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  • American Association for Cancer Research (AACR)  (6)
  • Bertran-Alamillo, Jordi  (6)
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  • American Association for Cancer Research (AACR)  (6)
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  • 1
    Online Resource
    Online Resource
    Nondisruptive p53 Mutations Are Associated with Shorter Survival in Patients with Advanced Non–Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 17 ( 2014-09-01), p. 4647-4659
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 17 ( 2014-09-01), p. 4647-4659
    Abstract: Purpose: TP53 mutations in early-stage non–small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group. Experimental Design: We retrospectively examined TP53 mutations and outcome in a training cohort of 318 patients with stage IIIB–IV NSCLC: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut). An independent validation cohort of 64 EGFR-mut patients was subsequently analyzed. Mutations were classified as “disruptive” and “nondisruptive” according to their predicted degree of disturbance of the p53 protein structure and function. Results: In the training cohort, TP53 mutations were found in 43 of the 125 EGFR-wt patients (34.4%). Of these, 28 had nondisruptive TP53 mutations and a median overall survival (OS) of 8.5 months, compared with 15.6 months for the remaining 97 patients (P = 0.003). In the EGFR-mut group, TP53 mutations were found in 50 of the 193 patients (25.9%). The OS for the 26 patients with TP53 nondisruptive mutations was 17.8 months versus 28.4 months for the remaining 167 patients (P = 0.04). In the validation cohort, the 11 patients with nondisruptive TP53 mutations had a median OS of 18.1 months compared with 37.8 months for the 53 remaining patients (P = 0.006). In multivariate analyses, nondisruptive TP53 mutations had an independent, significant association with a shorter OS. Conclusions: Nondisruptive mutations in the TP53 gene are an independent prognostic factor of shorter survival in advanced NSCLC. Clin Cancer Res; 20(17); 4647–59. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-2391
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 2
    Online Resource
    Online Resource
    Abstract 5698: Next generation sequencing of circulating-free DNA from advanced non small cell lung cancer patients using Gene Reader®
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5698-5698
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5698-5698
    Abstract: Background: Stand alone tests such as PCR-derived techniques, FISH or IHC are usually employed to determine clinically relevant alterations in non-small cell lung cancer (NSCLC). However, they target single genes and proteins. Mutiplex techniques can reduce the turnaround time and quantity of sample in this setting, but require a careful validation. Methods: A total of 41 cfDNA samples from serum and plasma from advanced NSCLC p were analyzed with the Actionable Insights Tumor Panel, which covers mutations in 15 clinically relevant genes, using the Gene Reader platform (Qiagen). The samples had been previously genotyped for EGFR, KRAS and BRAF mutations by stand alone, PNA-Taqman assays. Paired biopsies were available in 37 cases. The remaining 4 corresponded to p.T790M-positive blood samples of p progressing to EGFR TKIs. Results: Of the 41 samples taken into the GeneReader workflow, some had a DNA input concentration below specifications, in spite of this limitation, good results were obtained. 14 mutations were fully concordant between tissue, Taqman and GeneReader and the four p.T790M mutations were concordant between Taqman and GeneReader. Five mutations present in tissue were detected by GeneReader and not by Taqman and 11 mutations detected by Taqman were below the 1% detection threshold of GeneReader. Finally, 12 mutations present in tissue were not detected in cfDNA by any of the assays. Concordance between the stand alone tests and the Gene Reader in cfDNA was 64%, raising to 84% if mutations & lt;1% allelic fraction were excluded. Conclusions: Application of NGS to liquid biopsies is challenging and requires a careful validation. However, once fully validated, NGS will probably become the methodology of choice for cfDNA analysis in NSCLC patients at presentation and at progression. Citation Format: Clara Mayo de las Casas, Mónica Garzón, Nuria Jordana Ariza, Ariadna Balada, Jordi Bertran-Alamillo, Beatriz García, Sergio Villatoro, Erika Aldeguer, Sonia Rodriguez, Raquel Campos, Santiago Viteri Ramirez, Maria Gonzalez-Cao, Niki Karachaliou, Rafael Rosell Costa, Miguel Angel Molina-Vila. Next generation sequencing of circulating-free DNA from advanced non small cell lung cancer patients using Gene Reader® [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5698. doi:10.1158/1538-7445.AM2017-5698
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5698
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 3
    Online Resource
    Online Resource
    The Impact of EGFR T790M Mutations and BIM mRNA Expression on Outcome in Patients with EGFR -Mutant NSCLC Treated with Erlotinib or Chemotherapy in the Randomized Phase III EURTAC Trial
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 7 ( 2014-04-01), p. 2001-2010
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 7 ( 2014-04-01), p. 2001-2010
    Abstract: Purpose: Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the EGF receptor (EGFR) in patients harboring activating EGFR mutations. Experimental Design: We have evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations, and Bcl-2 interacting mediator of cell death (BCL2L11, also known as BIM) mRNA expression in 95 patients with EGFR-mutant non–small-cell lung cancer (NSCLC) included in the EURTAC trial (trial registration: NCT00446225). Results: T790M mutations were detected in 65.26% of patients using our highly sensitive method based on laser microdissection and peptide-nucleic acid-clamping PCR, which can detect the mutation at an allelic dilution of 1 in 5,000. Progression-free survival (PFS) to erlotinib was 9.7 months for those with T790M mutations and 15.8 months for those without, whereas among patients receiving chemotherapy, it was 6 and 5.1 months, respectively (P & lt; 0.0001). PFS to erlotinib was 12.9 months for those with high and 7.2 months for those with low/intermediate BCL2L11 expression levels, whereas among chemotherapy-treated patients, it was 5.8 and 5.5 months, respectively (P = 0.0003). Overall survival was 28.6 months for patients with high BCL2L11 expression and 22.1 months for those with low/intermediate BCL2L11 expression (P = 0.0364). Multivariate analyses showed that erlotinib was a marker of longer PFS (HR = 0.35; P = 0.0003), whereas high BCL2L11 expression was a marker of longer PFS (HR = 0.49; P = 0.0122) and overall survival (HR = 0.53; P = 0.0323). Conclusions: Low-level pretreatment T790M mutations can frequently be detected and can be used for customizing treatment with T790M-specific inhibitors. BCL2L11 mRNA expression is a biomarker of survival in EGFR-mutant NSCLC and can potentially be used for synthetic lethality therapies. Clin Cancer Res; 20(7); 2001–10. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-2233
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 4
    Online Resource
    Online Resource
    Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non–Small-Cell Lung Cancer Patients with EGFR Mutations
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 5 ( 2011-03-01), p. 1160-1168
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 5 ( 2011-03-01), p. 1160-1168
    Abstract: Purpose: Advanced non–small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (deletion in exon 19 or L858R) show an impressive progression-free survival of 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. We hypothesized that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. Experimental Design: We assessed the T790M mutation in pretreatment diagnostic specimens from 129 erlotinib-treated advanced NSCLC patients with EGFR mutations. The expression of eight genes and two proteins involved in DNA repair and four receptor tyrosine kinases was also examined. Results: The EGFR T790M mutation was observed in 45 of 129 patients (35%). Progression-free survival was 12 months in patients with and 18 months in patients without the T790M mutation (P = 0.05). Progression-free survival was 27 months in patients with low BRCA1 mRNA levels, 18 months in those with intermediate levels, and 10 months in those with high levels (P = 0.02). In the multivariate analysis, the presence of the T790M mutation (HR, 4.35; P = 0.001), intermediate BRCA1 levels (HR, 8.19; P & lt; 0.0001), and high BRCA1 levels (HR, 8.46; P & lt; 0.0001) emerged as markers of shorter progression-free survival. Conclusions: Low BRCA1 levels neutralized the negative effect of the T790M mutation and were associated with longer progression-free survival to erlotinib. We advocate baseline assessment of the T790M mutation and BRCA1 expression to predict outcome and provide alternative individualized treatment to patients based on T790M mutations and BRCA1 expression. Clin Cancer Res; 17(5); 1–9. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-10-2158
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 5
    Online Resource
    Online Resource
    Abstract 1450: Anti-EGF antibodies generated by vaccination significantly improve the activity of kinase inhibitors in preclinical models
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1450-1450
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1450-1450
    Abstract: Background: We have previously described that EGF blocks the activity of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant NSCLC cells, an effect that is reversed by anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) (1). In this study we aimed to determine the effect of EGF and anti-EGF Vac Abs in the activity of different kinase inhibitors in tumor cell lines with different genetic alterations. Methods: Anti-EGF VacAbs were obtained by immunizing rabbits with recombinant EGF. The cell lines used in this study were H2228 and H3122 (NSCLC, EML4-ALK positive), H23 (NSCLC, KRAS-G12C), DLD1 (colorectal carcinoma, KRAS-G13D), PC9 and PC9-GR4 (NSCLC, EGFR-mut). Tumor cell lines were treated with EGF, anti-EGF VacAbs and combinations with the kinase inhibitors alectinib, crizotinib, brigatinib (ALK inhibitors), trametinib (MEK inhibitor), dacomitinib and osimertinib (EGFR inhibitors). Cell viability was analyzed by MTT, changes of total and phosphorylated proteins were determined by Western blot and emergence of resistance by direct microscopic examination in low density cultures. Results: EGF significantly decreased the antitumor activity of alectinib, crizotinib and brigatinib in ALK translocated cells (H2228 and H3122), trametinib in KRAS mutant cells (H23 and DLD1) and osimertinib and dacomitinib in EGFR mutant cells (PC9). In combination with these TKIs, the anti-EGF VacAbs reversed the effects of EGF and significantly potentiated the antitumor activity of all the kinase inhibitors, blocking the activation of EGFR, Akt and Erk. Finally, the addition of the anti-EGF VacAbs to the culture medium delayed the appearance of resistant clones to kinase inhibitors. Conclusions: Anti-EGF VacAbs potentiate the antitumor effects of ALK, MEK and EGFR kinase inhibitors in tumor cell lines and delay the emergence of resistance in vitro. A clinical trial is currently testing anti-EGF vaccination in combination with afatinib in EGFR-mut advanced NSCLC patients.(1)Anti-Epidermal Growth Factor Vaccine Antibodies Enhance the Efficacy of Tyrosine Kinase Inhibitors and Delay the Emergence of Resistance in EGFR Mutant Lung Cancer Cells” Codony-Servat J, García-Roman S, Molina-Vila MÁ, et al. J Thorac Oncol. 2018. Citation Format: Jordi Codony-Servat, Silvia Garcia-Roman, Miguel Ángel Molina-Vila, Jordi Bertran-Alamillo, Ana Giménez-Capitán, Santiago Viteri, Andrés F. Cardona, Delvys Rodríguez, Manuel Cobo, Noemi Reguart, Niki Karachaliou, Erik d'Hondt, Rafael Rosell. Anti-EGF antibodies generated by vaccination significantly improve the activity of kinase inhibitors in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1450.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-1450
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 6
    Online Resource
    Online Resource
    Abstract 4596: Missense mutations in the p53 DNA-binding motifs (DBMs) are associated with shorter time to progression (TTP) in erlotinib-treated, EGFR-mutated patients
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 4596-4596
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 4596-4596
    Abstract: Background: Advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations has an average time to progression (TTP) of 14 months (mo) and overall survival of 27 mo when treated with erlotinib. However, EGFR mutations can only imperfectly predict outcome. In NSCLC cell lines, tyrosine kinase inhibitors (TKIs) induce p53 translocation from the cytoplasm to the nucleus and subsequent up-regulation of Fas and caspase activation leading to apoptosis. This mechanism was defective in p53-null cells. We tested whether mutations in the TP53 gene influence outcome to erlotinib in EGFR-mutated patients (p). Expression levels of the p53 repressor MDM2 were also examined. Methods: We assesed p53 status in pretreatment paraffin-embedded tumor samples from 93 erlotinib-treated, EGFR mutated advanced NSCLC p. Mutations in exons 5, 6, 7 and 8 were screened by High Resolution Melting analysis (HRM) followed by sequencing of the amplified products with non-wild type melt curves. All mutant samples were re-confirmed by standard PCR and sequencing. Expression levels of MDM2 mRNA were determined by quantitative RT-PCR. Results: Mutations in exons 5-8 of the TP53 gene were detected in 26 of 93 p (28%). We found an unusually high frequency of in-frame and frameshift deletions (23% of mutations), indicating that the spectrum of p53 mutations might be different in EGFR-mutated NSCLC. Mutations in the TP53 gene were not associated with sex, age, smoking status, histology, exon 19 vs. 21 mutation, or response, but, within the study population, were significantly less frequent in p with ECOG 2 or above. The mutations were also associated with the presence of the pretreatment T790M mutation. 14 p had mutations in one of the p53 DNA binding motifs (DBMs), and showed TTP to erlotinib of only 9 mo, compared to 19 months for wt p and 27 mo for those carrying a non-DBM mutation. Survival was 24 mo vs. 31 mo, and not-reached, respectively. Finally, MDM2 mRNA levels were significantly lower in tumors with p53 mutations, especially when these affected DBMs. In the case of wt p, high MDM2 expression correlated with a better TTP and survival. Conclusions: TP53 mutations co-exist with EGFR mutations in a significant number of p; and those in the DBMs are associated with poorer response to erlotinib. This finding paves the way for the possibility of combining erlotinib with a drug restoring p53 function in those p harboring DBM mutations in the TP53 gene. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4596. doi:1538-7445.AM2012-4596
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-4596
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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