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

  

Authors:	Rosell, R.; Molina, M. A.; Costa, C.; Simonetti, S.; Gimenez-Capitan, A.; Bertran-Alamillo, J.; Mayo, C.; Moran, T.; Mendez, P.; Cardenal, F.; Isla, D.; Provencio, M.; Cobo, M.; Insa, A.; Garcia-Campelo, R.; Reguart, N.; Majem, M.; Viteri, S.; Carcereny, E.; Porta, R.; Massuti, B.; Queralt, C.; De Aguirre, I.; Sanchez, J. M.; Sanchez-Ronco, M.; Mate, J. L.; Ariza, A.; Benlloch, S.; Sánchez, J. J.; Bivona, T. G.; Sawyers, C. L.; Taron, M.
Article Title:	Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations
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 mRNAlevels, 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. 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. ©2011 AACR.
Keywords:	immunohistochemistry; adult; controlled study; human tissue; protein expression; aged; unclassified drug; gene mutation; major clinical study; gene deletion; erlotinib; cancer patient; outcome assessment; protein analysis; dna repair; progression free survival; gene expression; lung non small cell cancer; epidermal growth factor receptor; cell protein; genetic association; protein tyrosine kinase; mutational analysis; brca1 protein; somatomedin c receptor; survival time; dna; messenger rna; interleukin 6; ku antigen; scatter factor receptor; phosphoprotein phosphatase; ubiquitin conjugating enzyme; phosphoprotein phosphatase 2a; dna dependent protein kinase; dna dependent protein kinase catalytic subunit; interleukin 6 signal transducer; ku86 protein; phosphoprotein phosphatase 2c; protein axl; protein ctip; protein inhibitor of activated stat; protein inhibitor of activated stat 1; protein inhibitor of activated stat 4; protein siah2; receptor associated protein 80; ubiquitin conjugating enzyme e2t
Journal Title:	Clinical Cancer Research
Volume:	17
Issue:	5
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2011-03-01
Start Page:	1160
End Page:	1168
Language:	English
DOI:	10.1158/1078-0432.ccr-10-2158
PROVIDER:	scopus
PUBMED:	21233402
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-79952264325&partnerID=40&md5=43d488d3ee6795b80612eae85adc4782
Notes:	--- - "Cited By (since 1996): 2" - "Export Date: 23 June 2011" - "CODEN: CCREF" - "Source: Scopus"

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