Analysis of molecular parameters potentially associated with resistance to therapy inadvanced non-small cell lung cancer in a real-world scenario

Keywords

non-small cell lung carcinoma (NSCLC) - TP53 somatic mutations - clinical outcomes

Introduction: Molecular profiling of non-small cell lung carcinoma (NSCLC), a leading cause of global cancer-related mortality, has significantly improved long-term clinical outcomes. However, understanding resistance mechanisms remains challenging. Mutations like MET, MDM2/4, KRAS/KEAP1, STK11, and KRAS, even in patients with EGFR and ALK genetic alterations, may contribute to resistance to immunotherapy and tyrosine kinase inhibitors (TKIs).

Objective: This real-world study aims to investigate associations between resistance mutations, clinical features, and outcomes in a diverse cohort, considering population heterogeneity and socio-economic factors.

Methods: This retrospective, cross-sectional study included 39 advanced NSCLC patients from a single oncology center in Belo Horizonte, Brazil. Treatment decisions were based on molecular tumor profiles following local practice. Clinical, histopathological, molecular, and treatment data were analyzed. Cox Regression Model assessed independent associations with progression-free survival (PFS) and overall survival (OS). Significance was set at p < 0.05.

Results: The cohort included 39 advanced NSCLC patients (average age 64.1 years, 48% women, 52% men, 98% adenocarcinoma). Common metastasis sites were the CNS (38%) and bones (46%). Platinum-based treatment, often with immunotherapy (46.1%), was prevalent. Among patients with targetable mutations, 41.6% received TKIs upfront. Key findings included 56.4% PD-L1 positivity, 74.3% TMB < 10, 28.2% EGFR mutations, 7.6% ALK mutations, and 64.1% somatic TP53 mutations. PFS was 17.7 months, and OS was 21.6 months. Radiotherapy increased the risk of progression by 5.6 times (p = 0.01), while TMB ≥10 and unusual site metastases were linked to poor OS. TP53 mutation was associated with worse OS (1.8 times, p = 0.11) but was not independently predictive in multivariate analysis.

Conclusions and Discussion: TMB ≥10 was associated with worse OS. Somatic TP53 mutations were prevalent in this cohort and linked to poorer clinical outcomes. These findings suggest a potential connection between TP53 mutations and reduced responses to TKIs, but not to immunotherapy, indicating a possible role in resistance mechanisms. Further studies with larger patient groups are ongoing to clarify these associations

Corresponding author: João Pedro Costa Apolinário (e-mail: [e-mail]).

 

MissingLinkText

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
06 May 2025