Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications.
OBJECTIVE
The tyrosine-kinase receptor c-kit and its ligand stem cell factor are coexpressed in many small cell lung cancer (SCLC) cell lines, leading to the hypothesis that this coexpression constitutes an autocrine growth loop. To further evaluate the frequency and pathogenic relevance of c-kit expression, tumor tissue together with the corresponding clinical data of SCLC patients was analyzed.


METHODS
Tumor tissue of 102 consecutive SCLC cancer patients was analyzed immunohistochemically using an affinity-purified polyclonal c-kit antibody. Immunostaining data were correlated with survival and other relevant clinical parameters.


RESULTS
A positive c-kit expression was observed in 37% of patients. c-kit expression was associated with decreased survival in the likelihood-ratio-forward selection model of the Cox regression including clinically relevant risk factors (c-kit expression, age, gender, stage, tumor stage, node stage, metastasis stage, weight loss, performance status, response to chemotherapy, lactate dehydrogenase, neuronspecific enolase, hemoglobin). Only c-kit expression [hazard ratio, 2.00; confidence interval (CI), 1.17-3.41; P = 0.012], response to chemotherapy (hazard ratio, 4.49; CI, 2.36-8.55; P < 0.001), and tumor stage (hazard ratio, 2.11; CI, 1.18-3.74; P = 0.008) were explanatory prognostic factors. These factors and all possible interactions between them were further analyzed in a second Cox regression model. As expected, response to chemotherapy had the highest impact on survival (hazard ratio, 3.06; CI, 1.69-5.54; P < 0.001). In patients with extensive disease, minor response to chemotherapy, and positive c-kit expression, the risk to die increased to 8.4 (hazard ratio, 2.74; CI, 1.52-4.91; P = 0.002). In a Kaplan-Meier analysis median survival of patients with minor response to chemotherapy and extensive stage was 288 days (CI, 255-321 days) when c-kit expression was negative compared with only 71 days (CI, 0-237 days) for c-kit-positive patients (log rank test: P = 0.003).


CONCLUSIONS
c-kit represents a new prognostic factor in SCLC. c-kit expression is of particular clinical relevance in patients with advanced disease and poor response to chemotherapy. Given the very limited therapeutic options and unfavorable prognosis of these patients, clinical studies aimed at targeting c-kit (e.g., STI571) are clearly warranted.
Micke
Patrick
P
III Medical Department, Pulmonary Division, University Hospital, D-55101 Mainz, Germany. p.micke@3-med.klinik.uni-mainz.de
Basrai
Maryam
M
Faldum
Andreas
A
Bittinger
Fernando
F
Rönnstrand
Lars
L
Blaukat
Andree
A
Beeh
Kai Michael
KM
Oesch
Franz
F
Fischer
Berthold
B
Buhl
Roland
R
Hengstler
Jan Georg
JG
D000368:Aged; D018288:Carcinoma, Small Cell / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis*; D013997:Time Factors
D019009:Proto-Oncogene Proteins c-kit