Identification of objective tumor regressions with epidermal growth factor receptor tyrosine kinases (EGFR TKI) in non^small cell lung cancer (NSCLC) patients has resulted in intense, worldwide clinical and basic research directed toward finding the optimal use of EGFR TKIs in NSCLC. EGFR TKI clinical trials have shown that higher response rates and longer survival are associated with specific patient characteristics and that using conventional chemotherapy simultaneously with EGFR TKIs in unselected patients does not increase survival. Molecular studies have revealed that EGFR-activating mutations and high EGFR gene copy number are frequently found in patients who have the best outcomes with EGFR TKIs. More recent studies suggest that KRAS mutations may identify the subset of patients who have the worst outcome with the EGFR TKI treatment. Currently, investigators are trying to determine the optimal approach to selecting patients for treatment with EGFR TKIs. Studies that have evaluated the potential predictive value of clinical features and/or molecular profiles in EGFR TKI-treated NSCLC patients are discussed in this review.Preclinical studies with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) suggested that these agents would be cytostatic (1, 2). The observation of significant, often dramatic, tumor regressions induced by EGFR TKIs in heavily pretreated patients with advanced non -small cell lung cancer (NSCLC) was therefore unexpected (3, 4). Since those initial observations, there have been several revealing findings with EGFR TKIs, including discovery of higher response rates in never smokers (5), Asians (6), women (6 -9), and patients with adenocarcinomas (7 -9). Similarly, the negative results in phase III trials comparing chemotherapy doublets plus an EGFR TKI versus chemotherapy alone (10 -13) were particularly disappointing because preclinical observations (14) and theoretical considerations suggested a relatively high chance of success with this strategy.The observation of higher response rates with EGFR TKIs in selected groups of patients, as well as the disappointing results with simultaneous chemotherapy and EGFR TKIs in unselected patients, led lung cancer researchers to study the potential predictive value of molecular profiles in patients treated with EGFR TKIs. However, negative findings about the predictive value of EGFR protein expression in gefitinib-treated patients raised considerable doubt about the role of molecular profiles in patient selection (15). With the discovery of EGFR-activating mutations in tumors from most patients who had EGFR TKIinduced tumor responses (16,17), skepticism was soon replaced by enthusiasm for molecular profile research in patients treated with EGFR TKIs. There is increasing evidence that EGFR mutations (18 -21) and high EGFR gene copy number (22, 23) are associated with higher response rates and longer survival.Although clinicians are delighted to have an effective new treatment and new insights about lung cancer biology, ...
