3511 - Characterization of KEAP1 and SMARCA4 Mutations in Primary Non-Small Cell Lung Cancer and Bone Metastases

Title: KEAP1 and SMARCA4 Mutations Are Independently Associated with Bone Metastases in Primary Non-Small Cell Lung Cancer

Purpose/Objective(s): Kelch-like ECH-associated protein 1 (KEAP1) is a key negative regulator of the NRF2 oxidative stress response pathway, and loss-of-function mutations promote tumor cell survival and therapeutic resistance. In non–small cell lung cancer (NSCLC), KEAP1 mutations occur in approximately 10–20% of cases and have been associated with poor prognosis. Co-mutations with SMARCA4 and STK11 are common and are thought to induce an immune-cold microenvironment leading to reduced efficacy of checkpoint inhibitors. However, the relationship between these mutations and organ-specific metastatic patterns, particularly bone metastases, remains unclear. We hypothesize that these genetic mutations may be associated with osseous metastases in primary non-small cell lung cancer. Identifying genomic predictors of osseous dissemination may help inform risk-adapted surveillance strategies.

Materials/Methods: We performed a retrospective analysis of 2,186 patients with initially stage I-III NSCLC who underwent comprehensive genomic profiling within the MSK-CHORD cohort. The primary outcome was the development of bone metastases. Clinicopathologic variables included age, sex, race, smoking status, histology, and mutation status of KEAP1, SMARCA4, and STK11. Multivariable logistic regression was conducted to evaluate independent associations between these genomic alterations and bone metastases.

Results: Among 2,186 patients, 452 (20.7%) developed bone metastases. KEAP1 mutations were present in 228 patients (10.4%) and were more frequent among patients with bone metastases compared with those without (14.8% vs 9.3%, p=0.001). On multivariable analysis adjusting for age, sex, race, smoking status, histology, and other co-mutation variables, KEAP1 mutation (OR 1.48, 95% CI 1.03–2.12, p=0.033) and SMARCA4 mutation (OR 1.58, 95% CI 1.03–2.38, p=0.031) were independently associated with increased odds of bone metastases. KEAP1 mutations co-occurred with SMARCA4 alterations in 29.6% of KEAP1-mutant tumors. Male sex (OR 1.57, p<0.001) and never-smoking status (OR 1.52, p=0.002) were also associated with bone metastases, whereas STK11 mutation was not significantly associated (OR 1.25, 95% CI 0.88-1.77, p=0.208).

Conclusion: In this large institutional cohort of patients with initially nonmetastatic NSCLC, KEAP1 and SMARCA4 primary tumor mutations were independently associated with subsequent development of bone metastases. These findings suggest that molecular profiling for KEAP1- and SMARCA4-driven tumors at diagnosis may help identify patients at elevated risk for osseous dissemination and inform consideration of more intensive surveillance strategies during follow-up.