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Clin Cancer Res. 2014 Apr 1;20(7):2001-10. doi: 10.1158/1078-0432.CCR-13-2233. Epub 2014 Feb 3.

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.

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1
Authors' Affiliations: Pangaea Biotech, Barcelona, Spain; Hospital Sant Pau, Barcelona, Spain; Hospital Vall d'Hebron, Barcelona, Spain; Molecular Oncology Research (MORe) Foundation, Barcelona, Spain; Pivotal, Madrid; Hospital General de Alicante, Alicante, Spain; Catalan Institute of Oncology, Badalona, Barcelona, Spain; Complejo Hospitalario Universitario, La Coruña, Spain; Centre François Baclesse, Caen, France; Drum Tower Hospital, Nanjing, China; Kyushu University, Fukuoka, Japan; Cancer Therapeutics Innovation Group, New York, New York, USA; and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, California, USA.

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 < 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.

PMID:
24493829
DOI:
10.1158/1078-0432.CCR-13-2233
[Indexed for MEDLINE]
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