Germline TP53 Polymorphism and Its Interaction With Somatic TP53 Mutations Shapes Response to Immune Checkpoint...

Germline TP53 p.R72P polymorphism has been associated with lung cancer susceptibility, somatic TP53 mutation acquisition, and differential apoptotic signaling. Its influence on pathologic response to neoadjuvant immune checkpoint inhibition (ICI) has not been previously evaluated. This study investigates the impact of germline TP53 p.R72P genotype on response to neoadjuvant ICI therapy in nonsmall cell lung cancer (NSCLC). NSCLC patients treated with neoadjuvant anti-PD-1 therapy followed by resection were stratified by germline p.R72P status and the presence of concomitant somatic TP53 mutations. Histopathologic review assessed immunotherapy-associated histopathologic features of tumor regression, and the findings were correlated with PD-L1 tumor proportion scores (TPS) and next-generation sequencing data. The subgroup harboring both germline p.R72P and somatic TP53 mutations achieved a complete pathologic response (cPR) rate of 75% (3 of 4 cases), numerically higher than that observed in p.R72P-positive/TP53-wild-type tumors (25%, 2 of 8 cases), p.R72P-negative/TP53-mutant tumors (50%, 4 of 8 cases), and p.R72P-negative/TP53-wild-type controls (0%, 0 of 6 cases) (p < 0.05). In this single-center, exploratory cohort, germline TP53 p.R72P status was associated with differences in pathologic response to neoadjuvant therapy. Tumors with combined germline p.R72P polymorphism and somatic TP53 mutation might represent a genomic subgroup with a higher cPR rate.