Originally published as JCO Early Release 10.1200/JCO.2005.01.388 on February 14 2005

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Predictive and Prognostic Impact of Epidermal Growth Factor Receptor Mutation in Non–Small-Cell Lung Cancer Patients Treated With Gefitinib

Sae-Won Han, Tae-You Kim, Pil Gyu Hwang, Soohyun Jeong, Jeongmi Kim, In Sil Choi, Do-Youn Oh, Jee Hyun Kim, Dong-Wan Kim, Doo Hyun Chung, Seock-Ah Im, Young Tae Kim, Jong Seok Lee, Dae Seog Heo, Yung-Jue Bang, Noe Kyeong Kim

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.

	ABSTRACT

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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.

	INTRODUCTION

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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 METHODS

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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
DNA was extracted from five paraffin sections of 10-µm thickness containing a representative portion of each tumor block, using the QIAamp DNA Mini kit (Qiagen, Hilden, Germany). One hundred nanograms of DNA were amplified in a 20-µL reaction solution containing 2 µL of 10x buffer (Roche, Mannheim, Germany), 1.7 to 2.5 mmol/L of MgCl₂, 0.3 µM of each primer pairs (exon 18, F: 5'-tccaaatgagctggcaagtg, R: 5'-tcccaaacactcagtgaaacaaa; exon 19, F: 5'- atgtggcaccatctcacaattgcc, R: 5'-ccacacagcaaagcagaaactcac; exon 21, F: 5'-gctcagagcctggcatgaa, R: 5'-catcctcccctgcatgtgt; exon 23, F: 5'-tgaagcaaattgcccaagac, R: 5'-tgacatttctccagggatgc), 250 µM of deoxynucleoside triphosphate, and 2.5 units of DNA polymerase (Roche). Amplifications were performed using a 5-minute initial denaturation at 94°C; followed by 30 cycles of 1 minute at 94°C, 1 minute at 55°C, and 1 minute at 72°C, and a 10-minute final extension at 72°C. Polymerase chain reaction (PCR) products were then 2% gel-purified with a QIAgen gel extraction kit (Qiagen). DNA templates were processed for the DNA sequencing reaction using the ABI-PRISM BigDye Terminator version 3.1 (Applied Biosystems, Foster, CA) with both forward and reverse sequence-specific primers. Twenty nanograms of purified PCR products were used in a 20-µL sequencing reaction solution containing 8 µL of BigDye Terminator v3.1 and 0.1 µM of the same PCR primer. Sequencing reactions were performed using a 2-minute initial denaturation at 96°C, followed by 25 cycles of 10 seconds at 94°C, 15 seconds at 50°C, and 3 minutes at 60°C. Sequence data were generated with the ABI PRISM 3100 DNA Analyzer (Applied Biosystems). Sequences were analyzed by Sequencer 3.1.1. software (Applied Biosystems) to compare variations.

Immunohistochemistry
Immunohistochemistry was performed and scored as previously described.⁸ In brief, antigen retrieval was performed by microwaving in 0.01 M citrate buffer adjusted to pH 6.0 for 15 minutes at 650 W. Endogenous peroxidase activity was quenched with 3% hydrogen peroxide in methanol for 15 minutes. After incubation with blocking solution for 10 minutes, sections were incubated with primary antibodies (1/50 dilution) at 4°C for 12 hours, followed by 10 minutes of incubation with biotinylated secondary antibody and then with streptavidin horseradish peroxidase for an additional 10 minutes. Staining was carried out with diaminobenzidine chromogen, and counter-staining with Mayer's hematoxylin. Primary antibodies used were rabbit polyclonal p-Akt (Ser473) antibody (immunohistochemistry specific) and rabbit polyclonal p-p44/42 MAPK (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 more than 5% of cells exhibited cytoplasmic or weak nuclear staining, and as 2+ if they exhibited strong nuclear staining (ie, more intense nuclear staining as compared with the cytoplasm) in more than 5% of cells.⁸

Statistical Analysis
The statistical analyses of categoric variables were performed using the Pearson's ² test or the Fisher's exact test where appropriate. Multivariate analysis was performed using a logistic regression model. The median durations of overall survival (OS) and time to progression (TTP) were calculated using the Kaplan-Meier method. Comparisons between different groups were made using the log-rank tests. Multivariate analysis was carried out using the stepwise Cox regression model. Two-sided P values of less than .05 were considered significant. All analyses were performed using SPSS for Windows, version 12.0 (SPSS Inc, Chicago, IL).

	RESULTS

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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).

View larger version (7K): [in this window] [in a new window]   Fig 1. Mutations of epidermal growth factor receptor in the current study. Numbers in parentheses indicate the number of patients with the mutation. Exons 18, 19, 21, and 23 were analyzed in the current study. (*) Novel mutations found in the current study. a.a., amino acid.

EGFR Mutation and Impact on Survival
Median TTP was 21.7 months in patients with EGFR mutation and 1.8 months in patients without mutation (P < .001; Fig 2). Median OS was 30.5 months in patients with EGFR mutation and 6.6 months in patients without mutation (P < .001). EGFR mutation was independently predictive of prolonged TTP (hazard ratio [HR], 0.23; 95% CI, 0.093 to 0.57) and OS (HR, 0.16; 95% CI, 0.046 to 0.52) in multivariate analyses with response to gefitinib as a covariate. Interestingly, when considering only those 21 patients who exhibited PRs, TTP and OS also varied according to mutational status. Median TTP was 8.4 months in responders without mutation, and 22.0 months in responders with mutation (P = .11; Fig 3). Median OS was 13.7 months for nonmutant responders and 30.5 months for mutant responders (P = .047). TTP and OS among responders were not affected by sex or smoking history (data not shown). These results suggest that EGFR mutation behaves not only as a predictor of responsiveness, but also as an important prognostic factor for survival in patients treated with gefitinib.

View larger version (14K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plots of (A) time to progression and (B) overall survival according to epidermal growth factor receptor mutational status. (*) Log-rank test.

View larger version (13K): [in this window] [in a new window]   Fig 3. Kaplan-Meier plots of (A) time to progression and (B) overall survival in responders according to epidermal growth factor receptor mutational status. (*) Log-rank test.

View larger version (13K): [in this window] [in a new window]   Fig 4. Kaplan-Meier plots of time to progression in (A) patients with epidermal growth factor receptor mutation and (B) in patients without mutation according to phosphorylated-Akt (p-Akt) expression (negative/1+ v 2+). *Log-rank test.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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.

	Authors' Disclosures of Potential Conflicts of Interest

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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.

	NOTES

 
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.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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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[Abstract/Free Full Text]

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[Abstract/Free Full Text]

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[Abstract/Free Full Text]

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[Abstract/Free Full Text]

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[Abstract/Free Full Text]

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[Abstract/Free Full Text]

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[Abstract/Free Full Text]

16. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline]

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Submitted September 21, 2004; accepted December 21, 2004.

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				D. Tassinari, E. Scarpi, S. Sartori, E. Tamburini, C. Santelmo, P. Tombesi, and L. Lazzari-Agli Second-Line Treatments in Non-small Cell Lung Cancer: A Systematic Review of Literature and Metaanalysis of Randomized Clinical Trials Chest, June 1, 2009; 135(6): 1596 - 1609. [Abstract] [Full Text] [PDF]

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