STK11 Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non-Small-Cell Lung Cancer

Area of Science:

• Oncology
• Genomics
• Thoracic Surgery

Background:

• Molecular predictors of relapse in early-stage non-small-cell lung cancer (ES-NSCLC), particularly in inoperable patients undergoing radiotherapy (RT), remain poorly understood.
• Comparing genomic profiles between operable and inoperable ES-NSCLC patients can reveal critical differences in disease biology and treatment response.

Purpose of the Study:

• To compare the genomic profiles of inoperable (RT-treated) and operable (surgically treated) early-stage non-small-cell lung cancer (ES-NSCLC).
• To identify molecular factors, specifically gene alterations, that predict oncologic outcomes in ES-NSCLC patients treated with radiotherapy.

Main Methods:

• Retrospective analysis of tumor genomic profiling data from 53 patients with non-squamous ES-NSCLC (Stage I-II) treated with either surgery or RT.
• Inclusion of a second RT cohort (n=39) to increase statistical power for clinical analyses.
• Correlation of identified prognostic gene alterations with clinical variables, focusing on relapse incidence, disease-free survival, and overall survival (OS) in a pooled RT cohort (N=62).

Main Results:

• The radiotherapy cohort showed a significantly higher frequency of somatic STK11 mutations (43%) compared to the surgery cohort (6.7%).
• Factors associated with increased STK11 mutations included supplemental oxygen use, extensive smoking history (20+ pack-years), and Black race.
• In the pooled RT cohort, STK11 mutations were strongly linked to inferior outcomes: higher 2-year relapse incidence (62% vs. 20%) and lower 2-year OS (52% vs. 85%), independently predicting poor prognosis.

Conclusions:

• STK11 inactivation in ES-NSCLC is associated with poor oncologic outcomes following radiotherapy and may be linked to clinical hypoxia, potentially explaining inoperability.
• Further validation in larger cohorts is warranted to confirm these findings.
• Investigation into effective adjuvant systemic therapies for patients with STK11 mutations is recommended.