PROGNOSTIC VALUE OF K-RAS 12 GENOTYPES IN PATIENTS WITH ADVANCED NONSMALL CELL LUNG-CANCER RECEIVING CARBOPLATIN WITH EITHER INTRAVENOUS OR CHRONIC ORAL DOSE ETOPOSIDE

Despite the knowledge of strong prognostic factors such as stage and performance status, the outcome of individual patients with non-small cell lung cancer is not yet predictable, although it has been observed that patients whose tumors contain K-ras gene mutations at codon 12 have a shortened survival. We compared response rate, toxicity and survival of patients with non-small cell lung cancer receiving carboplatin 325 mg/m2 on day 1 with either intravenous etoposide (100 mg/m2 days 1-3) or oral etoposide (50 mg/m2/day) for 21 consecutive days. Secondly, we sought to find whether K-ras mutations or their genotypes could help to distinguish tumor types with clinical implications on prognosis. 180 patients were entered in this randomized study. Tumor specimens obtained at the time of bronchoscopy were available in 71 cases. 167 patients were assessable for response. We obtained 24 objective responses out of 88 patients (27%) in the intravenous etoposide plus carboplatin arm and 14 out of 79 patients (18%) in the oral etoposide plus carboplatin arm. Neither the objective response rate nor the survival time showed a significant difference between the two groups. Toxicity consisted mainly of myelosuppression. We detected 20 ras gene mutations in the 71 (28%) tumors analyzed. None of the 7 patients with aspartic and serine ras mutations had objective response as compared with 2 of 13 patients (15%) whose tumors contained cysteine, valine and arginine mutations and 16 of the 51 patients (31%) who had no ras mutations. Patients whose tumors had aspartic and serine mutations had a median survival time of 18 weeks in contrast with 36 weeks for the remainder (P=0.04). This study highlights the fact that K-ras genotypes may be an important prognostic variable in patients with advanced non-small cell lung cancer.