Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas.
OBJECTIVE
Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) confer a strong sensitivity to gefitinib, a selective tyrosine kinase inhibitor of EGFR.


METHODS
We examined EGFR mutations at exons 18, 19, and 21 in tumor tissue from 68 gefitinib-treated, chemorefractory, advanced non-small cell lung cancer patients from the United States, Europe, and Asia and in a highly gefitinib-sensitive non-small cell lung cancer cell line and correlated their presence with response and survival. In addition, in a subgroup of 28 patients for whom the remaining tumor tissue was available, we examined the relationship among EGFR mutations, CA repeats in intron 1 of EGFR, EGFR and caveolin-1 mRNA levels, and increased EGFR gene copy numbers.


RESULTS
Seventeen patients had EGFR mutations, all of which were in lung adenocarcinomas. Radiographic response was observed in 16 of 17 (94.1%) patients harboring EGFR mutations, in contrast with 6 of 51 (12.6%) with wild-type EGFR (P < 0.0001). Probability of response increased significantly in never smokers, patients receiving a greater number of prior chemotherapy regimens, Asians, and younger patients. Median survival was not reached for patients with EGFR mutations and was 9.9 months for those with wild-type EGFR (P = 0.001). EGFR mutations tended to be associated with increased numbers of CA repeats and increased EGFR gene copy numbers but not with EGFR and caveolin-1 mRNA overexpression (P = not significant).


CONCLUSIONS
The presence of EGFR mutations is a major determinant of gefitinib response, and targeting EGFR should be considered in preference to chemotherapy as first-line treatment in lung adenocarcinomas that have demonstrable EGFR mutations.
Taron
Miguel
M
Catalan Institute of Oncology, Pathology Department, Hospital Germans Trias i Pujol, Badalona, Spain.
Ichinose
Yukito
Y
Rosell
Rafael
R
Mok
Tony
T
Massuti
Bartomeu
B
Zamora
Lurdes
L
Mate
Jose Luis
JL
Manegold
Christian
C
Ono
Mayumi
M
Queralt
Cristina
C
Jahan
Thierry
T
Sanchez
Jose Javier
JJ
Sanchez-Ronco
Maria
M
Hsue
Victor
V
Jablons
David
D
Sanchez
Jose Miguel
JM
Moran
Teresa
T
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D018900:Dinucleotide Repeats / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011799:Quinazolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
D000970:Antineoplastic Agents; D011799:Quinazolines; D012333:RNA, Messenger; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib