Impact of TP53, KEAP1 and STK11 mutations in localized-stage NSCLC: A European thoracic oncology platform lungscape...

TP53, STK11 and KEAP1 mutations are frequent in localized-stage non-small cell lung cancer (NSCLC). However, their prognostic and predictive role has not been fully investigated, particularly in relation to adjuvant treatment.

Tumor samples from a training cohort of 350 surgically resected ETOP Lungscape NSCLC patients and a validation cohort of 161 additional patients were genotyped using Next Generation Sequencing (NGS). TP53 mutations were classified as "disruptive" (d) or "non-disruptive" (nd) according to their predicted impact. Disruptive mutations are those leading to complete loss of function of the p53 protein.

Among the 350 patients of the training cohort, 11 % harbored mutations in KEAP1 and 14 % in STK11. Regarding TP53 status, 31 % were wild type, 35 % carried TP53-d and 34 % TP53-nd mutations. For the 161 patients receiving adjuvant chemotherapy, TP53-d mutations associated with better time to relapse (TTR). Significantly shorter TTR and overall survival (OS) were observed in KEAP1 mutant patients while STK11 mutations correlated with better outcomes. Among the 186 patients not receiving chemotherapy, significantly worse OS was observed in KEAP1 mutant patients, while TP53 or STK11 status did not affect outcome. In a baseline-matched sub-cohort (n = 206), selected within the training cohort, the interaction between TP53 mutations and chemotherapy was statistically significant for all endpoints. The findings for KEAP1 but not for TP53 were validated in a second cohort of 161 patients.

TP53-d and STK11 mutations might have a predictive impact in localized-stage NSCLC, but further investigation is needed. KEAP1 mutations associate with worse outcomes, especially in patients receiving adjuvant chemotherapy.