Epidermal growth factor receptor (EGFR) downstream molecules as response predictive markers for gefitinib (Iressa, ZD1839) in chemotherapy-resistant non-small cell lung cancer

Gefitinib has shown meaningful antitumor activity with tolerable toxicity in chemotherapy-refractory NSCLC in previous studies. Moreover, EGFR expression failed to show a correlation with response. In an attempt to identify predictive markers of response, we have investigated the tumoral expression of key signaling molecules of EGFR (EGFR, p-EGFR, p-Akt, p-Erk, p-STAT3) by immunohistochemistry and analyzed their correlations with response. Of 65 patients who received gefitinib (250 mg/day) for chemotherapy-refractory NSCLC, there were 14 partial responses (21.5%), 21 stable diseases (32.3%) and 21 progressive diseases (32.3%). Median durations of overall survival and time to progression were 6.7 months and 2.8 months, respectively. Immunohistochemistry was performed in 34 patients with evaluable tissue specimens. EGFR was overexpressed (2+ or 3+) in 32.4% and p-EGFR was positive in 26.5%. The expressions of p-Akt, p-Erk and p-STAT3 were positive (1+ or 2+) in 50%, 38.2% and 79.4%, respectively. The EGFR expression was not correlated with p-EGFR or the downstream molecules. EGFR or p-EGFR status did not correlate with response. Positive expression of p-Erk was significantly associated with poor response (38.1% in -, 14.3% in 1+, 0% in 2+; p = 0.046). Furthermore, tumors with positive p-Akt and negative p-Erk nuclear expression exhibited the best response (60%), whereas there was no response in the opposite [p-Akt (-), p-Erk (+)] cases. Intense nuclear staining of p-Akt (2+) was associated with prolonged TTP (HR 0.25, 95% confidence interval [CI] 0.08-0.79, p = 0.018) and OS (HR 0.16, 95% CI 0.04-0.62, p = 0.008). These results support the assumption that gefitinib responsiveness might be predicted by activated EGFR downstream molecules such as p-Akt and p-Erk.     

Epidermal growth factor receptor expression and mutational analysis in synovial sarcomas and malignant peripheral nerve sheath tumors

BACKGROUND: Synovial sarcomas (SnSrcs) and malignant peripheral nerve sheath tumors (MPNSTs) are rare mesenchymal tumors of adolescence and young adulthood. Previous work from our laboratory has demonstrated that SnSrcs express epidermal growth factor receptor (EGFR) and human EGFR (HER)-2/neu. The present study extends that work to examine the expression of EGFR in MPNSTs and the characterization of potential targets of the EGFR tyrosine kinase domain. METHODS: Tissue microarrays containing 48 cases of SnSrc and 32 cases of MPNST were stained for EGFR, EGFRvIII, and activated EGFR (pY1068-EGFR). Tumor DNA was extracted from fresh and formalin-fixed, paraffin-embedded tissue blocks and sequenced for exons 17-21 of EGFR and exon 2 of K-ras and b-raf. RESULTS: Immunohistochemistry (IHC) demonstrated that EGFR is expressed in a majority of SnSrcs and MPNSTs (71% and 62.5%, respectively). EGFRvIII immunoreactivity was negative. IHC was weakly immunopositive for activated EGFR (18.7% and 3.1%, respectively). Sequence analysis of the EGFR genomic DNA did not demonstrate mutations in exons 17-21. No K-ras or b-raf mutations were observed in either tumor type. CONCLUSIONS: Expression of EGFR in SnSrcs and MPNSTs with an intact EGFR/mitogen-activated protein kinase pathway has been hypothesized to contribute to the malignant potential of these tumors. Our study reveals the absence of known activating mutations in EGFR, which suggests that trials of small-molecule inhibitors would be of little clinical benefit. A clinical study of treatment with cetuximab is ongoing and may help elucidate whether blockade of EGFR with antibodies is likely to be more active.     

Epidermal growth factor receptor mutation analysis in cytological specimens and responsiveness to gefitinib in advanced non-small cell lung cancer patients

Background

Epidermal growth factor receptor (EGFR) mutation is the key predictor of EGFR tyrosine kinase inhibitors (TKIs) efficacy in non-small cell lung cancer (NSCLC). We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.

Methods

A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system (ARMS). We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate (ORR), disease control rate (DCR) and progression free survival (PFS).

Results

Of all patients, EGFR mutation rate was 28.6% (60/210) by direct sequencing and 45.2% (95/210) by ARMS (P<0.001) respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR (48.0% vs. 80.9%, P=0.004) and shorter median PFS (7.4 vs. 10.5 months, P=0.009) as compared with that of EGFR mutation positive patients by both detection methods.

Conclusions

Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.     

Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer

Acquired resistance to epidermal growth factor receptor (EGFR) targeted antibodies represents a clinical challenge in the treatment of gastrointestinal tumors such as metastatic colorectal cancer, but its molecular mechanisms are incompletely understood. We scanned KRAS exon 2/3/4, NRAS exon 2/3/4 and the overlapping epitopes of the EGFR antibodies cetuximab and panitumumab for mutations in pre- and post-treatment tumor tissue of 21 patients with gastrointestinal cancer treated with chemotherapy +/− EGFR antibodies by next-generation sequencing (“tumor tissue” cohort). We describe a novel EGFR exon 12 mutation acquired in tumors of 1 out of 3 patients treated with panitumumab. The EGFR G465R mutation introduces a positive charge within the overlap of the panitumumab and cetuximab epitopes. It abrogates antibody binding and mediates cross-resistance to both antibodies in EGFR G465R-transfected Ba/F3 cells. In circulating tumor DNA from an independent “liquid biopsy” cohort of 27 patients, we found this novel mutation in 1 out of 6 panitumumab-treated cases while about one third of patients show acquired RAS mutations. We show that acquired resistance by epitope-changing mutations also emerges during panitumumab treatment, which can be easily detected by a liquid biopsy approach even before clinical resistance occurs and this may help in tailoring EGFR-targeted therapies.     

EGFR酪氨酸激酶域基因变异及相关蛋白表达与gefitinib治疗晚期非小细胞肺癌疗效相关性的研究进展

Gefitinib是一种选择性EGFR酪氨酸激酶抑制剂,是目前非小细胞肺癌(NSCLC)靶向治疗的热点之一,临床研究发现,患者对gefitinib的疗效有明显的差异。本文对EGFR基因及其蛋白与gefitinib疗效的相关性进行了回顾,探讨预示gefitinib疗效的标志物,有助于gefitinib在NSCLC治疗中的最优化使用。     

Clinical outcomes and secondary epidermal growth factor receptor (EGFR) T790M mutation among first-line gefitinib,erlotinib and afatinib-treated non-small cell lung cancer patients with activating EGFR mutations

Gefitinib, erlotinib and afatinib are approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) bearing an activating epidermal growth factor receptor (EGFR) mutation. However, the clinical outcomes among the three EGFR tyrosine kinase inhibitors (TKIs) are still controversial. We aimed to evaluate clinical outcomes and secondary EGFR T790M mutation among the three EGFR TKIs. From May 2014 to January 2016, a total of 301 patients received treatment with gefitinib, erlotinib or afatinib, for first-line treatment of advanced NSCLC with an activating EGFR mutation, based on their clinicians’ choice. The median overall survival (OS) was 37.0 months. Although the baseline characteristics of patients were unequal, progression-free survival and OS did not differ among the 3 groups. Multivariate analysis found that gefitinib (adjusted odds ratio [aOR] 3.29, 95% confidence interval [CI], 1.15–9.46, p = 0.027), EGFR TKI treatment duration more than 13 months (aOR 3.16, 95% CI, 1.20–8.33, p = 0.020), male (aOR 3.25, 95% CI, 1.10–9.66, p = 0.034), initial liver metastasis (aOR 4.97, 95% CI 1.18–20.96, p = 0.029) and uncommon EGFR mutation (aOR 0.14, 95% CI, 0.02–0.97, compared to EGFR deletion 19, p = 0.047) were independent factors for secondary T790M mutation. In real-world practice, choosing first line EGFR TKI based on the patients’ clinical characteristics yielded good clinical outcomes. First-line gefitinib, longer EGFR TKI treatment duration, male, initial liver metastasis and uncommon EGFR mutations may be independent factors for secondary EGFR T790M mutation.     

Phenotype of bone metastases of nonsmall cell lung cancer: Epidermal growth factor receptor expression and KRAS mutational status

Bone metastasis is a frequent complication of lung cancer progression, however, studies on bone metastatic tissues are scanty. Here we have collected a small cohort of 11 non-small cell lung cancer cases where primary tumors and corresponding bone metastases were available for pathological analysis. We have tested two molecular markers: EGFR protein expression and K-RAS mutation at codon 12 using immunohistochemistry and RFLP-PCR, respectively. We have shown that using improved protocols, EGFR protein (both the extracellular as well as the cytoplasmic domain) is readily detectable in decalcified bone tissue. We found that the EGFR expression status is highly similar in bone metastases compared to the primary tumors, although the expression levels may change. Individual comparison of corresponding primary and metastatic NSCLC tissues indicated that downregulation of EGFR was a rare event (2/11) compared to upregulation (4/11) in bone metastases. On the other hand, our data indicate that the K-RAS mutational status of the primary tumor does not predict the status of the bone metastatic tissue of NSCLC, since we have observed both emergence of mutant clones in metastases from wild-type (wt) primary tumors and loss of mutant clones in metastases from mutant primaries in addition to the maintained mutant status. Our data support that at least two progression models occur in NSCLC, the samegene as well as the clonal selection one. It is noteworthy that in NSCLC cases with wtor mutant K-RAS, downregulation of EGFR expression was a rare event although upregulation in bone metastases was observed more frequently in wt K-RAS cases. equalcontribution of the two authors     

中国非小细胞肺癌患者表皮生长因子受体突变的研究

背景与目的:最近的研究结果表明,表皮生长因子受体(epidermalgrowthfactorreceptor,EGFR)基因酪氨酸激酶域的体细胞突变与非小细胞肺癌(non鄄smallcelllungcancer,NSCLC)患者对酪氨酸激酶抑制剂吉非替尼的敏感性密切相关。这些突变均发生在酪氨酸激酶域的ATP结合域附近,突变为19号外显子上的缺失突变,或18和21号外显子上的替代突变。研究发现,日本患者的突变率高于美国患者的突变率。本研究中我们分析中国NSCLC患者肺癌组织中EGFR突变情况。方法:收集2004年7月到10月间中山大学肿瘤防治中心52例可手术的NSCLC患者的新鲜组织标本,包括肿瘤组织标本和来自同一患者相应的正常肺组织标本。所有患者均未接受过吉非替尼治疗。采用PCR技术扩增EGFR基因的19和21号外显子,从正反两个方向对扩增片段进行DNA测序和分析。结果:52例1NNNSCLC患者中10例(19.2%)患者EGFR基因酪氨酸激酶域存在体细胞突变。10例突变中包括7例(70%)发生于19号外显子上的缺失突变,另外3例(30%)发生于21号外显子上的替代突变。腺癌(6/23,26.1%)、腺鳞癌(2/5,40.0%)和支气管肺泡癌(2/4,50.0%)的突变率高于鳞癌(0/20,0.0%)的突变率(P=0.025);非吸烟者的突变率(7/17,41.8%)高于吸烟者的突变率(3/35,8.6%)(P=0.009);而女性患者突变率(3/13,23.1%)与男性患者突变率(7/39,18.0%)无显著性差异(P=0.697)。结论:中国NSCLC患者EGFR的突变率较高,与日本患者的突变情况相似,明显高于高加索人种。     

Epidermal growth factor receptor (EGFR) gene promoter methylation and cetuximab treatment in colorectal cancer patients

Background:

Epidermal growth factor receptor (EGFR) promoter methylation may be responsible for the loss of EGFR expression in neoplastic cells. The primary aim of our study was to verify a possible correlation between EGFR gene promoter methylation and clinical outcome in metastatic colorectal cancer patients receiving chemotherapy with irinotecan and cetuximab.

Methods:

Colorectal samples from patients treated with irinotecan–cetuximab were analysed for EGFR promoter methylation and EGFR immunohistochemistry.

Results:

Fifty-two patients were analysed. Thirty patients (58%) showed EGFR promoter hypermethylation. In EGFR promoter methylated and EGFR promoter unmethylated patients, we observed a partial response in 3 (10%) and 13 (59%) patients, respectively (P=0.03), progressive disease was obtained in 19 (63%) and 2 (9%) patients, respectively, with EGFR promoter methylated and EGFR promoter unmethylated tumours (P=0.0001). Median progression-free survival was 2.4 months in patients showing EGFR promoter methylated tumours and 7.4 months for those who had EGFR promoter unmethylated tumours (P<0.0001; Figure 1). Median overall survival was 6.1 months in patients showing EGFR promoter methylated tumours and 17.8 months for those who had EGFR promoter unmethylated tumours (P<0.0001; Figure 2). EGFR promoter hypermethylation, after confirmation in larger data set, may represent a valuable asset in further studies investigating EGFR as a therapeutic target in colorectal cancer.Open in a separate windowFigure 1Kaplan–Meier curves for median progression-free survival (PFS) of colorectal cancer patients treated with irinotecan and cetuximab with EGFR promoter methylated and without EGFR promoter methylated tumours (2.4 vs 7.4 months, P<0.0001).Open in a separate windowFigure 2Kaplan–Meier curves for median overall survival (OS) of colorectal cancer patients treated with irinotecan and cetuximab with EGFR promoter methylated and without EGFR promoter methylated tumours (6.1 vs 17.8 months, P<0.0001).     

Epidermal growth factor receptor and insulinlike growth factor 1 receptor expression predict poor survival in pancreatic ductal adenocarcinoma

BACKGROUND:

The aim of this study was to evaluate the expression of epidermal growth factor receptor (EGFR) and insulinlike growth factor 1 receptor (IGF‐1R) proteins and IGF‐1R gene copy numbers in pancreatic ductal adenocarcinoma in relation to patients' characteristics and prognosis.

METHODS:

Immunohistochemical staining was performed on formalin‐fixed paraffin‐embedded tissue derived from tumor specimens recovered during surgery. Slides were evaluated for membranous EGFR and IGF‐1R staining using both the HercepTest and the semiquantitative H‐score systems. Chromogenic in situ hybridization was performed to quantify IGF‐1R gene copy number. The primary outcome was the association between EGFR expression, IGF‐1R expression—in both neoplastic epithelial and stromal cells—or IGF‐1R gene copy number and overall survival. Secondary outcomes included associations between EFGR and IGF‐1R expression and pathologic variables.

RESULTS:

A total of 105 patients were included. EGFR expression was present in 30.4% of cases and was associated with lymph node metastasis (P = .038). IGF‐1R was overexpressed in 53% of tumors and correlated with higher tumor grade (P = .033). High membranous expression of EGFR (P < .001) and/or IGF‐1R (P = .004), the cytoplasmic detection of EGFR (P = .027), and high expression levels of IGF‐1R in the tumoral stroma (P < .001) were all associated with shorter overall survival, being significantly better in patients who simultaneously do not express membranous EGFR or stromal IGF‐1R.

CONCLUSIONS:

EGFR and IGF‐1R expression, in neoplastic and stromal cells, seems to be an important prognostic factor. Cancer 2012;3484–3493. © 2011 American Cancer Society.     

Gefitinib as first-line treatment for patients with advanced non-small-cell lung cancer with activating epidermal growth factor receptor mutation: Review of the evidence

Gefitinib is a small molecule tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR). Since 2004, it was clear that a substantial proportion of non-small-cell lung cancers (NSCLC) obtaining objective response when treated with gefitinib harbour activating mutations in the EGFR gene. Consequently, EGFR mutation has been widely studied, together with other molecular characteristics, as a potential predictive factor for gefitinib efficacy. As of August 2010, four East Asian randomized phase III trials comparing gefitinib to platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) eligible for first-line treatment have been reported or published. Two of these trials were conducted without a molecular selection in patients with clinical characteristics (adenocarcinoma histology, never or light smoking) characterized by higher prevalence of EGFR mutation. In patients selected for the presence of tumor harbouring EGFR mutation, the administration of first-line gefitinib, as compared to standard chemotherapy, was associated with longer progression-free survival, higher objective response rate, a more favourable toxicity profile and better quality of life. The relevant improvement in progression-free survival with first-line administration of gefitinib has been confirmed in the other two randomized trials, dedicated to cases with EGFR mutation. In July 2009, European Medicines Agency granted marketing authorization for gefitinib for the treatment of locally advanced or metastatic NSCLC with sensitizing mutations of the EGFR gene, across all lines of therapy. Gefitinib currently represents the best first-line treatment option for this molecularly selected subgroup of patients.     

Epidermal growth factor receptor levels increase but epidermal growth factor receptor ligand levels decrease in mouse mammary tumors during progression from hormone dependence to hormone independence

Summary Twenty-six serially transplanted Grunder (GR) strain mouse mammary tumors were analyzed for epidermal growth factor receptor (EGFR) and EGFR-ligand levels, in addition to steroid hormone receptors (estrogen receptor, ER, progesterone receptor, PgR). In concordance with earlier studies, hormone dependent (HD) and hormone responsive (HR) tumors were found to be positive for both ER and PgR, whereas hormone independent (HI) tumors contained only 30% of the ER concentration that was found in the HD tumors. PgR was undetectable in HI tumors. HI tumors contained 2.5 to 3-fold higher EGFR levels than HD/HR tumors, an observation which shows remarkable concordance with studies on EGFR in human breast cancer. On the other hand, the level of EGFR-ligand(s) was positively associated with ER levels and was three-fold higher in HD/HR tumors than in HI tumors. The low EGFR in HD/HR tumors relative to HI tumors may be the result of downregulation by EGFR ligands produced under ER control. During progression to hormone independence this downregulation of EGFR is then abolished in absence of ER. The increase in EGFR may therefore be a secondary effect rather than a key event in the progression to hormone independence in this mouse mammary tumor model.Abbreviations EGF Epidermal Growth Factor - EGFR Epidermal Growth Factor Receptor - ER Estrogen Receptor - PgR Progesterone Receptor - HD Hormone Dependent - HR Hormone Responsive - HI Hormone Independent - HAP Hydroxylapatite - DCC Dextran Coated Charcoal - GR Grunder - TGF- Transforming Growth Factor-     

Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC)

PURPOSE: We report four cases of Brain Metastases (BM) from non-small cell lung cancer (NSCLC) responding to ZD 1839 therapy after standard therapy failure. PATIENTS AND METHODS: Four patients with BM from NSCLC, pretreated with two or more lines of chemotherapy, received ZD 1839 (Iressa), on a compassionate use basis, at the daily dose of 250 mg until disease progression. Three patients received Iressa after whole brain radiotherapy (WBRT) failure. RESULTS: After 3 months of ZD 1839 therapy, one patient had complete response on the brain with stabilization of extracranial disease, while the other three patients had partial response both on the brain and on extracranial sites. At the time of this analysis, two patients discontinued the treatment after 5 and 7 months for disease progression, while two patients are still on treatment with no evidence of treatment failure after 3+ and 12+ months. ZD 1839 was generally well tolerated, with skin toxicity recorded in two patients. CONCLUSION: ZD 1839 may be effective in NSCLC patients with pretreated BM. Large and prospective trials need to clarify the role of ZD 1839 in the treatment of BM from NSCLC.     

Epidermal growth factor receptor (EGFR) is an independent adverse prognostic factor in esophageal adenocarcinoma patients treated with cisplatin-based neoadjuvant chemotherapy

Neoadjuvant platin-based therapy is accepted as a standard therapy for advanced esophageal adenocarcinoma (EAC). Patients who respond have a better survival prognosis, but still a significant number of responder patients die from tumor recurrence. Molecular markers for prognosis in neoadjuvantly treated EAC patients have not been identified yet. We investigated the epidermal growth factor receptor (EGFR) in prognosis and chemotherapy resistance in these patients. Two EAC patient cohorts, either treated by neoadjuvant cisplatin-based chemotherapy followed by surgery (n=86) or by surgical resection (n=46) were analyzed for EGFR protein expression and gene copy number. Data were correlated with clinical and histopathological response, disease-free and overall survival.In case of EGFR overexpression, the prognosis for neoadjuvant chemotherapy responders was poor as in non-responders. Responders had a significantly better disease-free survival than non-responders only if EGFR expression level (p=0.0152) or copy number (p=0.0050) was low. Comparing neoadjuvantly treated patients and primary resection patients, tumors of non-responder patients more frequently exhibited EGFR overexpression, providing evidence that EGFR is a factor for indicating chemotherapy resistance.EGFR overexpression and gene copy number are independent adverse prognostic factors for neoadjuvant chemotherapy-treated EAC patients, particularly for responders. Furthermore, EGFR overexpression is involved in resistance to cisplatin-based neoadjuvant chemotherapy.     

Epidermal growth factor receptor pathway polymorphisms and the prognosis of hepatocellular carcinoma

The EGFR signaling pathway is important in the control of vital processes in the carcinogenesis of hepatocellular carcinoma (HCC), including cell survival, cell cycle progression, tumor invasion and angiogenesis. In the current study, we aim to assess if genetic variants in the genes of the EGFR signaling pathway are associated with the prognosis of HCC. We genotyped 36 single nucleotide polymorphisms (SNP) in four core genes (EGF, EGFR, VEGF, and VEGFR2) by using DNA from blood samples of 363 HCC patients with surgical resection. The associations between genotypes and overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confident intervals (CIs) were estimated for the multivariate survival analyses by Cox proportional hazards regression models, adjusting for age, gender, family history, HBsAg and AFP. We found that five SNPs in the VEGFR2 gene were significantly associated with clinical outcomes of HCC patients. Among them, four SNPs (rs7692791, rs2305948, rs13109660, rs6838752) were associated with OS (p=0.035, 0.038, 0.029 and 0.028, respectively), and two SNPs (rs7692791 and rs2034965) were associated with DFS (p=0.039 and 0.017, respectively). Particularly, rs7692791 TT genotype was associated with both reduced OS (p=0.037) and DFS (p=0.043). However, only one SNP rs2034965 with the AA genotype was shown to be an independent effect on DFS (p=0.009) in the multivariate analysis. None of the other 31 polymorphisms or 9 haplotypes attained from the four genes was significantly associated with OS or DFS. Our results illustrated the potential use of VEGFR2 polymorphisms as prognostic markers for HCC patients.     

Epidermal growth factor receptor gene mutation in non-small cell lung cancer using highly sensitive and fast TaqMan PCR assay

Epidermal growth factor receptor (EGFR) gene mutations have been found in a subset of non-small cell lung cancer (NSCLC) with good clinical response to gefitinib therapy. A quick and sensitive method with large throughput is required to utilize the information to determine whether the molecular targeted therapy should be applied for the particular NSCLC patients. Using probes for the 13 different mutations including 11 that have already been reported, we have genotyped the EGFR mutation status in 94 NSCLC patients using the TaqMan PCR assay. We have also genotyped the EGFR mutations status in additional 182 NSCLC patients, as well as 63 gastric, 95 esophagus and 70 colon carcinoma patients. In 94 NSCLC samples, the result of the TaqMan PCR assay perfectly matched with that of the sequencing excluding one patient. In one sample in which no EGFR mutation was detected by direct sequencing, the TaqMan PCR assay detected a mutation. This patient was a gefitinib responder. In a serial dilution study, the assay could detect a mutant sample diluted in 1/10 with a wild-type sample. Of 182 NSCLC samples, 46 mutations were detected. EGFR mutation was significantly correlated with gender, smoking status, pathological subtypes, and differentiation of lung cancers. There was no mutation detected by the TaqMan PCR assay in gastric, esophagus and colon carcinomas. TaqMan PCR assay is a rapid and sensitive method of detection of EGFR mutations with high throughput, and may be useful to determine whether gefitinib should be offered for the treatment of NSCLC patients. The TaqMan PCR assay can offer us a complementary and confirmative test.     

Epidermal Growth Factor Receptor Mutational Testing and Erlotinib Treatment Among Veterans Diagnosed With Lung Cancer in the United States Department of Veterans Affairs

Introduction

We examined mutational testing of the epidermal growth factor gene (EGFR) and erlotinib treatment among veterans diagnosed with non–small-cell lung cancer in the United States Department of Veterans Affairs (VA). Our objectives were to identify the prevalence of clinically actionable EGFR mutations, to determine whether testing and treatment were guideline concordant, to evaluate the impact of testing and treatment on survival, and to estimate the rate of testing.

Mutational analysis of the transforming growth factor beta receptor type I gene in primary non-small cell lung cancer

Transforming growth factor-β receptor-dependent signals are critical for cell growth and differentiation and are often disrupted during tumorigenesis. The entire coding region of TGFβRI and flanking intron sequences from 53 primary non-small cell lung cancer (NSCLC) tissues were examined for alterations using SSCP and direct sequencing. No somatic point mutations other than two silent mutations and a polymorphism were found in the TGFβRI gene. The two silent mutations located at codon 344 (AAT to AAC) and codon 406 (TTA to CTA), respectively, and the polymorphism was at the 24th base of intron 7 (G to A). To investigate whether the presence of this polymorphism is associated with NSCLC, we determined its allele distribution in all the 53 carcinomas and 89 normal controls. Interestingly, we found that the subjects with homozygous genotype A/A displayed more than 3-fold increased risk of developing NSCLC than the common wild genotype G/G. As the first report, the present study showed that TGFβRI gene is not a frequent site of spontaneous mutational inactivation while the detected polymorphism is frequent in the pathogenesis of NSCLC.