Gilda da Cunha Santos

BACKGROUND: A clinical trial that compared erlotinib with a placebo for non-small-cell lung cancer demonstrated a survival benefit for erlotinib. We used tumor-biopsy samples from participants in this trial to investigate whether responsiveness to erlotinib and its impact on survival were associated with expression by the tumor of epidermal growth factor receptor (EGFR) and EGFR gene amplification and mutations. METHODS: EGFR expression was evaluated immunohistochemically in non-small-cell lung cancer specimens from 325 of 731 patients in the trial; 197 samples were analyzed for EGFR mutations; and 221 samples were analyzed for the number of EGFR genes. RESULTS: In univariate analyses, survival was longer in the erlotinib group than in the placebo group when EGFR was expressed (hazard ratio for death, 0.68; P=0.02) or there was a high number of copies of EGFR (hazard ratio, 0.44; P=0.008). In multivariate analyses, adenocarcinoma (P=0.01), never having smoked (P<0.001), and expression of EGFR (P=0.03) were associated with an objective response. In multivariate analysis, survival after treatment with erlotinib was not influenced by the status of EGFR expression, the number of EGFR copies, or EGFR mutation. CONCLUSIONS: Among patients with non-small-cell lung cancer who receive erlotinib, the presence of an EGFR mutation may increase responsiveness to the agent, but it is not indicative of a survival benefit.

Epidermal growth factor receptor (EGFR) is a transmembrane protein with cytoplasmic kinase activity that transduces important growth factor signaling from the extracellular milieu to the cell. Given that more than 60% of non-small cell lung carcinomas (NSCLCs) express EGFR, EGFR has become an important therapeutic target for the treatment of these tumors. Inhibitors that target the kinase domain of EGFR have been developed and are clinically active. More importantly, such tyrosine kinase inhibitors (TKIs) are especially effective in patients whose tumors harbor activating mutations in the tyrosine kinase domain of the EGFR gene. More recent trials have suggested that for advanced NSCLC patients with EGFR mutant tumors, initial therapy with a TKI instead of chemotherapy may be the best choice of treatment. Therefore, mutation testing is mandatory to identify these patients, given that selection based only on clinico-pathologic characteristics is inadequate. We review the role of EGFR mutations in the diagnosis and management of NSCLC.

PURPOSE: To evaluate the effect of KRAS and epidermal growth factor receptor (EGFR) genotype on the response to erlotinib treatment in the BR.21, placebo-controlled trial. PATIENTS AND METHODS: We analyzed 206 tumors for KRAS mutation, 204 tumors for EGFR mutation, and 159 tumors for EGFR gene copy by fluorescent in situ hybridization (FISH). We reanalyzed EGFR deletion/mutation using two highly sensitive techniques that detect abnormalities in samples with 5% to 10% tumor cellularity. KRAS mutation was analyzed by direct sequencing. RESULTS: Thirty patients (15%) had KRAS mutations, 34 (17%) had EGFR exon 19 deletion or exon 21 L858R mutations, and 61 (38%) had high EGFR gene copy (FISH positive). Response rates were 10% for wild-type and 5% for mutant KRAS (P = .69), 7% for wild-type and 27% for mutant EGFR (P = .03), and 5% for EGFR FISH-negative and 21% for FISH-positive patients (P = .02). Significant survival benefit from erlotinib therapy was observed for patients with wild-type KRAS (hazard ratio [HR] = 0.69, P = .03) and EGFR FISH positivity (HR = 0.43, P = .004) but not for patients with mutant KRAS (HR = 1.67, P = .31), wild-type EGFR (HR = 0.74, P = .09), mutant EGFR (HR = 0.55, P = .12), and EGFR FISH negativity (HR = 0.80, P = .35). In multivariate analysis, only EGFR FISH-positive status was prognostic for poorer survival (P = .025) and predictive of differential survival benefit from erlotinib (P = .005). CONCLUSION: EGFR mutations and high copy number are predictive of response to erlotinib. EGFR FISH is the strongest prognostic marker and a significant predictive marker of differential survival benefit from erlotinib.