Gefitinib-treated Non-small Cell Lung Cancer Patients Research Articles

Circular RNA profiling identified as a biomarker for predicting the efficacy of Gefitinib therapy for non-small cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become important treatment options for non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutation. However, the detection of EGFR driver mutation is impeded by the lack of adequate tumor tissues, histopathological type, long detection period, and the heterogeneity of a tumor. Therefore, it is necessary to develop a more convenient method to guide the clinical use of EGFR-TKI. Circular RNAs (circRNAs) are characterized as a closed structure with covalently joined ends resistant to exonucleases may be a potential biomarker. In the present study, we aimed to screen circRNAs that may be associated with the efficacy of EGFR-TKI. The expression of circRNAs sequenced by circular microarray in plasma samples between gefitinib effective and ineffective groups were compared. RT-qPCR further validated the results in an independent cohort. Kaplan-Meier curves were used to analyze the association between circRNA and progression-free survival (PFS) of NSCLC patients treated with gefitinib. In total, 52 NSCLC patients treated with gefitinib were included for analysis. 1,377 circRNAs were differentially expressed in gefitinib effective and ineffective groups, among which 989 circRNAs were up-regulated, and 388 circRNAs were down-regulated in the effective group. Furthermore, two differentially expressed circRNAs, hsa_circ_0109320 and hsa_circ_0134501, were validated by RT-qPCR in an independent cohort of 38 gefitinib-treated NSCLC patients. Elevated hsa_circ_0109320 was associated with longer PFS in gefitinib-treated NSCLC patients. Taken together, hsa_circ_0109320 may be a potential biomarker for the efficacy of EGFR-TKI in NSCLC patients. This provides a new molecular typing method for individualized precision treatment.

Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients

Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control.

Divergence phenomenon of EGFR-TKI in the treatment of non small cell lung cancer

The present study investigated the characteristic of the divergent efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) Gefitinib in treating non small-cell lung cancer (NSCLC) and discussed the strategy. The divergent efficacy of gefitinib was analyzed in 4 NSCLC patients at Beijing Military Area General Hospital between 2006 and 2010. The divergence phenomenon may occur in gefitinib-treated NSCLC patients with bone or brain metastases. One patient with primary lung disease under control still benefited from continuing Gefitinib therapy after disease progression in metastatic bone lesion. The divergence of efficacy is a common phenomenon in Gefitinib-treated NSCLC patients. The evaluation criteria available for anti-cancer therapies may not be completely suitable for molecular targeted therapies. The underlying mechanism deserves further research to formulate the efficacy evaluation criteria and therapeutic strategy for the molecular targeted therapy. Key words: Non small-cell lung cancer, tyrosine kinase inhibitor, divergence phenomenon, gefitinib, targeted therapy.

Abstract 1662: Association of EGFR and ABCG2 polymorphisms with gefitinib toxicity in non-small cell lung cancer patients

Abstract The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, in non-small-cell lung cancer (NSCLC) patients is commonly associated with gastrointestinal (diarrhea) and skin (rash) toxicity. These adverse effects have a high interindividual variability, which might be partially explained by pharmacogenetic determinants. In particular, polymorphisms in EGFR and in ABCG2, an efflux transporter higly expressed in the gastrointestinal tract and able to transport gefitinib and other EGFR TKIs, might have an impact on gefitinib-associated toxicity. Therefore, the aim of our study was to evaluate associations between EGFR and ABCG2 polymorphisms with diarrhea and skin rash in gefitinib-treated NSCLC patients. Four polymorphisms in EGFR (CA repeat length in the intron-1 (CA)n, EGFR −191C/A, EGFR −216G/T and EGFR R497K) and one in ABCG2 (ABCG2 421C/A) were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor tissue from 96 NSCLC patients treated with gefitinib. Significant associations between EGFR and ABCG2 variants and toxicity were evaluated using the Fisher's exact test. In total, 87 and 85 patients had available data on polymorphisms and skin and gastrointestinal toxicity, respectively. Diarrhea occurred in 33 (38.8%) of the 85 patients, with 6 of them experiencing high toxicity (grade=2-3 diarrhea). Skin rash was reported for 46 (52.9%) of the 87 patients, with 22 patients having grade>1. The EGFR −191C/A polymorphism was strongly associated with grade>1 diarrhea (P<0.01). Five (33.3%) of the 15 patients carrying the CA or AA genotype developed severe diarrhea compared with only 1 (1.4%) of the 70 CC patients. The EGFR −216G/T polymorphism was also associated with high grade (>1) diarrhea as all the patients who experienced grade 2 or 3 diarrhea carried the GG variant, while only 30.4% (24 out of 79) of the patients with low toxicity carried this variant (P<0.01). Similar findings were found for the EGFR R497K polymorphism, with severe diarrhea being observed in 3 (30%) of the 10 patients with the AA genotype and in 3 (4.1%) of the 74 patients carrying the GG or GA variants (P=0.02). In contrast, none of these EGFR polymorphisms had a significant association with skin toxicity. Additionally, we found no association between EGFR (CA)n and the ABCG2 421C/A polymorphism with either gastrointestinal or skin toxicity. In conclusion, our results demonstrate a clear association between the EGFR −191C/A, −216G/T and R497K with diarrhea in gefitinib-treated NSCLC patients, suggesting that these polymorphisms might be useful as pharmacogenetic markers for the selection of patients for treatment. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1662.

Association of Polymorphisms inAKT1andEGFRwith Clinical Outcome and Toxicity in Non–Small Cell Lung Cancer Patients Treated with Gefitinib

EGFR mutations are strongly predictive of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor activity in non-small cell lung cancer (NSCLC), but resistance mechanisms are not completely understood. The interindividual variability in toxicity also points out to the need of novel pharmacogenetic markers to select patients before therapy. Therefore, we evaluated the associations between EGFR and AKT1 polymorphisms and outcome/toxicity in gefitinib-treated NSCLC patients. Polymorphic loci in EGFR, and AKT1, and EGFR and K-Ras mutations were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor from 96 gefitinib-treated NSCLC patients. Univariate and multivariate analyses compared genetic variants with clinical efficacy and toxicity using Fisher's, log-rank test, and Cox's proportional hazards model. AKT1-SNP4 association with survival was also evaluated in 127 chemotherapy-treated/gefitinib-naive patients, whereas its relationship with AKT1 expression and gefitinib cytotoxicity was studied in 15 NSCLC cell lines. AKT1-SNP4 A/A genotype was associated with shorter time-to-progression (P = 0.04) and overall survival (P = 0.007). Multivariate analyses and comparison with the gefitinib-nontreated population underlined its predictive significance, whereas the in vitro studies showed the association of lower AKT1 mRNA levels with gefitinib resistance. In contrast, EGFR-activating mutations were significantly correlated with response, longer time-to-progression, and overall survival, whereas EGFR -191C/A (P < 0.001), -216 G/T (P < 0.01), and R497K (P = 0.02) polymorphisms were strongly associated with grade >1 diarrhea. AKT1-SNP4 A/A genotype seems to be a candidate biomarker of primary resistance, whereas EGFR -191C/A, -216G/T, and R497K polymorphisms are associated with diarrhea when using gefitinib in NSCLC patients, thus offering potential new tools for treatment optimization.

Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors

BackgroundApproximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, resistance mechanisms are not well understood. We evaluated several potential biological markers of intrinsic EGFR-TKIs-resistance in NSCLC. Materials and methodspAKT, pERK, cSRC, E-cadherin, cMET[pY1003], cMET[pY1230/1234/1235], and cMET[pY1349] immunohistochemistry, cMET FISH analysis, and EGFR-, KRAS-, and cMET mutation analysis were carried out on tumor samples from 51 gefitinib-treated NSCLC patients. Biological parameters and survival end points were compared by univariate and multivariate analyses. cMET expression was also investigated in two additional series of patients. The in vitro antiproliferative activity of gefitinib alone or in combination with hepatocyte growth factor and the cMET antibody DN-30 was assessed in NSCLC cells. ResultsEGFR19 deletion and pAKT expression were significantly associated with response (P < 0.0001) and longer time to progression (TTP) (P = 0.007), respectively. Strong cMET[pY1003] membrane immunoreactivity was expressed in 6% of 149 tumors analyzed and was significantly associated with progressive disease (P = 0.019) and shorter TTP (P = 0.041). In vitro, the DN-30 combination synergistically (CI < 1) enhanced gefitinib-induced growth inhibition in all cMET[pY1003]-expressing cell lines studied. ConclusionsActivated cMET[pY1003] appears to be a marker of primary gefitinib resistance in NSCLC patients. cMET may be a target in treatment of NSCLC.

Serum tumor markers as predictors for survival in advanced non-small cell lung cancer patients treated with gefitinib

Though the imaging-based response (IBR) is the most frequently used index of the therapeutic effect in cancer patients, an index based on serum tumor markers might prove to be useful, especially in patients without measurable tumors. Paired pre- and post-treatment serum tumor markers (CEA, CA-125, and CA-199) were measured in 89 of 100 registered non-small cell lung cancer (NSCLC) patients who received gefitinib. Correlation and agreement analyses between the IBR at the 8th week and the tumor marker response (TMR) at the 4th or the 8th week were performed in patients with measurable lesions (n=68). Analysis of survival in relation to TMR was performed in all patients and in patients with no measurable lesions (n=21). IBR was closely correlated with individual tumor marker responses and the response of all 3 markers combined at 4 weeks (P values ranged from <0.001 to 0.002). The agreements were also significant (P values ranged from 0.001 to 0.004). In the whole group, 4-week TMR was predictive for progression-free survival (P values ranged from <0.0001 to 0.0086). In patients without measurable lesions, differences in progression-free survival and overall survival were closely correlated with the 4-week CA-125 response, CA-199 response, and TMR(overall) (P values ranged from 0.0002 to 0.0399). However, the correlation between the 8-week TMR and either IBR or survival was not significant. In gefitinib-treated NSCLC patients, correlation was good between 4-week TMR and IBR. Four-week TMR was predictive for survival. TMR may serve as a tool for assessing the gefitinib response in patients without measurable lesions.

Pharmacokinetics of gefitinib predicts the antitumor activity for advanced non-small cell lung cancer (NSCLC)

2009 Background: Little is known about the relationship between the pharmacokinetics and efficacy of gefitinib. Methods: Plasma trough levels of gefitinib were measured on days 0, 3 (D3), and 8 (D8) by HPLC in advanced NSCLC patients treated with gefitinib 250 mg daily. Eligibility criteria included: performance status (PS) ≤ 3, age ≤ 80, stage IIIB-IV, and written informed consent. Results: Fifty patients were enrolled, and 44 patients were assessable. The median [25%-75%] values of D3 and D8 was 662 [440–937] and 1064 [782–1405] ng/ml, respectively. D8/D3 rate was categorized by 1.587 of the median value. In 44 patients, the median time to progression (TTP) was 83 days, and the median overall survival (OS) was 224 days. The differences in TTP were compared by Kaplan-Meier method and log-rank test: D8/D3 (high D8/D3, median 209 days vs. low D8/D3, 43 days; P = 0.0299), smoking (never-smokers, 224 days vs. smokers, 32 days; P = 0.0467), and histology (adenocarcinoma, 97 days vs. non-adenocarcinoma, 27 days; P = 0.0096). Sex, age, PS, previous treatments, and the use of antacids were not significant. Multivariate analysis showed that TTP was associated with D8/D3 (hazard rate, 95%CI; 0.458, 0.234–0.898) and smoking (2.005, 1.030–3.903). Never-smokers with high D8/D3 showed the best TTP, and smokers with low D8/D3 showed the worst TTP. Never-smokers with low D8/D3 and smokers with high D8/D3 showed similar TTP curves. In contrast, OS was associated with smoking (hazard rate, 95%CI; 3.182, 1.506–6.724), but not D8/D3. Conclusions: High D8/D3 was independently associated with better TTP in gefitinib-treated NSCLC patients. Our findings suggest that pharmacokinetics of gefitinib may be involved in its anti-tumor activity. No significant financial relationships to disclose.

Epidermal growth factor receptor mutations and gene amplification in Japanese non-small cell lung cancer patients treated with gefitinib

17063 Background: To evaluate relationship between epidermal growth factor receptor (EGFR) gene status and clinical outcome in patients with non-small-cell lung cancer (NSCLC) treated with gefitinib. Also, to examine an involvement of human papilloma virus (HPV) in EGFR status of these patients. Methods: Twenty seven patients with NSCLC who had relapsed after surgery and received gefitinib were included. Genomic DNA was extracted from the 12 paraffin and the 15 frozen surgical specimens. PCR and sequencing for genotyping were done for EGFR (exon 18–21) and ERBB2 (exon 19–22) and KRAS (exon 1). Gene amplification for EGFR was analyzed by quantitative real-time PCR. HPV was detected by PCR and in-situ PCR. Results: Nine patients (33%) had EGFR mutations; seven patients had deletion mutations in exon 19, one patient had missense mutations (L858R) in exon 21. Two patients had missense mutations (G719S, exon 18 and L838P, exon 21) No mutations were identified in ERBB2 and KRAS. EGFR copy number in the tumor cells ranged from 1.1 to 9.7, and increased EGFR copy numbers (≥3) were observed in six patients ( 22.2%). Two patients (7%) had HPV, and had no mutation and no amplification. Response rate (67% {six of nine patients} v 18% {three of 17 patients}; p = 0.012) was significantly better in patients with EGFR mutations than in patients with wild-type EGFR. Overall survival (median 17 v 9 months) was better in patients with EGFR mutations than in patients with wild-type EGFR. EGFR copy number and presence of HPV were not associated with clinical outcome. Conclusions: EGFR mutations were significantly associated with better clinical outcome in gefitinib treated NSCLC patients. No significant financial relationships to disclose.

Associations between chromosome 7 aneusomy and EGFR copy number with survival and response to gefitinib in NSCLC

7171 Background: EGFR, the presumed target of gefitinib and erlotinib, has been studied (expression, gene copy number, &amp; mutations) for predicting response to these tyrosine kinase inhibitors (TKI), in non-small cell lung cancer (NSCLC). ’High polysomy’ and ’amplification’ of the EGFR gene, as defined by Cappuzzo et al. JNCI 97:643, using fluorescence in situ hybridization (FISH), showed significant association with objective response (Resp) and survival. We also measured EGFR and chromosome 7 (C7) copy numbers by FISH in 81 gefitinib-treated NSCLC patients (12 Resp). Using Cappuzzo’s FISH± parameter alone we saw similar trends but no statistical significance in the 81 patient group. Therefore we sought to optimize FISH parameters for these patients. Methods: FISH was performed (paraffin sections) using a 2-color probe set (Vysis LSI EGFR/CEP 7), median 80 cells per specimen. &gt;50 parameters were derived from the data (e.g. mean EGFR/cell, C7/cell etc) and compared, using different threshold values, to Resp and survival. Results: The best single parameter associated with survival was the average C7/cell. Applying upper and lower thresholds of 3.6 and 2.0 C7/cell to delineate moderate from extreme ratios yielded median survival of 177 and 465 d, respectively (Kaplan-Meier, p &lt; .002). A single threshold of 3.6, separating low from high, yielded survival of 201 and 522 d, respectively (p &lt; .01). For these thresholds C7/cell was not associated with Resp, however, thresholds could be found for which both survival and Resp were significant. The best single parameter associated with Resp was average EGFR/cell. Of the 70 patients with EGFR/cell≤6.0, 63 (90%) did not respond while 5 of 11 patients (45%) with EGFR/cell &gt;6.0 responded (p &lt; .01). No EGFR/cell threshold could be found for which both survival and Resp were significant. Many 2-parameter combinations provided significant associations with both survival and Resp. Conclusions: Several FISH-derived parameters were significantly associated with either survival or Resp to gefitinib and a subset were associated with both. These parameters must be tested on independent data sets to determine their value in directing TKI therapy. [Table: see text]

EGFR and erbB2 mutation status in Japanese lung cancer patients

Much evidence has accumulated that the epidermal growth factor receptor (EGFR) and its family members are strongly implicated in the development and progression of lung cancers. Somatic mutations of the EGFR gene were found in about 25-40% of Japanese lung cancer patients. More recently, erbB2 mutations are found in about 4% of European-derived lung cancer patients. We have investigated EGFR and erbB2 mutation status in 95 surgically treated nonsmall cell lung cancer (NSCLC) cases from Nagoya City University Hospital. Seventy-five adenocarcinoma cases were included. The presence or absence of EGFR and ernB2 mutations of kinase domains were analyzed by reverse transcription polymerase chain reaction (RT-PCR) amplifications and direct sequences. We have also investigated erbB2 mutation status in 27 surgically treated NSCLC cases followed by treatment with gefitinib from Kinki-chuo Chest Medical Center. EGFR mutations (CTG-->CGG; L858R) were found from 14 of 95 lung cancer patients. We also detected the deletion 1a-type mutations from 9 patients and deletion 4-type mutations from 6 patients in exon 19. In exon 20, 4 mutations including 2 novel mutations were found. Total EGFR mutations were present in 35 patients (36.8%). These mutation statuses were significantly correlated with gender (women 73.3% vs. men 20%, p < 0.0001), smoking status (never smoker 69.4% vs. smoker 16.9%, p < 0.0001), pathologic subtypes (adenocarcinoma 45.1% vs. nonadenocarcinoma 12.5%, p = 0.0089) and differentiation status of the lung cancers (well 51% vs. moderately or poorly 18.4%, p = 0.0021). On the other hand, erbB2 mutation was only found from 1 of 95 patients, at exon 20. This patient was female and a never smoker with adenocarcinoma. This 12 nucleotide insertion mutation (2324-2325 ins ATACGTGATGGC) was located in the exon 20 at kinase domain (775-776 ins YVMA). There was no erbB2 mutation in 27 gefitinib-treated NSCLC patients. In total, we have found only 1 erbB2 mutation from 122 (0.8%) Japanese NSCLC patients. There was a significantly higher erbB2 positive (2+/3+) ratio in EGFR mutant patients (13/25, 52.0%) compared to EGFR wild-type patients (10/62, 16.1%; p = 0.0247). The NSCLC specimen with erbB2 mutation showed 1+ immunoreactivity. The EGFR mutation status might correlate with the clinicopathologic features related to good response to gefitinib, such as gender, smoking history and pathologic subtypes of lung cancers. However, erbB2 mutation is rare from Japanese lung cancer and is of limited value for molecular target therapy.

Increases of Amphiregulin and Transforming Growth Factor-α in Serum as Predictors of Poor Response to Gefitinib among Patients with Advanced Non–Small Cell Lung Cancers

Serum levels of amphiregulin and transforming growth factor-alpha (TGF-alpha), which were identified previously to be expressed at high levels in non-small cell lung cancer (NSCLC) with poor response to gefitinib, were examined by ELISA using blood samples taken from 50 patients with advanced NSCLCs. Of 14 cases that revealed above the cutoff line for amphiregulin in serum, 12 responded poorly to gefitinib, whereas 18 of the 36 cases showing below the cutoff revealed partial response (PR) or stable disease (SD; P = 0.026). Thirteen of 15 patients who were positive for TGF-alpha responded poorly to gefitinib, whereas 18 of the 35 patients with negative TGF-alpha levels turned out to be relatively good responders (P = 0.014). Of 22 patients with positive values for either or both markers, 19 were poor responders. On the other hand, among 28 patients negative for both markers, 17 were classified into the PR or SD groups (P = 0.001). Gefitinib-treated NSCLC patients whose serum amphiregulin or TGF-alpha was positive showed a poorer tumor-specific survival (P = 0.037 and 0.002, respectively, by univariate analysis) compared with those whose serum amphiregulin or TGF-alpha concentrations were negative. Multivariate analysis showed an independent association between positivity for TGF-alpha and shorter survival times among NSCLC patients treated with gefitinib (P = 0.034). Amphiregulin or TGF-alpha positivity in NSCLC tissues was significantly higher in male, nonadenocarcinomas, and smokers. Our data suggest that the status of amphiregulin and TGF-alpha in serum can be an important predictor of the resistance to gefitinib among patients with advanced NSCLC.

Gefitinib treatment for non-small cell lung cancer -- a study including patients with poor performance status.

Gefitinib is effective in the treatment of advanced non-small cell lung cancer (NSCLC). However, most studies have only investigated patients who have good performance status or are evaluable. This study evaluated the efficacy of geftinib in a consecutive series of patients with NSCLC. The treatment response of all gefitinib-treated NSCLC patients from November 2001 to September 2003 at a single medical institute was retrospectively evaluated. All patients receiving at least 1 dose of gefitinib during the study period were included. A total of 66 NSCLC patients were treated, including 22 patients with Eastern Clinical Oncology Group performance status 3 or 4. No prior chemotherapy had been given in 14 patients because of their personal preference or poor general condition. The duration of treatment ranged from 1 day to 19.3 months (median, 2.5 months). The partial remission rate was 15.2% and the stable disease rate was 25.8%. The median survival for all patients was 5.9 months and the 1-year survival rate was 27.9%. Symptom improvement and response correlated well to survival. Female gender, non-smoking status, and performance status of 0-2 were associated with better survival. The disease control rate was 22.7% in patients with performance status of 3-4. Gefitinib can be recommended for the treatment of advanced NSCLC in patients for whom standard chemotherapy is not an option. Further study is required to determine the optimal selection criteria of patients and the timing of starting therapy.

Epidermal Growth Factor Receptor Gene Mutations and Increased Copy Numbers Predict Gefitinib Sensitivity in Patients With Recurrent Non–Small-Cell Lung Cancer

To evaluate epidermal growth factor receptor (EGFR) mutations and copy number as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC) receiving gefitinib. Sixty-six patients with NSCLC who experienced relapse after surgery and received gefitinib were included. Direct sequencing of exons 18 to 24 of EGFR and exons 18 to 24 of ERBB2 was performed using DNA extracted from surgical specimens. Pyrosequencing and quantitative real-time polymerase chain reaction were performed to analyze the allelic pattern and copy number of EGFR. Thirty-nine patients (59%) had EGFR mutations; 20 patients had deletional mutations in exon 19, 17 patients had missense mutations (L858R) in exon 21, and two patients had missense mutations (G719S or G719C) in exon 18. No mutations were identified in ERBB2. Response rate (82% [32 of 39 patients] v 11% [three of 27 patients]; P < .0001), time to progression (TTP; median, 12.6 v 1.7 months; P < .0001), and overall survival (median, 20.4 v 6.9 months; P = .0001) were significantly better in patients with EGFR mutations than in patients with wild-type EGFR. Increased EGFR copy numbers (> or = 3/cell) were observed in 29 patients (44%) and were significantly associated with a higher response rate (72% [21 of 29 patients] v 38% [14 of 37 patients]; P = .005) and a longer TTP (median, 9.4 v 2.6 months; P = .038). High EGFR copy numbers (> or = 6/cell) were caused by selective amplification of mutant alleles. EGFR mutations and increased copy numbers were significantly associated with better clinical outcome in gefitinib-treated NSCLC patients.

Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer

7086 Background: It has been reported that mutations in epidermal growth factor receptor (EGFR) play a critical role in predicting tumor response in patients receiving gefitinib for non-small cell lung cancer (NSCLC). We investigated the associations of EGFR mutations to tumor response and survival in gefitinib-treated NSCLC patients. Methods: We examined EGFR gene mutations in exons 18, 19 and 21 by DNA sequencing in paraffin-embedded tumor tissues of NSCLC patients who have received gefitinib. The results were correlated with the clinical parameters. Results: Mutations in the tyrosine kinase domain of EGFR were found in 29 of 54 cases (53.7%). Of them, twelve cases had a deletion in exon 19 and seventeen cases had a substitution in exon 18 and/or 21. Mutation was an independent predictor for disease control (P< 0.001) and tumor response (P= 0.020); the positive predictive values were 93% and 75% and negative predictive values were 60% and 65%, respectively. Compared with patients whose tumor bearing non-mutant EGFR, patients with EGFR mutations showed better progression-free survival (median 7.9 m vs. 1.8 m, P< 0.001) and overall survival (median 12 m vs. 4.7 m, P= 0.029). Moreover, in the gefitinib responders, patients with mutations had a longer response duration than patients without mutations (median 9.1 m vs. 2.9 m, P= 0.033). It was unlikely that patients with EGFR mutations in different exons have variable response or survival to gefitinib treatment. Conclusions: EGFR mutations can be used as a predictive and prognostic indicator in patients receiving gefitinib for NSCLC No significant financial relationships to disclose.

Epidermal growth factor receptor (EGFR)-activating mutations (mut) and response to gefitinib in lung adenocarcinoma

7076 Background: The potential relevance of EGFR mut to non-small-cell lung cancer (NSCLC) treatment has recently been identified. We have examined the presence of EGFR mut in Spanish chemoresistant gefitinib-treated NSCLC patients (p). Methods: A total of 83 p were selected on the basis of availability of tumor specimens. EGFR exons 19 and 21 were amplified from genomic DNA and automatic sequencing was performed. Results: EGFR somatic mut in the tyrosine kinase domain were found in 10 of 83 p (12%). 8 mut were deletions in or near E746-A750, 3 of which carried insertions. The 2 remaining mut were L858R. Mut were more frequently observed in women (70%), adenocarcinomas (90%) and non-smokers (60%). p had received a median of 2 prior chemotherapy regimens. Median follow-up was 5 months (m) (range, 4.7–28.2). Duration of gefitinib: p with mut, 8.5 m, p with wild-type (wt), 3.1 m (P<0.001). Response: p with mut, 80%; p with wt, 8.8% (P<0.001). Time to progression from the start of gefitinib: all p, 3.9 m; p with mut, 12.3 m (95%CI, 6.4–18.3); p with wt, 3.6 m (95%CI, 2.6–4.7) (P=0.002). Median survival: all p, 5.7 m; p with mut, 13 m (95%CI, 6.5–19.4); p with wt, 4.9 m (95%CI, 3.8–5.9) (P=0.02). The Cox model indicated a 3.7 times higher risk of progression for p with wt, even adjusted for covariates, including gender and number of prior chemotherapy lines (P=0.005). Relative risk of death was 3.1 times higher for p with wt (P=0.03). Conclusions: This first study of its kind in Spain confirms that the presence of EGFR mutations is a major determinant of gefitinib response. Based on these results, a clinical trial of first-line gefitinib in lung adenocarcinomas harboring EGFR mut will be performed. No significant financial relationships to disclose.

Mutation in the Tyrosine Kinase Domain of Epidermal Growth Factor Receptor Is a Predictive and Prognostic Factor for Gefitinib Treatment in Patients with Non–Small Cell Lung Cancer

Mutations in epidermal growth factor receptor (EGFR) can be used to predict the tumor response of patients receiving gefitinib for non-small cell lung cancer (NSCLC). We investigated the association between mutations in EGFR tyrosine kinase domain and tumor response and survival in gefitinib-treated NSCLC patients. EGFR mutations in exons 18 to 21 were analyzed by DNA sequencing of paraffin-embedded tumor tissues from gefitinib-treated NSCLC patients. The results were correlated with clinical variables. EGFR mutations were found in 61.1% (33 of 54) of cases; response rate and disease control rate were 56.8% and 68.5%, respectively. There was no significant difference in mutation rates between adenocarcinoma (29 of 43) and nonadenocarcinoma (4 of 11; P = 0.085). However, all four nonadenocarcinomas with EGFR mutations had no response to gefitinib. Presence of EGFR mutations was the only independent predictor for disease control (P = 0.003) and tumor response (P = 0.017) in multivariate analysis; positive predictive values were 87.9% and 70.8% and negative predictive values were 61.9% and 69.2%, respectively. In comparison with patients whose tumor was negative for EGFR mutations, patients with EGFR mutations had better progression-free survival (median, 7.6 versus 1.7 months; P = 0.011) and overall survival (median, 14.7 versus 4.7 months; P = 0.046). Mutations in EGFR tyrosine kinase correlate with treatment response and survival in gefitinib-treated NSCLC patients and can be used as a predictive and prognostic factor. Thus, analysis of EGFR tyrosine kinase mutations in lung adenocarcinoma is of clinical significance, as it can permit the customization of treatment with EGFR tyrosine kinase inhibitors.