of patients with an activating EGFR mutation received clinical benefits when treated with erlotinib/gefitinib, but the magnitude and the duration of the clinical response significantly vary among NSCLC patients [Articles:22594511, 23022519]. Mutation type (L858R vs. exon 19 del) seems to have little effect on the clinical outcome [Articles:21670455, 17106442, 17610986, 16785471]. However, majority of the NSCLC patients will develop resistance to erlotinib/gefitinib treatment and progress, this situation greatly limits the ability of these drugs to significantly prolong patient survival [Articles:22594511, 23022519].

The most frequent mechanism of acquired resistance to TKIs is the T790M (rs121434569) mutation [Articles:15737014, 15728811, 21430269, 18093943, 16258541, 17020982, 17085664, 18981003, 18992959, 19381876, 19589612, 20129249, 21248300, 21921847]. This mutation may reduce the binding capability of TKIs to the TK domain of EGFR by an allosteric mechanism [Article:15728811] and increase the affinity to ATP that requires much higher concentration of TKIs to inhibit EGFR [Article:18227510]. The T790M mutation was originally thought to be acquired by tumors cells during treatment with TKIs, however, when more sensitive methods were used for mutation detection, the presence of T790M mutation was shown in a small fraction of tumors cells before treatment with TKIs and usually co-exists in these cells with other activating mutations [Articles:21248300, 16912157]. The tumor cell clones carrying both the activating and the T790M mutations will eventually develop resistance to the TKIs and will be responsible for the progression or recurrence of the disease, this hypothesis was confirmed in which patients harboring T790M mutation before the start of the treatment had a significantly shorter PFS [Articles:22215752, 21233402, 18596266] and decreased response rate (RR) [Article:16912157] compared with those not having T790M mutation.

The T790M (rs121434569) mutation, along with other secondary mutations in EGFR, was observed as a germline mutation in four siblings of European descent family in which multiple members developed NSCLC [Article:16258541]. Neither T790M mutation was observed in a cohort of ~400 subjects [Article:16258541], nor dbSNP (build 137) presented its existence in general population.

Other resistance mechanism to EGFR-targeted therapy:
The T790M mutation is detectable in about 50% of patients with NSCLC patients who develop resistance to TKIs treatment [Articles:21430269, 18093943, 21248300], and may not explain all resistance cases. One of the mechanisms of resistance to TKIs involves the MET gene amplification that occurs 5-20% of patients [Article:17463250]. MET gene amplification leads to EGFR-independent activation of the PI3K/AKT pathway through MET/ErbB-3 heterodimers and may be responsible for the resistance to TKIs [Article:17463250]. MET amplification in NSCLC was identified in a very small proportion of tumor cells even before exposure to TKIs and this population of cells expands following TKIs treatment [Article:20129249]. The other mechanism involves the KRAS oncogene, which is mutated in approximately 15-30% of NSCLC [Article:16043828]. Mutations in KRAS and those in EGFR seem to be mutually exclusive, and KRAS mutation harboring patients do not respond to TKI therapy [Article:18804418]. KRAS is a downstream mediator of EGFR-induced cell signaling, and mutations confer constitutive activation of the signaling pathway(s), independent of EGFR activation [Article:19636327]. Additional potential mechanisms of resistance to TKIs have been also identified [Article:23022519]. Thus, NSCLC has a significant level of plasticity, being able to activate several different mechanisms leading to resistance to EGFR-TKIs.

EGFR gene copy number and protein expression in NSCLC:
Mutations, gene copy number, and protein expression are three EGFR-related biomarkers that have been extensively studied in clinical trials in order to obtain better predictive and prognostic values for treatment modalities. Although EGFR gene amplification frequently correlates with EGFR protein overexpression and tumor progression [Article:18381415], EGFR gene amplification and protein overexpression studies yielded controversial results in terms of prognostic significance and clinical benefits [Articles:22594511, 23022519, 21969500]. In this respect, the IPASS study (>1200 NSCLC patients) is a cornerstone trial in the assessment of biomarkers associated with EGFR-TKIs activity [Article:21670455]. EGFR mutations are the strongest predictive biomarker for PFS and objective RR to first-line gefitinib versus carboplatin/paclitaxel treatment and post hoc analysis suggested that the predictive value of EGFR gene copy number was driven by coexisting EGFR mutation [Article:21670455].

Germline SNPs:

EGFR contains over 800 SNPs found in >= 1% of samples (dbSNP build 137) and a few of them may have some biological importance.
Intron 1 (CA)n repeat (rs11568315): This is a simple sequence repeat polymorphism, dinucleotides range from 9 to 23, with majority clustered around 15 to 21 CA repeats (dbSNP build 137). Association of intron 1 CA repeat polymorphism to better clinical response in NSCLC patients treated with gefitinib was analyzed in four different studies, all has less than 100 study subjects [Articles:17375033, 19201048, 19473722, 17597605]. 16 or fewer CA repeats were considered short and combined together and, 17 or more CA repeats were considered long. NSCLC patients carrying one or two short alleles are more likely to have better clinical response (increased RR, increased PFS and increased OS) when treated with gefitinib as compared to patients who have two long alleles [Articles:17375033, 19201048, 19473722, 17597605]. Well-powered studies are needed to replicate the beneficial clinical effect of rs11568315 in NSCLC patients.

The -216G>T (rs712829): Patients with GT+TT genotypes are associated with increased PFS time when treated with gefitinib in NSCLC patients [Article:17375033] and, decreased severity of diarrhea when treated with erlotinib in neoplasm patients [Article:18309947] as compared patients with GG genotypes. Both studies involved few patients and well-powered studies are needed to replicate suggested associations [Articles:17375033, 18309947].

GWAS studies on tumor risk and EGFR: Two well-powered genome wide association studies (GWAS) showed that SNPs in EGFR were significantly associated to risk of glioma, most common primary brain tumors [Articles:21531791, 22886559], implications of these finding on treatment of glioma or other cancers are yet to be seen.

Conclusion

Extensive molecular, cancer genome sequencing and recent GWAS studies showed that EGFR is an important gene for many biological process and tumorigenesis. Better clinical output can be obtained in NSCLC patients who are harboring activating somatic EGFR mutations who are treated with TKIs. Nevertheless, additional therapies are needed for those patients who are wild type for the EGFR gene. Clinical & treatment associations with germline EGFR SNPs are not strong, more studies are necessary to clarify the role of germline SNPs in treatment of NSCLC.

Citation PharmGKB summary: very important pharmacogene information for the epidermal growth factor receptor. Pharmacogenetics and genomics. 2013. Hodoglugil Ugur, Carrillo Michelle W, Hebert Joan M, Karachaliou Niki, Rosell Rafael C, Altman Russ B, Klein Teri E. PubMed
History

Submitted by Ugur Hodoglugil

Variant Summaries rs121434568, rs121434569, rs2227983, rs28929495, rs712829
Drugs
Diseases
Pathways

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

  1. EGFR Inhibitor Pathway, Pharmacodynamics
    Model non-tissue specific cancer cell displaying genes that may be involved in the treatment using epidermal growth factor receptor specific tyrosine kinase inhibitors or monoclonal antibodies.
  1. Erlotinib Pathway, Pharmacokinetics
    Model human liver cell showing genes involved in the transportation and metabolism of Erlotinib.

External Pathways

Links to non-PharmGKB pathways.

  1. a6b1 and a6b4 Integrin signaling - (Pathway Interaction Database NCI-Nature Curated)
  2. agrin in postsynaptic differentiation - (BioCarta via Pathway Interaction Database)
  3. angiotensin ii mediated activation of jnk pathway via pyk2 dependent signaling - (BioCarta via Pathway Interaction Database)
  4. Arf6 signaling events - (Pathway Interaction Database NCI-Nature Curated)
  5. cbl mediated ligand-induced downregulation of egf receptors pathway - (BioCarta via Pathway Interaction Database)
  6. E-cadherin signaling events - (Pathway Interaction Database NCI-Nature Curated)
  7. E-cadherin signaling in keratinocytes - (Pathway Interaction Database NCI-Nature Curated)
  8. egf signaling pathway - (BioCarta via Pathway Interaction Database)
  9. EGFR downregulation - (Reactome via Pathway Interaction Database)
  10. EGFR interacts with phospholipase C-gamma - (Reactome via Pathway Interaction Database)
  11. EGFR-dependent Endothelin signaling events - (Pathway Interaction Database NCI-Nature Curated)
  12. Gab1 signalosome - (Reactome via Pathway Interaction Database)
  13. Grb2 events in EGFR signaling - (Reactome via Pathway Interaction Database)
  14. keratinocyte differentiation - (BioCarta via Pathway Interaction Database)
  15. LPA receptor mediated events - (Pathway Interaction Database NCI-Nature Curated)
  16. map kinase inactivation of smrt corepressor - (BioCarta via Pathway Interaction Database)
  17. mcalpain and friends in cell motility - (BioCarta via Pathway Interaction Database)
  18. Regulation of Telomerase - (Pathway Interaction Database NCI-Nature Curated)
  19. role of egf receptor transactivation by gpcrs in cardiac hypertrophy - (BioCarta via Pathway Interaction Database)
  20. Shc events in EGFR signaling - (Reactome via Pathway Interaction Database)
  21. Signaling by EGFR - (Reactome via Pathway Interaction Database)
  22. Signaling events mediated by PTP1B - (Pathway Interaction Database NCI-Nature Curated)
  23. sprouty regulation of tyrosine kinase signals - (BioCarta via Pathway Interaction Database)
  24. Syndecan-3-mediated signaling events - (Pathway Interaction Database NCI-Nature Curated)
  25. Thromboxane A2 receptor signaling - (Pathway Interaction Database NCI-Nature Curated)
  26. trefoil factors initiate mucosal healing - (BioCarta via Pathway Interaction Database)
No related genes are available

Curated Information ?

Curated Information ?

Publications related to EGFR: 124

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Prospective study of EGFR intron 1 (CA)n repeats variants as predictors of benefit from cetuximab and irinotecan in chemo-refractory metastatic colorectal cancer (mCRC) patients. The pharmacogenomics journal. 2014. Loupakis F, et al. PubMed
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Identification of a candidate single-nucleotide polymorphism related to chemotherapeutic response through a combination of knowledge-based algorithm and hypothesis-free genomic data. Journal of bioscience and bioengineering. 2013. Takahashi Hiro, et al. PubMed
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Clinical Implementation of Germline Cancer Pharmacogenetic Variants during the Next-Generation Sequencing Era. Clinical pharmacology and therapeutics. 2013. Gillis Nancy K, et al. PubMed
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The integrated landscape of driver genomic alterations in glioblastoma. Nature genetics. 2013. Frattini Veronique, et al. PubMed
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Emerging landscape of oncogenic signatures across human cancers. Nature genetics. 2013. Ciriello Giovanni, et al. PubMed
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PharmGKB summary: very important pharmacogene information for the epidermal growth factor receptor. Pharmacogenetics and genomics. 2013. Hodoglugil Ugur, et al. PubMed
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Intergenic polymorphisms in the amphiregulin gene region as biomarkers in metastatic colorectal cancer patients treated with anti-EGFR plus irinotecan. The pharmacogenomics journal. 2013. Sebio A, et al. PubMed
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Challenges in pharmacogenetics. European journal of clinical pharmacology. 2013. Cascorbi Ingolf, et al. PubMed
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Pharmacogenetics and pharmacogenomics: a bridge to individualized cancer therapy. Pharmacogenomics. 2013. Weng Liming, et al. PubMed
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ELF5 Suppresses Estrogen Sensitivity and Underpins the Acquisition of Antiestrogen Resistance in Luminal Breast Cancer. PLoS biology. 2012. Kalyuga Maria, et al. PubMed
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A Novel Fully Automated Molecular Diagnostic System (AMDS) for Colorectal Cancer Mutation Detection. PloS one. 2013. Kitano Shiro, et al. PubMed
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Pharmacogenomics knowledge for personalized medicine. Clinical pharmacology and therapeutics. 2012. Whirl-Carrillo M, et al. PubMed
Impact of Systematic EGFR and KRAS Mutation Evaluation on Progression-Free Survival and Overall Survival in Patients with Advanced Non-Small-Cell Lung Cancer Treated by Erlotinib in a French Prospective Cohort (ERMETIC Project-Part 2). Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2012. Cadranel Jacques, et al. PubMed
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Should epidermal growth factor receptor tyrosine kinase inhibitors be considered ideal drugs for the treatment of selected advanced non-small cell lung cancer patients?. Cancer treatment reviews. 2012. Rossi Antonio, et al. PubMed
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Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012. Imielinski Marcin, et al. PubMed
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Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation. Cancer chemotherapy and pharmacology. 2012. Cho Su-Hee, et al. PubMed
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Pharmacogenetics and pharmacogenomics: role of mutational analysis in anti-cancer targeted therapy. The pharmacogenomics journal. 2012. Savonarola A, et al. PubMed
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Multifactorial pharmacogenetic analysis in colorectal cancer patients receiving 5-fluorouracil-based therapy together with cetuximab-irinotecan. British journal of clinical pharmacology. 2012. Etienne-Grimaldi Marie-Christine, et al. PubMed
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Pharmacogenetics of EGFR in lung cancer: perspectives and clinical applications. Pharmacogenomics. 2012. Mayo Clara, et al. PubMed
First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012. Han Ji-Youn, et al. PubMed
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Plasma epidermal growth factor receptor mutation analysis and possible clinical applications in pulmonary adenocarcinoma patients treated with erlotinib. Oncology letters. 2012. Chen Yuh-Min, et al. PubMed
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Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. The lancet oncology. 2012. Rosell Rafael, et al. PubMed
Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012. Su Kang-Yi, et al. PubMed
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Pharmacogenetic analysis of BR.21, a placebo-controlled randomized phase III clinical trial of erlotinib in advanced non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2012. Liu Geoffrey, et al. PubMed
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Epidermal growth factor receptor mutation status in circulating free DNA in serum: from IPASS, a phase III study of gefitinib or carboplatin/paclitaxel in non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2012. Goto Koichi, et al. PubMed
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Quality of life with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis of North East Japan Study Group 002 Trial. The oncologist. 2012. Oizumi Satoshi, et al. PubMed
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Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity. The pharmacogenomics journal. 2011. Parmar S, et al. PubMed
Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011. Brugger Wolfram, et al. PubMed
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A noninvasive system for monitoring resistance to epidermal growth factor receptor tyrosine kinase inhibitors with plasma DNA. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2011. Nakamura Tomomi, et al. PubMed
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. The lancet oncology. 2011. Zhou Caicun, et al. PubMed
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Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011. Fukuoka Masahiro, et al. PubMed
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A phase 2 trial of erlotinib in patients with previously treated squamous cell and adenocarcinoma of the esophagus. Cancer. 2011. Ilson David H, et al. PubMed
Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011. Rosell Rafael, et al. PubMed
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Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011. Arcila Maria E, et al. PubMed
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Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational medicine. 2011. Sequist Lecia V, et al. PubMed
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Genomics and drug response. The New England journal of medicine. 2011. Wang Liewei, et al. PubMed
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Functional EGFR germline polymorphisms may confer risk for EGFR somatic mutations in non-small cell lung cancer, with a predominant effect on exon 19 microdeletions. Cancer research. 2011. Liu Wanqing, et al. PubMed
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Gender-specific genomic profiling in metastatic colorectal cancer patients treated with 5-fluorouracil and oxaliplatin. Pharmacogenomics. 2011. Gordon Michael A, et al. PubMed
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Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics. Pharmacogenomics. 2011. Becquemont Laurent, et al. PubMed
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Pharmacogenetic tests in cancer chemotherapy: what physicians should know for clinical application. The Journal of pathology. 2011. Lee Soo-Youn, et al. PubMed
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Pharmacogenomic contribution to drug response. Cancer journal (Sudbury, Mass.). 2011. Watson Roshawn G, et al. PubMed
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Use of epidermal growth factor receptor mutation analysis in patients with advanced non-small-cell lung cancer to determine erlotinib use as first-line therapy. PLoS currents. 2011. Ishibe Naoko, et al. PubMed
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Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy. The pharmacogenomics journal. 2010. Kim H K, et al. PubMed
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Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. PubMed
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A large-scale candidate gene approach identifies SNPs in SOD2 and IL13 as predictive markers of response to preoperative chemoradiation in rectal cancer. The pharmacogenomics journal. 2010. Ho-Pun-Cheung A, et al. PubMed
Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. The New England journal of medicine. 2010. Maemondo Makoto, et al. PubMed
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Targeted cancer therapies in the twenty-first century: lessons from imatinib. Clinical pharmacology and therapeutics. 2010. Stegmeier F, et al. PubMed
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Acquired resistance to gefitinib: the contribution of mechanisms other than the T790M, MET, and HGF status. Lung cancer (Amsterdam, Netherlands). 2010. Onitsuka Takamitsu, et al. PubMed
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Predictors of gefitinib outcomes in advanced non-small cell lung cancer (NSCLC): study of a comprehensive panel of molecular markers. Lung cancer (Amsterdam, Netherlands). 2010. Tiseo Marcello, et al. PubMed
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Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010. Douillard Jean-Yves, et al. PubMed
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. The lancet oncology. 2010. Mitsudomi Tetsuya, et al. PubMed
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SNPs in genes coding for ROS metabolism and signalling in association with docetaxel clearance. The pharmacogenomics journal. 2010. Edvardsen H, et al. PubMed
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Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer cell. 2010. Turke Alexa B, et al. PubMed
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Association of EGFR and HER2 polymorphisms with risk and clinical features of thyroid cancer. Genetic testing and molecular biomarkers. 2009. Rebaï Maha, et al. PubMed
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The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38. International journal of cancer. Journal international du cancer. 2009. LaBonte Melissa J, et al. PubMed
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Clinicopathologic and molecular features of epidermal growth factor receptor T790M mutation and c-MET amplification in tyrosine kinase inhibitor-resistant Chinese non-small cell lung cancer. Pathology oncology research : POR. 2009. Chen Hua-Jun, et al. PubMed
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Grb7 upregulation is a molecular adaptation to HER2 signaling inhibition due to removal of Akt-mediated gene repression. PloS one. 2010. Nencioni Alessio, et al. PubMed
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Evolving novel anti-HER2 strategies. The lancet oncology. 2009. Jones Kellie L, et al. PubMed
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Polymorphisms of EGFR predict clinical outcome in advanced non-small-cell lung cancer patients treated with Gefitinib. Lung cancer (Amsterdam, Netherlands). 2009. Ma Fei, et al. PubMed
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The increasing role of pharmacogenetics in the treatment of gastrointestinal cancers. Gastrointestinal cancer research : GCR. 2009. Yalçin Suayib. PubMed
Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The New England journal of medicine. 2009. Mok Tony S, et al. PubMed
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Screening for epidermal growth factor receptor mutations in lung cancer. The New England journal of medicine. 2009. Rosell Rafael, et al. PubMed
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Clinically available pharmacogenomics tests. Clinical pharmacology and therapeutics. 2009. Flockhart D A, et al. PubMed
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Prospective phase II study of gefitinib in non-small cell lung cancer with epidermal growth factor receptor gene mutations. Lung cancer (Amsterdam, Netherlands). 2009. Sugio Kenji, et al. PubMed
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Beyond trastuzumab: overcoming resistance to targeted HER-2 therapy in breast cancer. Current cancer drug targets. 2009. Bedard Philippe L, et al. PubMed
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Personalized cancer therapy gets closer. Nature. 2009. Hayden Erika Check. PubMed
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Measurements of EGFR expression on circulating tumor cells are reproducible over time in metastatic breast cancer patients. Pharmacogenomics. 2009. Payne Rachel E, et al. PubMed
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Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC). BMC cancer. 2009. Glaysher Sharon, et al. PubMed
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Genetic polymorphisms in the EGFR (R521K) and estrogen receptor (T594T) genes, EGFR and ErbB-2 protein expression, and breast cancer risk in Tunisia. Journal of biomedicine & biotechnology. 2009. Kallel Imen, et al. PubMed
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Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008. Costa Daniel B, et al. PubMed
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Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008. Kim Edward S, et al. PubMed
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An integrated genomic analysis of human glioblastoma multiforme. Science (New York, N.Y.). 2008. Parsons D Williams, et al. PubMed
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Somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine kinase inhibitor response to TKIs in non-small cell lung cancer: an analytical database. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2008. Murray Samuel, et al. PubMed
Detection of mutations in EGFR in circulating lung-cancer cells. The New England journal of medicine. 2008. Maheswaran Shyamala, et al. PubMed
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First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008. Sequist Lecia V, et al. PubMed
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Tumor suppressor FUS1 signaling pathway. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2008. Ji Lin, et al. PubMed
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The cancer biomarker problem. Nature. 2008. Sawyers Charles L. PubMed
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Epidermal growth factor receptor polymorphisms and clinical outcomes in non-small-cell lung cancer patients treated with gefitinib. The pharmacogenomics journal. 2008. Liu G, et al. PubMed
Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008. Miller Vincent A, et al. PubMed
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Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008. Graziano Francesco, et al. PubMed
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Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008. Rudin Charles M, et al. PubMed
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Emerging concepts of regulation of angiotensin II receptors: new players and targets for traditional receptors. Arteriosclerosis, thrombosis, and vascular biology. 2007. Mogi Masaki, et al. PubMed
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Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer science. 2007. Mitsudomi Tetsuya, et al. PubMed
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Pharmacogenetics of EGFR and VEGF inhibition. Drug discovery today. 2007. Pander Jan, et al. PubMed
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Impact of EGFR gene polymorphisms on anticancer drug cytotoxicity in vitro. Molecular diagnosis & therapy. 2008. Puyo Stéphane, et al. PubMed
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MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proceedings of the National Academy of Sciences of the United States of America. 2007. Bean James, et al. PubMed
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Relationship of EGFR mutations, expression, amplification, and polymorphisms to epidermal growth factor receptor inhibitors in the NCI60 cell lines. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007. Liu Wanqing, et al. PubMed
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Efficacy and safety of single-agent pertuzumab, a human epidermal receptor dimerization inhibitor, in patients with non small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007. Herbst Roy S, et al. PubMed
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Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib (IRESSA). British journal of cancer. 2007. Kimura H, et al. PubMed
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The epidermal growth factor receptor intron1 (CA) n microsatellite polymorphism is a potential predictor of treatment outcome in patients with advanced lung cancer treated with Gefitinib. European journal of pharmacology. 2007. Nie Qiang, et al. PubMed
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Trastuzumab--mechanism of action and use in clinical practice. The New England journal of medicine. 2007. Hudis Clifford A. PubMed
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Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: a meta-analysis based on updated individual patient data from six medical centers in mainland China. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2007. Wu Yi-Long, et al. PubMed
Intron 1 CA dinucleotide repeat polymorphism and mutations of epidermal growth factor receptor and gefitinib responsiveness in non-small-cell lung cancer. Pharmacogenetics and genomics. 2007. Han Sae-Won, et al. PubMed
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MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science (New York, N.Y.). 2007. Engelman Jeffrey A, et al. PubMed
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Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2007. Hirsch F R, et al. PubMed
Predictive factors associated with prolonged survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib. British journal of cancer. 2007. Satouchi M, et al. PubMed
The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer. International journal of cancer. Journal international du cancer. 2007. Ichihara Shuji, et al. PubMed
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Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. The oncologist. 2007. Sequist Lecia V, et al. PubMed
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Gefitinib for non-small-cell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp. British journal of cancer. 2006. Sutani A, et al. PubMed
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Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006. Balak Marissa N, et al. PubMed
Clinical predictors versus epidermal growth factor receptor mutation in gefitinib-treated non-small-cell lung cancer patients. Lung cancer (Amsterdam, Netherlands). 2006. Han Sae-Won, et al. PubMed
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Novel heteroduplex method using small cytology specimens with a remarkably high success rate for analysing EGFR gene mutations with a significant correlation to gefitinib efficacy in non-small-cell lung cancer. British journal of cancer. 2006. Oshita F, et al. PubMed
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Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006. Kosaka Takayuki, et al. PubMed
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Evaluation of the epidermal growth factor receptor gene mutation and copy number in non-small cell lung cancer with gefitinib therapy. Oncology reports. 2006. Endo Katsuhiko, et al. PubMed
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Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer research. 2006. Inukai Michio, et al. PubMed
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Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab. Pharmacogenetics and genomics. 2006. Zhang Wu, et al. PubMed
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Lack of somatic mutations in EGFR tyrosine kinase domain in hepatocellular and nasopharyngeal carcinoma. Pharmacogenetics and genomics. 2006. Lee Soo-Chin, et al. PubMed
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Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nature genetics. 2005. Bell Daphne W, et al. PubMed
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Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005. Bell Daphne W, et al. PubMed
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Clinicopathologic significance of the mutations of the epidermal growth factor receptor gene in patients with non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2005. Tomizawa Yoshio, et al. PubMed
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Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005. Eberhard David A, et al. PubMed
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Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clinical cancer research : an official journal of the American Association for Cancer Research. 2005. Taron Miguel, et al. PubMed
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Erlotinib in previously treated non-small-cell lung cancer. The New England journal of medicine. 2005. Shepherd Frances A, et al. PubMed
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Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2005. Chou Teh-Ying, et al. PubMed
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A functional common polymorphism in a Sp1 recognition site of the epidermal growth factor receptor gene promoter. Cancer research. 2005. Liu Wanqing, et al. PubMed
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EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proceedings of the National Academy of Sciences of the United States of America. 2004. Pao William, et al. PubMed
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Induction of apoptosis by ionizing radiation and CI-1033 in HuCCT-1 cells. Biochemical and biophysical research communications. 2004. Murakami Masateru, et al. PubMed
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EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, N.Y.). 2004. Paez J Guillermo, et al. PubMed
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Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England journal of medicine. 2004. Lynch Thomas J, et al. PubMed
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Phosphorylation of extracellular signal-regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3 are differently inhibited by an epidermal growth factor receptor inhibitor, EKB-569, in tumor cells and normal human keratinocytes. Molecular cancer therapeutics. 2004. Nunes Maria, et al. PubMed
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Antagonism of rat beta-cell voltage-dependent K+ currents by exendin 4 requires dual activation of the cAMP/protein kinase A and phosphatidylinositol 3-kinase signaling pathways. The Journal of biological chemistry. 2003. MacDonald Patrick E, et al. PubMed
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Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism. Clinical cancer research : an official journal of the American Association for Cancer Research. 2003. Liu Wanqing, et al. PubMed
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The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Molecular cancer therapeutics. 2001. Rusnak D W, et al. PubMed
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Anti-oestrogen stimulation of ERBB2 ectodomain shedding from BT-474 human breast cancer cells with ERBB2 gene amplification. European journal of cancer (Oxford, England : 1990). 1996. Wärri A M, et al. PubMed

LinkOuts

UniProtKB:
EGFR_HUMAN (P00533)
Ensembl:
ENSG00000146648
GenAtlas:
EGFR
GeneCard:
EGFR
MutDB:
EGFR
ALFRED:
LO004625R
HuGE:
EGFR
Comparative Toxicogenomics Database:
1956
ModBase:
Q9GZX1
HumanCyc Gene:
HS07358
HGNC:
3236

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