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The following is a summary of “Clinicopathologic and genomic analyses of SMARCA4-mutated non-small cell lung carcinoma implicate the needs for tailored treatment strategies,” published in the March 2025 issue of the Lung Cancer by Ahn et al.

This study investigates the clinicopathologic and therapeutic significance of SMARCA4 mutations in non-small cell lung carcinoma (NSCLC), focusing on truncated and non-truncated SMARCA4 mutations. A total of 575 NSCLC cases were analyzed, identifying 50 patients (2.3%) with SMARCA4-truncated mutations and 63 (2.9%) with non-truncated SMARCA4 mutations. The SMARCA4-truncated group was characterized by a lower prevalence of targetable driver alterations, a higher tumor mutation burden (TMB), and a higher frequency of programmed death-ligand 1 (PD-L1) expression. These tumors predominantly exhibited poorly differentiated adenocarcinoma histology and were associated with male gender and a history of smoking. Immunohistochemical analysis revealed that 56% of patients in the SMARCA4-truncated group exhibited significant immunoreactivity to tumor-associated antigens such as MAGEA4, CT45A, and PRAME, suggesting potential targets for immunotherapy.

Both SMARCA4-truncated and SMARCA4-non-truncated subgroups demonstrated significantly worse OS and progression-free survival (PFS) when treated with pemetrexed-platinum chemotherapy compared to patients with wild-type SMARCA4. However, the prognostic implications varied, as the non-truncated SMARCA4 subgroup displayed intermediate characteristics between the truncated and wild-type groups. A higher carcinoma antigen (CAK) radiation dose, extended fluoroscopy time, increased dose-area product (DAP), and elevated ED were significantly associated with higher SMARCA4-truncated NSCLC cases.

These findings highlight that siRNA-induced HBsAg reduction contributes to the persistence and efficacy of the humoral immune response, particularly in patients receiving therapeutic vaccines. Importantly, despite the poor prognosis associated with pemetrexed-platinum chemotherapy in both SMARCA4-mutated subgroups, a substantial proportion of patients (approximately 40%) maintained anti-HBs antibody levels ≥100 IU/L for at least 72 weeks. These results underscore the potential role of therapeutic vaccines in modulating HBV-specific immune responses when combined with siRNA therapy, highlighting the need for further investigation into optimal treatment strategies for patients with NSCLC harboring SMARCA4 mutations. Future studies should focus on validating the proposed prognostic model through robust clinical trials and evaluating the efficacy of emerging immunotherapies in this subset of patients with NSCLC.

Source: lungcancerjournal.info/article/S0169-5002(25)00066-2/abstract