Predictive factors associated with gefitinib response in patients with advanced non-small-cell lung cancer (NSCLC)

Lian Chen＊, Rui Chen＊, Zhe Zhu＊, Yichen Zhang, Zhengwei Wen, Yun Li, Xiaoming Li, Yuwen Luo, Liyu Ma, Shuguang Lin, Xin Chen

1Southern Medical University, Guangzhou 510515, China;2Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China;3Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China;4Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China

＊These authors contributed equally to this work.

Correspondence to: Shuguang Lin. Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 zhongshan Er Road, Guangzhou 510080, China. Email: gdpph@21cn.com; Xin Chen. Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, 253 Gongye Road, Guangzhou 510282, China. Email: chen_xin1020@hotmail.com.

Predictive factors associated with gefitinib response in patients with advanced non-small-cell lung cancer (NSCLC)

Lian Chen1,2＊, Rui Chen3＊, Zhe Zhu4＊, Yichen Zhang1,2, Zhengwei Wen2, Yun Li4, Xiaoming Li2, Yuwen Luo4, Liyu Ma2, Shuguang Lin2, Xin Chen4

1Southern Medical University, Guangzhou 510515, China;2Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China;3Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China;4Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China

＊These authors contributed equally to this work.

Correspondence to: Shuguang Lin. Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 zhongshan Er Road, Guangzhou 510080, China. Email: gdpph@21cn.com; Xin Chen. Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, 253 Gongye Road, Guangzhou 510282, China. Email: chen_xin1020@hotmail.com.

Purpose:A number of different clinical characteristics have been reported to singly correlate with therapeutic activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced non-small-cell lung cancer (NSCLC). This study aimed to identify predictive factors associated with prognostic benefts of geftinib.

Patients and methods:EGFR gene typing in 33 advanced NSCLC patients received gefitinib (250 mg/day) were analyzed with mutant-enriched PCR assay. Gefitinib response was evaluated with potential predictive factors retrospectively.

Results:The overall objective response rate (ORR) and median progression-free survival (PFS) in the 33 patients treated by geftinib were 45.5% and 3.0 (2.0-4.0) months. The ORR and median PFS in EGFR gene mutation patients were signifcantly higher/longer than those in EGFR gene wild-type patients (P＜0.01). Similarly, the ORR and median PFS in non-smoker patients were signifcantly higher/longer than those in smoker patients (P＜0.05, P＜0.01, respectively). However, no difference for ORR and median PFS occurred between male and female patients. Logistic multivariate analysis showed that only EGFR mutated gene was signifcantly associated with the ORR (P＜0.01). Both EGFR mutated gene and non-smoker were the major factors that contributed to PFS (P＜0.05).

Conclusions:EGFR mutated gene and non-smoker status are potential predictors for geftinib response in NSCLC patients.

Epidermal growth factor receptor inhibitor (EGFR inhibitor); gene mutation; geftinib; non-small-cell lung cancer (NSCLC); smoking; gender

View this article at:http://dx.doi.org/10.3978/j.issn.1000-9604.2014.08.09

Introduction

Gefitinib (Iressa) is an orally active small-molecule compound that inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) by competing with adenosine triphosphate (ATP) at the ATP-binding site, which played a central role in advancing non-smallcell lung cancer (NSCLC) treatment over the last several years (1). Recent studies have shown that compared with counterparts, female cancer patients have favorable outcomes after gefitinib treatment (2-4) because females are more likely to have EGFR mutations (5-7) and most of females are non-smokers (8,9). However, in our clinical experience we did not observe that there was a gender difference in geftinib response. This paper aims to identifythe predictive factors that really contribute to gefitinib response in Chinese NSCLC patients including smoking status and gender.

Patients and methods

Patients’ characteristics

Thirty-three patients with advanced NSCLC patients, who were hospitalized in our hospital, were enrolled in this study. Among them, 21 (63.6%) were men and 12 (36.4) were women, with a median age of 59 years old (ranging from 29-76 years old). There were 20 (60.6%) non-smokers, 13 (39.4%) former/current smokers. Nonsmokers are defned as those who reported smoked less than 100 cigarettes during their lifetime. Former smokers are defned as ever smokers who no longer smoked. Histological and/or cytological type was determined according to the World Health Organization/International Association for the Study of Lung Cancer classifications, with 23 (69.7%) adenocarcinomas, 9 (27.3%) squamous-cell carcinomas and 1 (3.0%) large-cell carcinomas. Current tumor stage was determined according to the TNM classification of malignant tumors. Two (6.1%) patients were classifed as at Stage I, 3 (9.1%) at Stage II, 9 (27.3%) at Stage III and 19 (57.6%) at Stage IV. All cases with informed consent were received geftinib monotherapy (250 mg/day orally) without regard to the gender, smoking history and EGFR mutation status. The drug response was evaluated according to the response evaluation criteria in solid tumors guidelines. Objective response is defined as patients with complete response or partial response, meanwhile progressionfree survival (PFS) is defined as the time from the initial administration of chemotherapy to the earliest occurrence of disease progression or death from any cause. The protocol was approved by the Institutional Review Board, and fully informed written consent was obtained for all cases.

EGFR gene analysis

Before gefitinib monotherapy (250 mg/day), plasma was taken from each patient and EGFR gene typing was performed with mutant-enriched PCR assay (10). The majority of EGFR gene mutations consist of an inframe deletion in exon 19 and a point mutation involving the replacement of leucine with arginine at codon 858 (L858R) in exon 21 (11). PCR products were detected with polyacrylamide gel electrophoresis analysis.

Statistical analysis

The differences in objective response (complete response + partial response) by each predictive factor (gender, smoking status and mutation status) were examined with the Fisher’s exact test or Pearson’s chi-square test. Multivariate analysis of the predictive factors, including gender (male vs. female), smoking history (smokers vs. non-smokers) and EGFR mutation (positive vs. negative) were conducted using the Cox regression model. All analysis was determined to be statistically significant where the P value was ＜0.05. Analyses were conducted using the SPSS 11.0.

Results

EGFR gene mutation analysis

Mutated EGFR gene including either EGFR gene exon 19 deletion or exon 21 mutation, or both. Plasma samples were collected from 33 patients and EGFR gene mutations occurred in 16 patients (48.5%). Seventeen patients (51.5%) were wild type gene type. No difference between the male and female in mutated gene incidence. But there was signifcant difference between non-smoker and smokers in mutated gene incidence (Table 1).

Geftinib treatment response

Fifteen patients had objective response in 33 patients receiving gefitinib chemotherapy. Among them only 1 patient had complete response, 14 patients had partial response. Thirteen patients had stable disease, and 5 patients had progressed disease. The objective response rate(ORR) was 45.5% with PFS 3 (2.0-4.0) months. Among 16 patients with EGFR gene mutations, 1 case had complete response, 11 cases had partial response, while 2 cases had stable disease, 4 cases had no significant change. The ORR was 75.0%. Yet in the rest 17 patients without EGFR gene mutations, the ORR was 17.6% (Table 2). Univariate analysis showed that, for all 33 cases, compared with EGFR wild type gene group or smoker group, EGFR mutated gene group or non-smoker group seemed to be associated with improved gefitinib treatment response. Multivariate regression analysis showed that EGFR mutated gene other than non-smoker is the only independent predictive factor for ORR (Table 2).

Table 2 Relationship between clinical characteristics and objective response in patients treated by geftinib (n=33)

Table 3 Relationship between clinical characteristics and progression-free survival in patients treated by geftinib (n=33)

PFS in EGFR mutated gene group or non-smoker group was signifcantly longer than that in EGFR wild type gene group or smoker group (P＜0.01). Cox-2 regression model analysis showed that both EGFR mutated gene and nonsmoker are independent factors for PFS (Table 3).

Effect of smoking on geftinib treatment response in NSCLC patients with EGFR mutated gene or wild-type gene

All 33 patients treated by geftinib had been quadripartited into EGFR wild type gene/smoker group, EGFR wild type gene/non-smoker group, EGFR mutated gene/smoker group and EGFR mutated gene/non-smoker group. The ORR was increased from 11.1%, 25%, 50% to 83.3% correspondingly (Table 4). Twelve patients with EGFRmutated gene/non-smoker had longest PFS among the four groups (P＜0.01) (Table 4).

Table 4 The effect of smoking on geftinib response in NSCLC patients with different EGFR gene status

Discussion

We detected EGFR gene mutations in 33 NSCLC patients with mutant-enriched PCR assay and the positive mutation rate reached 45.5%, which was similar to the result of Scorpion ARMS technique established by Horiike et al. (12). Mutantenriched PCR assay is a sensitive, specifc, and inexpensive clinical well-developed technique (10). We further evaluated the correlation between EGFR gene mutation status and gefitinib response, as well as the predictive factors for geftinib. In this study EGFR mutated gene patients treated by geftinib had better ORR (75.0%) and PFS (4 months) than EGFR wild type gene patients (17.6% and 2 months). Multivariate regression analysis confirmed EGFR mutated gene was independent predictive factors for ORR and PFS.

Many retrospective studies have showed that EGFR mutated gene is more common in female than male patients (5-7). However, our study did not fnd the gender difference of EFGR mutation rate, as well as ORR and PFS. Is there any ethnic variation for gefitinib response? It is worth further studying in future.

Smoking status was an important predictive factor of geftinib response in NSCLC patients. Our study suggested that, as regards ORR or PFS, NSCLC non-smoker patients have better sensitivity to gefitinib than smoker patients. Multivariate regression analysis confirmed that smoking was an independent predictive factor of PFS in NSCLC patients. Smoking significant shortened PFS in NSCLC EGFR mutated gene patients. However, smoking status did not signifcantly affect ORR and PFS in NSCLC patients with EGFR wild type gene.

Our results should be interpreted in the context of some limitations. First, our study used gefitinib which is no longer widely available in the United States after lack of survival beneft was reported in previously treated patients with non-selected NSCLC (13). However, some preplanned subgroup analyses revealed survival benefits in Asian and non-smoker patients (3). Gefitinib is still widely used in China. Second, more information on the geftinib response is needed from the whole country with the highest lung cancer-related deaths rate in China. Third, our samples were just collected from a university hospital, which means that patients’ selection bias cannot be completely ruled out because urban patients may more easily exposed to industrial pollution compared with rural patients. Finally, our sample size was small (total 33 patients).

Conclusions

Despite limitations, our results indicated that EGFR mutation is an important predictive factor of gefitinib response in NSCLC patients, and smoking history will affect gefitinib response. This strategy has great potential to explain the geftinib resistance but further basic research and clinical trials are urgently needed.

Acknowledgements

Disclosure: The authors declare no confict of interest.

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Cite this article as:Chen L, Chen R, Zhu Z, Zhang Y, Wen Z, Li Y, Li X, Luo Y, Ma L, Lin S, Chen X. Predictive factors associated with gefitinib response in patients with advanced non-small-cell lung cancer (NSCLC). Chin J Cancer Res 2014;26(4):466-470. doi: 10.3978/j.issn.1000-9604.2014.08.09

10.3978/j.issn.1000-9604.2014.08.09

Submitted Jul 02, 2014. Accepted for publication Aug 10, 2014.