© 2006 Foundation for Promotion of Cancer Research
Epidermal Growth Factor Receptor Mutations and Response to Chemotherapy in Patients with Non-Small-Cell Lung Cancer
1 Department of Internal Medicine and 2 Department of Pathology, Seoul National University Hospital, 3 Department of Internal Medicine, Seoul National University Boramae Hospital and 4 Cancer Research Institute, Seoul National University and College of Medicine, Seoul, Korea
For reprints and all correspondence: Dong-Wan Kim, Assistant Professor, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul, 110-744, South Korea; E-mail: dwkimmd{at}chol.com
Received December 12, 2005; accepted February 24, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: The association of epidermal growth factor receptor (EGFR) mutations with the response to conventional cytotoxic chemotherapeutic agents in non-small-cell lung cancer patients has not been investigated. We retrospectively analyzed the associations between response to chemotherapy and molecular markers associated with gefitinib responsiveness including EGFR mutations.
Methods: EGFR (exons 18, 19 and 21) and K-ras mutations (exon 2) were studied by direct sequencing and p-Erk and p-Akt expressions were studied by immunohistochemistry in archival paraffin embedded tissues. Response rate (RR) and time-to-progression (TTP) of prior chemotherapy by platinum, paclitaxel and gemcitabine were analyzed with respect to the presence of EGFR and K-ras mutations, and p-Erk and p-Akt expressions.
Results: Of 90 patients investigated, 75 received platinums and 45 received paclitaxel as first-line chemotherapy agents. The RRS and TTPS of platinum- and paclitaxel-containing regimens were not affected by EGFR or K-ras mutations, nor by p-Erk or p-Akt expression. Fifty-seven patients received gemcitabine as first- or second-line chemotherapy. RR was not affected by EGFR or K-ras mutations or by p-Akt expression. However, all responders to gemcitabine exhibited (+) p-Erk expression [RR 30.6% for p-Erk (+) versus 0% for p-Erk (–), P = 0.01]. TTP was not affected by EGFR or K-ras mutations or by p-Erk or p-Akt expression.
Conclusions: EGFR mutations did not affect response to conventional chemotherapeutic agents, namely platinums, paclitaxel and gemcitabine. Our results also suggest that it may be undesirable to use gemcitabine in patients with tumors not expressing p-Erk.
Key Words: EGFR • mutation • K-ras • Erk • Akt
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Gefitinib (Iressa®, ZD1839) is a specific inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) and has shown favorable efficacy in patients with chemotherapy-refractory non-small-cell lung cancer (NSCLC) (1,2). It is also being evaluated as a first-line therapy in selected patients (3–6).
It has been reported that activating mutations in the EGFR TK domain are present in a subset of NSCLC patients, which in turn is associated with responsiveness to gefitinib (7–18). Moreover, significant survival advantage of gefitinib treatment in patients with EGFR mutation is reported in recent studies (15–18). In view of the significant benefits reaped in NSCLC patients with EGFR mutations by gefitinib treatment, gefitinib as an optimal front-line treatment option in such patients may be considered, which, however, remains to be examined in prospective studies.
Regarding the clinical and biological features, the presence of an EGFR mutation did not affect overall survival in NSCLC patients who underwent curative intent resection and who did not receive gefitinib or other EGFR-targeting agents (10,12). However, it is uncertain whether patients with an EGFR mutation also show better response to conventional cytotoxic chemotherapy. Furthermore, it would be of much help to find out molecular predictive markers for regimens commonly used in NSCLC patients in order to select patients with a greater chance of benefit.
We have previously shown that the presence of an EGFR mutation conferred a significant survival benefit in consecutive NSCLC patients treated with gefitinib (16). In addition to EGFR mutations, p-Akt and p-Erk expressions, and K-ras mutations also affected gefitinib responsiveness (16,19). Here, we extended our analysis to associations between prior responses to cytotoxic chemotherapeutic agents and molecular markers previously identified in these patients and reported previously. We retrospectively analyzed response rate (RR) and time-to-progression (TTP) with prior conventional chemotherapy in NSCLC patients treated with gefitinib with respect to EGFR and K-ras mutations and p-Akt and p-Erk expressions.
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PATIENTS AND METHODS |
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PATIENTS AND TREATMENT
Of 219 advanced NSCLC patients who received gefitinib monotherapy between December 2001 and July 2004, 90 patients were assessable for EGFR mutations (16). p-Akt and p-Erk expressions were evaluated in 87 of these 90 patients and K-ras mutations in 69 of the 90 patients (19). All patients had pathologically proven locally advanced or metastatic NSCLC and had normal baseline hematologic, renal and hepatic functions.
Data concerning prior chemotherapeutic regimens and subsequent responses to chemotherapy were obtained by thorough review of medical records and appropriate imaging studies including chest X-rays and computed tomography. Tumor response was evaluated according to the WHO criteria (20). The study protocol was reviewed and approved by the institutional review board of Seoul National University Hospital. The recommendations of the Declaration of Helsinki for biomedical research involving human subjects were also followed.
DNA SEQUENCING
Mutational analysis was performed as described previously (16). Briefly, DNA was extracted from five 5 µm paraffin sections, containing a representative portion of each tumor block, using QIAamp DNA Mini kits (Qiagen, Hilden, Germany). One hundred nanograms (ng) of DNA were amplified in a 20 µl reaction solution containing 2 µl of 10x buffer (Roche, Mannheim, Germany), 1.5 mM of MgCl2, 0.3 µM of each complementary primer pair, 250 µM of deoxynucleoside triphosphate and 2.5 units of DNA polymerase (Roche). Amplifications were performed using a 5 min (min) initial denaturation at 94°C; followed by 30 cycles of 1 min at 94°C, 1 min at 55°C, and 1 min at 72°C; and a 10 min final extension at 72°C. PCR products were purified using a QIAgen gel extraction kit (Qiagen) and processed for DNA sequencing using ABI-PRISM BigDye Terminator v3.1 (Applied Biosystems, Foster, CA) with both forward and reverse sequence-specific primers. Sequence data were generated using an ABI-PRISM 3100 DNA Analyzer (Applied Biosystems). Sequences were analyzed using Sequencer 3.1.1 software (Applied Biosystems) in order to compare variations.
IMMUNOHISTOCHEMISTRY
Immunohistochemistry was performed and scored as described previously (21). In brief, antigen retrieval was performed by microwaving 10 µm sections in 0.01 M citrate buffer adjusted to pH 6.0 for 15 min at 650 W. Endogenous peroxidase activity was quenched with 3% hydrogen peroxide in methanol for 15 min. After incubation with blocking solution for 10 min, sections were incubated with primary antibodies (1/50 dilution) at 4°C for 12 h, with biotinylated secondary antibody at room temperature for 10 min, and then with streptavidin horseradish peroxidase for 10 min. Staining was carried out with diaminobenzidine chromogen, and counter-staining was carried out with Mayer's hematoxylin. The primary antibodies used were rabbit polyclonal p-Akt (Ser473) antibody (immunohistochemistry specific) and rabbit polyclonal p-Erk1/2 (Thr202/Tyr204) antibody, both of which were purchased from Cell Signaling Technology (Beverly, MA). Blocking solution, secondary antibody, streptavidin horseradish peroxidase and diaminobenzidine chromogen were all from the Cap-Plus Kit (Zymed Laboratories, San Francisco, CA). Each slide was scored as 1+ if >5% of cells exhibited cytoplasmic or weak nuclear staining and as 2+ if they exhibited strong nuclear staining (i.e. more intense nuclear staining than cytoplasmic staining) in >5% of cells.
STATISTICAL ANALYSIS
The statistical analyses of categorical variables were performed using the Pearson's 
2 test or Fisher's exact test as appropriate. TTP was calculated as the period from the date of starting the therapy to the first observation of disease progression. The median durations of TTP were calculated using the Kaplan–Meier method. Comparisons between groups were made using log-rank tests. Overall survival was not included in the analysis as patients with an EGFR mutation showed significantly prolonged survival due to subsequent gefitinib treatment (16) Two-sided P-values of <0.05 were considered significant. All analyses were performed using SPSS for Windows, version 12.0 (SPSS Inc, Chicago, IL).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENT CHARACTERISTICS
Baseline characteristics of the patients were described previously.16 Briefly, 54 male and 36 female patients were included (median age: 60 years). Histologic diagnosis included 55 adenocarcinomas, 10 bronchioloalveolar carcinomas, 21 squamous cell carcinomas and 4 others. Five patients were of stage IIIb and 85 stage IV.
Of the 90 patients previously reported, 81 patients received chemotherapy alone as an initial treatment for advanced or metastatic disease, 5 patients received chemotherapy with radiotherapy and 4 patients received gefitinib.
The regimens used as a first-line therapy included paclitaxel and cisplatin in 28 patients, paclitaxel and carboplatin in 21, gemcitabine and cisplatin in 13, gemcitabine and carboplatin in 4, vinorelbine and cisplatin in 7, docetaxel and cisplatin in 2, and other regimens in 6 patients.
The regimens used as a second-line therapy included gemcitabine and vinorelbine in 23 patients, gemcitabine and carboplatin in 9, paclitaxel and carboplatin in 9, gemcitabine and cisplatin in 9, docetaxel in 7, paclitaxel and cisplatin in 5, docetaxel and carboplatin in 4, docetaxel and cisplatin in 2, and other regimens in 4 patients. (Table 1)
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The patients were categorized into three groups and subsequent analyses were performed. Those who received cisplatin or carboplatin as a first-line regimen were analyzed because platinum doublets are the standard treatments in advanced NSCLC, and the two agents have similar mechanisms of action.22 Those who received other commonly used chemotherapeutic agents, i.e. paclitaxel and gemcitabine, were also analyzed. Thus, 78 patients received platinum-containing regimens as a first-line therapy and 75 were evaluable for response. Forty-nine patients received paclitaxel as a first-line therapy and all of them were evaluable. Fifty-eight patients received gemcitabine as a first- or second-line therapy (17 patients as a first-line and 41 patients as a second-line therapy) and 57 were evaluable. Four excluded patients had incomplete medical records or an inadequate follow-up.
EGFR MUTATIONS, K-RAS MUTATIONS, P-AKT EXPRESSION AND P-ERK EXPRESSION
EGFR mutations were found in 17 patients (18.9%). The mutations included deletions in exon 19 in 7 patients, L858R in 6, G719A in 3 and A859T in 1. P-Akt expression was strong (2+) in 27 patients and p-Erk expression was positive in 53 patients. Nine patients (15.9%) harbored mutations in K-ras codons 12 and 13. Four patients exhibited G12D, two G12V, two G12A and one G13C. (Table 2)
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RESPONSE TO CONVENTIONAL CHEMOTHERAPY ACCORDING TO EGFR MUTATIONS, -KRAS MUTATIONS, P-AKT EXPRESSION AND P-ERK EXPRESSION
Table 2 shows overall RRs according to the markers. Overall RR to first-line chemotherapy in patients with EGFR mutations was 42.9% and that without mutations was 34.4% (P = 0.55). None of the other markers affected the response rates significantly.
FIRST-LINE PLATINUM-CONTAINING CHEMOTHERAPY
Seventy-five patients received cisplatin- or carboplatin-containing chemotherapy as a first-line therapy.
RR was not affected by the presence of an EGFR mutation [42.9% for EGFR mutation (+) versus 34.4% for EGFR mutation (–); P = 0.55], a K-ras mutation [25.0% for K-ras mutation (+) versus. 38.5% for K-ras mutation (–); P = 0.70], p-Erk expression [36.0% for p-Erk (–) versus 34.0 % for p-Erk (+); P = 0.87] or p-Akt expression [36.2% for p-Akt (–/1+) versus 32.0% for p-Akt (2+); P = 0.72] (Table 3).
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TTP was not affected by the presence of an EGFR mutation [7.97 months for EGFR mutation (+) versus 6.67 months for EGFR mutation (–); P = 0.96], a K-ras mutation [4.63 months for K-ras mutation (+) versus 7.17 months for K-ras mutation – P = 0.15], p-Erk expression [7.63 months for p-Erk (–) versus 6.70 months for p-Erk (+); P = 0.49] or p-Akt expression [7.17 months for p-Akt (–/1+) versus 6.80 for p-Akt (2+); P = 0.51] (Fig. 1).
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FIRST-LINE PACLITAXEL-CONTAINING CHEMOTHERAPY
Forty-nine patients received paclitaxel-containing chemotherapy as a first-line therapy.
Of 10 patients with an EGFR mutation 5 responded to paclitaxel-containing regimens [RR, 50% for EGFR mutation (+) versus 38.5% for EGFR mutation (–) P=0.51]. P-Erk [40% for p-Erk (–) versus 38.7% for p-Erk (+); P = 0.93] or p-Akt [36.7% for p-Akt (–/1+) versus 43.8% for p-Akt (2+); P = 0.64] did not affect response to paclitaxel-containing regimens. Neither did the presence of a K-ras mutation [25% for K-ras mutation (+) versus 48.4% for K-ras mutation (–); P = 0.43] (Table 3).
TTP was not affected by the presence of an EGFR mutation [9.70 months for mutation (+) versus 6.27 months for mutation (–); P = 0.81], a K-ras mutation [4.63 months for mutation (+) versus 7.17 months for mutation (–); P = 0.16], p-Erk expression [7.17 months for p-Erk (–) versus 6.70 months for p-Erk (+); P = 0.36] or p-Akt expression [4.97 months for p-Akt (–/1+) versus 7.17 months for p-Akt (2+); P = 0.23] (Fig. 2).
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FIRST- OR SECOND-LINE GEMCITABINE-CONTAINING CHEMOTHERAPY
Fifty-seven patients received gemcitabine as a first- or second-line therapy.
RR was not affected by the presence of an EGFR mutation [30.8% for EGFR mutation (+) versus 15.9% for EGFR mutation (–); P = 0.25], a K-ras mutation [37.5% for K-ras mutation (+) versus 17.9% for K-ras mutation (–); P = 0.34] or p-Akt expression [15.8% for p-Akt (–/1+) versus 29.4% for p-Akt (2+); P = 0.29] (Table 3).
TTP was not affected by an EGFR mutation [7.40 months for EGFR mutation (+) versus 4.60 months for EGFR mutation (–); P = 0.25], a K-ras mutation [5.07 months for K-ras mutation (+) versus 5.43 months for K-ras mutation (–); P = 0.86], p-Erk expression [4.60 months for p-Erk (–) versus 5.86 months for p-Erk (+); P = 0.36] or p-Akt expression [5.43 months for p-Akt (–/1+) and p-Akt (2+); P = 0.58] (Fig. 3).
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Of note, all responders to gemcitabine exhibited p-Erk expression, and RR to gemcitabine differed significantly according to p-Erk status [RR 30.6% for p-Erk (+) versus 0.0% for p-Erk (–), P = 0.01].
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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We analyzed responses to conventional cytotoxic chemotherapeutic agents in relation to the presence of an EGFR mutation, but could not find any statistically significant differences in RR or TTP according to EGFR TK domain mutation status. In addition, we investigated other signaling molecules of p-Erk, p-Akt and K-ras. Only p-Erk status was found to be significantly associated with the response to gemcitabine. TTP was not affected by p-Akt, p-Erk expression status or K-ras mutation. TTP for first-line platinum-containing or paclitaxel-containing regimens tended to decrease in the presence of a K-ras mutation, though not reaching statistical significance, which might be due to the small sample size.
The EGFR TK domain mutations are related to increased response rate and survival to gefitinib (15–18). RR reached 65% in patients with an EGFR mutation (16). From previous reports, EGFR mutation status may act as a predictive marker of sensitivity to gefitinib. However, no predictive marker for conventional cytotoxic chemotherapeutic agents is commonly used in NSCLC patients. Moreover, RRs to regimens used as a first-line therapy do not reach that of gefitinib (22). The present study revealed no differences in RR or TTP for chemotherapy according to EGFR mutational status and therefore it is conceivable that patients with an EGFR mutation may benefit more from gefitinib than from conventional chemotherapeutic agents. Large scale prospective studies of gefitinib as a front-line therapy in advanced NSCLCs are warranted.
The mutational activation of K-ras was reported to be associated with an adverse effect on survival in NSCLC patients and a lack of sensitivity to gefitinib or erlotinib (23,24). In our study, the presence of a K-ras mutation was found to exert an adverse effect on patients treated with first-line platinum-containing or paclitaxel-containing regimens in agreement with the previous reports, although not reaching statistical significance probably due to the small sample size analyzed (25).
P-Erk and p-Akt expression status showed no correlation to chemotherapy responses, except for p-Erk expression status and gemcitabine-containing regimens, where p-Erk expression was significantly related to gemcitabine response, although higher RR did not translate into longer TTP. Interestingly, all responders to gemcitabine-containing regimens showed p-Erk expression. Analysis of patients who received gemcitabine as a second-line regimen only also revealed significant association between p-Erk and response (data not shown). Our results suggest that it may be undesirable to use gemcitabine in patients whose tumors do not express p-Erk. In a previous study, patients with tumors not expressing p-Erk were found to respond poorly to gefitinib and it is possible that patients who are resistant to gefitinib with tumors not expressing p-Erk may benefit from gemcitabine (21). The mechanism linking p-Erk expression and gemcitabine is not known, though it was reported that Erk activation by phosphorylation during chemotherapy mediates gemcitabine-induced apoptosis in NSCLC cells (26). However, the association between pretreatment p-Erk status and gemcitabine sensitivity has not been investigated. Considering the small patient number and retrospective design of the present study, further studies with a larger number of patients are warranted to confirm the effect of p-Erk status on response and survival with gemcitabine treatment.
P-Akt has been reported to confer chemoresistance and radioresistance in NSCLC cell lines (27). In a recent study, p-Akt protein levels assessed by western blotting and semiquantitative densitometry were associated with a favorable prognosis in patients with NSCLC who underwent surgery alone, but p-Akt expression by immunohistochemistry did not correlate with the prognosis (28). Our data did not show any significant difference in RRs or TTPs for chemotherapic agents according to p-Akt expression by immunohistochemistry.
In conclusion, the presence of an EGFR mutation did not affect responses to platinums, paclitaxel or gemcitabine. In addition, our results suggest that it may be undesirable to use gemcitabine for patients with tumors not expressing p-Erk.
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Acknowledgments |
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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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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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