ASCO 2017: Mismatch repair (MMR) detection in urothelial carcinoma (UC) and correlation with immune checkpoint blockade (ICB) response

Chicago, IL ( Immune-checkpoint blockade (ICB) continues to be the promising new therapeutic option for many advanced malignancies, including bladder urothelial cancer. With growing evidence for its use in advanced and metastatic urothelial carcinoma (UC), there is shifting emphasis on better patient selection.

With the knowledge that ICB ramps up a patient’s own immune response by blocking tumor evasion mechanisms, there has been renewed interest in the concept of mutational load. In cancers with high mutational burden, such as UC, there are a higher number of neoantigens (or novel peptides that can be recognized as foreign) that can augment ICB response. In specific, within each tumor type, a certain subset of patients with high mutation burdens (“mutator phenotypes”) have been identified, and of these, 13% have mismatch repair deficiency signature. 1 Patients with deficiency in the mismatch repair (MMR) genes are likely to have a higher mutational burden, and potentially a better response to ICB.2

In this study, the MSKCC group utilized an established pipeline tool called MSISensor (derives MSI [microsatellite instability] status from standard tumor-normal paired sequence data) to evaluate next-generation sequencing data from 447 tumors from 424 UC patients. Of these patients, 31% were NMIBC, 27% were MIBC, 27% were metastatic, and 14% were upper tract UC. By assessing MSI status, they then correlated the MSI score to mutational burden and subsequently to ICB response.

They classified MSI based on the following cutoffs: MSI high (MSI-H) tumors have scores >10, MSI stable (MSS) have scores <3, while patients with scores from 3-10 were categorized as MS intermediate (MSI-I).

Of the cohort, 11 (3%) were MSI-High, 11 (3%) were MSI-I and the remainder were MSS. Upon correlation with mutational burden, there was a strong correlation. Only two MSS had high mutational burden, while all the MSI-H patients had high mutational burden.
Next, he looked at all the MSI-H and MSI-I patients, as well as the 2 MSS patients with high mutational burden. Of the 11 MSI-H patients, 9 had upper tract UC (UTUC) and 9 had Lynch syndrome. Of the 11 MSI-I patients, 3 had UTUC and 3 had Lynch syndrome. One of the two patients with high mutation load but MSS had Lynch syndrome.

A total of 108 patients received immune checkpoint blockade therapy (ICB), and while there was a varying response, all 5 MSI-H patients treated with ICB had a strong objective response. In fact, three patients with Lynch syndrome treated with ICB had complete responses.

Take-Home Points:

1. Microsatellite instability (MSI) scores are associated with mutational burden, and both may serve as potential biomarkers for ICB therapy.
2. An MSI score >= 10 (MSI-H) has a predictive value of >90% for MMR-D in UC using the MSK-IMPACT, and have a very high likelihood of Lynch syndrome
- UC with MMR-D may be associated with more aggressive presentation and higher germline mutation rates of known predisposing genetic conditions (Lynch Syndrome, etc.). Therefore, these patients may warrant genetic testing.
3. Based on a small selected patient series, ICB therapy may provide a more durable response for MMR-D / MSI-H UC patients.

Presented By: Gopa Iyer

Co-Author(s): Francois Audenet, Sumit Middha, Maria Isabel Carlo, Ashley Marie Regazzi, Samuel Funt, Hikmat Al-Ahmadie, David B. Solit, Jonathan E. Rosenberg, Dean F. Bajorin

Institution(s): Memorial Sloan Kettering Cancer Center (MSKCC), NYC, NY

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto
Twitter: @tchandra_uromd

1. Zehir A, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017 May 8. doi: 10.1038/nm.4333. [Epub ahead of print]
2. Le DT, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. doi: 10.1056/NEJMoa1500596. Epub 2015 May 30.

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA