Mismatch repair (MMR) detection in urothelial carcinoma (UC) and correlation with immune checkpoint blockade (ICB) response.

Abstract

4511 Background: High mutation burden correlates with response to ICB in UC. Loss of function alterations or epigenetic silencing of MMR genes results in MMR deficient (MMR-D) UC, leading to a microsatellite instability (MSI) mutation signature. We used a CLIA-certified pipeline (MSISensor) to interrogate Next Generation sequencing (NGS) data from UC tumors to identify MMR-D patients (pts). We correlated MMR-D with mutation load and response to ICB. Methods: 447 tumors from 424 UC pts underwent prospective NGS using the MSK-IMPACT exon capture assay and genomic interrogation of microsatellite (MS) sites using MSIsensor, which assesses the number/length of MS within the targeted regions of tumor-normal sample pairs. Loci are considered unstable (somatic) if k-mer distributions are significantly different between tumor and matched normal using a standard multiple testing correction of χ2 p-values. The fraction of unstable sites is reported as an MSIsensor score. MSI high tumors have scores >10 while <3 are denoted MS stable. Scores from 3-10 were categorized as MS intermediate. Results: Thirteen pts (3%) had an MSI score >10 and a median mutation count of 52 (36.5-73.5) vs 8 (5-13) in 410 non-MMR-D pts (p<0.01). Ten pts (71%) had upper tract UC. Of 9 pts with germline sequencing performed, 8 (89%) had heritable loss of function mutations in MMR proteins (Lynch syndrome, LS). One pt had a somatic MSH2 mutation. Fifteen pts had MS scores from 3-10: 3 had LS, one a BRCA1 germline alteration, and 9 did not have germline testing available. Two pts with MSI scores <3 had extremely high mutation loads (213 and 414) and both had POLE mutations. Five pts received ICB therapy for metastatic and all achieved near-complete or complete responses. No MMR-D pt has died at 27 months follow-up vs 125 non-MMR-D pts (p=0.014). Conclusions: The MSI Sensor assay can discriminate MSI high from MMR proficient UC. While rare, MMR-D UC is characterized by a high mutation load, strong association with Lynch syndrome, and durable responses to ICB, similar to data in colon cancer. An MMR-D signature should trigger genetic testing for Lynch syndrome. ICB should be considered early in the treatment course of patients with MMR-D metastatic UC.