MUTATED K-RAS GENE ANALYSIS IN A RANDOMIZED TRIAL OF PREOPERATIVE CHEMOTHERAPY PLUS SURGERY VERSUS SURGERY IN STAGE IIIA NONSMALL CELL LUNG-CANCER

The observation that the proteins encoded by ras genes play a central role in the signalling pathways used by cells to respond to growth fac tors and the fact that mutated ras proteins are constantly promoting c ell division have led to a PCR-based hunt for additional clinical info rmation. In the present study, K-ras analysis draws the following conc lusions: (1) K-ras point mutation frequency was higher in the surgery group (10 of 24 patients) than in the chemotherapy-surgery group (3 of 20 patients). (2) Mutated K-ras was predominantly observed at codon 1 2 but five mutations appeared at codon 61. (3) Mutations were identifi ed in the squamous cell carcinoma histological NSCLC subtype except in four cases corresponding to adenocarcinoma, (4) A multifarious patter n of substitutions, especially at codon 12, were noted with aspartic K 12 substitutions more prone to develop bone metastases. (5) Although a genotypic K-ras classification of NSCLC may not yet be formulated, o ur accumulated data (unpublished) suggest a trend toward it. (6) Patie nts with mutated K-ras tumors in the surgery group had no different su rvival than those with normal K-ras. However our pooled data as well a s other authors' results assert that mutated K-ras constitute an addit ional prognostic datum that deserves to be included together with TNM classification. In the design of new preoperative (neoadjuvant) chemot herapy trials, stratification of tumors by K-ras status deserves to be further investigated in order to correlate with response, relapse and survival. Mutated K-ras genotype merits further research. Finally, th e paradigm of uneven histological distribution and mutated K-ras spect ra among researchers should serve as a stimulus to search for further contributions in this field.