Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer immunology research	8	8	2020 Aug	1075-1084	Cancer Immunol Res

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.

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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
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, Dec 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 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
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
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	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	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	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	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