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