medwireNews: Truncating TP53 mutations are associated with shorter survival in people with localized non-small-cell lung cancer (NSCLC) while mutations in KEAP1 are linked to poor outcomes in both localized and advanced disease, German researchers report.
“Our data suggests that molecular stratification based on TP53 and KEAP1 mutation status should be implemented for localized and advanced stage NSCLC to optimize and modify clinical decision making,” write Reinhard Buettner and colleagues, from University Hospital Cologne, in the Journal of Thoracic Oncology.
Their retrospective cohort study included 6297 people who were diagnosed with NSCLC between 1998 and 2020. Of these, 52% had TP53 mutations and 17% KEAP1 mutations. Of the TP53 mutations, 72% were missense mutations, 20% were truncating mutations, and the remainder were other types of mutations.
In 1518 surgically treated patients with localized disease (stage I–IIIA), median overall survival (OS) was significantly shorter in people with TP53 truncating mutations than in those with wild-type TP53 or other TP53 mutations, at 1181 versus 1474 and 1486 days, respectively.
At 2 years, approximately 40% of patients with TP53 truncating mutations had died, compared with approximately 25% of those in the other two groups.
Mean disease-free survival (DFS) was also significantly shorter among the people with TP53 truncating mutations relative to those with wild-type TP53 (657 vs 791 days) but not versus those with other TP53 mutations (630 days).
In the same localized disease cohort, Buettner and team found that people with KEAP1 mutations had significantly shorter median OS times than those who were wild-type for KEAP1, at 755 versus 1264 days. Mean DFS was 473 and 732 days, respectively.
After adjustment for sex, age, histology, stage, and EGFR, BRAF V600E, and ALK/ROS mutation status, the researchers found that TP53 truncating mutations were associated with a significant 1.43-fold increased risk for death, and KEAP1 mutations were associated with a significant 1.69-fold increased risk, relative to the respective wild-types.
The investigators point out that “[t]he increased relative hazard of harbouring truncating TP53 mutations or KEAP1 mutations was comparable to the increased relative hazard of [disease] stage I vs. stage II.”
Among the 4818 advanced stage (IIIB–IV) patients, TP53 truncating mutations were not significantly associated with OS. Median OS was 448 days among participants with truncating mutations compared with 506 and 436 days among those with TP53 wild-type and other mutations, respectively.
Conversely, KEAP1 mutations were associated with significantly shorter survival in the people with advanced disease, with median OS at 257 and 446 days in the mutated and wild-type cohorts, respectively, and a corresponding 1.40-fold increased risk for death in the adjusted analysis.
Further stratification of individuals with KEAP1 mutations by TP53 status showed that median OS was significantly longer when KEAP1-mutated tumors harbored co-occurring non-truncating TP53 mutations relative to TP53 wild-type or truncating mutations, at 342 versus 201 and 189 days, respectively.
“Therefore, within the KEAP1 [mutated] cohort, co-occurring missense TP53 mutations seem to level out the deleterious effects of the KEAP1 mutation,” Buettner and co-authors remark.
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