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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. |
| Journal | Cancer immunology research |
| Vol | 8 |
| Issue | 8 |
| Date | 2020 Aug |
| URL | |
| 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 |
|---|
| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
|---|
| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
|---|
| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| 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, May 2023). | |
| 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 2023). | |
| 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 2023). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| ARID1A inact mut | head and neck squamous cell carcinoma | not predictive | unspecified immune checkpoint inhibitor | Clinical Study - Cohort | Actionable | In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including ARID1A, did not correlate with improved survival in 2 separate cohorts of patients with head and neck squamous cell carcinoma treated with systemic immune checkpoint inhibitors, with adjusted HRs for overall survival of 0.74 (p=0.631, n=31) and 0.76 (p=0.622, n=68), respectively (PMID: 32321774). | 32321774 |
| ARID1A inact mut | gastroesophageal adenocarcinoma | not predictive | unspecified immune checkpoint inhibitor | Clinical Study - Cohort | Actionable | In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including ARID1A, did not correlate with improved survival in 2 separate cohorts of patients with gastroesophageal adenocarcinoma treated with systemic immune checkpoint inhibitors, with adjusted HRs for overall survival of 0.70 (p=0.403, n=66) and 0.46 (p=0.071, n=59), respectively (PMID: 32321774). | 32321774 |
| ARID1A inact mut | colorectal adenocarcinoma | unknown | unspecified immune checkpoint inhibitor | Clinical Study - Cohort | Actionable | In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including ARID1A, correlated with improved survival in one cohort of patients with colorectal adenocarcinoma treated with systemic immune checkpoint inhibitors but not the other, with adjusted HRs for overall survival of 0.30 (p=0.03, n=35) and 0.56 (p=0.244, n=63), respectively (PMID: 32321774). | 32321774 |
| ARID1A inact mut | melanoma | not predictive | unspecified immune checkpoint inhibitor | Clinical Study - Cohort | Actionable | In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including ARID1A, did not correlate with improved survival in 2 separate cohorts of patients with melanoma treated with systemic immune checkpoint inhibitors, with adjusted HRs for overall survival of 1.70 (p=0.192, n=86) and 1.02 (p=0.939, n=192), respectively (PMID: 32321774). | 32321774 |
| ARID1A inact mut | lung non-small cell carcinoma | unknown | unspecified immune checkpoint inhibitor | Clinical Study - Cohort | Actionable | In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including ARID1A, correlated with worse survival in one cohort of patients with non-small cell lung cancer treated with systemic immune checkpoint inhibitors but not the other, with adjusted HRs for overall survival of 1.44 (p=0.018, n=334) and 1.84 (p=0.379, n=255), respectively (PMID: 32321774). | 32321774 |
| ARID1A inact mut | renal cell carcinoma | unknown | unspecified immune checkpoint inhibitor | Clinical Study - Cohort | Actionable | In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including ARID1A, correlated with improved survival in one cohort of patients with renal cell carcinoma treated with systemic immune checkpoint inhibitors but not the other, with adjusted HRs for overall survival of 0.33 (p=0.004, n=68) and 1.04 (p=0.906, n=118), respectively (PMID: 32321774). | 32321774 |
| ARID1A inact mut | transitional cell carcinoma | not predictive | unspecified immune checkpoint inhibitor | Clinical Study - Cohort | Actionable | In a retrospective analysis, somatic loss-of-function mutations in the genes of the mSWI/SNF complex, including ARID1A, did not correlate with improved survival in 2 separate cohorts of patients with transitional cell carcinoma treated with systemic immune checkpoint inhibitors, with adjusted HRs for overall survival of 1.44 (p=0.34, n=56) and 0.82 (p=0.559, n=93), respectively (PMID: 32321774). | 32321774 |