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.

• Authors: Sarah Abou Alaiwi, Amin H Nassar, Wanling Xie, Ziad Bakouny, Jacob E Berchuck, David A Braun, Sylvan C Baca, Pier Vitale Nuzzo, Ronan Flippot, Tarek H Mouhieddine, Liam F Spurr, Yvonne Y Li, Taiwen Li, Abdallah Flaifel, John A Steinharter, Claire A Margolis, Natalie I Vokes, Heng Du, Sachet A Shukla, Andrew D Cherniack, Guru Sonpavde, Robert I Haddad, Mark M Awad, Marios Giannakis, F Stephen Hodi, X Shirley Liu, Sabina Signoretti, Cigall Kadoch, Matthew L Freedman, David J Kwiatkowski, Eliezer M Van Allen, Toni K Choueiri
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 8 Issue 8 Pg. 1075-1084 (08 2020) ISSN: 2326-6074 [Electronic] United States
• PMID: 32321774 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• ARID1A protein, human
• ARID1B protein, human
• ARID2 protein, human
• Biomarkers, Tumor
• DNA-Binding Proteins
• Immune Checkpoint Inhibitors
• Nuclear Proteins
• PBRM1 protein, human
• SMARCB1 Protein
• SMARCB1 protein, human
• Transcription Factors
• SMARCA4 protein, human
• DNA Helicases

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics, immunology)
• Cohort Studies
• DNA Helicases (genetics)
• DNA-Binding Proteins (genetics)
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Middle Aged
• Mutation
• Neoplasms (genetics, immunology, therapy)
• Nuclear Proteins (genetics)
• SMARCB1 Protein (genetics)
• Survival Rate
• Transcription Factors (genetics)
• Young Adult