Prognostic impact of TP53 co-mutation and interleukin gene expression in EGFR-mutant advanced lung cancer.

Abstract

e20674 Background: EGFR-mutant non–small cell lung cancer (NSCLC) demonstrates marked biological heterogeneity despite targeted therapy. Co-occurring TP53 mutations are among the most frequent concurrent genomic alterations and are associated with aggressive tumor biology, early resistance, and inferior progression-free survival (PFS). Inflammatory signaling mediated by interleukins may further influence tumor behavior and therapeutic outcomes. However, the combined prognostic impact of TP53 co-mutation and interleukin expression in EGFR-mutant advanced lung cancer remains insufficiently defined. Methods: This prospective study enrolled 100 treatment-naïve stage IV NSCLC patients and 10 healthy controls. Among these, 38 patients had EGFR-mutant disease and received standard-of-care third-generation EGFR tyrosine kinase inhibitors. Peripheral blood RNA was extracted and reverse-transcribed to cDNA. Expression of IL1β, IL6, IL8, and IL10 was quantified using SYBR Green–based real-time PCR, with GAPDH as the housekeeping gene. Relative expression was calculated using the 2⁻ΔΔCt method. Interleukin levels were categorized as underexpressed or overexpressed based on predefined cut-offs. TP53 mutation status was determined by molecular profiling. PFS was analyzed using the Kaplan–Meier method and compared across molecular and inflammatory subgroups. Results: Among 38 EGFR-mutant patients, 14 harbored concurrent TP53 mutations, while 24 had EGFR mutation alone. The median age was 57 years, with 26 males and 12 females. Patients with EGFR + TP53 co-mutation had significantly shorter median PFS compared to EGFR-only patients (6 vs 13 months; p = 0.002). Within the co-mutated subgroup, overexpression of IL6 and IL8 was associated with the poorest outcomes (IL6: 4 vs 8 months, p = 0.01; IL8: 5 vs 9 months, p = 0.03). EGFR-only patients with underexpressed interleukins demonstrated the most favorable PFS. Conclusions: TP53 co-mutation significantly compromises PFS in EGFR-mutant advanced lung cancer treated with third-generation EGFR TKIs. This adverse prognostic effect is further accentuated by overexpression of pro-inflammatory interleukins, particularly IL6 and IL8. Integrated molecular and inflammatory profiling may enhance risk stratification and identify patients at high risk for early treatment failure.