Intron 1 CA dinucleotide repeat polymorphism and mutations of epidermal growth factor receptor and gefitinib responsiveness in non-small-cell lung cancer.
OBJECTIVE
Limited availability of tumoral tissue in non-small-cell lung cancer and presence of epidermal growth factor receptor mutation-independent responses call for investigation of other molecular predictive marker of gefitinib responsiveness. Therefore, CA repeat polymorphism in intron 1 was analyzed for its association with gefitinib responsiveness together with epidermal growth factor receptor mutation in Korean patients.


METHODS
For 86 advanced non-small-cell lung cancer patients treated with gefitinib, epidermal growth factor receptor mutation was analyzed by direct sequencing (exons 18-21) from tumor tissue and CA repeat polymorphism was assessed by fragment length analysis from tumor and/or normal tissue.


RESULTS
CA repeat status was identical in 33 patients with matched tumor and normal tissue. CA repeat was low (sum of both alleles < or =37) in 40 (46.5%) and high (sum > or =38) in 46 (53.5%) patients. Although epidermal growth factor receptor mutation was more frequent in high CA repeat patients [17.5% (7/40) in low vs. 28.3% (13/46) in high, P=0.18], response rate was higher in low CA repeat patients [25.0% (10/40) in low vs. 13.0% (6/46) in high, P=0.16]. In multivariate analysis, low CA repeat was associated with better objective response (odds ratio 7.1, 95% confidence interval 1.2-40.8; P=0.029) and time-to-progression (hazard ratio 0.54, 95% confidence interval 0.34-0.88; P=0.014), independent of the epidermal growth factor receptor mutational status. CA repeat status was not associated with epidermal growth factor receptor expression.


CONCLUSIONS
Low number of CA repeats in intron 1 of epidermal growth factor receptor is associated with gefitinib responsiveness in non-small-cell lung cancer patients independent of epidermal growth factor receptor mutation.
Han
Sae-Won
SW
Department of Internal Medicine, Seoul National University Hospital and Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea.
Jeon
Yoon Kyung
YK
Lee
Kyung-Hun
KH
Keam
Bhumsuk
B
Hwang
Pil Gyu
PG
Oh
Do-Youn
DY
Lee
Se-Hoon
SH
Kim
Dong-Wan
DW
Im
Seock-Ah
SA
Chung
Doo Hyun
DH
Heo
Dae Seog
DS
Bang
Yung-Jue
YJ
Kim
Tae-You
TY
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018900:Dinucleotide Repeats / Q000235:genetics*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007438:Introns / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic; D011799:Quinazolines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib