Mammalian SWI/SNF Complex Genomic Alterations and Immune Checkpoint Blockade in Solid Tumors

Abstract

Prior data have variably implicated the inactivation of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex with increased tumor sensitivity to immune checkpoint inhibitors (ICI). Herein, we examined the association between mSWI/SNF variants and clinical outcomes to ICIs. We correlated somatic loss-of-function (LOF) variants in a predefined set of mSWI/SNF genes (ARID1A, ARID1B, SMARCA4, SMARCB1, PBRM1, and ARID2) with clinical outcomes in patients with cancer treated with systemic ICIs. We identified 676 patients from Dana-Farber Cancer Institute (DFCI, Boston, MA) and 848 patients from a publicly available database from Memorial Sloan Kettering Cancer Center (MSKCC, New York, NY) who met the inclusion criteria. Multivariable analyses were conducted and adjusted for available baseline factors and tumor mutational burden. Median follow-up was 19.6 (17.6-22.0) months and 28.0 (25.0-29.0) months for the DFCI and MSKCC cohorts, respectively. Seven solid tumor subtypes were examined. In the DFCI cohort, LOF variants of mSWI/SNF did not predict improved overall survival (OS), time-to-treatment failure (TTF), or disease control rate. Only patients with renal cell carcinoma with mSWI/SNF LOF showed significantly improved OS and TTF with adjusted HRs (95% confidence interval) of 0.33 (0.16-0.7) and 0.49 (0.27-0.88), respectively, and this was mostly driven by PRBM1 In the MSKCC cohort, where only OS was captured, LOF mSWI/SNF did not correlate with improved outcomes across any tumor subtype. We did not find a consistent association between mSWI/SNF LOF variants and improved clinical outcomes to ICIs, suggesting that mSWI/SNF variants should not be considered as biomarkers of response to ICIs.

Figure 1.. Spectrum of genomic alterations in the mSWI/SNF complex across tumor histologies.

A. Frequency and variant types detected across the 6 mSWI/SNF complex genes in the DFCI (N=676) and MSKCC (N=848) cohorts. Number of patients per each gene is indicated. B. Frequency of detected mSWI/SNF subcomplex mutations across tumor histologies in the DFCI cohort. Number of patients for each tumor type indicated. C. Frequency of detected mSWI/SNF subcomplex mutations across tumor histologies in the MSKCC cohort. Number of patients for each tumor type indicated. GAs: genomic alterations.

Figure 2.. Analysis of survival outcomes in patients with loss of function (LOF) mSWI/SNF and wild-type (WT) across different tumor histologies.

A. Adjusted hazard ratios (HR) for time to treatment failure in the DFCI cohort (N=676). B. Adjusted HRs for overall survival in the DFCI cohort. C. Adjusted HRs for overall survival in the MSKCC cohort (N=848). Chi-square Wald statistic. CI: confidence interval. Cohort adjustments indicated. Error bars represent SD.

Figure 3:. Clinical outcomes in the renal cell carcinoma (RCC) cohort.

A. Time to treatment failure (TTF) in patients with loss of function (LOF) mSWI/SNF complex and WT genes in the DFCI cohort. B. Overall survival (OS) in in patients with LOF mSWI/SNF complex and WT genes in the DFCI cohort. C. TTF in patients with LOF and WT PBRM1 in the DFCI cohort. D. OS in in patients with LOF and WT PBRM1 in the DFCI cohort. E. OS in patients with LOF mSWI/SNF complex and WT genes in the MSKCC cohort. F. OS in patients with LOF and WT PBRM1 in the MSKCC cohort. G. OS and overall response rate (ORR) across tumor mutational burden (TMB) tertiles in PBRM1 LOF vs. WT genes in the DFCI cohort. Md.: median; NR: not reached; mos: months. (A-F) Number of patients indicated below each graph. OS and TTF estimated with the Kaplan-Meier method along with 95% CI. Chi-square Wald statistic. P-value threshold for significance was 0.05.