1. Mammalian SWI/SNF Complex Genomic Alterations and Immune Checkpoint Blockade in Solid Tumors
- Author
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Sylvan C. Baca, Sabina Signoretti, Abdallah Flaifel, Sachet A. Shukla, Pier Vitale Nuzzo, Matthew L. Freedman, Guru Sonpavde, Jacob E. Berchuck, Heng Du, Mark M. Awad, Amin Nassar, Natalie I. Vokes, Yvonne Y. Li, Sarah Abou Alaiwi, John A. Steinharter, Marios Giannakis, Ronan Flippot, Toni K. Choueiri, Wanling Xie, Robert I. Haddad, David J. Kwiatkowski, Taiwen Li, David A. Braun, Eliezer M. Van Allen, Andrew D. Cherniack, X. Shirley Liu, Cigall Kadoch, F. Stephen Hodi, Claire A. Margolis, Ziad Bakouny, Liam F. Spurr, and Tarek H. Mouhieddine
- Subjects
Adult ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,ARID1A ,Immunology ,Article ,PBRM1 ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Renal cell carcinoma ,Neoplasms ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Immune Checkpoint Inhibitors ,Survival rate ,Aged ,Aged, 80 and over ,SWI/SNF complex ,business.industry ,DNA Helicases ,Nuclear Proteins ,Cancer ,SMARCB1 Protein ,Middle Aged ,medicine.disease ,Immune checkpoint ,DNA-Binding Proteins ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,SMARCA4 ,business ,Transcription Factors - 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.
- Published
- 2020