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Screening for EGFR amplifications with a novel method and their significance for the outcome of glioblastoma patients.

Bieńkowski M, Piaskowski S, Stoczyńska-Fidelus E, Szybka M, Banaszczyk M, Witusik-Perkowska M, Jesień-Lewandowicz E, Jaskólski DJ, Radomiak-Załuska A, Jesionek-Kupnicka D, Sikorska B, Papierz W, Rieske P, Liberski PP - PLoS ONE (2013)

Bottom Line: At the molecular level, EGFRvIII expression was associated with a better prognosis (HR = 0.37; p = 0.04).Importantly, the results emphasise the necessity to distinguish both mechanisms of the increased EGFR gene copy number (amplification and polysomy).To conclude, although the data presented here require validation in different groups of patients, they strongly advocate the consideration of the patient's tumour molecular characteristics in the selection of the therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pathology and Neuropathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland. michal.bienkowski@gmail.com

ABSTRACT
Glioblastoma is a highly aggressive tumour of the central nervous system, characterised by poor prognosis irrespective of the applied treatment. The aim of our study was to analyse whether the molecular markers of glioblastoma (i.e. TP53 and IDH1 mutations, CDKN2A deletion, EGFR amplification, chromosome 7 polysomy and EGFRvIII expression) could be associated with distinct prognosis and/or response to the therapy. Moreover, we describe a method which allows for a reliable, as well as time- and cost-effective, screening for EGFR amplification and chromosome 7 polysomy with quantitative Real-Time PCR at DNA level. In the clinical data, only the patient's age had prognostic significance (continuous: HR = 1.04; p<0.01). At the molecular level, EGFRvIII expression was associated with a better prognosis (HR = 0.37; p = 0.04). Intriguingly, EGFR amplification was associated with a worse outcome in younger patients (HR = 3.75; p<0.01) and in patients treated with radiotherapy (HR = 2.71; p = 0.03). We did not observe any difference between the patients with the amplification treated with radiotherapy and the patients without such a treatment. Next, EGFR amplification was related to a better prognosis in combination with the homozygous CDKN2A deletion (HR = 0.12; p = 0.01), but to a poorer prognosis in combination with chromosome 7 polysomy (HR = 14.88; p = 0.01). Importantly, the results emphasise the necessity to distinguish both mechanisms of the increased EGFR gene copy number (amplification and polysomy). To conclude, although the data presented here require validation in different groups of patients, they strongly advocate the consideration of the patient's tumour molecular characteristics in the selection of the therapy.

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Related in: MedlinePlus

Kaplan-Meier diagrams depicting differences in survival times related to the EGFR amplification and clinical aspects.The attached table presents statistical data for each diagram. Cox’s proportional hazard refers to multivariate analysis. The calculated HR values pertain to the second subgroup listed, while the HR values of the first subgroup equal to 1. ♦ - complete responses; Δ - censored responses. A. EGFR amplification in patients aged 60 years and less; B. EGFR amplification in patients treated with radiotherapy; C. comparison of patients not treated with radiotherapy with those with the EGFR amplification treated with radiotherapy; D. EGFR amplification in a cumulative group of younger patients and those treated with radiotherapy.
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pone-0065444-g004: Kaplan-Meier diagrams depicting differences in survival times related to the EGFR amplification and clinical aspects.The attached table presents statistical data for each diagram. Cox’s proportional hazard refers to multivariate analysis. The calculated HR values pertain to the second subgroup listed, while the HR values of the first subgroup equal to 1. ♦ - complete responses; Δ - censored responses. A. EGFR amplification in patients aged 60 years and less; B. EGFR amplification in patients treated with radiotherapy; C. comparison of patients not treated with radiotherapy with those with the EGFR amplification treated with radiotherapy; D. EGFR amplification in a cumulative group of younger patients and those treated with radiotherapy.

Mentions: In this part, the aforementioned analysis was performed in separate groups in relation to the age of the patients (with the threshold of 60 years, being the median age in the analysed group). Intriguingly, EGFR amplification appeared to have an opposite effect on survival in both groups. It seems to be associated with a shorter survival in younger patients and with a longer survival in older patients. Multivariate analysis confirmed the significance of EGFR amplification only in younger patients (HR = 3.75, p = 0.01) (Table 1, Fig. 4A).


Screening for EGFR amplifications with a novel method and their significance for the outcome of glioblastoma patients.

Bieńkowski M, Piaskowski S, Stoczyńska-Fidelus E, Szybka M, Banaszczyk M, Witusik-Perkowska M, Jesień-Lewandowicz E, Jaskólski DJ, Radomiak-Załuska A, Jesionek-Kupnicka D, Sikorska B, Papierz W, Rieske P, Liberski PP - PLoS ONE (2013)

Kaplan-Meier diagrams depicting differences in survival times related to the EGFR amplification and clinical aspects.The attached table presents statistical data for each diagram. Cox’s proportional hazard refers to multivariate analysis. The calculated HR values pertain to the second subgroup listed, while the HR values of the first subgroup equal to 1. ♦ - complete responses; Δ - censored responses. A. EGFR amplification in patients aged 60 years and less; B. EGFR amplification in patients treated with radiotherapy; C. comparison of patients not treated with radiotherapy with those with the EGFR amplification treated with radiotherapy; D. EGFR amplification in a cumulative group of younger patients and those treated with radiotherapy.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675194&req=5

pone-0065444-g004: Kaplan-Meier diagrams depicting differences in survival times related to the EGFR amplification and clinical aspects.The attached table presents statistical data for each diagram. Cox’s proportional hazard refers to multivariate analysis. The calculated HR values pertain to the second subgroup listed, while the HR values of the first subgroup equal to 1. ♦ - complete responses; Δ - censored responses. A. EGFR amplification in patients aged 60 years and less; B. EGFR amplification in patients treated with radiotherapy; C. comparison of patients not treated with radiotherapy with those with the EGFR amplification treated with radiotherapy; D. EGFR amplification in a cumulative group of younger patients and those treated with radiotherapy.
Mentions: In this part, the aforementioned analysis was performed in separate groups in relation to the age of the patients (with the threshold of 60 years, being the median age in the analysed group). Intriguingly, EGFR amplification appeared to have an opposite effect on survival in both groups. It seems to be associated with a shorter survival in younger patients and with a longer survival in older patients. Multivariate analysis confirmed the significance of EGFR amplification only in younger patients (HR = 3.75, p = 0.01) (Table 1, Fig. 4A).

Bottom Line: At the molecular level, EGFRvIII expression was associated with a better prognosis (HR = 0.37; p = 0.04).Importantly, the results emphasise the necessity to distinguish both mechanisms of the increased EGFR gene copy number (amplification and polysomy).To conclude, although the data presented here require validation in different groups of patients, they strongly advocate the consideration of the patient's tumour molecular characteristics in the selection of the therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pathology and Neuropathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland. michal.bienkowski@gmail.com

ABSTRACT
Glioblastoma is a highly aggressive tumour of the central nervous system, characterised by poor prognosis irrespective of the applied treatment. The aim of our study was to analyse whether the molecular markers of glioblastoma (i.e. TP53 and IDH1 mutations, CDKN2A deletion, EGFR amplification, chromosome 7 polysomy and EGFRvIII expression) could be associated with distinct prognosis and/or response to the therapy. Moreover, we describe a method which allows for a reliable, as well as time- and cost-effective, screening for EGFR amplification and chromosome 7 polysomy with quantitative Real-Time PCR at DNA level. In the clinical data, only the patient's age had prognostic significance (continuous: HR = 1.04; p<0.01). At the molecular level, EGFRvIII expression was associated with a better prognosis (HR = 0.37; p = 0.04). Intriguingly, EGFR amplification was associated with a worse outcome in younger patients (HR = 3.75; p<0.01) and in patients treated with radiotherapy (HR = 2.71; p = 0.03). We did not observe any difference between the patients with the amplification treated with radiotherapy and the patients without such a treatment. Next, EGFR amplification was related to a better prognosis in combination with the homozygous CDKN2A deletion (HR = 0.12; p = 0.01), but to a poorer prognosis in combination with chromosome 7 polysomy (HR = 14.88; p = 0.01). Importantly, the results emphasise the necessity to distinguish both mechanisms of the increased EGFR gene copy number (amplification and polysomy). To conclude, although the data presented here require validation in different groups of patients, they strongly advocate the consideration of the patient's tumour molecular characteristics in the selection of the therapy.

Show MeSH
Related in: MedlinePlus