共查询到20条相似文献,搜索用时 15 毫秒
1.
2.
3.
Despite advances in chemotherapeutics, overall survival for advanced lung cancer patients remains poor. Consequently, efforts have focused on the use of targeted therapies to improve response rates and survival. The epidermal growth factor receptor (EGFR) is overexpressed in a variety of cancers, including lung, and may play a critical role in the pathogenesis of disease. Small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa(R)), have response rates of between 10 and 27% in Phase II trials, and anecdotal reports of dramatic and sustained responses. Two recent studies published simultaneously, identified mutations in the ATP-binding cleft of the EGFR that are associated with clinical response to gefitinib. This finding has extraordinary implications and serves as a critical step toward individualized, patient-specific treatment plans based on the molecular constitution of the tumor of each individual. 相似文献
4.
Kondo M Yokoyama T Fukui T Yoshioka H Yokoi K Nagasaka T Imaizumi K Kume H Hasegawa Y Shimokata K Sekido Y 《Lung cancer (Amsterdam, Netherlands)》2005,50(3):385-391
The epidermal growth factor receptor (EGFR) gene has recently been reported to be mutated in a subset of non-small cell lung cancers (NSCLC), with the mutations being correlated with the patients’ drug sensitivity to gefitinib, an EGFR kinase inhibitor. In this study, we searched for EGFR mutations in patients with lung cancer using primary tumor specimens obtained at initial surgery and examined whether their recurrent tumors showed a response to gefitinib depending on the presence of the activating mutation. Among 12 lung cancers that were treated with gefitinib after recurrence, we found that all four tumors which showed a response to gefitinib had an activating mutation in EGFR, whereas none of the remaining eight tumors had a mutation. Southern blot analysis showed that two of the four responsive tumors had the EGFR gene amplification. We also examined another 73 NSCLC specimens (47 males and 26 females; 53 adenocarcinomas and 20 non-adenocarcinomas) which were not treated with gefitinib to determine whether NSCLCs with an EGFR mutation have different clinicopathological properties and/or unique genetic alterations of the other cancer-associated genes. We found that 13 (18%) of 73 tumors had a mutation of the EGFR gene, with the most being detected in female adenocarcinomas. Comparing the alterations in KRAS and P53 with the EGFR mutation, we found that 10 tumors with the KRAS mutation did not have an EGFR mutation, suggesting that each mutation occurs exclusively during the development of lung cancer. These results suggest that the mutation analysis of the EGFR gene using the specimens obtained at surgery might be useful in selecting the appropriate treatment(s) for recurrent lung cancer patients. 相似文献
5.
Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. 总被引:19,自引:0,他引:19
Toshimi Takano Yuichiro Ohe Hiromi Sakamoto Koji Tsuta Yoshihiro Matsuno Ukihide Tateishi Seiichiro Yamamoto Hiroshi Nokihara Noboru Yamamoto Ikuo Sekine Hideo Kunitoh Tatsuhiro Shibata Tokuki Sakiyama Teruhiko Yoshida Tomohide Tamura 《Journal of clinical oncology》2005,23(28):6829-6837
PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: EGFR mutations and increased copy numbers were significantly associated with better clinical outcome in gefitinib-treated NSCLC patients. 相似文献
6.
Takamochi K Suzuki K Sugimura H Funai K Mori H Bashar AH Kazui T 《Lung cancer (Amsterdam, Netherlands)》2007,58(1):149-155
Gefitinib is the first approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who failed to respond to conventional chemotherapy. Gefitinib has fairly effective anti-tumour activity in patients with tumours harboring EGFR gene mutations. However, there has been no data about the preoperative gefitinib treatment in NSCLC patients. We reported here two cases of surgical resection of residual disease after dramatic response to gefitinib in patients with lung adenocarcinoma harboring EGFR gene mutation. Because both of our patients initially had advanced local tumour burden (bulky N2 disease), complete resection would not have been technically feasible. However, preoperative gefitinib treatment made it possible to achieve complete resection in both patients. We believe that clinical trials are required to evaluate the role of preoperative treatment of EGFR-TKIs in patients with locally advanced NSCLC harboring EGFR gene mutation. 相似文献
7.
Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. 总被引:26,自引:0,他引:26
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 《Journal of clinical oncology》2005,23(11):2493-2501
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. 相似文献
8.
特异性阻断肿瘤生长的表皮生长因子受体(EGFR)抑制剂在非小细胞肺癌(NSCLC)的治疗中具有极大潜力。目前,有两种通过修正细胞内外酪氨酸激酶信号传导过程来达到阻断此信号传导通路的治疗方法已被应用于NSCLC的治疗中。现以吉非替尼、西妥昔单抗等药物为例,综述EGFR抑制剂在NSCLC治疗中单独及与化疗或其他靶向治疗药物联合应用的临床研究进展。 相似文献
9.
10.
11.
特异性阻断肿瘤生长的表皮生长因子受体(EGFR)抑制剂在非小细胞肺癌(NSCLC)的治疗中具有极大潜力。目前,有两种通过修正细胞内外酪氨酸激酶信号传导过程来达到阻断此信号传导通路的治疗方法已被应用于NSCLC的治疗中。现以吉非替尼、西妥昔单抗等药物为例,综述EGFR抑制剂在NSCLC治疗中单独及与化疗或其他靶向治疗药物联合应用的临床研究进展。 相似文献
12.
David M Jackman Beow Y Yeap Lecia V Sequist Neal Lindeman Alison J Holmes Victoria A Joshi Daphne W Bell Mark S Huberman Balazs Halmos Michael S Rabin Daniel A Haber Thomas J Lynch Matthew Meyerson Bruce E Johnson Pasi A J?nne 《Clinical cancer research》2006,12(13):3908-3914
PURPOSE: Somatic mutations in the epidermal growth factor receptor (EGFR) have been detected in patients with non-small cell lung cancer (NSCLC) and are associated with sensitivity to treatment with gefitinib or erlotinib. Our study explored the relationship between the two most common types of somatic EGFR mutations, exon 19 deletions and the L858R point mutation, and outcomes of patients following treatment with gefitinib or erlotinib. EXPERIMENTAL DESIGN: Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations. Patients with exon 19 deletion or L858R mutations were identified. The response rate, time to progression, and overall survival were determined for the two groups. RESULTS: We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months; P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus 10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted [18 of 23 (78%) versus 3 of 9 (33%); P = 0.04]. No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated patients. CONCLUSIONS: Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared with those with the L858R mutation. Pooling of greater numbers of patients and completion of prospective trials are needed to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib, erlotinib, and other EGFR inhibitors. 相似文献
13.
Interstitial lung disease (ILD) refers to a diverse range of pulmonary fibrotic disorders and may be hard to accurately diagnose, as distinguishing it from other pulmonary diseases can be difficult. Estimations of the incidence in populations are confounded by the complexity of the different forms of the disorder. In addition, ILD is a comorbid disease of lung cancer and is seen after most forms of chemotherapy and radiotherapy for advanced lung cancer. Incidences of >or=10% have been reported; however, whatever the true incidence, both chemotherapy and radiotherapy enhance the risk of developing ILD. ILD has also been reported with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, including erlotinib (Tarceva, OSI-774) and gefitinib (IRESSA). In a large number of gefitinib-treated patients (n > 185,000) an incidence of approx 1% has been observed (approx 2% in Japan; 0.3% in the rest of the world). Nevertheless, as with other treatments for advanced non-small-cell lung cancer, the clinical benefit outweighs the risk of ILD. In this article, we review the data on ILD with EGFR inhibitors and other common lung cancer treatments. 相似文献
14.
Hideharu Kimura Kazuo Kasahara Makoto Kawaishi Hideo Kunitoh Tomohide Tamura Brian Holloway Kazuto Nishio 《Clinical cancer research》2006,12(13):3915-3921
Cases of non-small-cell lung cancer (NSCLC) carrying the somatic mutation of epidermal growth factor receptor (EGFR) have been shown to be hyperresponsive to the EGFR tyrosine kinase inhibitor gefitinib (IRESSA). If EGFR mutations can be observed in serum DNA, this could serve as a noninvasive source of information on the genotype of the original tumor cells that could influence treatment and the ability to predict patient response to gefitinib. Serum genomic DNA was obtained from Japanese patients with NSCLC before first-line gefitinib monotherapy. Scorpion Amplified Refractory Mutation System technology was used to detect EGFR mutations. Wild-type EGFR was detected in all of the 27 serum samples. EGFR mutations were detected in 13 of 27 (48.1%) patients and two major EGFR mutations were identified (E746_A750del and L858R). The EGFR mutations were seen significantly more frequently in patients with a partial response than in patients with stable disease or progressive disease (P = 0.046, Fisher's exact test). The median progression-free survival was significantly longer in patients with EGFR mutations than in patients without EGFR mutations (200 versus 46 days; P = 0.005, log-rank test). The median survival was 611 days in patients with EGFR mutations and 232 days in patients without EGFR mutations (P > 0.05). In pairs of tumor and serum samples obtained from 11 patients, the EGFR mutation status in the tumors was consistent with those in the serum of 8 of 11 (72.7%) of the paired samples. Thus, EGFR mutations were detectable using Scorpion Amplified Refractory Mutation System technology in serum DNA from patients with NSCLC. These results suggest that patients with EGFR mutations seem to have better outcomes with gefitinib treatment, in terms of progression-free survival, overall survival, and response, than those patients without EGFR mutations. 相似文献
15.
Gefitinib is effective in treating patients with non-small-cell lung cancer (NSCLC). The response rate and improvement in survival are related to several aspects, including race, gender, smoking status, and histology; however, little is known about the relationship between survival and length of gefitinib treatment. We conducted this retrospective study to examine this relationship and identify the predictive factors influencing survival and tumor response in chemonaive and chemotherapy patients who had stage IIIb or IV NSCLC with unknown epidermal growth factor receptor mutants. This analysis was aimed to clarify the difference between first- and second-line gefitinib therapy. Among the 918 newly diagnosed, inoperable NSCLC patients from March 2003 to December 2006, 437 (47.6%) had ever received gefitinib therapy. One hundred forty-nine patients (34.0%) who selected gefitinib as first- or second-line therapy were included in the analysis. The overall survival rates of first- and second-line gefitinib therapy were 12.8 months and 20.7 months, respectively (P = .110). The shorter overall survival may be caused by the omission of platinum-based doublet chemotherapy in 37 patients from the first-line group (39.4%). There was also no significant difference in progression-free survival (6.8 months versus 4.9 months; P = .415), and the objective tumor response and disease control rates were similar. Better prognosis and tumor response was associated with female gender, adenocarcinoma, nonsmokers, and good performance status. The difference in overall survival between patients undergoing second-line treatment compared with those undergoing first-line treatment preceding chemotherapy was significant (P = .041). The overall survival, progression-free survival, and tumor response rates were similar in the patients who received gefitinib as initial therapy or after conventional chemotherapy. 相似文献
16.
Ichihara S Toyooka S Fujiwara Y Hotta K Shigematsu H Tokumo M Soh J Asano H Ichimura K Aoe K Aoe M Kiura K Shimizu K Date H Shimizu N 《International journal of cancer. Journal international du cancer》2007,120(6):1239-1247
We investigated the relationships between genetic factors and clinical outcome in Japanese non-small-cell lung cancer (NSCLC) patients treated with gefitinib. Ninety-eight NSCLC patients who had been treated with gefitinib, were screened for mutations in epidermal growth factor receptor (EGFR) exons 18-21, KRAS exon2, and polymorphisms including the CA simple sequence repeat in intron1 (CA-SSR1) and single nucleotide polymorphisms in the promoter region (-216G/T and -191C/A), using a PCR-based assay and direct sequencing. The EGFR copy number status was also evaluated using a fluorescence in situ hybridization assay. EGFR and KRAS mutations were found in 38 (38.8%) and 8 (8.2%) of the 98 patients, respectively. A high EGFR copy number status was identified in 31 (41.3%) of the 75 assessable patients. Drug-sensitive EGFR mutations limited to exon19 deletions and L858R were independent predictive factors of a stronger sensitivity to gefitinib (p = 0.0002), the overall survival (OS) (p = 0.0036), and prolonged progression-free survival (PFS) (p < 0.0001). The EGFR copy number status was not related to a sensitivity to gefitinib and prolonged OS and PFS. Regarding polymorphisms, patients with a short CA-SSR1 showed a prolonged OS as compared with those with a long length in patients with a drug-sensitive EGFR mutation, although this difference was not significant (p = 0.13). Thus, drug-sensitive EGFR mutations predict a favorable clinical outcome and a high EGFR copy number may not be related to clinical benefits in gefitinib-treated Japanese patients with NSCLC. Our findings also suggest that the CA-SSR1 length may influence the clinical outcome in patients with a drug-sensitive EGFR mutation. 相似文献
17.
Miyanaga A Gemma A Ando M Kosaihira S Noro R Minegishi Y Kataoka K Nara M Okano T Miyazawa H Tanaka T Yoshimura A Kobayashi K Iwanami H Hagiwara K Tsuboi E Kudoh S 《Oncology reports》2008,19(2):377-383
It is known that an epidermal growth factor receptor (EGFR) gene mutation(s) is present in a percentage of non-small cell lung cancers (NSCLCs). Gefitinib, an inhibitor of the tyrosine kinase activity of EGFR, is effective on most of them. The EGFR mutation status alone cannot fully predict the response to gefitinib and the prognosis for the patients. We hypothesized that information on the expression levels of phosphorylated-EGFR and -Akt, and E-cadherin, alone or in combination with information on the EGFR mutation, may refine our ability of prediction. We investigated 24 NSCLCs that had recurred after surgery and were treated with gefitinib. Specimens resected by surgery were subjected to the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp reaction to determine the EGFR mutation status, and to immunohistochemical staining of phosphorylated-EGFR and -Akt, and E-cadherin to determine their expression levels. The EGFR mutation status was predictive of responsive disease (complete response: CR + partial response: PR) and controlled disease (CR + PR + stable disease: SD). Positive E-cadherin staining was predictive of longer time to progression (12.4 vs. 5.9 months, p<0.05) and overall survival (OS) (18.4 vs. 13.0 months, p<0.05). Together the patients with an EGFR mutation and the patients with positive E-cadherin staining defined a patient group with a median OS of 18.4 months and excluded the patient group with the median OS of 3.7 months. Neither p-Akt nor p-EGFR staining was associated with the response and survival. In patients with surgically resected NSCLC tumors, the EGFR mutation status and E-cadherin staining can select patients who will benefit from gefitinib therapy. 相似文献
18.
Ryo Ko Hirotsugu Kenmotsu Yasushi Hisamatsu Hiroaki Akamatsu Shota Omori Kazuhisa Nakashima Takuya Oyakawa Kazushige Wakuda Takehito Shukuya Akira Ono Hisao Imai Tetsuhiko Taira Tateaki Naito Haruyasu Murakami Keita Mori Masahiro Endo Yasuhisa Ohde Kazuhisa Takahashi Toshiaki Takahashi 《International journal of clinical oncology / Japan Society of Clinical Oncology》2015,20(4):668-673
19.
Kiwamu Akagi Hiroshi Sakai Junko Sudo Yasuo Hommura Futoshi Kurimoto Hiroshi Komagata Hirohiko Akiyama Shuichi Yoneda 《Targeted oncology》2007,2(3):145-151
Recent studies have demonstrated that epidermal growth factor receptor (EGFR) mutations are a predictive molecular marker
of tumor response to gefitinib treatment in non-small-cell lung cancer (NSCLC). Early studies of EGFR mutations have been
analyzed by direct sequencing with surgically resected specimens. However, it is often difficult to obtain sufficient and
tumor-enriched tissue specimens from inoperative NSCLC patients for mutation analysis. Therefore, we set out to develop a
simple, sensitive and reliable method based on polymerase chain reaction (PCR) and restriction endonuclease treatment to detect
important EGFR mutations for gefitinib treatment, including G719S, deletion or insertion in exons 19 and 20, T790M, L858R
and L861Q using bronchoscopic specimens. Two hundred and eleven bronchoscopic samples cytologically diagnosed as malignant
were analyzed and mutations detected from 60 patients (28.4%). The present assay could detect deletion in exon 19 and L858R
mutations in the presence of at least 1% and 5% mutant cells, respectively, from a background of normal cells. Comparison
of mutation detection between bronchoscopic and surgical specimens from 42 patients indicated that the sensitivity of this
assay using bronchoscopic specimens was 95% (18/19) with a specificity of 100% (23/23). Furthermore, deletion variants in
exon 19 could be distinguished by native polyacrylamide gel electrophoresis. Consequently, this simple, sensitive and reliable
assay can provide important information pertaining to optimal therapeutic strategies. 相似文献
20.
Song Dong Xu-Chao Zhang Hua Cheng Jian-Quan Zhu Zhi-Hong Chen Yi-Fang Zhang Zhi Xie Yi-Long Wu 《Cancer chemotherapy and pharmacology》2012,70(5):707-716