Characterization of c-kit Expression in Small Cell Lung Cancer: Prognostic and Therapeutic Implications

• Published in: Clinical cancer research Vol. 9; no. 1; pp. 188 - 194
• Main Authors: MICKE, Patrick, BASRAI, Maryam, HENGSTLER, Jan Georg, FALDUM, Andreas, BITTINGER, Fernando, RÖNNSTRAND, Lars, BLAUKAT, Andree, BEEH, Kai Michael, OESCH, Franz, FISCHER, Berthold, BUHL, Roland
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-01-2003
• Subjects: Aged; Biological and medical sciences; Cancer and Oncology; Cancer och onkologi; Carcinoma, Small Cell - diagnosis; Carcinoma, Small Cell - metabolism; Carcinoma, Small Cell - pathology; Clinical Medicine; Female; Humans; Immunohistochemistry; Klinisk medicin; Lung Neoplasms - diagnosis; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms/diagnosis/metabolism/pathology; Male; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Pneumology; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins c-kit - biosynthesis; Time Factors; Tumors of the respiratory system and mediastinum; Human; Lung disease; Prognosis; Respiratory disease; Enzyme; Transferases; Treatment efficiency; Biological marker; Malignant tumor; Gene expression; Bronchopulmonary; Growth factor receptor; C-Onc gene; Bronchus disease; Predictive factor; Small cell carcinoma; Protein-tyrosine kinase; Small Cell/diagnosis/metabolism/pathology; Carcinoma
• ISSN: 1078-0432; 1557-3265; 1557-3265

Purpose: 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.
Experimental Design: 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.