Clinical predictors versus epidermal growth factor receptor mutation in gefitinib-treated non-small-cell lung cancer patients
Introduction
Epidermal growth factor receptor is frequently overexpressed in various malignancies including non-small-cell lung cancer (NSCLC). Its activation has important role in various steps of carcinogenesis and progression [1]. EGFR targeted therapeutic approach by inhibition of EGFR activation with the specific tyrosine kinase inhibitor gefitinib has proven clinically successful especially in NSCLC. Objective responses were more frequently seen in subgroups of patients [2], [3]. Therefore, selection of appropriate target population for the treatment may lead to improved treatment outcomes.
Clinical predictors of better outcome with gefitinib treatment in NSCLC have been identified in the two randomized phase II trials and the compassionate Expanded Access Program [4], [5], [6], [7], [8], [9], [10]. These include East-Asian ethnicity, female sex, adenocarcinoma or bronchioloalveolar carcinoma histology and never-smoking history. Planned subgroup analysis of the phase III gefitinib trial, Iressa Survival Evaluation in Lung Cancer, showed significant survival benefit in never-smokers and Asians [11]. In addition, higher objective responses were seen in females, adenocarcinomas, never-smokers and Asians [11]. In the phase III trial of erlotinib, response rates were also higher in females, adenocarcinomas, never-smokers and Asians although the survival benefit of erlotinib treatment was not limited to these subgroups [12]. Moreover, phase II trial of first-line gefitinib in Korean never-smokers with adenocarcinomas have shown promising results suggesting that patient selection according to clinical parameters may be an effective strategy [13].
Molecular predictors of gefitinib sensitivity include mutations in the tyrosine kinase domain of EGFR and increase in gene copy number of EGFR [14], [15], [16], [17], [18], [19], [20], [21], [22]. Presence of EGFR mutation in exons 18, 19 and 21 was significantly associated with higher response rate in gefitinib-treated NSCLC patients [14], [15], [16], [17], [18], [19]. Although its prognostic significance is controversial, gefitinib-treated NSCLC patients with EGFR mutations seem to have longer survival compared with the patients without mutations [17], [18], [19]. EGFR mutations were predominantly found in Asians, females, adenocarcinomas and never-smokers, which explains the association between the clinical predictors and gefitinib sensitivity [14], [15], [16], [17], [18], [19]. Another molecular predictor of gefitinib sensitivity is increase in gene copy number of EGFR [19], [20], [21], [22]. As EGFR mutation and high gene copy number are significantly associated with each other [19], [20], [22], appropriately designed study is needed to uncover which molecular marker has predominant role in determining gefitinib-sensitivity. It is possible that different ethnicities have different mechanisms of EGFR pathway addiction and resulting gefitinib-sensitivity. Identification of resistance mechanism, such as K-ras mutation could also be helpful in selecting most suitable patient for gefitinib treatment [22], [23], [24].
Gefitinib shows favorable outcome in aforementioned selected patient population among NSCLC patients. Considering the dramatic clinical responses, gefitinib could be considered prior to other chemotherapeutics in patients with clinical predictors of gefitinib responsiveness or EGFR mutation. However, no direct comparison between clinical predictors and EGFR mutation for prediction of gefitinib responsiveness has been reported and it is unclear whether patient selection should be based on clinical predictors or EGFR mutation. Therefore, we have analyzed clinical predictors and EGFR mutation in gefitinib-treated Korean NSCLC patients to investigate which leads to better patient selection.
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Patients
One hundred and twenty consecutive NSCLC patients treated with gefitinib and assessable for EGFR mutational status in exons 18, 19 and 21 were included in the present analysis. Mutational data of 90 patients had been reported previously elsewhere [17]. All patients had pathologically proven locally advanced or metastatic NSCLC. Baseline patient characteristics are listed in Table 1. Treatment consisted of 250 mg of gefitinib daily continued until disease progression, intolerable toxicity or
Clinical predictors
In accordance of previous reports, response rates were significantly higher in female, adenocarcinoma and never-smokers (Table 2). For more detailed prediction of gefitinib responsiveness, we have classified patients according to the number of favorable clinical predictors (female, adenocarcinoma and never-smoker). Response rate showed a significant trend towards increase as the number of clinical predictors increased (Fig. 1A). Female never-smokers with adenocarcinoma (three clinical
Discussion
Previous studies have shown that objective response to gefitinib is more frequently seen in Asians, females, adenocarcinomas and never-smokers [4], [5], [6], [7], [8], [9], [10], [11], [12]. In the present study, response rate showed significant increase as number of clinical predictors increased. Moreover, adjusted HR showed significant improvement of TTP and OS according to increase in number of clinical predictors. Our results demonstrate that number of clinical predictors can be used as a
Acknowledgement
This study was supported in part by a grant from the Korean Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (03-PJ10-PG13-GD01-0002).
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High incidence of EGFR mutations in Korean men smokers with no intratumoral heterogeneity of lung adenocarcinomas: Correlation with histologic subtypes, EGFR/TTF-1 expressions, and clinical features
2012, Journal of Thoracic OncologyCitation Excerpt :Although men or smokers have not been considered as ideal candidates for treatment with EGFR-TKIs, this result suggests that EGFR mutation test should be performed in all the adenocarcinoma patients regardless of gender or smoking history. Because EGFR mutation, not demographical features, is independently associated with a favorable prognosis of adenocarcinoma patients treated with EGFR-TKIs.29,30 If we want to aim for a policy of no EGFR-mutated patients being left behind, we must increase the number of candidates for the EGFR mutation test as well as improve the sensitivity of the test.
EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment: A systematic review and meta-analysis in non-small-cell lung cancer
2011, Annals of OncologyCitation Excerpt :Our initial search yielded 255 studies concerning EGFR-targeted TKI treatment in NSCLC that were assessed in full text. As indicated in the search flow diagram (Figure 1), 22 studies reported at least one of the outcomes of interest and were finally included in the meta-analysis [12, 28–48]. The search flow diagram is summarized in Figure 1 and the characteristics of eligible studies are summarized in Table 1.
Clinicopathologic factors affecting the progression-free survival of patients with advanced non-small-cell lung cancer after gefitinib therapy
2011, Clinical Lung CancerCitation Excerpt :As shown in Table 3, the most common side effects were ILD and grade 3 skin rash and we found 2 correlations among factors: one is between gefitinib therapy and patient age, and the other is between gefitinib therapy and EGFR mutational status. Many reports have indicated that patients with advanced NSCLC who harbor EGFR-activating mutations have a better PFS after gefitinib therapy16,24–26 and EGFR TKIs have significant efficacy in specific subgroups of patients, such as the Asian population, patients with adenocarcinomas, nonsmokers, and females8,9,13 and have indicated that the presence of somatic mutations in the EGFR is a strong predictor for both clinical and in vitro sensitivity to EGFR-TKIs.6–9,22,23,27–37 Furthermore, patients with EGFR mutations showed a significantly longer survival than those with wild-type EGFR when treated with EGFR TKIs.30,33,38
Erlotinib after Gefitinib failure in female never-smoker Asian patients with pulmonary adenocarcinoma
2009, Lung CancerCitation Excerpt :Gefitinib and erlotinib are commonly used tyrosine kinase inhibitors (TKIs) of EGFR. It has been well reported that clinical or molecular factors including female gender, never smoker, Asian race, adenocarcinoma histology, EGFR mutations, and EGFR gene amplification are predictive of responses to gefitinib and erlotinib [1–5]. Despite dramatic and durable responses to gefitinib in patients with favorable clinical factors for TKIs, the majority of those patients eventually developed progression after initial responses to gefitinib [2,3].