Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients

Cortés, Javier; Gómez, Carlos Gegúndez; Rosell, Rafael; Valero, Pedro; García-Girón, Carlos; Velasco, A.; Izquierdo, Àngel; Díz, Pilar; Camps, Carlos; Castellanos, Daniel A.; Alberola, Vicente; Cardenal, F.; Gonzalez-Larriba, J. L.; Vieitez, José María; Maeztu, I.; Sánchez, José Javier; Queralt, Cristina; Mayo, Clara; Méndez, Pedro Rafael Casado; Morán, Teresa; Tarón, Miquel

doi:10.1093/annonc/mdi221

Cited by 222 publications

(126 citation statements)

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“…The PCR and sequencing protocol was performed to amplify and sequence exons 19 and 21 of EGFR,exons 1 and 2 of KRAS, and exons 15 of BRAF in order to detect EGFR, KRAS and BRAF mutations using the primers described previously (10)(11)(12). Purified PCR products were sequenced on an automatic DNA sequencer (ABI 3130 Genetic Analyzer, Applied Biosystems).…”

Section: Mutation Analysismentioning

confidence: 99%

The Relationship Between Common EGFR, BRAF, KRAS Mutations and Prognosis in Advanced Stage Non-Small Cell Lung Cancer with Response to the Treatment in Turkey.

Doğan¹

2014

UHOD

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The aim of the study was to evaluate EGFR (exon 19 deletion, exon 21 L858R point mutation), KRAS and braf mutation rates besides their relationship with survival and response to the treatment in non small cell lung cancer (NSCLC). We evaluated 513 NSCLC patients followed-up between January 2004 and November 2009 according to our registration data, retrospectively. Only 42 advanced stage NSCLC patients had enough tumor tissue material in paraffin blocks for all mutation analysis. The patients were evaluated retrospectively for clinicopathological features, EGFR, KRAS and BRAF mutations, erlotinib treatment, time to progression (TTP) and overall survival (OS).Mutation rates were as 7.14% (two patients) for EGFR exon 19 deletion; 4.76% (one patient)for KRAS codon 61 deletion and 2.38% for BRAF V600E mutation. They had neither EGFR exon 21 point mutation nor different mutations together. Median follow-up was 26 months (5-83) for all patients. It was 43 months (23-83) for the patients who had erlotinib and 23 months (5-61) for those who did not. Ten (23.8%) patients had erlotinib. There was significant survival difference between the patients taking erlotinib and the others (28 ± 3 months versus 15 ± 4 months, p= 0.05). TTP and OS were longer in the patients who had mutations, however the difference was not significant (p= 0.119 and p= 0.06). To our knowledge, this is the first study evaluating EGFR, KRAS and BRAF mutations in advanced stage NSCLC in Turkey .

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Section: Mutation Analysismentioning

confidence: 99%

The Relationship Between Common EGFR, BRAF, KRAS Mutations and Prognosis in Advanced Stage Non-Small Cell Lung Cancer with Response to the Treatment in Turkey.

Doğan¹

2014

UHOD

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“…Approximately 10% of NSCLCs from the United States and Europe harbor EGFR somatic mutations, as do approximately 30-50% of tumors from patients from East Asia. [7][8][9][10][11][12][13][14][15][16][17][18] The clinical responses in patients with NSCLC treated with gefitinib and erlotinib are highly correlated with the presence of EGFR somatic mutations 6,7,[12][13][14][15][16]19,20 and/or increased copy number of EGFR. 19,21,22 While therapies directed against a target activated by somatic mutations often yield dramatic clinical responses, many patients eventually become resistant to these therapies upon the acquisition of secondary mutations in the original target gene.…”

Section: Introductionmentioning

confidence: 99%

Allele-dependent variation in the relative cellular potency of distinct EGFR inhibitors

Yuza¹,

Glatt²,

Jiang³

et al. 2007

Cancer Biology & Therapy

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Targeted cancer therapies impede cancer cell growth by inhibiting the function of activated oncogene products. Patients with non-small cell lung cancer and somatic mutations of EGFR can have a dramatic response to treatment with erlotinib and gefitinib; different somatic mutations are associated with different times to progression and survival. In this study, the relative and absolute potencies of two distinct EGFR tyrosine kinase inhibitors, erlotinib and an investigational irreversible inhibitor, HKI-272, were found to vary significantly in a panel of Ba/F3 cells transformed by representative EGFR somatic mutations. HKI-272 more potently inhibited the primary exon 20 insertion mutants, the secondary erlotinib-resistance mutants including T790M and many erlotinib-sensitive mutants including L858R. In contrast, erlotinib is a more potent inhibitor of the major exon 19 deletion mutants than is HKI-272. Analyses of EGFR autophosphorylation patterns confirmed the mutation-specific variation in relative potency of these tyrosine kinase inhibitors. Our finding that distinct EGFR inhibitors are more effective in vitro for different mutant forms of the protein suggests that tyrosine kinase inhibitor treatment could be tailored to specific EGFR mutations. More broadly, these results imply that the development and deployment of targeted therapies should focus on inhibition of specific cancer-causing mutations, not only on the mutated target.

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“…These studies also showed signifi cantly higher overall survival rate in EGFR-mutant patients compared to wild type patients (>2 years vs. 8 months) (Uramoto and Mitsudomi, 2007). And among the lung carcinoma patients, Asian ethnic group showed EGFR mutation frequencies of 22-67% followed by patients in South Europe (10-24%), and patients in North America (3-25%) (Marchetti et al, 2005;Lynch, et al, 2004;Paez et al, 2004;Pao et al, 2004;Uramoto and Mitsudomi, 2007;Cortes-Funes et al, 2005;Eberhard et al, 2005;Sequist et al, 2006). These results provided valuable insights how to screen patients who would respond well to the treatment and paved the way to the future strategies of cancer treatment based on the predictive biomarkers of patients and not simply based on the tumor types.…”

Section: Future Cancer Therapy: Personalized Medicinementioning

confidence: 89%

Future Cancer Therapy with Molecularly Targeted Therapeutics: Challenges and Strategies

Kim¹

2011

Biomolecules and Therapeutics

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In a pharmaceutical industry in which nine out of ten attempts to bring a product to market fail, oncology is among the most challenging therapeutic area (Kola and Landis, 2004;Kamb et al., 2007). In the recent article published in the Nature Rev. Drug Discov. (Arrowsmith, 2011), 83 Phase III and submission failures during 2007 to 2010 were divided according to therapeutic area and reason for failure. Largest numbers of failures was in the area of cancer (28%) followed by neurodegeneration (18%). The 66% of the failures across all therapeutic areas were attributed to lack of effi cacy and 21% of the failures were due to safety issues. Therefore, there is a desperate need for new drugs, especially in the cancer treatment.As a rational approach to cancer therapy in the middle of the last century, a new class of drug discoveries emerged to exploit the differential dependence of proliferating cancer cells on vital functions such as DNA metabolism, replication, chromosome segregation and cytokinesis. These efforts ultimately produced range of nucleoside analogues, DNA-modifying chemicals and natural products -the traditional chemotherapeutic (cytotoxic) agents. The mechanism of action of these Invited ReviewBiomol Ther 19(4), 371-389 (2011) www.biomolther.org drugs-inhibition of essential cellular functions-dictates a narrow therapeutic window (Kamb et al., 2007). A new strategy for cancer therapy has emerged during the past decade based on molecular targets that are less likely to be essential in all cells in the body, therefore more apt to confer a wider therapeutic window than traditional cytotoxic drugs (Kamb et al., 2007;Reichert and Wenger, 2008).In this review, some of the strategies and the opportunities in the molecular targeted oncology drug discovery are discussed. EXCEPTIONAL HETEROGENEITY AND ADAPTABIL-ITY OF CANCER: MAJOR CHALLENGES IN ONCOL-OGY DRUG DISCOVERYCancer is an extraordinarily heterogeneous disease with somatic alterations arise as individual cancer develops (Greenman et al., 2007;Kamb et al., 2007;Harris and McCormick, 2010). This exceptional heterogeneity of cancer is refl ected in observed differences in drug responses, and is the probable cause of acquired resistance. It is also presumably related to drug sensitivity and tumor aggressiveness which display a wide range of variation among malignancies.Due to the heterogeneity both among the cells of an individual tumor and among different cancers, the effi cacy predictions made from xenograft animal models often fail (Kamb, 2005), which presents signifi cant challenges in the oncology drug discovery where advancement of compounds largely based on a pharmacological effect in the xenograft models. Even though xenograft represents signifi cant aspects of the tumor from which it was derived, it probably captures only a fraction of the total genetic and epigenetic heterogeneity of a given tumor subtype. Low response rate in phase I oncology trials is refl ective of poor predictability of clinical effi cacy based on these xenograft mo...

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Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients

Abstract: EGFR TK mutational analysis is a novel predictive test for selecting lung adenocarcinoma patients for targeted therapy with EGFR TK inhibitors.

Cited by 222 publications

References 20 publications

The Relationship Between Common EGFR, BRAF, KRAS Mutations and Prognosis in Advanced Stage Non-Small Cell Lung Cancer with Response to the Treatment in Turkey.

The Relationship Between Common EGFR, BRAF, KRAS Mutations and Prognosis in Advanced Stage Non-Small Cell Lung Cancer with Response to the Treatment in Turkey.

Allele-dependent variation in the relative cellular potency of distinct EGFR inhibitors

Future Cancer Therapy with Molecularly Targeted Therapeutics: Challenges and Strategies

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