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Originally published as JCO Early Release 10.1200/JCO.2005.01.388 on February 14 2005 © 2005 American Society of Clinical Oncology. Predictive and Prognostic Impact of Epidermal Growth Factor Receptor Mutation in Non–Small-Cell Lung Cancer Patients Treated With Gefitinib
From the Department of Internal Medicine, Department of Pathology, and Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital; Department of Internal Medicine, Seoul Municipal Boramae Hospital; Department of Internal Medicine, Seoul National University Bundang Hospital; Cancer Research Institute, Seoul National University College of Medicine; Petagen Inc, Seoul, Korea Address reprint requests to Tae-You Kim, MD, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu Seoul, 110-744 Korea; e-mail: kimty{at}snu.ac.kr.
PURPOSE: This study was undertaken to investigate the effects of epidermal growth factor receptor (EGFR) mutation and its downstream signaling on response and survival in non–small-cell lung cancer (NSCLC) patients treated with gefitinib. PATIENTS AND METHODS: For 90 consecutive NSCLC patients who had received gefitinib, EGFR mutation was analyzed by DNA sequencing of exons 18, 19, 21, and 23 in the EGFR tyrosine kinase domain. Expressions of phosphorylated (p) -Akt and p-Erk were determined via immunohistochemistry. Response rate, time to progression (TTP), and overall survival were compared between each group according to EGFR mutation, as well as p-Akt and p-Erk expression. RESULTS: Seventeen patients (18.9%; 95% CI, 10.8 to 27.0) harbored EGFR mutations. These mutations include deletions in exon 19 in seven patients, L858R in six patients, G719A in three patients, and a novel A859T in one patient. Response rate in patients with EGFR mutation was 64.7% (11 of 17 patients; 95% CI, 42.0 to 87.4), in contrast to 13.7% (10 of 73 patients; 95% CI, 5.8 to 21.6) in patients without mutation (P < .001). Moreover, these 17 patients with EGFR mutation had significantly prolonged TTP (21.7 v 1.8 months; P < .001) and overall survival (30.5 v 6.6 months; P < .001) compared with the remaining 73 patients without mutation. Although no significant correlation was detected between EGFR mutation and expressions of p-Akt or p-Erk, p-Akt overexpression was associated with prolonged TTP in patients with EGFR mutation. CONCLUSION: Our data further support the importance of EGFR mutation with regard to gefitinib sensitivity. In addition to its predictive role, EGFR mutation confers significant survival benefits on NSCLC patients treated with gefitinib.
Gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE) is a specific inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. It has shown favorable efficacy especially in non–small-cell lung cancer (NSCLC).1 After two phase II trials, Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) 1 and 2, and the compassionate Expanded Access Program, gefitinib monotherapy is rising as a treatment option for chemotherapy-refractory NSCLC.2-4 It is also being evaluated as a first-line treatment in selected patients.5 As only a limited number of patients benefited from gefitinib monotherapy, and because gefitinib is a specifically targetedagent, researchers have sought predictive markers of response in order to optimize patient selection for treatment. Female sex, adenocarcinoma histology, and being a never-smoker have been reported to be associated with response, but the reasons for these associations have remained obscure.2,3,6 Molecular predictive markers have also been investigated. EGFR, the specific target of gefitinib, was the first marker to be investigated, but the results were disappointing, as its expression failed to show any correlation with response.7,8 Since EGFR activity, after autophosphorylation, is mediated by downstream signal transduction cascades including the PI3K/Akt, Ras/Raf/Erk, and Jak/STAT pathways, EGFR downstream molecules had also been investigated as a predictive marker for response to gefitinib.8-11 The results of these investigations were controversial. While some have reported the possible roles of phosphorylated (p) -Akt or p-Erk as predictive markers, others have failed to find any association. Recently, activating mutations of EGFR were found to have a significant association with response to gefitinib, suggesting its promising role as a predictive marker of response.12-14 Higher rates of mutation were seen in females, adenocarcinomas, the Japanese population, and never-smokers, which may explain the clinical response predictive factors. Furthermore, in vitro experiments with EGFR mutant cell lines revealed preferential phosphorylation of selected tyrosine residues in the carboxy-terminal of EGFR and resulting activations of PI3K/Akt and STAT pathways.15 This may explain, in part, previous reports of correlations between EGFR downstream molecules and efficacy of gefitinib.8,9 However, EGFR mutation has not been examined in unselected patients treated with gefitinib. Moreover, the effect of EGFR mutation on survival has not been reported. Thus, in order to confirm and enrich our knowledge of EGFR mutation in gefitinib-treated patients, we have investigated EGFR mutational status in a set of consecutive NSCLC patients who had received gefitinib at our institutions, regardless of their response. Correlations between EGFR mutation and response to gefitinib and survival were analyzed. In addition, its correlation with expression of p-Akt and p-Erk were investigated.
Patients and Treatment From December 2001 to July 2004, 219 advanced NSCLC patients received gefitinib monotherapy at the two participating institutions (Seoul National University Hospital or Seoul Municipal Boramae Hospital, Seoul, Korea), including 88 patients who participated in the Expanded Access Program. Among them, 90 patients were assessable for response, and had paraffin-embedded tissue adequate for mutational analysis. All patients had pathologically proven locally advanced or metastatic NSCLC. All patients included in the study also had normal baseline CBCs, and renal and hepatic functions. The treatment consisted of 250 mg of gefitinib daily, which was continued until disease progression, intolerable toxicity, or patient refusal. Patients were re-evaluated every 4 weeks by chest x-ray or computed tomography (CT) and adequate blood tests for tumor response and toxicity. Tumor response was evaluated according to the WHO criteria, and all responses were confirmed at least 4 weeks after initial assessment.16 Smoking histories were obtained by thorough reviews of medical records. In those patients who had been recorded as a never-smoker, smoking history was once again confirmed by the patient or a close family member in case the patient had died. Formalin-fixed, paraffin-embedded tissue blocks obtained before any systemic chemotherapy or radiotherapy were retrieved from the archives of the Departments of Pathology at the two institutions: 79 from primary tumor, five from lymph node, and six from metastatic sites (three bone, two liver, and one brain). All histology was once again reviewed by the two pathologists (P.G.H. and D.H.C) blinded to any clinical information. Adenocarcinomas with bronchioloalveolar features were classified as bronchioloalveolar carcinoma (BAC). The study protocol was reviewed and approved by the institutional review board at the Seoul National University Hospital. Recommendations of the Declaration of Helsinki for biomedical research involving human subjects were also followed.
DNA Sequencing
Immunohistochemistry
Statistical Analysis
Patient Characteristics and Efficacy of Gefitinib Baseline characteristics of the 90 patients are as described in Table 1. The majority of the patients were male (54 patients, 60.0%) and adenocarcinoma was the major histologic type (65 patients including 10 BAC, 72.2%). The 10 BACs consisted of three pure BACs and seven adenocarcinomas with BAC features. Never-smokers made up 47.8% (43 patients) of patients. There was no treatment withdrawal as a result of toxicity, and only one patient was withdrawn due to her refusal of treatment. With regard to best overall response, 21 patients exhibited partial responses (PR; 23.3%; 95% CI, 14.6 to 32.0), 27 patients maintained stable disease (SD; 30.0%; 95% CI, 20.5 to 39.5), and 42 patients had progressive disease (PD; 46.7%; 95% CI, 36.4 to 57.0; Table 2). Females (response rate [RR], 36.1% v 14.8% [male]; P = .019), never-smokers (RR, 32.6% v 14.9% [smokers]; P = .048), and patients with adenocarcinoma (RR, 29.2% v 8.0% [nonadenocarcinoma]; P = .033) exhibited better responses. No response was detected in 19 male smokers with histologies other than adenocarcinoma. In the multivariate analysis, female sex was the only factor significantly associated with response (odds ratio [OR], 3.25; 95% CI, 1.18 to 8.95). Median TTP was 2.7 months (95% CI, 1.9 to 3.6) and OS was 7.4 months (95% CI, 4.6 to 10.2). Median OS in patients with PR, SD, and PD were 22.1 (95% CI, 11.5 to 32.8), 12.3 (95% CI, 7.8 to 16.9), and 4.8 (95% CI, 4.0 to 5.7) months, respectively (P < .001).
EGFR Mutation Analysis Deletion in exon 19 was the most common mutation, found in seven patients (Table 3; Fig 1). L858R (2573T>G) in exon 21 was found in six patients and G719A (2156G>C) in three patients. Other mutations found were E709K (2125G>A) in exon 18 and A859T (2575G>A) in exon 21, in one patient each. One patient was found to harbor two mutations in the tested exons (E709K and G719A). All mutations were heterozygous. In addition, synonymous single nucleotide polymorphism in exon 23 (2709C>T, T903) was seen in four patients. Excluding this polymorphism, the overall mutation rate was 18.9% (17 of 90 patients; 95% CI, 10.8 to 27.0). Mutation rates were higher in females (33.3% v 9.3% [male]; P = .004), never-smokers (25.6% v 12.8% [smokers]; P = .12), and patients with adenocarcinoma (21.5% v 12.0% [nonadenocarcinoma]; P = .38). No mutations were observed in 19 male smokers with histologies other than adenocarcinoma.
EGFR Mutation and Response to Gefitinib Of 17 patients harboring EGFR mutations, 11 patients (64.7%) exhibited PR, whereas 10 (13.7%) of 73 patients without mutation had PR after treatment with gefitinib (P < .001; Table 4). Multivariate analysis with clinical variables of sex, histology, and smoking history yielded mutational status as the sole predictive factor of response to gefitinib (OR, 10.9; 95% CI, 2.97 to 40.2). Moreover, among six patients with mutation not exhibiting a PR, three patients had minor responses (decrease in tumor size but not reaching the criteria for a PR), one patient showed a dramatic decrease in serum carcinoembryogenic antigen level and symptomatic improvement, and two patients experienced PD. Collectively, all but two patients harboring EGFR mutations (15 of 17 patients, 88.2%) experienced substantial clinical benefits from the treatment. At the time of data analysis, 10 of 17 patients with mutation had experienced PD. Six patients showed progression in their lung lesions, two had aggravation of pre-existing bone metastases, one developed multiple new metastases in bone, and one had aggravation of pre-existing brain metastasis.
From previous reports and this study, most of the EGFR mutations were found in three hot-spots: G719, L747 – A750, and L858.12-14 Among 16 patients with these mutations, 15 (93.8%) benefited from gefitinib treatment. Therefore, EGFR mutation in these three hot-spots appears to be more sensitive in determining gefitinib responsiveness.
EGFR Mutation and Impact on Survival
EGFR Mutation and Association With p-Akt/p-Erk Expression Immunohistochemical data were assessable in 87 patients. When expression of p-Akt or p-Erk was compared with sex, histology, smoking history, and EGFR mutation, only p-Erk positivity (1+/2+) was significantly associated with nonadenocarcinoma histology (adenocarcinoma 54.0% v nonadenocarcinoma 79.2%; P = .031). p-Erk expression was also inversely associated with response (RR, 32.4% in negative v 17.0% in 1+/2+; P = .096), and TTP (6.1 months in negative v 2.3 months in 1+/2+; P = .029; Table 5). Negative p-Erk expression (negative v 1+/2+) independently showed a significant association with response (OR, 3.71; 95% CI, 1.05 to 13.1) and was significantly predictive of prolonged TTP (HR, 0.54; 95% CI, 0.32 to 0.93) in multivariate analyses considering EGFR mutational status as a covariate. OS was not associated with p-Erk expression (data not shown). On the other hand, p-Akt expression was not associated with response, TTP, or OS. However, in patients harboring EGFR mutations, overexpression of p-Akt (2+) was associated with prolonged TTP (26.9 v 5.1 months [negative/1+]; P = .010; Fig 4). In contrast, in patients without EGFR mutation, no responders exhibited p-Akt overexpression (P = .053; Table 6), and we observed a tendency toward shorter TTP in patients exhibiting p-Akt overexpression (1.2 v 2.1 months [negative/1+]; P = .056; Fig 4). OS was not affected by p-Akt expression in either group (data not shown).
Prediction of Response in Patients Without EGFR Mutation Among 21 responders, 10 (47.6%) exhibited no EGFR mutations. The response rate in the 73 patients without mutation was 13.7% (95% CI, 5.8 to 21.6). All responses were detected in patients with non-BAC adenocarcinoma (10 of 44 patients; RR, 22.7%; 95% CI, 13.1 to 32.3; P = .005). Response rates were higher in females (20.8%) and never-smokers (21.9%; Table 6). Never-smokers with non-BAC adenocarcinoma had a RR of 25.9% (seven of 27 patients), whereas the other patients had a 6.5% RR (three of 46 patients; P = .032). Median TTP of each group was 1.7 and 1.9 months, respectively (P = .25), and median OS was 5.7 and 6.6 months, respectively (P = .48). Incorporation of immunohistochemical data into clinical factors, which were not significantly associated with one another, resulted in a response rate of 40% (four of 10 patients) in never-smokers with non-BAC adenocarcinoma exhibiting negative or weak (-/1+) p-Akt and negative p-Erk expression. The other patients showed an 8.3% response rate (five of 60 patients; P = .020). The median TTP of the former patients was 7.3 months, compared with 1.6 months in the latter (P = .030). Median OS in the two groups were 10.1 months and 6.5 months, respectively (P = .14). In summary, patients with no history of smoking, non-BAC adenocarcinoma, and low expressions of p-Akt and p-Erk are most likely to benefit from gefitinib, despite not harboring EGFR mutations.
In the search for predictive markers of response to gefitinib, recent studies have demonstrated a significant association of EGFR mutation with response to gefitinib in NSCLC.12-14 Collectively, 20 of 24 gefitinib-sensitive tumors harbored EGFR mutation, in contrast to none in the 19 tumors with no response. All mutations in the responders were found in exons 18, 19, and 21. In this study, we have confirmed and extended the above reports, and investigated the roles of p-Akt and p-Erk expressions within the context of EGFR mutational status. Mutations found in this study were similar to those found in previous ones. In-frame deletions in exon 19 were most frequently observed, appearing in seven patients. All deletions were found between E746 and P753, and all included amino acids L747-A750. L858R mutation was found in six patients. All patients with these two mutations reaped substantial benefits from treatment with gefitinib. Three patients harbored missense mutation in exon 18 (G719A, 2156G>C), which differs from the previous report of 2155G>T (G719C), and two of these patients had a partial response.12 It may be speculated that mutations in G719 are also associated with gefitinib sensitivity. Functional analyses of G719A and G719C mutation are warranted in future studies. E709K and A859T were novel mutations found in this study. Since E709K was found in a patient with G719A who had a temporary response to gefitinib, its association with response or resistance needs to be determined in future investigations. Two mutations, G719A and A859T, were seen in patients with progressive disease. These two patients exhibited unfavorable immunohistochemical profiles (ie, weak [1+] p-Akt and positive [1+/2+] p-Erk). The gefitinib-resistant patient with G719A may have a resistance mechanism obviating the gefitinib-sensitizing mutation. With regard to A859T, as it is adjacent to the gefitinib-sensitivity determining L858, A859 might also have some role in interaction with gefitinib or a adenosine triphosphate. Further investigation of the consequent alterations caused by substitution of threonine for arginine is warranted. In our patient population, EGFR mutation was found in only 52.4% (11 of 21 patients) of responders, which is lower than the 83.3% (20 of 24 patients) of previous reports.12-14 As tumor specimens analyzed were those obtained at initial diagnosis or surgery, the 10 responders without mutations might have acquired EGFR mutations in the course of their disease progression, thereby rendering them sensitive to gefitinib. In addition, DNA sequencing had not been performed in a duplicate manner, partly due to the small amount of DNA extractable from small biopsy specimens. This may also have potentially underestimated the mutation rate. However, we believe it to be quite unlikely that mutations outside the exons tested herein would explain the 10 nonmutant responders, as previous reports failed to find any mutations outside these exons, except in one of 300 patients (0.3%) in exon 20 (R776C), in 60 specimens from gefitinib- or erlotinib-treated patients, and 240 specimens with no exposure to these drugs.12-14 Our analyses of TTP and OS reveal significant differences, according to EGFR mutational status. It is expected that patients with EGFR mutation would exhibit longer TTP and OS, as EGFR mutation is significantly associated with gefitinib responsiveness. However, an unexpected finding was that TTP and OS were also distinguishable among responders, according to EGFR mutational status; responders with EGFR mutations having more favorable TTP and OS. This suggests that there may be two distinct groups of responders, namely, EGFR mutants and nonmutants. The current EGFR nonmutants may have other mechanisms of gefitinib sensitivity, which confer lower levels of sensitivity than those associated with EGFR mutation, or these non-mutants may acquire EGFR mutation in the course of their disease progression, with merely an adjunctive role compared with the primary role in patients with EGFR mutation from the outset. Analysis of tumor specimens obtained just before treatment, and investigation of other possible gefitinib-sensitizing mechanisms such as EGFR gene amplification, may provide answers to these questions. We have also analyzed which baseline characteristics may be predictive for response in patients without EGFR mutation. All responses were observed in patients with non-BAC adenocarcinomas. Previous studies have reported that BAC is associated with gefitinib responsiveness, and EGFR mutation is frequently found in BACs.6,14 In our observations, the frequency of EGFR mutation in BACs (three of 10 patients, 30%) was similar to that seen in non-BAC adenocarcinomas (11 of 55 patients, 20%; P = .44), and no patient with BAC, but rather without EGFR mutation, was observed to respond to gefitinib. Among patients without EGFR mutation, never-smokers with non-BAC adenocarcinoma histology had a RR of 25.9%, whereas those who had smoked or had histologies other than non-BAC adenocarcinoma had the worst RR of 6.5%. We believe that this latter group of patients should leave gefitinib as the last treatment option, as they are least likely to respond. In the present study, overexpression of p-Akt (2+) was associated with prolonged TTP in patients with EGFR mutation. As EGFR mutation was demonstrated to activate the PI3K/Akt pathway, those with p-Akt overexpression could be regarded as being more EGFR mutation dependent, and thus more sensitive to gefitinib.15 In contrast, in patients without EGFR mutation, patients with p-Akt overexpression had poor prognoses. This might be due to the EGFR independent activation of PI3K/Akt pathway rendering them more resistant to gefitinib.17-20 Thus, it may be natural that different investigators had previously reported conflicting results regarding the association between p-Akt and efficacy of gefitinib, as different study populations may differ in EGFR mutational status or other Akt activating mechanisms, which no study had taken into account.8-11 p-Erk expression was negatively associated with response and TTP, even after EGFR mutational status had been taken into account. This confirms the possibility that EGFR-independent activation of the Ras/Raf/Erk pathway may contribute to gefitinib resistance.19,21 In conclusion, EGFR mutation is significantly associated with response to gefitinib, and is strongly predictive of prolonged survival in NSCLC patients treated with gefitinib. Considering the substantial benefits of treatment with gefitinib in patients with EGFR mutation, we propose that all NSCLC patients, especially those with adenocarcinoma, should be tested for EGFR mutational status, and in patients with EGFR mutation, gefitinib must be considered as the treatment option before any other.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Research Funding: Tae-You Kim, AstraZeneca. For a detailed description of this category, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
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); and by AstraZeneca Pharmaceuticals, Seoul, Korea. Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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3. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003 4. Cortes-Funes H, Soto Parra H: Extensive experience of disease control with gefitinib and the role of prognostic markers. Br J Cancer 89:S3-S8, 2003 (suppl 2) 5. Lee DH, Han JY, Lee HG, et al: Gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers. Clin Cancer Res: in press
6. Miller VA, Kris MG, Shah N, et al: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22:1103-1109, 2004 7. Bailey LR, Kris M, Wolf M, et al: Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib (‘Iressa’, ZD1839) monotherapy for pretreated advanced non-small-cell lung cancer: IDEAL 1 and 2. Proc Am Assoc Cancer Res 44:1362, 2003 (abstr LB-170) 8. Han SW, Hwang PG, Chung DH, et al: Epidermal growth factor receptor (EGFR) downstream molecules as response predictive markers for gefitinib (Iressa®, ZD1839) in chemotherapy resistant non-small-cell lung cancer. Int J Cancer 113:109-115, 2005[CrossRef][Medline]
9. Cappuzzo F, Magrini E, Ceresoli GL, et al: Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 96:1133-1141, 2004 10. Pao W, Zakowski M, Cordon-Cardo C, et al: Molecular characteristics of non-small cell lung cancer (NSCLC) patients sensitive to gefitinib. Proc Am Soc Clin Oncol 23:619, 2004 (abstr 7025) 11. Franklin WA, Chansky K, Gumerlock PH, et al: Association between activation of ErbB pathway genes and survival following gefitinib treatment in advanced BAC (SWOG 0126). Proc Am Soc Clin Oncol 23:618, 2004 (abstr 7015)
12. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004
13. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004
14. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004
15. Sordella R, Bell DW, Haber DA, et al: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305:1163-1167, 2004 16. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 17. Vivanco I, Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489-501, 2002[CrossRef][Medline] 18. Bianco R, Shin I, Ritter CA, et al: Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22:2812-2822, 2003[CrossRef][Medline]
19. Janmaat ML, Kruyt FA, Rodriguez JA, et al: Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: Limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res 9:2316-2326, 2003
20. She QB, Solit D, Basso A, et al: Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. Clin Cancer Res 9:4340-4346, 2003 21. Magne N, Fischel JL, Dubreuil A, et al: Influence of epidermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumour cells on the antiproliferative effect of ZD1839 ("Iressa"). Br J Cancer 86:1518-1523, 2002[CrossRef][Medline] Submitted September 21, 2004; accepted December 21, 2004. This article has been cited by other articles:
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