Mismatch-repair deficiency (d-MMR) was uncommon among samples of muscle-invasive, high-grade urothelial carcinoma (HGUC) of the bladder, but, when present, had a strong correlation with cytotoxic T-lymphocyte infiltration and PD-L1 tissue expression, according to a recent study.

Use of PD-1/PD-L1 inhibitors for HGUC has yielded some durable responses, but use of PD-1/PD-L1 as a biomarker of response is imperfect, according to the study. 

In order to identify additional biomarkers to find patients who might respond to checkpoint inhibitor immunotherapy, researchers analyzed tumor samples for presence of d-MMR and sought to correlate it with CD8 expression and tissue PD-L1 protein expression. 

“We hypothesized that d-MMR tumours would contain a higher number of CD8-positive lymphocytes and would exhibit increased rates of PD-L1 tissue positivity compared with MMR-intact HGUC,” the researchers wrote. 


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Using samples for 201 cases, the researchers found that only 4 cases — or approximately 2% — were d-MMR. Three of these cases had combined MLH1/PMS2 loss and one had MSH2/MSH6 loss.

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Mean CD8 count was significantly higher in the tumors that were d-MMR compared with those that were not (108 vs 35 cells/case; P =.007). In addition, 75% of d-MMR cases tested positive for PD-L1 expression compared with only 25% of cases that were not d-MMR (P =.031).

Based on these results, the researchers concluded that “it is unlikely that routine MMR staining of primary HGUC muscle invasive carcinomas would yield significant clinical benefit but larger studies are required to fully investigate the potential clinical utility of d-MMR as a predictive biomarker of immune therapy response.”

Reference

Hodgson A, Vesprini D, Liu SK, Xu B, Downes MR. Correlation of mismatch repair protein deficiency, PD-L1 and CD8 expression in high-grade urothelial carcinoma of the bladder [published online January 9, 2020]. doi: 2020;10.1136/jclinpath-2019-206256