# Case Report: Lasting complete response to pembrolizumab in mismatch repair-deficient cardiac sarcoma: a genomic characterization

## TL;DR

A woman with cardiac sarcoma achieved a lasting complete response to pembrolizumab after genomic testing revealed mismatch repair-deficiency and high tumor mutational burden.

## Contribution

This case report highlights the potential of immunotherapy in mismatch repair-deficient sarcomas through genomic characterization.

## Key findings

- The patient achieved a complete response to pembrolizumab that persisted for over seven years.
- Genomic testing revealed high tumor mutational burden, FAT1 and NOTCH2 mutations, and a microsatellite instability signature.
- Mismatch repair-deficiency and CD8+ tumor-infiltrating lymphocytes were confirmed as predictive markers for immunotherapy response.

## Abstract

Sarcomas are traditionally considered “cold” tumors with poor response to immunotherapy. However, evidence accumulating over the last years shows that immune checkpoint inhibitors (ICIs) may have a role in selected sarcoma patients according to predictive markers. Here, we report the case of a woman diagnosed with a primary cardiac undifferentiated sarcoma. Following failure of standard first line chemotherapy, high-throughput sequencing (HTS) revealed a high tumor mutational burden (TMB), pathogenic mutations in FAT1 and NOTCH2 and a microsatellite instability (MSI)-associated signature. Immunohistochemistry confirmed mismatch repair-deficiency (MMRd) and abundant CD8+ tumor-infiltrating lymphocytes (TILs), in the absence of tertiary lymphoid structures. The patient was, therefore, treated with the ICI pembrolizumab, reaching a complete response that continues to persist at last follow-up, more than seven years from initial diagnosis and nearly six years from initiation of ICI treatment. This case illustrates the importance of performing HTS in rare sarcomas given the availability of efficient therapies, such as those for tumors displaying high TMB or MMRd/MSI. In agreement with other reports, it supports the contention that MMRd/MSI status and high numbers of TILs are valuable predictive markers of response to immunotherapy in sarcomas.