Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations

Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
Clinical Cancer Research (Impact Factor: 8.72). 02/2011; 17(5):1160-8. DOI: 10.1158/1078-0432.CCR-10-2158
Source: PubMed


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.
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.
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 < 0.0001), and high BRCA1 levels (HR, 8.46; P < 0.0001) emerged as markers of shorter progression-free survival.
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.

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Available from: Sara Simonetti, Sep 30, 2015
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    • "However, the p.T790M mutation is the most prevalent mechanism. p.T790M mutation was reported in 2.7%–40% of TKI-naïve patients.20,85 Currently, almost all patients with activating mutations (deletion in exon 19 or point mutation in exon 21) eventually develop acquired resistance while receiving EGFR-TKI therapy,20 and about 50% of these patients have a secondary mutation in exon 20 (p.T790M).86–90 "
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    ABSTRACT: Non-small-cell lung cancer (NSCLC) has entered the age of individual treatment, and increasing point mutations of specific oncogenes and rearrangement of some chromosomes are biomarkers used to predict the therapeutic effect of targeted therapy. At present, there is a consensus among clinicians that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown favorable efficacy in NSCLC patients with EGFR mutation, and some relevant research has suggested that the presence of EGFR mutations is a favorable prognostic marker. However, the association of EGFR mutation status with the responsiveness to conventional chemotherapy agents and survival in NSCLC patients is still unclear. This review provides an overview of and assesses the role of EGFR as a prognostic marker for postoperative patients and as a predictive marker for response to cytotoxic chemotherapy. In addition, we review the comparison of response to chemotherapy between EGFR mutations in exon 19 and in exon 21 and the predictive role of p.T790M mutation.
    Drug Design, Development and Therapy 09/2014; 8:1595-1611. DOI:10.2147/DDDT.S69690 · 3.03 Impact Factor
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    • "However, not all patients with EGFR mutations respond to EGFR directed TKIs and the duration of the response varies markedly. Several mechanisms have been suggested for this reduced sensitivity including somatic mutations in genes downstream of EGFR [5], presence of the resistance causing EGFR mutation T790M [6] [7] and MET amplification [8]. Furthermore, a germline polymorphism in the BIM gene has also been demonstrated to affect sensitivity [9]. "
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    ABSTRACT: Objectives Somatic mutations in the epidermal growth factor receptor (EGFR) are predictors of efficacy for treatment with the EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer (NSCLC). A CA repeat polymorphism in intron 1 of the EGFR gene influences the transcription of the EGFR gene. This study evaluates the association between the CA repeat polymorphism and outcome in NSCLC patients treated with erlotinib. Materials and methods Number of CA repeats in the EGFR gene was evaluated with PCR-fragment length analysis by capillary electrophoresis in 432 advanced NSCLC patients treated with erlotinib irrespective of EGFR mutation status. Patients were dichotomized into harboring short allele (CA ≤ 16 in any allele) or long alleles (CA > 16 in both alleles). Number of repeats was correlated with clinical characteristic and outcome. A subgroup analysis was performed based on the somatic EGFR mutation status. Results In EGFR mutation positive patients (N = 62) we demonstrate a significantly higher median progression free survival (HR = 0.39 (0.22-0.70); p = 0.002) and overall survival (HR = 0.43, (0.23-0.78); p = 0.006) in patients also harboring a short CA repeat length versus a long (median follow-up time of 52.2 months). The result remained highly significant in a multivariate Cox proportional hazards model. This correlation was not seen in EGFR mutation negative patients. Conclusion Our study demonstrate that in EGFR mutation positive NSCLC patients treated with erlotinib a low number of CA repeats in intron 1 of the EGFR gene is a predictor for both longer progression free survival and overall survival.
    Lung cancer (Amsterdam, Netherlands) 09/2014; DOI:10.1016/j.lungcan.2014.06.016 · 3.96 Impact Factor
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    • "This secondary mutation is believed to exert its effect by enhancing ATP kinase affinity, thereby decreasing sensitivity to the ATP-competitive EGFR TKIs (40). Importantly, the development of secondary resistance mutations in the EGFR kinase domain has implications in the re-challenging of patients with previously sensitive disease and has fueled research in the development of second and third generation inhibitors (41–45). Despite encouraging phase II data of one such second-generation inhibitor (dacomitinib) in previously treated patients (41, 42), emerging phase III data suggests that there is no overall survival benefit associated with its use in previously treated EGFR W/T patients or those with acquired EGFR-TKI resistance (23). "
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    ABSTRACT: Our ability to detect and directly target the oncogenic alterations responsible for tumor proliferation has contributed significantly to the management of lung cancer in the last decade. The therapeutic efficacy of molecularly targeted therapy is, however, mainly limited to patients harboring certain genetic mutations and is generally short-lived. Herein, we review primary and secondary drug resistance using the most well-studied of the molecularly targeted agents, the tyrosine kinase inhibitors targeting the epidermal growth factor (EGF) receptor, and the anaplastic lymphoma kinase (ALK) rearrangement, the current limitations of targeted therapies and their consequences on the management of patients with lung cancer.
    Frontiers in Oncology 07/2014; 4:190. DOI:10.3389/fonc.2014.00190
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