Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications.
ABSTRACT 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.
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.
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).
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.
Article: A phase I-II and pharmacokinetic study of imatinib mesylate in combination with irinotecan in patients with relapsed or refractory small-cell lung cancer[show abstract] [hide abstract]
ABSTRACT: Background: The purpose of this study was to determine the maximum tolerated doses (MTDs); the dose limiting toxicities (DLTs); the possible pharmacokinetic (PK) interactions; and to evaluate the clinical activity of the imatinib plus irinotecan combination in pre-treated patients with extensive stage SCLC. Patients & Methods: Patients with refractory/relapsed SCLC were eligible. During the phase I part of the study, escalated doses of imatinib were administered daily in combination with irinotecan every 14 days. DLT and pharmacokinetic parameters of both drugs were determined during the first treatment cycle. During the phase II part of the study, the determined MTDs of the drugs were used to treat eligible patients. Results: During the phase I part of the study (n=11 patients), the MTDs for imatinib and irinotecan were defined at 400mg/day and 150mg/m2 every 2 weeks, respectively. Grade 4 neutropenia and treatment delay due to grade 3 neutropenia were the DLTs. PK analysis for imatinib, irinotecan and their major metabolites revealed no statistically significant drug interactions. Among the 28 patients treated in the context of the phase II study, one complete and two partial responses (overall response rate=8.8%; 95% CI; 0-18.4%) were observed. c-kit expression on tumour cells, which was detected by immunohistochemistry in 17 (71%) of the 24 patients with available tissue material, was not correlated with response to treatment. The median overall survival was 4.8 months (range, 0.8-14.4 months) and the median time to tumour progression 2.2 months (range, 0.5-10.6 months). Grade 3-4 neutropenia and grade 2- 3 diarrhoea occurred in 10 (29.4%) patients each. There were no episodes of febrile neutropenia or treatment-related deaths. Conclusions: The MTDs of the imatinib plus irinotecan combination were 400mg once daily and 150mg/m2 every 2 weeks, respectively. The regimen has modest antitumour activity even in patients whose tumours expressing the c-kit receptor. A better understanding of the biology of the c-kit expression in SCLC and the resistance mechanisms of imatinib is warranted.Forum of Clinical Oncology. 06/2012; 3(2):18-27.