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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    • "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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    • "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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    • "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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