Non-responsiveness to gefitinib in a patient with lung adenocarcinoma having rare EGFR mutations S768I and V769L

Asahina, Hajime; Yamazaki, Koichi; Kinoshita, Ichiro; Yokouchi, Hiroshi; Dosaka‐Akita, Hirotoshi; Nishimura, Masaharu

doi:10.1016/j.lungcan.2006.09.005

Cited by 57 publications

(35 citation statements)

References 19 publications

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“…In addition, S768I and V769L mutations may be associated with resistance to gefitinib since such mutations are refractory to EGF-induced ubiquitination and degradation (27). In our study, small deletions centered around 5 codons in exon 19 (amino acid residues 747-751), similar to previous studies which found that deletions in exon 19 are the most common types of mutations identified in all of the large Table VI.…”

Section: Discussionsupporting

confidence: 89%

Overexpression of EGFR pathway-related genes in the circulation is highly correlated with EGFR mutations and overexpression in paired cancer tissue from patients with non-small cell lung cancer

Chen

Chiu²,

Yen³

et al. 2010

Oncol Rep

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Abstract. Epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) have been established as a treatment option in patients with advanced non-small cell lung cancer (NSCLC). Clinically, PCR and RFLP are commonly used to evaluate the efficacy of TKIs, and these methods require cancer tissues to proceed. In the event a peripheral blood test is able to replace current evaluation methods, a greater clinical application advantage may be achieved. Therefore, in this study, we selected 30 EGFR pathway-related genes and constructed activated EGFR chips to identify overexpression of EGFR pathway-related genes from the peripheral blood of 72 NSCLC patients and 100 normal subjects. According to ROC curve analysis, the best chip interpretation cutoff value was 11 genes. Correlation analysis showed high significance among EGFR mutations, overexpression and the overexpression of EGFR pathway-related genes (p<0.0001). The potential application of this new technique may provide an accurate, instantaneous and convenient drug evaluation tool.

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Section: Discussionsupporting

confidence: 89%

Overexpression of EGFR pathway-related genes in the circulation is highly correlated with EGFR mutations and overexpression in paired cancer tissue from patients with non-small cell lung cancer

Chen

Chiu²,

Yen³

et al. 2010

Oncol Rep

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“…The tumor progressed 6 months later, and he continued with further chemotherapy treatments. Cases 18 and 22 failed to respond to chemotherapy (gemcitabine plus cisplatin for case 18 and paclitaxel with carboplatin for case 22), and both of them expired due to cancer-related respiratory complications.…”

Section: Resultsmentioning

confidence: 99%

Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Mutations Is Associated with Poor Gefitinib Treatment Response

Wu¹,

Wu²,

Yang³

et al. 2008

Clinical Cancer Research

280

212

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Purpose: Clinical reports about responsiveness to gefitinib treatment in patients of non-small cell lung cancer (NSCLC) with mutations in exon 20 of epidermal growth factor receptor (EGFR) are limited. To increase understanding of the influence of exon 20 mutations on NSCLC treatment with gefitinib, we investigated the clinical features of lung cancer in patients with exon 20 mutations and analyzed the gefitinib treatment response. Experimental Design: We surveyed the clinical data and mutational studies of NSCLC patients with EGFR exon 20 mutations in the National Taiwan University Hospital and reviewed the literature reports about EGFR exon 20 mutations and the gefitinib treatment response. Results: Twenty-three patients with mutations in exon 20 were identified. Nine (39%) had coexisting mutations in EGFR exons other than exon 20. Sixteen patients received gefitinib treatment, and a response was noted in 4 patients. The gefitinib response rate of NSCLC with exon 20 mutations was 25%, far lower than those with deletions in exon 19 and L858R mutations. Interestingly, different exon 20 mutations and coexisting mutations seemed to have a different influence on gefitinib response. Conclusions: EGFR exon 20 mutations of NSCLC patients result in poorer responsiveness to gefitinib treatment, but variability exists between different individuals.

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“…According to the published reports, there is an average 34% gefitinib response rate for the exon 20 mutation, which is much lower than that for classical mutations in exons 19 and 21. (37)(38)(39) These results suggest that EGFR target therapy is not an encouraging treatment for patients with inoperable LELCs. Our experience with the chemotherapy regimen, a combination of gemcitabine and cisplatin, showed a good partial response without accompanying adverse reactions.…”

Section: Discussionmentioning

confidence: 99%

Unique p53 and epidermal growth factor receptor gene mutation status in 46 pulmonary lymphoepithelioma‐like carcinomas

Chang¹,

Wu²,

Shih³

et al. 2010

Cancer Science

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p53 and epidermal growth factor receptor (EGFR) are common genes involved in the pathogenesis of lung cancer, but their roles in lymphoepithelioma-like carcinomas (LELC) are unclear. In this study, we investigate the roles of p53 and EGFR in LELC carcinogenesis. Forty-six pulmonary LELCs were identified to evaluate p53 and EGFR aberrations. p53 mutations were identified in three patients, which all occurred in exon 8. EGFR mutations were detected in 8 of 46 cases with a majority of exon 21 mutations but without L858R. The other cases harbored mutations in exons 20 and 18. Only one case gained a deletion in exon 19. Notably, EGFR mutation was more commonly observed in patients with tumor size £3 cm (P = 0.014). In addition, there was a trend of more common EGFR overexpression in female (22 ⁄ 30) than in male patients (7 ⁄ 16, P = 0.061). However, there was no correlation between p53 ⁄ EGFR mutations and protein expressions, suggesting the presence of complex mechanisms. p53 and EGFR mutations are uncommon in LELCs, indicating that these genes are not the important events in carcinogenesis for this tumor subtype. The EGFR mutation in 35% patients with LELC tumors <3 cm in size suggests the potential benefits to EGFR tyrosine kinase inhibitors of inoperable LELCs. (Cancer Sci 2011; 102: 282-287) T he majority of tumors have evidence of mutational inactivation of tumor suppressor genes and activation of oncogenes. Mutation of one p53 allele and loss of the normal p53 allele occur in many tumors including lung cancers. These alterations apparently contribute to the development of cancer by interfering with the tumor suppressor activity of p53. In addition, overexpression of mutant p53 may cause cellular transformation, whereas transfection and expression of a normal p53 gene in cells having a mutated p53 can suppress cellular transformation and inhibit cell proliferation.(1) It has been reported that somatic mutations and increased expression of p53 are frequently found in approximately 23% and 65% of non-small-cell lung cancer (NSCLC), respectively. Epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, is involved in promoting cell division, migration and angiogenesis, and inhibiting apoptosis.(5) Loss of control of EGFR because of deregulation, amplification, or mutations may result in malignant change of cells.(6) Gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE, USA), an inhibitor of EGFR tyrosine kinase, has a novel antitumor effect on NSCLC. The better treatment outcomes of tyrosine kinase inhibitor in NSCLC patients are strongly associated with mutations at the EGFR tyrosine kinase domain (exons 18-21) in EGFR of tumor tissues. (7,8) Depending on the tumor subtypes and different ethnicity, Caucasian NSCLC patients have an EGFR mutation frequency of <10% compared with a mutation rate of at least 30% in East Asian patients. (2,9,10) Lymphoepithelioma-like carcinoma of the lung (LELC) was first reported in 1987.(11) It is a rare form of NSCLC predominantly affecting young non-smoking Asi...

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Non-responsiveness to gefitinib in a patient with lung adenocarcinoma having rare EGFR mutations S768I and V769L

Cited by 57 publications

References 19 publications

Overexpression of EGFR pathway-related genes in the circulation is highly correlated with EGFR mutations and overexpression in paired cancer tissue from patients with non-small cell lung cancer

Overexpression of EGFR pathway-related genes in the circulation is highly correlated with EGFR mutations and overexpression in paired cancer tissue from patients with non-small cell lung cancer

Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Mutations Is Associated with Poor Gefitinib Treatment Response

Unique p53 and epidermal growth factor receptor gene mutation status in 46 pulmonary lymphoepithelioma‐like carcinomas

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