Abstract
BackgroundIn Non-small cell lung cancer (NSCLC), an overactive epidermal growth factor receptor (EGFR) pathway is a component of the malignant phenotype. Two tyrosine kinase inhibitors (TKIs) of EGFR, gefinitib and erlotinib, have been used with variable benefit.MethodsWe have analyzed outcome data of a population of NSCLC patients that received these TKIs to determine the benefit derived and to define the clinical and molecular parameters that correlate with response. Tumor tissue from a subgroup of these patients was analyzed by immunohistochemistry to measure the expression level of EGFR and four activated (phosphorylated) members of the pathway, pEGFR, pERK, pAKT, and pSTAT3.ResultsErlotinib was slightly superior to gefitinib in all measures of response, although the differences were not statistically significant. The most robust clinical predictors of time to progression (TTP) were best response and rash (p < 0.0001). A higher level of pEGFR was associated with longer TTP, while the total EGFR level was not associated with response. Higher levels of pAKT and pSTAT3 were also associated with longer TTP. In contrast, a higher level of pERK1/2 was associated with shorter TTP.ConclusionThese observations suggest the hypothesis that tumor cells that have activated EGFR pathways, presumably being utilized for survival, are clinically relevant targets for pathway inhibition. An accurate molecular predictive model of TKI response should include activated members of the EGFR pathway. TKIs may be best reserved for tumors expressing pEGFR and pAKT or pSTAT, and little pERK. In the absence of molecular predictors of response, the appearance of a rash and a positive first scan are good clinical indicators of response.
Highlights
In Non-small cell lung cancer (NSCLC), an overactive epidermal growth factor receptor (EGFR) pathway is a component of the malignant phenotype
Patient Data At the Maine Center for Cancer Medicine, clinical data were compiled for 160 NSCLC patients that had received either gefitinib or erlotinib between 1996 and 2002 and organized into a database constructed in FileMaker Pro 8
We found a positive association between time to progression (TTP) and the level of phosphorylated EGFR (pEGFR): in general, the higher the level of this protein, the longer the TTP
Summary
In Non-small cell lung cancer (NSCLC), an overactive epidermal growth factor receptor (EGFR) pathway is a component of the malignant phenotype. In addition to classic cytotoxic agents, approved systemic therapies to treat NSCLC include inhibitors of the epidermal growth factor receptor (EGFR) pathway. Gefitinib and erlotinib are reversible inhibitors of the kinase domain of EGFR that compete with ATP for binding to the catalytic pocket. These small molecules inhibit EGFR autophosphorylation and, they inhibit receptor dimerization, and the downstream signaling that would have otherwise stimulated proliferation (through the activation of Erk) and anti-apoptotic mechanisms (through activation of Akt and Stat)
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