Translational lung cancer research · 2026
Impact of different TP53 mutation subtypes on response and outcome in advanced lung adenocarcinoma receiving first-line immunotherapy or chemo-immunotherapy.
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Quan Xiru, Xuzhang Wendi, Shen Shengping, Yang Ying, Yu Yongfeng, Lu Shun
Аннотация
BACKGROUND: Immunotherapy, either as a monotherapy or in combination with chemotherapy, has become the standard first-line treatment for advanced lung adenocarcinoma (LUAD) without driver mutations. Although TP53 is frequently mutated in LUAD, the clinical significance of different TP53 mutation subtypes in the setting of first-line immunotherapy remains poorly defined. This study aimed to evaluate the association between TP53 mutation subtypes and treatment outcomes in patients with locally advanced or metastatic LUAD receiving first-line immunotherapy or chemo-immunotherapy.
METHODS: A total of 129 locally advanced or metastatic LUAD patients with TP53 mutations receiving first-line immunotherapy or chemo-immunotherapy between January 2018 and November 2022 at Shanghai Chest Hospital were retrospectively analyzed. TP53 mutation status was confirmed by next-generation sequencing (NGS). Kaplan-Meier analysis and Cox proportional hazards model were employed to analyze the effect of TP53 mutation subtypes on treatment outcomes.
RESULTS: TP53 mutations were categorized into four groups: missense, nonsense, frameshift, and others. Missense mutations were the most frequent subtype (78/129, 60.5%), followed by frameshift (23/129, 17.8%), nonsense (18/129, 14.0%), and others (10/129, 7.8%). Patients with TP53 frameshift mutations exhibited worse progression-free survival (PFS) (median PFS, 6.0 vs. 13.5 months; P=0.002) and overall survival (OS) (median OS, 13.3 vs. 39.9 months; P<0.001) than those with non-frameshift mutations. A significantly higher proportion of patients in the frameshift group experienced progressive disease (PD) as their best overall response than in the non-frameshift group (30.4% vs. 7.6%, P=0.006). In multivariate analysis, TP53 frameshift mutations remained independently associated with inferior PFS [hazard ratio (HR) =2.229, 95% confidence interval (CI): 1.337-3.715, P=0.002] and OS (HR =3.278, 95% CI: 1.730-6.210, P<0.001).
CONCLUSIONS: In this retrospective cohort, TP53 frameshift mutations were associated with poorer survival in patients with advanced LUAD receiving first-line immunotherapy or chemo-immunotherapy, suggesting distinct prognostic implications across TP53 mutation subtypes.
METHODS: A total of 129 locally advanced or metastatic LUAD patients with TP53 mutations receiving first-line immunotherapy or chemo-immunotherapy between January 2018 and November 2022 at Shanghai Chest Hospital were retrospectively analyzed. TP53 mutation status was confirmed by next-generation sequencing (NGS). Kaplan-Meier analysis and Cox proportional hazards model were employed to analyze the effect of TP53 mutation subtypes on treatment outcomes.
RESULTS: TP53 mutations were categorized into four groups: missense, nonsense, frameshift, and others. Missense mutations were the most frequent subtype (78/129, 60.5%), followed by frameshift (23/129, 17.8%), nonsense (18/129, 14.0%), and others (10/129, 7.8%). Patients with TP53 frameshift mutations exhibited worse progression-free survival (PFS) (median PFS, 6.0 vs. 13.5 months; P=0.002) and overall survival (OS) (median OS, 13.3 vs. 39.9 months; P<0.001) than those with non-frameshift mutations. A significantly higher proportion of patients in the frameshift group experienced progressive disease (PD) as their best overall response than in the non-frameshift group (30.4% vs. 7.6%, P=0.006). In multivariate analysis, TP53 frameshift mutations remained independently associated with inferior PFS [hazard ratio (HR) =2.229, 95% confidence interval (CI): 1.337-3.715, P=0.002] and OS (HR =3.278, 95% CI: 1.730-6.210, P<0.001).
CONCLUSIONS: In this retrospective cohort, TP53 frameshift mutations were associated with poorer survival in patients with advanced LUAD receiving first-line immunotherapy or chemo-immunotherapy, suggesting distinct prognostic implications across TP53 mutation subtypes.