1067 - Association of SMARCA4 Primary Tumor Mutations with Brain Metastases in Initially Non-Metastatic Non-Small Cell Lung Cancer

05:10pm - 05:15pm ET

Room 153

Presenter(s)

Maneeth Ellendula, BS - Yale School of Medicine, New Haven, CT

M. Ellendula¹, V. Lee², P. Oh², T. J. Robinson², T. J. Hayman², and H. S. M. Park^2,3; ¹Yale School of Medicine, New Haven, CT, ²Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, ³Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale School of Medicine, New Haven, CT

Purpose/Objective(s):

Brain metastases are a major cause of morbidity in patients with non-small cell lung cancer (NSCLC). While clinical risk factors for intracranial relapse are recognized, molecular predictors remain incompletely defined and may inform risk-adapted surveillance and potentially earlier intervention. SMARCA4, a core subunit of the SWI/SNF chromatin remodeling complex, has been associated with aggressive tumor biology, inferior outcomes in NSCLC, and worse survival among patients with melanoma brain metastases. We hypothesized that primary tumor SMARCA4 alterations are associated with an increased risk of brain metastases in NSCLC.

Materials/Methods:

We retrospectively analyzed patients with initially stage I–III NSCLC from a large institutional clinicogenomic database. The primary outcome assessed was the development of brain metastases. Baseline demographic, clinical, and molecular characteristics were compared between groups. Multivariable logistic regression was performed to identify genomic alterations associated with brain metastasis risk using age, gender, and race as covariates. Statistical analyses were performed in Python 3.7 and R 4.4.2.

Results:

Among 2,186 patients, 288 (13.2%) developed brain metastases. Median age at diagnosis was 73.0 years (Q1–Q3: 67.0–79.0) in the overall cohort and 71.0 years (Q1–Q3: 64.8–77.0) among those who developed brain metastases (p < 0.001). The cohort was 60.7% female, 82.5% White, and 72.8% former or current smokers. SMARCA4 mutations were significantly enriched in patients who developed brain metastases (11.5% vs 4.8%, p < 0.001) and frequently co-occurred with in TP53 (56.8%), KRAS (32.8%), KEAP1 (29.6%), and STK11 (28.0%). On multivariable logistic regression adjusting for age, sex, race, smoking status, histology, and common co-alterations, SMARCA4 remained independently associated with an increased risk of brain metastases (OR 2.32, 95% CI 1.47–3.58, p = 0.001). Younger age (OR 0.98 per year, p = 0.002) and TP53 mutation (OR 1.57, 95% CI 1.19–2.08, p = 0.002) were also independently associated with brain metastasis risk.

Conclusion:

SMARCA4 mutation is independently associated with the development of brain metastases in patients with initially non-metastatic NSCLC. These findings support consideration of molecularly informed CNS surveillance strategies. Earlier identification of intracranial disease in high-risk patients may allow detection of metastases before the onset of neurologic symptoms, potentially reducing morbidity and preserving quality of life. Integration of genomic biomarkers such as SMARCA4 into clinical decision-making may enable more personalized management of NSCLC.