Alkylating Agent-Induced High Tumor Mutational Burden in Medullary Thyroid Cancer and Response to Immune Checkpoint Inhibitors: Two Case Reports

Abstract

Background:

Patients with metastatic medullary thyroid cancer (MTC) who progressed under tyrosine kinase inhibitors can benefit from an alkylating agent such as dacarbazine or temozolomide.

Patient Findings:

We describe two patients with metastatic MTC who developed a hypermutant phenotype after alkylating agent treatment. This phenotype was characterized by a high tumor mutational burden (TMB) and a mutational signature indicative of alkylating agent mutagenesis (single-base substitution 11). Both patients received immune checkpoint inhibitors, with partial morphological responses, clinical benefit, and progression-free survival of 6 and 9 months, respectively.

Summary and Conclusions:

Based on the described observations, we suggest that a hypermutant phenotype may be induced after alkylating agent treatment for MTC and the sequential use of immunotherapy should be further explored as a treatment option for MTC patients with increased TMB.