The Landscape of EGFR Pathways and Personalized Management of Non-small-cell Lung Cancer

Liang Cheng; Shaobo Zhang; Riley Alexander; Yongxue Yao; Gregory T MacLennan; Chong-xian Pan; Jiaoti Huang; Mingsheng Wang; Rodolfo Montironi; Antonio Lopez-Beltran


Future Oncol. 2011;7(4):519-541. 

In This Article

EGFR Pathway Alteration & Implications

EGFR, located at chromosome 7p12, spans approximately 200 kb and contains 28 exons. It is a member of the ErbB family of four closely related TK receptors: EGFR (ErbB1), HER2/c-neu (ErbB2), HER3 (ErbB3) and HER4 (ErbB4).[42,43] EGFR is activated by binding of its specific ligands. Structurally, EGFR is composed of an N-terminal extracellular ligand-binding domain, a transmembrane lipophilic segment, and a C-terminal intracellular region containing a TK domain. Multiple ligands that bind and activate EGFR have been described, including EGF and TGF-α. Upon ligand binding to EGFR, the receptors form homo- or hetero-dimers, which activate their intrinsic intracellular protein TK. The ligand binding-induced dimerization results in cross-autophosphorylation of key tyrosine residues in the cytoplasmic domain, which function as docking sites for downstream signal transducers.[44] This activation of EGFR results in initiation of signaling cascades involving several downstream pathways.[4,26,45–50] Through its influence on these pathways, EGFR induces a number of crucial cellular responses, such as proliferation, differentiation, motility and enhanced cell survival (Figure 2).[50–53]

Figure 2.

EGFR and its signaling pathway. Structurally, an EGF receptor (EGFR) monomer is composed of an extracellular domain consisting of two ligand-binding subdomains: a transmembrane lipophilic segment and an intracellular region containing tyrosine kinase domains that occupy exons 18–24. The binding of ligands to EGFR results in autophosphorylation of key tyrosine residues in the cytoplasmic domain and activation of its intrinsic, intracellular protein tyrosine kinase activity. EGFR activation results in initiation of signaling cascades. These function to further modulate cell proliferation and survival through two downstream intermediate pathways: the PI3K–AKT–mTOR pathway and the RAS–RAF–MEK–MAPK pathway. These two intermediate pathways influence several key aspects of the cell cycle that include cell proliferation, apoptosis, migration and survival, and more complex processes such as angiogenesis.
P: Phosphorylation.

One of the major molecular alterations in the carcinogenesis of NSCLC is the activation mutation of EGFR. The mechanisms that regulate EGFR expression, such as epigenetic alteration and aberrant transcription factors, have been studied, but with inconclusive results. The significance of miRNA-128b was reported by Weiss et al., who found loss of miRNA-128b in two out of three NSCLC cell lines and in tumors from 55% of NSCLC patients.[54] miRNA-128b directly regulated EGFR expression, and loss of miRNA-128b correlated with better tumor responsiveness to gefitinib treatment and improved survival (23.4 vs 10.5 months).[54]

A strong genetic association with particular germline mutations has been shown to influence the susceptibility to EGFR TKIs (i.e., those that confer mutations in EGFR signaling). Liu et al. found that the frequencies of the -216T and CA-19 alleles are significantly higher in patients with any mutation, in particular in those with exon 19 microdeletions.[55] The -216T allele is preferentially amplified in human lung cancer specimens and cancer cell lines. These results suggest that the local haplotype structures across the EGFR gene may favor the development of carcinogenesis and thus significantly confer risk to the occurrence of EGFR mutations in NSCLC, particularly the exon 19-microdeleted cases.[55] A novel germline transmission of the EGFR mutation V843I in a family with multiple members with lung cancer has been reported.[56] The proband was a 70-year-old woman who had multiple adenocarcinomas with EGFR mutations. These observations suggest that germline EGFR V843I mutation may result in altered EGFR signaling in cases of multicentric adenocarcinoma, bronchioloalveolar carcinoma and atypical adenomatous hyperplasia, and may also play a role in the development of lung cancer in multiple family members.[56]

EGFR plays a key role in the growth and survival of many solid tumor types.[21,57] Mutations affecting EGFR activity or expression can result in cancer.[58] The EGFR TK modulates cell proliferation and survival through two downstream intermediate pathways: the PI3K–AKT–mTOR pathway and the RAS–RAF–MEK–MAPK pathway.[59] These downstream cell signaling pathways influence several critical cellular processes, including cell proliferation, apoptosis, migration and survival. They are also involved in more complex processes such as angiogenesis and tumorigenesis. Studies on EGFR oncogene activation have been focused on gene mutations, DNA copy number alterations, protein expression alterations and genetic alterations of downstream signaling molecules.

Results from a Phase III trial evaluating the EGFR TKI, gefitinib, indicated that approximately 10% of patients responded to the therapy, and no survival benefit was observed.[30] Follow-up analysis identified mutations in the TK domain of EGFR in eight out of nine responders, whereas no mutations were detectable in seven patients who did not respond to gefitinib therapy.[12]

The most widely used EGFR TKIs are gefitinib and erlotinib. These agents are reversible inhibitors that compete with ATP at the active site of the TK receptor domain.[6] They are primarily used in patients who have failed platinum-based chemotherapy.[60] In a randomized Phase III study, erlotinib significantly improved median survival from 4.7 (placebo) to 6.7 months in patients with NSCLC who had previously failed one or two chemotherapy regimens.[61] Gefitinib improved disease-related symptoms in heavily pretreated symptomatic patients with NSCLC.[30] However, in the Phase III Iressa Survival Evaluation in Advanced Lung Cancer (ISEL) trial, which included pretreated patients with recurrent disease, gefitinib failed to demonstrate a survival benefit in the overall unselected patient population compared with placebo-treated controls.[62] Recently, however, results from the randomized Phase III IRESSA NSCLC Trial Evaluating Response and Survival against Taxotere (INTEREST) indicate that gefitinib is not inferior to docetaxel in terms of overall survival, suggesting that this TKI may also be a viable option for previously treated patients with advanced NSCLC.[63]

The data from 222 publications indicate that EGFR mutations are predictive of patient response to single-agent EGFR TKI treatment in advanced NSCLC.[64]

EGFR Mutations

The EGFR mutations responsible for the constitutive activation of receptor TK are also most frequently associated with sensitivity to EGFR TKIs.[65] These mutations are associated with response rates of >70% in patients treated with either erlotinib or gefitinib.[28,66]

Receptors containing different mutations appear to have different signaling properties, but most mutations seem to affect the ATP-binding cleft, which is also where targeting TKIs bind (Figure 3).[49]

Figure 3.

Mechanism of EGFR-activating mutations and EGFR-targeted therapy. (A) EGFR mutations render EGFR tyrosine kinase constitutively activated. Activated EGFR phosphorylates key tyrosine residues (P) in the tyrosine domain, which initiates downstream effectors. (B) At present, two categories of agents are used for inhibiting EGFR signaling: humanized antibodies and small-molecule TKIs. Antibodies inhibit ligand-dependent activation of EGFR by blocking the ligand-binding site and preventing activation. TKIs block the magnesium–ATP-binding pocket of the intracellular tyrosine kinase domain, further inhibiting autophosphorylation. This inhibition disrupts tyrosine kinase activity and abrogates intracellular downstream signaling.
TKI: Tyrosine kinase inhibitor.

In vitro studies have demonstrated that mutant EGFR has enhanced TK activity, leading to a greater sensitivity to anti-EGFR inhibition. As mentioned previously, the four most common mutations seem to be those most closely associated with TKI sensitivity. The discovery that many objective responders to TKIs harbored EGFR mutations in exons 19 and 21 was a major breakthrough in patient selection for EGFR targeting therapy.[67,68] The most frequent mutation, located in exon 19, eliminates four amino acids – leucine, arginine, glutamic acid and alanine – downstream from the lysine residue at position 745.[67,69–72] Patients with an EGFR mutation who were treated with TKI had much higher response rates and longer progression-free survival than those without a mutation (Table 1).[69]

Both retrospective and prospective studies have demonstrated that NSCLC patients carrying the described EGFR gene mutations have a significantly higher response rate to gefitinib and/or erlotinib compared with patients with wild-type EGFR.[12,15,16,28,67,68,73–76] Some patients experienced rapid complete or partial responses that were durable.[26] The discovery of somatic mutations in EGFR that correlated with sensitivity to TKIs identified a plausible and reproducible explanation for these observations.

The most commonly used methods to detect mutations are direct sequencing and real-time PCR.[73,77] Other methods include single-strand conformational polymorphism analysis[78,79] and high-resolution melting amplicon analysis.[17,80] Scorpion ARMS® (QIAGEN, Germany), a multitargeted real-time PCR detection kit, allows the detection of the most prevalent somatic mutations in the EGFR that are common in human cancers. The high sensitivity and specificity of the kit permits the detection of mutations against a background of wild-type genomic DNA. The kit uses DxS Scorpions® (QIAGEN) technology to detect exon 19 deletions and mutations in exons 19–21 (T790M, L858R, L861Q, G719X and S768I) and any one of three insertions into exon 19 (2307_2308ins9, 2319_2320insCAC and 2310_2311insGGT). Relative to the direct sequencing method, the other two techniques allow for the rapid detection of EGFR mutations with high sensitivity and specificity. However, confirmation of mutations via direct sequencing is necessary.[24,80,81] Standardization is essential for the clinical application of EGFR mutation tests. However, at present, there is no official guideline for these EGFR mutation tests. The number of mutation sites that are needed in the testing protocol still remains to be established. Large-scale clinical trials are also needed.

Jackman et al. studied 223 chemotherapy-naive patients with advanced NSCLC.[28] Sensitizing EGFR mutations were associated with a 67% response rate, with a time to progression (TTP) of 11.8 months and overall survival of 23.9 months. Exon 19 deletions were associated with a longer median TTP and overall survival compared with L858R (exon 21) mutations. Wild-type EGFR was associated with poor outcomes (response rate: 3%; TTP: 3.2 months), irrespective of KRAS status. EGFR genotype was more effective than clinical characteristics at selecting appropriate patients for consideration of first-line therapy with an EGFR TKI.

Studies indicate that more than 75% of patients responsive to TKI therapy have activating mutations in EGFR.[13,77] However, some rare types of EGFR mutations can confer resistance to EGFR-targeted therapies after treatment with TKIs when combined with the common activating mutations.[82–85] Clinically, patients with EGFR exon 20 mutations do not respond to gefitinib.[72] Moreover, the appearance of a secondary mutation in exon 20 (T790M) accounts for approximately 50% of acquired drug resistance.[77,86] Screening for the emergence of such mutations in circulating tumor cells from the blood of patients during the course of treatment may allow earlier identification of acquired resistance.[83,87]

Results of some preclinical studies suggest that the clinical benefit observed with EGFR TKIs is not restricted to those patients harboring EGFR mutations. This may be due to molecular factors outside of gene mutations. EGFR amplification and receptor/ligand overexpression, both of which allow for a 'gain of function' to occur, are implicated in creating a scenario of EGFR dependence that causes the sensitivity to single-agent EGFR inhibitors.[44,88] However, the data from the IRESSA Pan-Asia Study (IPASS) clearly demonstrate that patients with increased EGFR copy numbers and no EGFR mutations do not benefit from EGFR TKIs.[89]

EGFR Copy Number Alterations

EGFR is frequently over-represented or amplified in NSCLC, which is commonly associated with EGFR overexpression.[90] Increased EGFR copy numbers may result from gene amplification or polysomy of chromosome 7. The incidence of EGFR amplification ranges from 12 to 59%, depending on the patients selected and the technology used.[64,88,91,92] Some, but not all, studies have revealed that positive EGFR amplification is associated with significantly better survival after treatment with a TKI.[88,93] Gain of EGFR copy number has been consistently associated with a favorable outcome after EGFR TKI therapy; it has also been proposed to be a potential biomarker of TKI responsiveness.[91,94]

Somatic EGFR mutations consistently correlate with improved response rates; by contrast, the results of studies investigating EGFR copy number as a predictor of response to TKIs have been inconsistent.[25,95] Overall, EGFR mutations seem to have higher sensitivity and specificity for predicting response to TKIs than EGFR copy number gain status.[64] High copy numbers of EGFR have been detected in approximately 30% of NSCLC patients using FISH, and are reportedly associated with better responses to TKI therapy,[73,96] although the EGFR mutation status of those cases was unclear. Approximately 70% of patients with EGFR copy number gain also had EGFR somatic mutations, a fact that clouds the true significance of EGFR copy number gain. IPASS demonstrated that EGFR mutation was the strongest predictor of improved progression-free survival. There was a high degree of overlap between EGFR mutation positivity and high EGFR gene copy numbers: of 245 patients with high EGFR copy numbers whose EGFR mutation status was also known, 190 (78%) were also EGFR mutation-positive. This suggests that the improved outcome in high EGFR copy number patients is being driven by the EGFR mutation-positive overlap.[89] Some researchers have suggested that high EGFR copy numbers can be used as a predictive biomarker for response and survival benefit in patients with NSCLC who receive EGFR TKI therapy.[88] However, the data from the IPASS trial clearly demonstrate that patients with increased EGFR copy numbers and no EGFR mutations do not benefit from EGFR TKIs.[89] Hirsch et al. suggested that although EGFR mutations and high copy numbers are both predictive of response to erlotinib in NSCLC, EGFR copy number was a more powerful predictor of differential survival benefit from erlotinib.[88]

There are several methods for detecting and determining EGFR copy number and dosage, including FISH,[73,88,97] chromogenic in situ hybridization[92,98] and real-time quantitative PCR.[20,99,100] When EGFR copy number was measured by PCR, it was found that increased EGFR copy number was significantly associated with prolonged survival, indicating a potential prognostic value of EGFR copy number.[64,101] The patients with EGFR gain demonstrated a higher disease control rate (67 vs 26%), longer TTP (9.0 vs 2.5 months) and prolonged survival time (18.7 vs 7.0 months).[64] It is noteworthy that EGFR copy number is used as a predictor for response to TKI therapy largely because it is correlated with EGFR mutations – EGFR mutations are the best predictors. Hirsch et al. investigated 229 chemotherapy-naive patients with advanced-stage NSCLC in a Phase II clinical trial.[88] Among the 76 patients analyzed by FISH, 59.2% had increased EGFR copy numbers, as indicated by four or more gene copies per cell in >40% of the cells. Response was higher in EGFR-amplified patients (45%) versus the EGFR-unamplified patients (26%). Those patients with EGFR amplification had a median progression-free survival time of 6 months compared with 3 months for patients without amplification. Median overall survival was 15 months for the EGFR-amplified group, while it was only 7 months for patients without amplification.[102]

Despite a majority of studies demonstrating that high EGFR copy number correlates with better response and increased survival in NSCLC patients treated with EGFR TKIs, debate remains about its true predictive value. Some studies suggest that when compared with EGFR mutations, EGFR gene copy number is a less sensitive and less specific marker and may not be considered clinically suitable for patient selection.[64] Douillard et al. also reported that EGFR mutation demonstrates greater predictive power than EGFR copy number in therapy response and progression-free survival.[103] Further studies are necessary to resolve these discrepant findings.

EGFR Overexpression

The clinical implications of EGFR overexpression have been studied extensively. However, the results have been inconclusive thus far. Immunohistochemistry-based assays measuring EGFR expression could not reliably predict the response to EGFR TKI therapy. Overexpression of EGFR has been demonstrated in 40–80% of cases of NSCLC and has been associated with a poor prognosis.[104–106] The initial assumption was that EGFR antibodies would be more effective in tumors with robust overexpression of EGFR. However, early clinical studies were unable to demonstrate a distinct correlation between EGFR expression and the likelihood of response to EGFR inhibition with targeted antibodies.[107] In addition, studies suggest that immunohistochemistry-based assays measuring EGFR expression do not serve as reliable predictors of response to cetuximab therapy.[108]

Increased response rates after treatment with a TKI have been demonstrated in patients with positive EGFR immunostaining in some studies, but not in others.[104,105,109,110] In multivariate analyses, EGFR expression level was associated with an objective response or adverse prognosis in NSCLC.[93,110] Several investigations into the prognostic significance of EGFR expression revealed no association with survival benefit.[102,105,111] Therefore, EGFR overexpression by itself is not prognostic of survival in NSCLC. It has been suggested that the nonoptimized cut-off value for EGFR-positive immunostaining and/or lack of standardization in staining procedures and guidelines may explain the discordance among these studies.[111]

EGFR Mutation-specific Antibodies

Since the use of EGFR overexpression as a prognostic marker has largely been unproductive, considerable efforts have been made to develop antibodies that react specifically with the mutant form of EGFR. Cell Signaling Technology, Inc. (MA, USA) has developed two mutant-specific antibodies against the most common mutant forms of EGFR: the 15-base pair/5-amino acid deletion (E746-A750del) in exon 19 and the L858R point mutation in exon 21.[112] Yu et al. investigated EGFR genotypes of 40 NSCLC tumor samples by immunohistochemistry with these antibodies and confirmed the immunohistochemistry results by DNA sequencing.[112] Detection of mutant EGFR by these two antibodies was performed by western blotting, immunofluorescence and immunohistochemistry. The sensitivity and specificity of these antibodies in a 340-sample panel of paraffin-embedded NSCLC tumors was 92 and 99%, respectively, compared with direct sequencing and mass spectrometry-based DNA sequencing. These results demonstrate that mutation-specific antibodies provide a rapid, sensitive, specific and cost–effective method to identify lung cancer patients who may respond to EGFR-targeted therapies. Brevet et al. evaluated the two mutation-specific monoclonal antibodies for the detection of EGFR mutations by immunohistochemistry on 218 paraffin-embedded lung adenocarcinomas.[112] The EFGR L858R mutant antibody showed a sensitivity of 95%, a positive predictive value of 99% and a specificity of 76%, with a positive cut-off of (2+).[113] A positive threshold of (2+) will effectively reduce the false-positive rate and enhance the predictive power of immunohistochemistry assays to 100%, with a minimal reduction in sensitivity. The immunostaining scoring was based on cytoplasmic and/or membrane staining intensity as follows: (0+) = no staining or faint staining intensity in <10% of tumor cells; (1+) = faint staining in >10% of tumor cells; (2+) = moderate staining; and (3+) = strong staining. Therefore, immunohistochemistry using mutation-specific antibodies can be used to screen for patients who may be candidates for EGFR inhibitors.[113]

Phosphorylated Form of EGFR

Aberrant activation of EGFR is a recognized component of cancer development and progression.[59] In addition, recent data indicate that both EGFR mutations and the activation status of EGFR, defined by phosphorylation, might have a strong impact on the clinical course of NSCLC.[114] The two major EGFR signaling pathways, PI3K–AKT–mTOR and RAS–RAF–MAPK, mediate EGFR effects on cell proliferation and survival. The activation of these pathways is dependent on the phosphorylation status of the components. Investigations to date indicate that the major molecular alteration involved in the carcinogenesis of NSCLC is an activation mutation. The mechanisms that regulate EGFR expression, such as epigenetic alteration and aberrant transcription factors have been studied but are not yet conclusive.

Phosphorylation at tyrosine 845 in the kinase domain of EGFR may stabilize the activation loop, which maintains the receptor in an active state and provides a binding surface for substrate proteins.[115] Phosphorylation of two additional tyrosines, 1068 and 1173, mediates the direct binding of growth factor receptor-bound protein 2. Furthermore, tyrosine 1068 is involved in the activation of the MAPK signaling pathway.[116]

Detection of activated EGFR is conducted by using anti-phospho-EGFR antibodies directed at EGFR in its phosphorylated state. Phosphorylations in the carboxyl-terminus of EGFR play a key role in the recruitment of signaling molecules and activation of downstream signaling pathways.[115,117] In a study by Endoh et al., involving 97 NSCLC cases, patients with phospho-EGFR-positive tumors demonstrated a prolonged survival, although the follow-up period was relatively short.[117] Hijiya et al. investigated 21 cases of NSCLC for correlations between the presence of EGFR mutations and the EGFR phosphorylation status by immunohistochemistry with antibodies recognizing EGFR that was phosphorylated at tyrosine 992 and tyrosine 1173, respectively.[118] The mutation status of EGFR was strongly correlated with immunoreactivity for phosphorylated tyrosine 992, indicating a clear potential for using anti-phospho-EGFR antibodies as a surrogate marker of EGFR mutations and thus predicting the clinical response to tyrosine antagonist therapy.

The immunohistochemical evaluation of NSCLC with anti-phospho-EGFR antibodies is potentially useful in the clinical prediction of responsiveness to EGFR-targeted therapy. However, further testing and evaluation are needed to determine its true clinical implication.


The newly characterized EGFR mutant, EGFRvIII, results from an in-frame deletion of exons 2–7 of the coding sequence, which has been found to be generated by gene rearrangement or aberrant mRNA splicing.[119,120] The variant form has a deletion of 267 amino acids in the extracellular domain of normal EGFR, creating a unique epitope at the fusion junction. A number of functional differences between EGFRvIII and EGFR have been characterized.[120,121] Although EGFRvIII fails to bind EGF, its intracellular TK is constitutively activated, allowing the receptor to undergo tyrosine autophosphorylation.[122,123] These studies provide further evidence that EGFRvIII expressed in NSCLC is phosphorylated and, hence, activated. The data suggest that the sustained activation of EGFRvIII may play a role in the pathogenesis of NSCLC and, therefore, EGFRvIII is a potential therapeutic target for NSCLC.[114] Antibodies directed to this tumor-specific variant of EGFR provide an alternative targeting strategy. It has been demonstrated that systemic treatment of mice bearing tumors expressing EGFRvIII with monoclonal antibodies specific for EGFRvIII inhibited tumor growth and extended animal survival.[124,125] Antibodies that have an affinity for EGFRvIII, but without an affinity to wild-type EGFR, provide an alternative tool for detecting this mutation variant.[126]

The role of EGFRvIII mutations in the pathogenesis of NSCLC is unclear. Reported incidences of EGFRvIII mutation in NSCLC vary from 0 to 42%.[127,128] These differences may be due to differences in the tumor composition (histological type) or to technical considerations, such as the threshold for the result interpretations. Studies using immunohistochemical assays with EGFRvIII mutant-specific antibodies suggest that this mutation is present in multiple other tumor types and is not exclusive to NSCLC.[114,129] However, owing to the large size and complex genomic structure (28 exons spanning ~190 kb) of EGFR and its large intron 1 (123 kb), where genomic deletions frequently occur, it has been difficult to assess and verify the existence of the EGFRvIII mutations at the genomic level.[127] To evaluate the clinical impact of EGFRvIII in NSCLC, Okamoto et al. investigated EGFRvIII expression in 76 cases of NSCLC by immunohistochemistry, using a monoclonal antibody specific for this EGFR variant. EGFRvIII expression was found in 39% (30/76) of NSCLC; however, genetic analysis of EGFRvIII mutations only generated a 3% positive rate compared with the 39% immunopositivity rate.[114] Okamoto et al. found that EGFRvIII was also observed in several normal tissue components of the lung, which raised the question of the clinical implications for this detection methodology.[114]

Studies of small-molecule TKIs have demonstrated clinical responses in NSCLC patients whose tumors bear EGFR kinase domain mutations. However, the efficacy of these inhibitors against tumors with the EGFRvIII mutation remains unclear. Ji et al. determined that EGFRvIII mutations were present in 5% (3/56) of human squamous cell lung carcinomas, but found no EGFRvIII mutations in a large cohort of human lung adenocarcinomas (0/123).[127] In their study, EGFRvIII-bearing tumors seemed relatively resistant to some TKIs, but responsive to others.[130] In an in vivo system, treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of EGFRvIII-driven murine tumors within 1 week.[126] A total of 7 days of erlotinib treatment led to an average reduction of 45% in tumor volume in the three treated mice. By contrast, those treated with HKI-272 demonstrated a reduction of 88%. The Ba/F3 cells, transformed with the EGFRvIII mutant, were relatively resistant to gefitinib and erlotinib in vitro, but sensitive to HKI-272, suggesting that TKI treatment is potentially efficacious for cancers harboring the EGFRvIII mutation.


  • Current studies of alterations of the EGFR pathway have been focused on gene mutations, gene copy-number alterations, protein expression alterations and downstream genetic alterations.

  • Four activating mutations – exon 18 (G719A/C), exon 21 (L858R and L861Q), and in-frame deletions in exon 19 – are the dominant mutations present in NSCLCs.

  • Patients with an EGFR mutation, who were treated with TKIs, had much higher response rates and longer progression-free survival than patients without EGFR mutations who had the same treatment.

  • Acquisition of a new mutation in exon 20 can confer resistance to TKI treatment.

  • Overexpression of EGFR has been found in 40–80% of cases, but its usefulness as a predictive marker remains controversial.

  • Sustained activation of EGFRvIII is implicated in the pathogenesis of squamous cell carcinoma and, thus, EGFRvIII is a potential therapeutic target in this subset of NSCLCs.


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