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Ref Type | Journal Article | ||||||||||||
PMID | (32321774) | ||||||||||||
Authors | Abou Alaiwi S, Nassar AH, Xie W, Bakouny Z, Berchuck JE, Braun DA, Baca SC, Nuzzo PV, Flippot R, Mouhieddine TH, Spurr LF, Li YY, Li T, Flaifel A, Steinharter JA, Margolis CA, Vokes NI, Du H, Shukla SA, Cherniack AD, Sonpavde G, Haddad RI, Awad MM, Giannakis M, Hodi FS, Liu XS, Signoretti S, Kadoch C, Freedman ML, Kwiatkowski DJ, Van Allen EM, Choueiri TK | ||||||||||||
Title | Mammalian SWI/SNF Complex Genomic Alterations and Immune Checkpoint Blockade in Solid Tumors. | ||||||||||||
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Abstract Text | 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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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ATM | L2890I | missense | unknown | ATM L2890I lies within the PI3K/PI4K catalytic domain of the Atm protein (UniProt.org). L2890I has been identified in sequencing studies (PMID: 32321774, PMID: 33272240), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Jun 2024). | |
ATR | R1647C | missense | unknown | ATR R1647C lies within the FAT domain of the Atr protein (UniProt.org). R1647C has been identified in sequencing studies (PMID: 32321774), but has not been biochemically characterized and therefore, its effect on Atr protein function is unknown (PubMed, Feb 2024). | |
AXL | V421L | missense | unknown | AXL V421L lies within fibronectin type-III domain 2 of the Axl protein (UniProt.org). V421L has been identified in sequencing studies (PMID: 32321774), but has not been biochemically characterized and therefore, its effect on Axl protein function is unknown (PubMed, Jul 2024). | |
ERBB4 | E693D | missense | unknown | ERBB4 E693D lies within the cytoplasmic domain of the Erbb4 protein (UniProt.org). E693D has been identified in sequencing studies (PMID: 32321774), but has not been biochemically characterized and therefore, its effect on Erbb4 protein function is unknown (PubMed, Jan 2024). | |
ERBB4 | R196C | missense | unknown | ERBB4 R196C lies within the extracellular domain of the Erbb4 protein (UniProt.org). R196C has been identified in sequencing studies (PMID: 32321774), but has not been biochemically characterized and therefore, its effect on Erbb4 protein function is unknown (PubMed, Mar 2024). | |
IDH2 | A370T | missense | unknown | IDH2 A370T does not lie within any known functional domains of the Idh2 protein (UniProt.org). A370T has been identified in sequencing studies (PMID: 32321774), but has not been biochemically characterized and therefore, its effect on Idh2 protein function is unknown (PubMed, Apr 2024). |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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