Reference Detail

Ref Type

Journal Article

PMID

(32554706)

Authors

Goswami S, Chen Y, Anandhan S, Szabo PM, Basu S, Blando JM, Liu W, Zhang J, Natarajan SM, Xiong L, Guan B, Yadav SS, Saci A, Allison JP, Galsky MD, Sharma P

Title

ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science translational medicine	12	548	2020 Jun 17		Sci Transl Med

URL

Abstract Text

Immune checkpoint therapy (ICT) can produce durable antitumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of ICT in mUCC, we lack predictive biomarkers to guide patient selection. The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Through multi-platform immuno-genomic analyses of baseline tumor tissues, we identified the mutation of AT-rich interactive domain-containing protein 1A (ARID1A) in tumor cells and expression of immune cytokine CXCL13 in the baseline tumor tissues as two predictors of clinical responses in a discovery cohort (n = 31). Further, reverse translational studies revealed that CXCL13-/- tumor-bearing mice were resistant to ICT, whereas ARID1A knockdown enhanced sensitivity to ICT in a murine model of bladder cancer. Next, we tested the clinical relevance of ARID1A mutation and baseline CXCL13 expression in two independent confirmatory cohorts (CheckMate275 and IMvigor210). We found that ARID1A mutation and expression of CXCL13 in the baseline tumor tissues correlated with improved overall survival (OS) in both confirmatory cohorts (CheckMate275, CXCL13 data, n = 217; ARID1A data, n = 139, and IMvigor210, CXCL13 data, n = 348; ARID1A data, n = 275). We then interrogated CXCL13 expression plus ARID1A mutation as a combination biomarker in predicting response to ICT in CheckMate275 and IMvigor210. Combination of the two biomarkers in baseline tumor tissues suggested improved OS compared to either single biomarker. Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A may improve prediction capability for patients receiving ICT.

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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	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ARID1A mutant	bladder urothelial carcinoma	predicted - sensitive	Nivolumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, metastatic urothelial carcinoma patients from the CheckMate275 trial harboring an ARID1A mutation (n=39) demonstrated a greater overall survival (11.4 mo vs 6.0 mo; P=0.03) compared to patients with wild-type ARID1A (n=100) when treated with Opdivo (nivolumab) (PMID: 32554706; NCT02387996).	32554706
ARID1A mutant	bladder urothelial carcinoma	predicted - sensitive	Atezolizumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, metastatic urothelial carcinoma patients from the IMvigor210 trial harboring an ARID1A mutation (n=62) demonstrated a greater overall survival (15.4 mo vs 8.2 mo; P=0.03) compared to patients with wild-type ARID1A (n=213) when treated with Tecentriq (atezolizumab) (PMID: 32554706; NCT02108652).	32554706