SMARCA4/SMARCB1 alterations detected through tissue comprehensive genomic profiling (CGP): A single-center study of prevalence and clinical characteristics

SMARCA4 (also known as BRG1) and SMARCB1 are proteins with transcription-regulation through helicase and ATPase activity in the SWI/SNF chromatin-remodelling complex. Alterations in these genes have been described as prognostic and related to tumor differentiation and metastasis. Inactivation has a role in the development, early dedifferentiation and metastasis of up to 20% solid tumors. We performed an observational retrospective study at Hospital Clinico Universitario San Carlos (Madrid) in 703 advanced solid tumor patients undergoing NGS testing of their disease between July 2019 and December 2021. We analyzed clinical data of SMARCA4/B1 altered tumors as well as their response to systemic treatment, tumor mutational burden (TMB) and accompanying genetic alterations. We identified 51 patients with SMARCA4 (n=41) and SMARCB1 (n=10) alterations respectively. The most common tumor was NSCLC (n=18, 35.3%), followed by ovarian cancer (n=6, 11.8%), sarcoma (n=6, 11.8%) or endometrial cancer (n=5, 9.8%). The median age was 65 years (range 31-89), there was a similar proportion of men (n=23, 45.1%) and women (n=28, 54.9%) and there was a dominance of tobacco exposure (n=31, 60.8%). Median TMB was 7.57 mut/Mb (range 0-189.1), but for NSCLC was 12.61 mut/Mb (range 1.26-60.52). SMARCA4 alterations consisted of point mutations in 34 cases, followed by 4 amplifications, 2 rearrangements and single cases of a frameshift mutation, truncation and a splicing event. Point mutations in SMARCB1 were the most frequent event (n=6). The most frequently co-altered genes were globally TP53 (n=29, 56.9%), followed by CDKN2A/2B alterations (n=21, 41.1%) and ATM mutations (n=12, 23.5%). Immune checkpoint blockade was administered in 21 patients and 9 of them got long-term responses. In our cohort, patients with alterations in SMARCA4/SMARCB1 genes presented a trend to high TMB and prolonged responses to immunotherapy, especially in the subgroup of NSCLC. The information from CGP reports can enrich the clinical profiling of patients.