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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 Science translational medicine
Vol 12
Issue 548
Date 2020 Jun 17
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