ARID1A Mutation plus CXCL13 Expression Act as Combinatorial Biomarkers to Predict Responses to Immune Checkpoint Therapy in Metastatic Urothelial Carcinoma - Expert Commentary

The introduction of immune checkpoint inhibitors (ICIs) has improved the outcomes for a subset of metastatic urothelial carcinoma (mUCC) patients. There is a need for a predictive tool to identify those who will benefit from these treatments. A recent study published by Goswami et al. in Science Translational Medicine assessed the use of biomarkers as a predictive tool for response to ICIs in music patients.

The investigators performed an immunogenomic analysis of tumor tissues (n=31) from a discovery cohort. They found that mutations in AT-rich interactive domain-containing protein 1A (ARID1A) correlate with improved overall survival in patients with mUCC receiving ICIs. These mutations resulted in decreased ARID1A expression. No ARID1A mutations were found in tumors from non-responders. The study also found that the expression of CXCL13 in baseline tumor tissues correlated with improved overall survival. They discovered that CXCL13 null (CXCL13−/−) mice bearing murine bladder tumors (MB49) were resistant to ICIs, whereas Knockdown of ARID1A increased sensitivity to ICIs. 

The investigators validated these findings in two validation cohorts from the CheckMate275 and IMvigor210 studies. They confirmed a significant association between ARID1A mutations, expression of CXCL13, and higher overall survival. When combining ARID1A mutation and expression of CXCL13 was predictive of overall survival compared to either biomarker alone. ARID1A mutations frequently occur in urothelial cancer. This study highlights their contribution to the sensitivity to ICIs.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

References: 

  1. 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. “ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC.” Sci Transl Med. 2020 Jun 17;12(548):eabc4220. doi: 10.1126/scitranslmed.abc4220. PMID: 32554706
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