Selecting Patients for Treatment with Epidermal Growth Factor Tyrosine Kinase Inhibitors

Abstract

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, ...

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

“…EGFR amplification, preferentially of a mutant allele, is correlated with but does not reliably predict EGFR overexpression [17]. Mutations in the EGFR gene are rare in colorectal cancer but occur regularly in other cancer types, such as lung cancer [18][19][20][21].…”

“…For these reasons, EGFR mutations have limited to no prognostic power and also do not predict EGFR-targeted treatment outcomes in patients with colorectal cancer [19]. In non-small-cell lung cancer, however, EGFR mutations and gene amplification are closely linked with favorable response to small-molecule tyrosine kinase inhibitors [18,20,21,36]. Of note, a recent study reported a strong correlation between EGFR mutation status and phosphorylation of the EGFR at tyrosine 992 (pEGFRtyr992) as detected by IHC [37].…”

“…As discussed above, EGFR protein expression, gene amplification, and mutations have limited predictive value in colorectal cancer, although they remain useful markers of treatment response in lung cancer [10,13,18]. The search for predictive biomarkers in colorectal cancer is now directed mainly toward key signaling components downstream of the EGFR.…”

Individualized therapy in non-small-cell lung cancer: future versus current clinical practice

“…Although some studies have suggested that EGFR mutations are prognostic rather than being predictive factors (Eberhard et al, 2005;Shepherd and Tsao, 2006), many have shown that they are in fact predictive of favorable clinical outcomes with EGFR TKIs (Bonomi et al, 2007) (see the article by Gazdar (2009) within this issue for a full review of this topic). In four separate studies of EGFR TKIs in patients with metastatic NSCLC, a significantly longer OS was observed in patients harboring EGFR mutations (Cortes-Funes et al, 2005;Han et al, 2005;Mitsudomi et al, 2005;Takano et al, 2005).…”

EGFR-targeting drugs in combination with cytotoxic agents: from bench to bedside, a contrasted reality

“…A major advance for a patient selection with the objective to draw greater benefits from a combination between anti-EGFR drugs and conventional chemotherapeutic agents comes from the tumour determination of EGFR and K-Ras mutational status. In lung cancer patients, molecular studies have revealed that EGFR-activating mutations are frequently found in patients who have the best outcomes with EGFR TKIs combined with conventional chemotherapy (Bonomi et al, 2007). Several groups from Europe and the United States have reported that the absence of K-Ras mutation was a condition necessary to obtain a clinical response to the association between cetuximab and irinotecan in irinotecan refractory patients (Lièvre et al, 2008).…”