Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing.
BACKGROUND
EGFR T790M is the most common mutation associated with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Baseline EGFR T790M mutations in EGFR TKI-naïve patients have been reported, but the frequency and their association with response to EGFR TKIs remain unclear.


METHODS
The frequency of baseline EGFR T790M as detected by routine molecular genotyping was determined by reviewing clinical results obtained at our institution from 2009 to 2013. We also collected outcome data for treatment with EGFR TKIs.


RESULTS
To define the incidence of EGFR T790M, we reviewed 2774 sequentially tested patients with lung cancer who underwent molecular testing using a mass spectrometry-based assay, and 11 (0.5%) had baseline EGFR T790M. Compiling results from several molecular techniques, we observed EGFR T790M in tumors from 20 patients who had not previously been treated with an EGFR TKI. In all cases, EGFR T790M occurred concurrently with another EGFR mutation, L858R (80%, 16/20), or exon 19 deletion (20%, 4/20). Two percent of all pre-treatment EGFR-mutant lung cancers harbored an EGFR T790M mutation. Thirteen patients received erlotinib monotherapy as treatment for metastatic disease. The response rate was 8% (1/13, 95% confidence interval 0%-35%). For the patients who received erlotinib, the median progression-free survival was 2 months and the median overall survival was 16 months.


CONCLUSIONS
De novo EGFR T790M mutations are rare (<1%) when identified by standard sensitivity methods. TKI therapy for patients with baseline EGFR T790M detected by standard molecular analysis has limited benefit.
Thoracic Oncology Service, Division of Solid Tumor Oncology, Departments of Medicine.
H A
HA
Yu
M E
ME
Arcila
M D
MD
Hellmann
M G
MG
Kris
M
M
Ladanyi
G J
GJ
Riely
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D012189:Retrospective Studies; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
EGFR; EGFR T790M; biomarker; lung cancer; resistance to targeted therapies