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

Disclosures

Future Oncol. 2011;7(4):519-541. 

In This Article

Overview of EGFR & NSCLC

The EGFR and members of its family play an important role in carcinogenesis through their involvement in the modulation of cell proliferation, apoptosis, cell motility and neovascularization.[10] EGFR alterations have been implicated in the pathogenesis and progression of many malignancies.[11–14] Although the exact molecular pathways by which the mutant receptors lead to carcinogenesis are not completely understood, it is clear that mutant variants of EGFR have enhanced tyrosine kinase (TK) activity.

The presence of activating mutations in EGFR was initially reported in 2004.[12,15,16] Various groups also found amplification and overexpression of EGFR.[17–21] Clinical and pathological factors such as female gender, never having smoked, East Asian ethnicity and adenocarcinoma or bronchioloalveolar histology, correlated with objective responses to single-agent TK inhibitor (TKI) therapy in NSCLC and also with the presence of somatic EGFR mutations.[10,11,15,22,23]EGFR mutations rarely occurred in squamous cell carcinoma, large-cell carcinomas or adenocarcinomas with KRAS mutations.[5,12,15,20,22–31] Of great benefit to researchers in evaluating possible contributing mutations in NSCLC and acquired resistance to targeted therapies is the Catalogue of Somatic Mutations in Cancer (COSMIC[201]). COSMIC is designed to store and display somatic mutation information and related details relating to human cancers; it is a very useful tool for both researchers and clinicians. As more advanced molecular techniques reveal further molecular mutations, centralized databases such as COSMIC will allow clinicians and researchers to stay abreast of currently available information.

Lung adenocarcinomas frequently possess EGFR mutations and frequently exhibit increased EGFR copy number.[32] A study of 334 cases of lung adenocarcinomas using PCR-based assays to detect deletions within exon 19 and the L858R mutation in exon 21 of the EGFR gene found that 23% of these tumors contained a mutation. Of those, 71% were exon 19 deletions and 29% comprised the L858R mutation in exon 21.[32] In addition, EGFR amplification, defined as greater than five EGFR signals per nucleus by FISH, was detected in 52% of EGFR-mutated tumors, but in only 6% of those lacking the mutations. EGFR mutations were present in 26% of 86 bronchioloalveolar carcinomas.[24] It appears that EGFR mutations occur much less frequently in squamous cell carcinoma than in adenocarcinoma, with a reported incidence of 0–14%.[24,33] The third type of NSCLC, large-cell carcinoma, harbors EGFR mutations very rarely, if ever.[23,34] Marchetti et al. investigated a series of 31 large-cell carcinomas and found no EGFR mutations in any case.[24]

Motoi et al. reported that EGFR mutations are particularly frequent in adenocarcinoma of the papillary subtype.[5] In a group of NSCLC patients, 13 out of 36 (35%) papillary cancers harbored EGFR mutations, in contrast to three out of 63 nonpapillary cancers (5%). Kim et al. found that papillary subtype is a significant predictor of response to gefitinib in lung adenocarcinoma, although they did not link the incidence of response to the EGFR mutation status.[35]

The clinical implications of EGFR overexpression have been studied extensively, but the results are inconclusive thus far. Recent use of phosphor-specific antibody has facilitated analysis of the correlation between phosphorylation and EGFR mutation status. In a study of 218 cases of NSCLC, McMillen et al. correlated EGFR expression status with mutation status.[36] Phosphorylation at Y1045 was noted in 52% of cases, 71% of which exhibited the presence of an EGFR mutation. Phosphorylation of Y1068 was seen in 55% of cases, but it was present in 73% of those cases with an EGFR mutation. The data demonstrate that among Chinese patients, immunohistochemical detection of p-1045 and p-1068 expression predicts EGFR mutations.

Activation mutations identified within the kinase domain of the EGFR gene led researchers to propose and develop therapeutic strategies targeting EGFR TK. Therapeutic strategies targeting the EGFR pathway offered exciting new options for the treatment of NSCLC. EGFR alterations have prompted the development of two classes of anti-EGFR agents: monoclonal anti-EGFR antibodies (e.g., cetuximab and panitumumab) and small-molecule TKIs of EGFR (e.g., gefitinib and erlotinib, among others). According to large-cohort Phase III clinical trials,[37–40] the response rates range from 15 to 37.5%. Clinical trials were initiated that employed novel agents targeting the EGFR TK. The results of these clinical trials indicated that many of the tumors harboring mutant EGFR are highly sensitive to EGFR TKIs, with 10–30% demonstrating a significant clinical response.[15,41]

Summary

  • Constitutive activation of EGFR TK in NSCLC is associated with carcinogenesis of NSCLC.

  • The incidence of EGFR mutations in NSCLC is dependent upon gender, smoking history, tumor type and ethnic background.

  • Female gender, zero or very light smoking history, East Asian ethnicity, adenocarcinoma or bronchioloalveolar histology correlates with objective responses to single-agent TKI therapy in NSCLC.

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