New Paper Alert! Understanding MSI and MMR in Urothelial Carcinoma: Systematic Review and Meta-analysis

Understanding MSI & MMR in Urothelial Carcinoma: Systematic Review and Meta-analysis

Authors: Elias B A Chandran, Giovanni Maria Iannantuono, Saad O Atiq, Dilara Akbulut, Ninet Sinaii, Nicholas I Simon, Abdul Rouf Banday, Salah Boudjadi, Sandeep Gurram, Amin H Nassar, Jonathan E Rosenberg, Gisela Butera, Min Yuen Teo, Guru Sonpavde, Jonathan A Coleman, and Andrea B Apolo.

Published in BMJ Oncology on April 30, 2024 .

Introduction:

Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) are genetic alterations that occur in some cancers, including urothelial carcinoma (UC). These characteristics are associated with increased sensitivity to immune checkpoint inhibitors (ICIs) but may confer resistance to chemotherapy.

This systematic review and meta-analysis aimed to estimate the prevalence of dMMR and MSI-H in urothelial carcinoma, evaluate treatment responses, and assess survival outcomes.

Design and Methods:

The authors conducted a comprehensive literature search across multiple databases, screening 1,745 studies and including 110 relevant publications.

They performed meta-analyses to estimate the pooled weighted prevalence of dMMR, MSI-H, and mismatch repair (MMR) gene alterations in UC, bladder cancer (BC), and upper tract urothelial carcinoma (UTUC).

Additionally, they evaluated the response rates to ICIs and chemotherapy, as well as survival outcomes in patients with dMMR or MSI-H UC.

What We Learned:

1. Prevalence:

• The pooled weighted prevalence of dMMR in urothelial carcinoma was 6.03%, with higher rates in UTUC (8.95%) than in BC (2.30%).
• The pooled weighted prevalence of MSI-H in urothelial carcinoma was 4.54%, with higher rates in UTUC (8.36%) than in BC (2.11%).
• MSI-H occurred more frequently in localized disease compared to metastatic disease for both BC and UTUC.

2. Treatment Response:

• In metastatic urothelial carcinoma patients with dMMR or MSI-H treated with ICIs, the pooled response rate was 64.7% (22/34 patients).
• In contrast, the response rate to chemotherapy in this subgroup was only 11.1% (1/9 patients).

3. Survival Outcomes:

• Some studies suggested favourable overall survival in patients with dMMR or MSI-H urothelial carcinoma compared to those without these characteristics.
• However, the authors noted a lack of uniformity in survival data, limiting their ability to draw definitive conclusions.

Key Highlights:

• dMMR and MSI-H are more prevalent in UTUC than in BC, occurring in approximately 9% and 2% of cases, respectively.
• MSI-H is more common in localized UC compared to metastatic disease, suggesting a potential role in disease progression.
• Patients with dMMR or MSI-H metastatic UC demonstrate remarkable sensitivity to ICIs, with response rates exceeding 60%.
• In contrast, these patients exhibit resistance to chemotherapy, with low response rates of around 11%.

Key Takeaway Messages:

• dMMR and MSI-H are important biomarkers in UC, with differential prevalence rates based on primary tumor site and disease stage.
• Identifying these characteristics is crucial, as they may predict sensitivity to ICIs and resistance to chemotherapy in metastatic UC.
• The findings support the development of clinical trials investigating novel immunotherapeutic approaches for dMMR or MSI-H UC patients, potentially sparing them from toxic treatments or radical surgeries.
• Consideration should be given to universal germline testing in UC, particularly in patients with a positive personal or family history of Lynch syndrome-related malignancies.

Summary By Amalya Sargsyan, MD

Mismatch repair deficiency and microsatellite instability in urothelial carcinoma: a systematic review and meta-analysis