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

Despite the knowledge of strong prognostic factors such as stage and p erformance status, the outcome of individual patients with non-small c ell lung cancer is not yet predictable, although it has been observed that patients whose tumors contain K-ras gene mutations at codon 12 ha ve a shortened survival. We compared response rate, toxicity and survi val 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 h elp 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 p atients were assessable for response. We obtained 24 objective respons es out of 88 patients (27%) in the intravenous etoposide plus carbopla tin arm and 14 out of 79 patients (18%) in the oral etoposide plus car boplatin arm. Neither the objective response rate nor the survival tim e showed a significant difference between the two groups. Toxicity con sisted mainly of myelosuppression. We detected 20 ras gene mutations i n the 71 (28%) tumors analyzed. None of the 7 patients with aspartic a nd serine ras mutations had objective response as compared with 2 of 1 3 patients (15%) whose tumors contained cysteine, valine and arginine mutations and 16 of the 51 patients (31%) who had no ras mutations. Pa tients whose tumors had aspartic and serine mutations had a median sur vival 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 i mportant prognostic variable in patients with advanced non-small cell lung cancer.