Complex mutations in the epidermal growth factor receptor gene in non-small cell lung cancer.
BACKGROUND
Mutation of the epidermal growth factor receptor (EGFR) gene can predict the efficacy of EGFR-tyrosine kinase inhibitors. Different mutations have been shown to co-occur in a single tumor. However, the frequency of these so-called "complex mutations" and the efficacy of gefitinib in treating patients with these mutations are unclear.


METHODS
We investigated the frequency of complex mutations in 783 patients with non-small cell lung cancer seen at our institutes between April 2006 and May 2009. Mutational analysis was performed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Gefitinib efficacy was evaluated in patients found to have complex mutations.


RESULTS
EGFR: mutations were detected in 318 (41%) patients, with 21 (6.6%) of these individuals having complex mutations. Sixteen of these 21 patients received gefitinib. The response rate (RR) was 67% (95% confidence interval [CI], 35-90%) and median progression-free survival was 12.2 months (95% CI, 1.3 months to undeterminable). Analysis of RR according to mutation type revealed that patients with deletional mutation in exon 19 (Del-19) and a point mutation in exon 21 (L858R) had a better RR (86%, 6 of 7) than those with other complex mutation patterns such as a point mutation in exon 18 (G719S) + L858R (40%, 2 of 5) (p = 0.2222). The median progression-free survival was also longer in these patients (16.5 months; 95% CI, 1.1 months to undeterminable versus 3.8 months; 95% CI, 0.7-10.0 months) (p = 0.0459).


CONCLUSIONS
Complex EGFR mutations are not rare. Gefitinib has different efficacy according to the type of complex EGFR mutations. Patients with Del-19 and L858R mutations may benefit more from gefitinib than other types of complex mutations.
Hata
Akito
A
Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Chuo-ku, Kobe, Japan.
Yoshioka
Hiroshige
H
Fujita
Shiro
S
Kunimasa
Kei
K
Kaji
Reiko
R
Imai
Yukihiro
Y
Tomii
Keisuke
K
Iwasaku
Masahiro
M
Nishiyama
Akihiro
A
Ishida
Tadashi
T
Katakami
Nobuyuki
N
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017354:Point Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011799:Quinazolines / Q000627:therapeutic use*; D017384:Sequence Deletion / Q000235:genetics*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib