Gefitinib (ZD1839): Therapy in selected patients with non-small cell lung cancer (NSCLC)?

Dongiovanni, Diego; Lilleri, Daniele; Barone, C.; Dongiovanni, Vincenzo; Fissore, C.; Sapino, Anna; Macrì, Luigia; Bussolati, G.; Buffoni, L; Gaspari, Fabio; Grillo, R.; Birocco, Nadia; Addeo, Alfredo; Ciuffreda, Libero; Schena, Marina

doi:10.1016/j.lungcan.2007.12.007

Cited by 21 publications

(12 citation statements)

References 46 publications

(54 reference statements)

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“…Point mutations in exon 18 (G719A/C) occur in ~5% of cases, which are associated with oncogenic potential in both cell culture and transgenic mouse studies (14,18,23) and are also correlated with moderate TKI sensitivity (23,24). A large number of studies has reported a significantly higher response rate (ORR >80%), OS and TTP in patients with activating EGFR mutations compared to the wild-type individuals (ORR <10%) (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

Section: Clinically-relevant Target Drugsmentioning

confidence: 99%

Target therapy in NSCLC patients: Relevant clinical agents and tumour molecular characterisation

Ulivi

Zoli

Capelli

et al. 2013

Molecular and Clinical Oncology

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Abstract. In recent years, a number of new agents that target specific molecular pathways in non-small cell lung cancer (NSCLC) have been investigated. Much effort has been focused on identifying specific markers that are predictive of treatment response, given that a tailored approach would maximise the therapeutic index and cost-effectiveness. Gefitinib and erlotinib are selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) and have produced good results in selected cases in terms of objective response rate and overall survival. At present, EGFR gene mutations are considered the most important predictors of clinical response to TKI therapy and tumour characterisation for these alterations is mandatory prior to any decision making. Echinoderm microtubule-like protein 4-anaplastic lymphoma kinase (EML4-ALK) translocation is another alteration capable of predicting the efficacy of anti-ALK agents, such as crizotinib. Moreover, emerging target agents, such as MET inhibitors, are likely to increase the amount of molecular characterisation required before a decision is made on treatment. The main limiting factor for adequate characterisation of metastatic NSCLC patients is the small quantity of tumour cells available for molecular analysis. In this study, we provided an overview of the most important and clinically relevant target agents in NSCLC patients as well as the most important mechanisms of resistance. The issue of the scant amount of biological samples available for analysis as well as alternative sampling approaches such as plasma-or serum-derived DNA were also examined.

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Section: Clinically-relevant Target Drugsmentioning

confidence: 99%

Target therapy in NSCLC patients: Relevant clinical agents and tumour molecular characterisation

Ulivi

Zoli

Capelli

et al. 2013

Molecular and Clinical Oncology

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“…51,52 As a rule, EGFR and KRAS mutations are mutually exclusive, and, furthermore, it has been suggested that activation of either the EGFR or RAS signaling pathways has similar effects on lung tumorigenesis. 34 Moreover, EGFR mutations are common in tumors from patients who have smoked less than 100 cigarettes in their lifetime ("never smokers"), 26 while KRAS mutations more frequently occur in individuals with a history of substantial cigarette use. 53 The presence of KRAS mutations is associated with resistance to EGFR-TKI treatment, [54][55][56] probably due to the fact that constitutive activation of the pathway by mutated KRAS neutralizes the inhibitory effects exerted by EGFR inhibition.…”

Section: Kras Mutationsmentioning

confidence: 99%

Predictive molecular markers for EGFR-TKI in non-small cell lung cancer patients: new insights and critical aspects

Ulivi

Calistri

Zoli

et al. 2010

J Nucleic Acids Invest

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In recent years, a number of novel agents have been investigated that target specific molecular pathways in non-small cell lung cancer (NSCLC). A great deal of effort has been focused on identifying specific markers that predict treatment response, given that a tailored approach would maximize both the therapeutic index and the cost-effectiveness. The epidermal growth factor receptor (EGFR) pathway has emerged as a key regulator of cancer cell proliferation and invasion, and several specific EGFR inhibitors have been examined. Gefitinib and erlotinib are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs), demonstrating good results in selected cases both in terms of objective response rate and of overall survival. At present, EGFR gene mutations are the best positive predictive factors for TKI therapy, and a number of other potential biomarkers are being investigated as additional positive or negative predictors of response. The correct selection of patients that could benefit from these innovative therapies, based on an accurate molecular characterization, is mandatory to provide the best clinical management. Currently, the main factor limiting the characterization of metastatic NSCLC patients is the small quantity of tumor cells available for molecular analysis. In this paper we provide an overview of the most important molecular predictive markers for EGFR-TKIs therapy in NSCLC patients, and focus attention on biological samples suitable for analysis and alternative sampling approaches such as plasma-or serum-derived DNA.

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“…Most EGFR mutations consist of small in-frame deletions or substitutions clustered around the ATP-binding site in exons 18, 19 and 21. Patients with these mutations show an 80% response rate to TKIs, compared to only 10% of patients with wild-type EGFR (1,4,5). On the other hand, EGFR exon 20 mutations and K-ras mutations, have been shown to be related to acquired or intrinsic resistance to TKIs (6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Assessment of EGFR and K-ras mutations in fixed and fresh specimens from transesophageal ultrasound-guided fine needle aspiration in non-small cell lung cancer patients

et al. 2012

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Abstract.In non-small cell lung cancer (NSCLC) patients, somatic EGFR and K-ras mutations predict therapeutic effectiveness and resistance, respectively, to EGFR tyrosine kinase inhibitors (TKIs). Transesophageal ultrasound-guided fine needle aspiration (EUS-FNA) is a validated technique for diagnosis and staging of NSCLC. In the present study, we compared the feasibility and reliability of EGFR and K-ras gene mutation analysis in fixed and fresh mediastinal lymph nodes and extra-lymph nodal samples obtained by EUS-FNA in patients suspicious for NSCLC. Thirty-six patients were enrolled into the study. For each patient, DNA was extracted from both fresh samples and fixed cytological smears. Exons 18-21 of EGFR and exon 2 of K-ras were amplified by PCR and mutation status was determined by direct sequencing and pyrosequencing. All cases were eligible for analysis. NSCLC was diagnosed in 32 patients (25 adenocarcinomas and 7 squamous cell carcinomas) and 4 patients were free of malignancy. Of the 25 patients with adenocarcinoma, EGFR mutations were detected in 2 (8%) fresh tumor samples and in 3 (12%) fixed cytological smears. K-ras mutations were detected in 8 (32%) fresh samples, and in 9 (36%) fixed cytological smears. Fixed and stained cytological samples seem to be more reliable than fresh material for molecular analysis.

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Gefitinib (ZD1839): Therapy in selected patients with non-small cell lung cancer (NSCLC)?

Cited by 21 publications

References 46 publications

Target therapy in NSCLC patients: Relevant clinical agents and tumour molecular characterisation

Target therapy in NSCLC patients: Relevant clinical agents and tumour molecular characterisation

Predictive molecular markers for EGFR-TKI in non-small cell lung cancer patients: new insights and critical aspects

Assessment of EGFR and K-ras mutations in fixed and fresh specimens from transesophageal ultrasound-guided fine needle aspiration in non-small cell lung cancer patients

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