Prognostic Impact of KRAS-TP53 Co-Mutations in Patients with Early-Stage Non-Small Cell Lung Cancer: A Single-Center Retrospective Study

<b>Background/Objectives</b>: The clinical value of <i>KRAS</i> mutations in lung adenocarcinoma, alone or in combination with other mutations, has been assessed especially in advanced stages. This study evaluates how <i>KRAS</i> and the presence of co-mutations could affect survival in early-stage lung. <b>Methods</b>: We analyzed a real-world cohort including all staged NSCLC patients diagnosed and treated from 2018 to 2022 at our Institute with availability of NGS molecular data. Statistical analyses were made using log-rank test, the two-tailed Fisher's exact test and Kaplan-Meier survival curves. <b>Results</b>: <i>KRAS</i> mutations were observed in 179/464 cases (38.6%). The majority of <i>KRAS</i> co-mutations were in <i>TP53</i> (74%) and <i>STK11</i> (14.3%) genes. <i>KRAS</i>+<i>TP53</i> co-mutations were more frequent compared to <i>KRAS</i>-only tumors in stage IV NSCLC (<i>p</i> = 0.01). In early stage and locally advanced cases (stage I-III), better prognosis was associated to <i>KRAS</i>-only mutated NSCLC and to <i>KRAS</i>+<i>STK11</i> mutated cases compared to <i>KRAS</i>+<i>TP53</i> (<i>p</i> = 0.008). In particular, patients carrying <i>KRAS</i>+<i>TP53</i> in stage I and II displayed a shorter survival, similar to patients diagnosed at stage III. <b>Conclusions</b>: Routine NGS provides important information for potential actionable mutations but also for the prognostic and predictive role of the presence of co-occurring mutations. In particular, the presence of <i>KRAS</i>+<i>TP53</i> in stage I and II NSCLC may be considered an unfavorable prognostic marker possibly leading to adapt the perioperative chemo-immunotherapy.