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Clinical Cancer Research Vol. 11, 4289-4294, June 15, 2005
© 2005 American Association for Cancer Research

Human Cancer Biology

Gefitinib-Sensitive Mutations of the Epidermal Growth Factor Receptor Tyrosine Kinase Domain in Chinese Patients with Non–Small Cell Lung Cancer

Xin Lin Mu1, Long Yun Li1, Xiao Tong Zhang1, Men Zhao Wang1, Rui E. Feng2, Quan Cai Cui2, Hai Sheng Zhou3 and Bing Qing Guo4

Authors' Affiliations: Departments of 1 Respiratory Diseases and 2 Pathology, Peking Union Medical College Hospital; 3 National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China and 4 Department of Pathology, Bengbu Medical College, An Hui, China

Requests for reprints: Xin Lin Mu, Department of Respiratory Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Shuai Fu Yuan No. 1, 100730 Beijing, China. Phone: 86-10-65295030; Fax: 86-10-65295030; E-mail: xinlin169{at}163.com.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Studies have shown that mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain are associated with response of lung cancer to gefitinib (Iressa, AstraZeneca Corp., Shanghai, China). A higher incidence of EGFR mutation was observed in non–small cell lung cancer (NSCLC) patients of Japanese origin compared with those of American origin. However, no data about such mutations in Chinese patients with NSCLC could be obtained.

Methods: Primary NSCLC tissues were obtained for analysis of mutations in exons 18 to 21 of EGFR from a total of 76 patients, of whom 54 did not receive gefitinib therapy and 22 did. PCR products were sequenced directly and mutations were confirmed by an independent PCR and sequence analysis. All types of mutation were cloned and sequenced.

Results: A total of 10 types of mutation were found in the series of patients, including two different silent mutations in exon 20 from 11 patients. More than half of the silent mutations (6 of 11) in exon 20 coexisted with other mutations. Mutations were more frequent in adenocarcinoma (17 of 35; 48.6%) compared with squamous carcinoma (1 of 19; 5.3%) among untreated patients. Similar mutations were observed in all seven gefitinib-treated patients with partial response, and no mutations were detected in all eight patients with progressive disease (P < 0.001), except two silent mutations. Three mutations were observed in seven patients with stable disease.

Conclusions: Mutations in the epidermal growth factor receptor tyrosine kinase domain in lung adenocarcinomas from Chinese patients were more frequent than reported previously in lung adenocarcinomas from American patients. Such mutations were well correlated with tumor response to gefitinib.

Key Words: EGFR-TK inhibitor • mutation incidence • gefitinib Expanded Access Programme

Epidermal growth factor receptor (EGFR), which is highly expressed in 43% to 89% of non–small cell lung cancers (NSCLC), plays a critical role in the development of cancer and mediates the behavior of tumor cells, including increased proliferation, decreased apoptosis, enhanced motility, and angiogenesis (1). Preclinical studies showed that disruption of EGFR tyrosine kinase (EGFR-TK) activation could inhibit proliferation of tumor cells and induce apoptosis (2). Targeting EGFR has become a new modality to treat NSCLC (3, 4).

Gefitinib (Iressa, AstraZeneca Corp., Shanghai, China) is an EGFR-TK inhibitor that inhibits TK activity of EGFR by reversibly competing with ATP at the ATP-binding cleft within the EGFR protein (5). Although high EGFR expression is prevalent in NSCLC, 12% to 18% of patients achieved an objective tumor response with 250 mg/d gefitinib (6–8). In fact, the status of EGFR was not correlated with tumor response in treatment of tumor xenografts (9, 10). Clinical data also showed that EGFR expression is not a significant predictive factor for response to gefitinib (11, 12).

Recently, two studies showed that mutations in the EGFR-TK domain were associated with response to gefitinib in patients with advanced NSCLC (13, 14). Pao et al. (15) extended data on gefitinib sensitivity and showed that such mutations were more common in lung cancer from "never smokers" with adenocarcinoma histology, which was consistent with clinical findings (16). These gefitinib-sensitive mutations were clustered in exons 18, 19, and 21 of the EGFR gene that involved a critical part of the EGFR-TK domain (13, 14). In the study by Paez et al. (14), EGFR mutations were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. The higher incidence of EGFR mutations in Japanese patients may account for the findings in the phase II trial IDEAL 1 (IRESSA Dose Evaluation in Advanced Lung cancer; ref. 6), in which the response rate for Japanese patients was higher than that of non-Japanese patients (27.5% versus 10.4%, respectively). Our experience from the gefitinib Expanded Access Programme, in which patients with advanced NSCLC who had no alternative treatment options were able to receive gefitinib on a compassionate-use basis, also showed a higher response rate in Chinese patients with NSCLC (17) than had previously been reported in the IDEAL trials (6, 7). Thus, we postulated higher mutation rates in Chinese NSCLC patients. In this study, we assessed mutations in exons 18 to 21 of the EGFR gene in patients with NSCLC, both with and without gefitinib treatment, to confirm the correlation between gefitinib responsiveness and EGFR mutations.


   Materials and Methods
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Results
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Tumor specimens. A total of 76 primary NSCLC tissues consisting of 73 paraffin-embedded and 3 frozen tumor specimens were obtained during diagnosis or surgical procedure before any treatment of advanced lung cancer from Peking Union Medical College Hospital (n = 47) and the Affiliated Hospital of Bengbu Medical College (n = 29). All samples were from patients of Chinese origin with NSCLC and informed consent was obtained. Fifty-four patients did not receive gefitinib therapy, including 19 with squamous carcinomas, 13 with bronchioalveolar carcinoma, and 22 with other adenocarcinomas. Twenty-two patients, who received 250 mg/d gefitinib as part of the gefitinib Expanded Access Programme, had the following pathologic subtypes: 6 squamous carcinoma, 2 bronchioalveolar carcinomas, and 14 other adenocarcinomas. According to Response Evaluation Criteria in Solid Tumors guidelines (18), the efficacy of gefitinib therapy in the 22 patients involved 7 patients with partial response, 7 with stable disease, and 8 with progressive disease.

DNA extraction and PCR amplification of epidermal growth factor receptor exons 18 to 21. H&E-stained tissue slides of each tumor specimen were reviewed by pathologists (R.E. Feng, Q.C. Cui, and B.Q. Guo) and only specimens with >80% tumor component were used for DNA extraction and mutation analysis. Genomic DNA from tumor tissue was extracted with EZ Spin Column Genomic DNA Isolation kit (Sangon, Beijing, China). According to the protocol, four 10 µm sections deparaffinized with xylene or 25 mg frozen tumor tissues were mixed with digestion buffer containing 0.5 mg/mL proteinase K. After overnight digestion at 55°C, DNA was isolated with EZ Spin Column.

Exons 18 to 21 were amplified by nested PCR. Primer sequences for EGFR exons 18, 19, and 20 were obtained from Paez et al. (14) and for EGFR exon 21 from Lynch et al. (13). PCR analyses were done in a volume of 50 µL with 35 cycles, consisting of a denaturation step at 94°C for 45 seconds, primer annealing step at 58°C for 40 seconds, and an elongation step at 72°C for 1 minute. The final step was extended at 72°C for 7 minutes.

Direct sequencing of PCR products. For sequencing of exons 18 to 21 of EGFR, an uncloned nested PCR fragment was used as a template. The PCR products were separated by 1.5% agarose gel electrophoresis and the excised DNA bands were purified using Column DNA Gel Extraction kit (BioAsia, Beijing, China). All sequencing reactions were done using a Big Dye Terminator Cycle Sequencing kit (PE Biosystems, Foster City, CA). The reactions were carried out in an automated DNA analyzer (ABI Prism 377; PE Biosystems).

Mutation cloning and sequencing. To confirm the mutations and to identify whether different clones existed in the same exon, all types of mutation identified by PCR product sequencing were cloned using pGEM-T vector (Promega Corporation, Madison, WI) and 6 to 12 clones were sequenced using universal T7 primer according to the manufacturer's instructions.


   Results
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 Materials and Methods
 Results
Discussion
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Mutations in all tumor specimens. Out of all 76 cases, EGFR mutations were detected in 28 tumor tissues. According to changes of amino acid sequence induced by mutations, the observed mutations consisted of eight types: six types of in-frame deletion in exon 19, including simple deletions (E746-A750, L747-P753insS, E746-T751insA) and deletions coupled with point mutations (L747-E749, A750P, T751I; L747-A750, T751P; L747-S752, P753Q; Fig. 1A-C), and two types of substitution mutation—L858R and L861Q—in exon 21 (Fig. 1D and E). All 15 in-frame deletions were found in exon 19, most of which have been described previously (13–15, 19, 20). Two overlapping 15-nucleotide deletions starting at nucleotide 2,235 or 2,236 resulted in the same elimination of EGFR codons E746-A750, which consisted of >50% (8 of 15) of deletions. A novel in-frame deletion—L747-E749, A750P, T751I—occurred in two patients not treated with gefitinib, which resulted from deletion of nucleotides 2,237 to 2,247 and two substitution mutations at 2248G>C and 2252C>T. For complex mutations in exon 19, clone sequencing confirmed the PCR sequencing results and showed that each tumor tissue harbored only one mutation in the exon. All deletions resulted in elimination of the highly conserved LREA motif within the EGFR-TK domain.



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  		Fig. 1. Mutations of the EGFR-TK domain in NSCLC. A and B, nucleotide and amino acid alignments of deletion mutations in exon 19. C, a novel heterozygous in-frame deletion plus missense mutation (double peaks) in exon 19; clone sequence confirmed only one type of mutation in the specimen. D and E, two heterozygous missense mutations (double peaks) in exon 21. F and G, two homozygous silent mutations (one peak) in exon 20.

 
The most frequent mutation in exon 21 was a 2573T>G substitution resulting in L858R (13 of 14). The other point mutation—L861Q change—was only found in one female patient.

Eleven silent mutations occurred in exon 20: 2316C>T transition (Fig. 1F) in 1 patient and 2361G>A transition (Fig. 1G) in 10 patients. These did not alter the final amino acids of proline at codon 772 (P772P) and glutamine at codon 787 (Q787Q), respectively. In contrast to mutations in exons 19 and 21, which were heterozygous, five mutations in exon 20, including the 2316C>T substitution, were homozygous. Six mutations of 2361G>A coexisted with other mutations in exons 19 or 21, compared with only one patient who harbored two mutations in exons 19 and 21 (L747-E749, A750P, T751I, and L858R). No mutations were detected in exon 18 in the series of patients.

Mutations in gefitinib-treated patients. To ascertain the predictive effect of mutations in the EGFR-TK domain on responsiveness to gefitinib, we retrospectively assessed such mutations in 22 gefitinib-treated patients. All seven patients with partial response harbored mutations, including two in-frame deletions (E746-A750 and L747-P753insS), five missense mutations (L858R), and two silent mutations (Q787Q) that coexisted with L858R (Table 1). All the three types of activating mutation have been described previously and are considered to be associated with gefitinib sensitivity (13–15). No activating mutations, except two silent mutations (one 2316C>T, one 2361G>A), were detected in two patients with progressive disease. Fisher's exact test revealed a significant difference in EGFR activating mutation frequency between gefitinib responders (with partial response) and nonresponders (with progressive disease; P < 0.0001). We also screened for such activating mutations in seven patients with stable disease. Three mutations (one L858R and two E746-A750) were detected (3 of 7; 42.9%). If the disease control rate (including complete responses, partial response, and stable disease) was used as an end point of response to evaluate gefitinib efficacy, mutations were also statistically more frequent in patients with disease control than nonresponders (P = 0.002).


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  		Table 1. Characteristics of gefitinib-treated patients and mutation status

 
Epidermal growth factor receptor mutations in patients without gefitinib treatment. To identify the prevalence of EGFR gene mutation, we assessed mutations from exons 18 to 21 in 54 Chinese patients with primary NSCLC, including 31 men and 23 women. No patients received any antitumor therapy before tumor tissues were collected. These NSCLC specimens consisted of 35 adenocarcinomas and 19 squamous carcinomas. Eighteen tumors harbored mutations, including 8 substitution mutations and 11 in-frame deletion mutations, and tumor tissue from patient C16 harbored 2 mutations (L747-E749, A750P, T751I, and L858R; Table 2). Seven silent mutations (2361G>A, Q787Q) in exon 20 were found in the series of patients, four of which coexisted with other mutations. In this group of patients, mutations were more frequent in adenocarcinomas (17 of 35; 48.6%) than in squamous carcinomas (1 of 19; 5.3%; P = 0.001). The highest incidence of mutation was observed in bronchioalveolar carcinoma (7 of 13; 53.8%), but there was no significant difference compared with other adenocarcinomas (10 of 22; 45.5%). No difference in the incidence of EGFR mutations was found between male and female patients [10 of 31 (32.3%) and 8 of 23 (34.8%), respectively; P = 0.846].


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  		Table 2. Mutation status in patients who had not received gefitinib

 

   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
This is a report about mutation status in the EGFR-TK domain in NSCLC samples from patients of Chinese origin. Our study has extended data on the correlation between EGFR mutations and gefitinib responsiveness in these patients. The mutations in the EGFR-TK domain were well correlated with tumor response to gefitinib. All seven patients with partial response harbored EGFR mutations and no mutations were found in the eight patients with progressive disease, except two silent mutations. At the American Society of Clinical Oncology conference in 2004, Jänne reported five NSCLC patients with stable disease while receiving erlotinib (21). No mutations in the EGFR-TK domain were found in any of these patients. In this study, we investigated the mutation status in patients with stable disease. In contrast to Jänne's study, we detected three mutations in seven patients with stable disease. Data from published reports revealed that patients who harbored EGFR mutations could benefit from gefitinib therapy and that no mutations were found in patients with progressive disease (13, 14). Our study also showed that mutations were strongly correlated with tumor response, including three patients with stable disease, and no mutations in patients with progressive disease. Intriguingly, not all patients experiencing prolonged disease stabilization harbored such mutations. Although exact incidence of mutations in patients with stable disease could not be established because of the small sample size in our study, it is apparent that at least a subset of patients with stable disease did not harbor such mutations. Furthermore, three patients in Pao et al. (15) and one patient in Lynch et al. (13), who achieved a partial response with gefitinib therapy, did not harbor mutations in the EGFR-TK domain. Thus, there must be other factors affecting tumor response to gefitinib.

Studies published recently showed that the phosphorylation status of the EGFR downstream molecule Akt/PKB was associated with tumor response to gefitinib (10, 22). Expression status of PTEN may be another candidate molecular predictor for gefitinib responsiveness. PTEN acts as an antagonist of PI-3K and results in decreased Akt activity (23, 24). Restoration of PTEN function in PTEN-null tumor cells expressing high levels of EGFR could restore tumor responsiveness to gefitinib. The same result was also observed with anti-Her2 therapy (25). Our previous study showed that AG1478-resistant human epidermoid carcinoma A431 cells induced in our laboratory expressed reduced PTEN compared with AG1478-sensitive A431.5 Further study showed that A431 cells, which highly expressed EGFR and were highly sensitive to EGFR-TK inhibitors (26), did not harbor a mutation in the EGFR-TK domain (data not shown).

As >30% of patients achieved stable disease during gefitinib 250 mg/d therapy and >40% of symptomatic patients experienced improvement in their symptoms in the two IDEAL trials (6, 7), patients may receive benefit from gefitinib therapy in the absence of EGFR mutations. Further investigation of molecular markers as predictors of response is warranted to ensure patients gain the greatest benefit from gefitinib therapy. The significance of the discovery of the association between specific mutations in the EGFR gene and tumor response to gefitinib may lie in the following aspects: (a) determine which patients can benefit from combining gefitinib with chemotherapy or radiotherapy; (b) determine which patients can benefit from gefitinib as first-line therapy; and (c) determine which patients can receive gefitinib as adjuvant or new adjuvant therapy.

Mutation data from published reports (13–15, 19, 20) and our study show that 90% (215 of 239) of EGFR-TK mutations are found in two hotspots: in-frame deletions (47%; 113 of 239) that cluster from amino acid residues 746 to 753 and eliminate the LREA motif, except one mutation—S752-I759—reported by Paez et al. (14) and L858R mutation (102 of 239; 43%) within the activation loop of the EGFR-TK domain. No difference in the frequency of such mutations was found between East Asian populations and European-derived populations (in-frame deletion: 47% versus 50%; L858R: 43% versus 42%).

Data presented here also support our postulation, based on our experience with gefitinib treatment as a part of the gefitinib Expanded Access Programme. EGFR mutations were found more frequently in our series of patients of Chinese origin [18 of 54 (33.3%) in all NSCLCs and 17 of 35 (48.6%) in adenocarcinomas] than in patients of American origin [1 of 61 (1.6%) in all NSCLCs and 1 of 29 (3.4%) in adenocarcinomas; ref. 14]. These data may account for the higher response rate in Chinese patients participating in the gefitinib Expanded Access Programme. Although the exact reasons for the differences between races are not clear, it could be predicted that patients of Asian origin would gain more benefit from gefitinib therapy.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

5 X.L. Mu and X.T. Zhang, unpublished data. Back

Received 12/ 7/04; revised 2/17/05; accepted 3/22/05.


   References
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