Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer

Abstract

Epidermal growth factor receptor (EGFR) and HER2 are cell surface receptor tyrosine kinases (TKs) that transduce growth signals through dimerization with HER family receptors. The heterodimerization of EGFR with HER2 induces a more potent activation of EGFR TK than does EGFR homodimerization. When tumor cells overexpress both EGFR and HER2, they exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). Certain patient subsets are particularly responsive to EGFR TKIs. Analyses of biomarkers from patients in clinical studies of EGFR TKIs show correlations between objective tumor response and EGFR overexpression, as detected by immunohistochemistry and increased gene copy number measured by fluorescence in situ hybridization analysis. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. Therefore, the measurement of EGFR and HER2 protein expression and the gene copy number in NSCLC tumors may have a prognostic value in NSCLC and a predictive value for identifying patients likely to benefit from an EGFR TKI. These considerations suggest that the simultaneous inhibition of EGFR and HER2 may warrant further study in patients with NSCLC.

An Apoferritin‐based Drug Delivery System for the Tyrosine Kinase Inhibitor Gefitinib

“…[ 24 ] On the other hand, cancer cells that express low levels of EGFR together with overexpression of HER2 are sensitive to this drug and indeed, high sensitivity of SKBR3 cells to Gefi tinib was observed. [ 24,25 ] HER2 remains the preferred dimerization partner of other ErbB receptors. Although both homo-and hetero-dimerization activate the EGFR network, heterodimers are found to be more potently mitogenic and HER2 heterodimers generate the strongest biological activity compared to other heterodimers.…”

“…[ 20,22,23 ] Gefi tinib is used for treatment of EGFR and HER2 overexpressing breast cancers. [ 24,25 ] However, the therapeutic window of this drug is drastically narrowed by poor bioavailability, acquired resistance due to insuffi cient or ineffective cellular uptake and systemic toxicity resulting from interactions between drug and healthy tissue. [ 19,26 ] Also, orally administered Gefi tinib is taken up extensively by human serum albumin and hence other delivery systems such as liposomes have been investigated.…”

VEGFA gene locus (6p12) amplification identifies a small but highly aggressive subgroup of colorectal patients

“…Such an approach has previously highlighted gene copy number gain and amplification of the epidermal growth factor receptor (EGFR) as a predictor of clinical response in patients with non-small cell lung cancers, and metastatic colorectal cancer. 20,21 To date, however, the frequency and prognostic relevance of VEGFA gene locus (6p12) amplification in colorectal cancers as well as its correlation to other RAS/MAPK signalling molecules has not been investigated. 22 Therefore, the aim of this study was: (1) to determine the frequency of VEGFA gene locus amplification in a large cohort of colorectal cancers, (2) determine the effect of gene amplification on clinical outcome using two independent colorectal cancer patient cohorts and (3) determine the relationship between VEGFA gene amplification and KRAS or BRAF gene mutation as well as with other protein markers of the RAS/MAPK signalling pathway.…”

Predictive molecular markers for EGFR-TKI in non-small cell lung cancer patients: new insights and critical aspects

“…However, the multivariate analysis did not reveal any correlation between EGFR expression and survival. 13,16 These conflicting results, together with the availability of many different commer- cial anti-EGFR antibodies, indicate that IHC may not be the best method to determine a patient's eligibility to receive EGFR TKI therapy.…”