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.
OBJECTIVE
Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the EGF receptor (EGFR) in patients harboring activating EGFR mutations.


METHODS
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.
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.
Carlota
C
Costa
Miguel Angel
MA
Molina
Ana
A
Drozdowskyj
Ana
A
Giménez-Capitán
Jordi
J
Bertran-Alamillo
Niki
N
Karachaliou
Radj
R
Gervais
Bartomeu
B
Massuti
Jia
J
Wei
Teresa
T
Moran
Margarita
M
Majem
Enriqueta
E
Felip
Enric
E
Carcereny
Rosario
R
Garcia-Campelo
Santiago
S
Viteri
Miquel
M
Taron
Mayumi
M
Ono
Petros
P
Giannikopoulos
Trever
T
Bivona
Rafael
R
Rosell
D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D000072224:Bcl-2-Like Protein 11; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D011799:Quinazolines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis; D016896:Treatment Outcome
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D012333:RNA, Messenger; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors