Despite pre-clinical data and case reports of response to EGFR inhibitors, the EGFR inhibitor gefitinib does not appear to be effective in the treatment of advanced AML .

EGFR mutations in GBM cluster in the extracellular (EC) domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). In vitro and in vivo studies reveal anchorage-independent growth and tumorigenic potential when the A289 and G598 variants are stably expressed in NIH-3T3 cells. The A289 and G598 mutations sensitize Ba/F3 cells to erlotinib in vitro according to some reports, although other reports state glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). The A289 variant has been reported to show sensitivity towards BAY846, a tyrosine kinase inhibitor in brain tumors. In addition, according to some reports, inhibitors which bind to the inactive EGFR conformation potently inhibit EGFR EC mutants and induce cell death in EGFR mutant GBM cells.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to EGFR inhibitors. Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. Erlotinib Afatinib Gefitinib Osimertinib

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M.

EGFR D770N in Exon 20 has been reported. The significance is unknown.

EGFR exon 20 insertion testing identifies a distinct subset of lung adenocarcinomas, accounting for at least 9% of all EGFR-mutated cases and by molecular modeling, are predicted to have potentially different effects on erlotinib binding. Studies show that in contrast to the more classic activating EGFR mutations, these insertions have been associated with de novo resistance to approved EGFR-TKIs (erlotinib and gefitinib). In a recent study, patients with advanced lung adenocarcinoma harboring exon 20 insertions demonstrated no response or partial response following treatment with TK inhibitors. Exon 20 insertion mutations in EGFR may be associated with clinical trials (https://clinicaltrials.gov/).

EGFR exon 20 insertion testing identifies a distinct subset of lung adenocarcinomas, accounting for at least 9% of all EGFR-mutated cases and by molecular modeling, are predicted to have potentially different effects on erlotinib binding. Studies show that in contrast to the more classic activating EGFR mutations, these insertions have been associated with de novo resistance to approved EGFR-TKIs (erlotinib and gefitinib). In a recent study, patients with advanced lung adenocarcinoma harboring exon 20 insertions demonstrated no response or partial response following treatment with TK inhibitors. This rare complex mutation (p.H773_V774delinsLM) results in the H773L/V774 mutation compound at the same allele, potentially weakening the inactive state and leading to constitutional activation of EGFR. A recent clinical report suggests this mutation is insensitive to the reversible TKI gefitinib, but can be suppressed by the irreversible TKI osimertinib, leading to sustained disease control (Yang et al., Lung Cancer, 121:1-4, 2018). Exon 20 insertion mutations in EGFR may be associated with clinical trials (https://clinicaltrials.gov/).

In GBM, EGFR mutations typically cluster in the extracellular domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). EGFR exon 20 insertions have not been previously reported in GBM. The clinical significance of this mutation with regards to response to anti-EGFR therapy in GBM is unknown. In general, EGFR exon 20 mutations have been reported in approximately 9% of all EGFR-mutated cases of lung cancer and studies show that in contrast to the more classic activating EGFR mutations, these insertions have been associated with de novo resistance or only partial response to approved EGFR-TKIs (erlotinib and gefitinib) in lung cancer.

The EGFR D761 mutation is associated with acquired resistance to EGFR-TKIs (Balak et al., 2006). The functional significance of this alteration is being investigated.

A low frequency mutation detected in lung and gastric cancer. Functional significance of this alteration has not yet been described. However, a single NSCLC patient with this mutation in a clinical trial shows partial response to gefitinb therapy

It is unclear what effect the EGFR P753S varaints has on the EGFR protein. However the location of the variant in the splice site acceptor of Exon 19 may activate the kinase domain. The identification of the EGFR P735S mutation in the context of a dramatic response to cetuximab in a patient with cutaneous squamous cell carcinoma, indicates a new potential pairing of EGFR mutation and targeted therapy for patients with cSCC.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions , EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The L861Q mutation is one of the less common mutations which is an activating mutation that is believed to confer sensitivity to the targeted EGFR tyrosine kinase inhibitors although this mutation may confer reduced response to these inhibitors compared to the more common mutations.

Compound (dual) mutations in EGFR have been previously reported in lung adenocarcinoma and typically include a strong activating mutation combined with a weaker activating mutation. These cases appear to respond well to the EGFR targetted therapies if they include mutations that are known to provide sensitivity to EGFR inhibitor therapies. L858R is a well known activating mutation in exon 21 that is associated with sensitivity to EGFR inhibitors. In vitro functional characterization of mutations at E709 have also been reported to be activivating mutations that are also associated with sensitivity to EGFR inhibitors in vitro. Mutations in E709 often occur together with other muations in EGFR including the L858R mutation.

In GBM, EGFR mutations typically cluster in the extracellular domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). However, the p.E709K mutation in the tyrosine kinase domain of EGFR has not been previously reported in GBM. In vitro functional characterization of mutations at E709 have been reported to be activivating mutations that are associated with sensitivity to EGFR inhibitors in vitro in some cell systems. The clinical significance of this mutation with regards to response to anti-EGFR therapy in GBM is unknown.

Based on reports in the literature, EGFR and KRAS mutations can occasionally coexist in the same bronchial-pulmonary carcinoma. The biological implications of this coexistence are still poorly understood mainly because these cases are not frequent. It is therefore necessary to study larger series of cases with the two mutations to better understand the biological, clinical and therapeutic implications. Patients with coexisting EGFR and KRAS variants may have a partial response to EGFR TKI.

Greater than 40% of glioblastomas (GBM) harbor focal amplification of the EGFR locus and there is evidence to suggest that these are driver alterations in these patients, making the EGFR pathway a potential therapeutic target in some clinical settings. Moreover, this alteration is relatively specific for GBM with very few other diffusely infiltrative gliomas having been shown to carry focal amplification of this locus (<3%). In GBM, this alteration frequently occurs in combination with other alterations of EGFR including polysomy 7, intragenic inframe deletions (e.g. EGFRvIII), and/or somatic point mutations. Based on current evidence, the independent predictive value of EGFR amplification in GBM is unclear. The relationship between individual and concurrent EGFR alterations and clinical response to small molecular inhibitors targeting EGFR is currently under investigation in clinical trials.

EGFR has been reported to show increased expression in a subset of bladder cancers and may be a targetable alteration in some clinical settings.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR tyrosine kinase inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. EGFR S768I (exon 20) occurs in 1–2% of EGFR mutant lung cancers and is often coincident with other EGFR mutations. EGFR S768I is reported to be sensitive to EGFR-TKIs. EGFR G724S (exon 18) is very rare and its significance is unknown.

The epidermal growth factor receptor (EGFR) is a cell surface receptor belonging to the ErbB family tyrosine kinase receptors. EGFR is involved in cell growth control through its role in the two main intracellular pathways, the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase- (PI3K-) protein kinase B (AKT) pathway. The over-expression or mutation of EGFR may be responsible for the constitutive activation of these pathways. In the colorectal cancer, the EGFR has been found to be frequently over expressed, and may be associated with tumor stage and prognosis. In a subset of such patients, the addition of anti-EGFR monoclonal antibodies to the conventional chemotherapeutic regimens may expand response rates and increase progression-free survival. Somatic EGFR mutations are infrequent in colorectal cancers. The frequency varies from 0.34 to 3.3% in Western population, and from 12% to 22.4% in Asians. R776H is a recurrent mutation in the hinge region of the kinase domain and is known to activate EGFR in a ligand independent manner. In some cases, the possibility of R776H variant being of germline origin, cannot be excluded. The clinicopathologic correlation of EGFR mutations in colorectal cancers continues to be explored.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR exon 19 in-frame insertions have been described in about 1% of EGFR-mutant lung cancers. They appear to be more common in nonsmoking women. These exon 19 insertions appear to be sensitizing mutations and have been shown to respond to TKIs in some studies.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR exon 18 mutations account for 3.6% of all the EGFR mutations in lung adenocarcinomas. Of these, G719 mutations account for the majority of them and are sensitive to anti-EGFR inhibitors. Exon 18 deletions are rare (<0.1%) and but they are potentially responsive to anti-EGFR TKIs in some small clinical case studies. Of note, they appeared to be more sensitive to second-generation TKIs, especially afatinib and neratinib, than to first- and third-generation TKIs based on in vitro experiments.

Copy number gain (amplification) of EGFR has been reported in up to 30% of esophageal adenocarcinomas and less than 5% of gastric adenocarcinomas. According to some studies increased EGFR protein expression may be associated with decreased survival. This alteration may have therapeutic implications in some settings.

EGFR mutations have been reported in up to 5% of gastric cancers. The prognostic and predictive implications of EGFR mutations in gastric cancer have not been fully determined. Multiple clinical trials involving EGFR small molecule inhibitors and monoclonal antibodies are present, but limited and conflicting data preclude the therapeutic significance of EGFR mutations in gastric cancer. In NSCLC, an acquired T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. Third generation TKIs (e.g. osimertinib) have been shown to be effective in lung adenocarcinomas with the EGFR T790M mutation. A germline EGFR T790M mutation results in a rare lung cancer hereditary syndrome associated with increased risk in never-smokers. The presence of a germline EGFR T790M mutation also predicts for resistance to standard TKIs. The significance of EGFR T790M in gastric cancer should be considered in a relevant clinical context. Drug Resistance: Afatinib Erlotinib Gefitinib

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR L747P (c.2239_2240 TT>CC) is a rare missense compound substitution mutation in the Exon 19 and has been reported to be resistant to some EGFR inhibitors.

EGFR mutations have been reported in up to 5% of gastric cancers. The prognostic and predictive implications of EGFR mutations in gastric cancer have not been fully determined. Multiple clinical trials involving EGFR small molecule inhibitors and monoclonal antibodies are present, but limited and conflicting data preclude the therapeutic significance of EGFR mutations in gastric cancer.

EGFR mutations have been reported in 1-3% of thyroid cancers. The prognostic and predictive significance of EGFR mutations in thyroid cancer is not clear and correlation with other clinical and laboratory findings is necessary. Clinical trials involving protein kinase inhibitor are available for patients with tumors harboring EGFR mutations.

In colorectal cancer, EGFR gene amplification is associated with sensitivity EGFR-targeted therapies, such as Erbitux and Vectibix.

EGFR mutations have been reported in up to 21% of glioblastoma tumors (GBM). In GBM, EGFR mutations typically cluster in the extracellular domain and include in-frame deletions and missense mutations. However, mutations (such as V774M) in the tyrosine kinase domain of EGFR have been previously reported in GBM. The clinical significance of this mutation with regards to response to TKI therapy in GBM needs further elucidation. Results should be interpreted in conjunction with other laboratory and clinical findings.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR tyrosine kinase inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. EGFR S768I (exon 20) occurs in 1–2% of EGFR mutant lung cancers and is often coincident with other EGFR mutations. S768I and V769L have previously been identified in the same NSCLC tumors. There are conflicting data regarding the sensitivity to EGFR-TKIs of tumors harboring S768I and V769L mutations. Correlation with other clinical and laboratory findings is necessary.

EGFR mutations in GBM cluster in the extracellular (EC) domain and include in-frame deletions (such as the common “variant III” del 6-273) and missense mutations (A289V, A289D, T263P, G598V). Mutations involving residue R108 have been reported in GBM, frequently occurring with other EGFR mutations at amino acids A289, P596, and G598. In vitro studies have shown that R108K mutation leads to increased ligand-binding affinity and shows anchorage-independent growth and tumorigenic potential when stably expressed in NIH-3T3 cells. The predictive and prognostic significance of this mutation at R108 needs further elucidation. Correlation with other clinical and laboratory findings is recommended.

Erlotinib Afatinib Gefitinib

This gene is a known cancer gene.

This gene is a known cancer gene.

The epidermal growth factor receptor (EGFR) is a cell surface receptor belonging to the ErbB family tyrosine kinase receptors. EGFR is involved in cell growth control through its role in the two main intracellular pathways, the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase- (PI3K-) protein kinase B (AKT) pathway. The over-expression or mutation of EGFR may be responsible for the constitutive activation of these pathways. In colorectal cancer, EGFR has been found to be frequently over expressed, and may be associated with tumor stage and prognosis. Somatic EGFR mutations are infrequent in colorectal cancers. The frequency of EGFR mutations in colorectal cancer varies from 0.34 to 3.3% in Western population, and from 12% to 22.4% in Asians. In a subset of patients with EGFR mutations in colorectal cancer, the addition of anti-EGFR monoclonal antibodies to the conventional chemotherapeutic regimens may expand response rates and increase progression-free survival. EGFR V765M lies within the protein kinase domain of the protein. In lung cancer, the V765M has been reported as a sensitizing mutation to EGFR tyrosine kinase inhibitors. The correlation of EGFR gene mutations with clinicopathologic characteristics in colorectal cancers continues to be explored.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR K757M has been reported as a rare variant lung adenocarcinoma, but the significance remains to be elucidated.

EGFR (HER1), epidermal growth factor receptor, is a tyrosine kinase receptor, which activates RAS/RAF/MEK and PI3K/AKT/mTOR pathways, leading to increased cell proliferation and growth. EGFR G721S lies within the protein kinase domain of the EGFR protein. G721S has been identified in the scientific literature in lung cancer, but has not been biochemically characterized and therefore, its effect on EGFR protein function is unknown. EGFR mutations are rare and in prostate adenocarcinoma and are identified in only about 1% of cases. The clinicopathologic significance of the EGFR G721S variant in prostate cancer remains to be fully elucidated.

Afatinib Erlotinib Gefitinib

Afatinib Erlotinib Gefitinib

Sensitive to: Afatinib Erlotinib Gefitinib

Afatinib Erlotinib Gefitinib AP32788

Afatinib Erlotinib Gefitinib

Afatinib Erlotinib Gefitinib

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR exon19 deletions, exon 21 L858R and Exon 18 mutations correlate strongly with sensitivity to specific EGFR inhibitors, and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. Compound (dual) mutations in EGFR have been previously reported in lung adenocarcinoma and typically include a strong activating mutation combined with a weaker activating mutation. These cases appear to respond well to the EGFR targeted therapies. Mutations at E709 in exon 18 often occur together with other mutations in EGFR. This particular complex deletion insertion variant results in both the E709V and G719C in the protein, as well as a K713R variant, which also has been reported previously.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR inhibitors (eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. EGFR Exon 19 deletions, EGFR Exon 21 L858R and EGFR Exon 18 G719 mutations correlate strongly with sensitivity to specific EGFR inhibitors and the response rate to therapy with TKIs has been reported to be up to 80% in such cases. The T790M mutation in exon 20 is associated with resistance to some EGFR inhibitors. However, third generation TKI (eg, osimertinib) can specifically target T790M. EGFR R108K (C.323G>A) is a rare missense mutation in Exon 3. In a study of 1006 lung carcinomas, R108K mutation was found concomitantly with other EGFR mutations - most notably p.L858R (Illei et.al). However, its prognostic and therapeutic significance remains to be fully elucidated.

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR tyrosine kinase inhibitors (TKIs, eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. Exon 20 mutations are more commonly associated with resistance to tyrosine kinase inhibitors (TKIs), but may respond to third generation TKI (eg, osimertinib). This EGFR variant (G796S) lies within the tyrosine kinase domain and has been reported in rare cases of lung adenocarcinomas, squamous cell carcinoma of head and neck and prostate adenocarcinoma. In silico studies suggest G796S mutation may confer resistance to TKIs. However, additional studies are needed to further elucidate the oncogenicity of the mutation and therapeutic implications of this rare variant.