Immunotherapy response in microsatellite-stable poorly differentiated thyroid carcinoma with mismatch repair deficiency and high tumor mutational burden

TL;DR

A rare thyroid cancer patient responded well to immunotherapy despite lacking typical biomarkers, suggesting new genetic factors could predict treatment success.

Contribution

This case highlights somatic mutations in DNA repair genes as potential biomarkers for immunotherapy response in microsatellite-stable PDTC.

Findings

A PDTC patient with microsatellite stability and high tumor mutational burden showed a sustained partial response to pembrolizumab.

Loss of MSH2/MSH6 and mutations in MSH2 and ATM were associated with immunotherapy response despite MSS status.

The case suggests DNA repair gene mutations may serve as alternative biomarkers for immunotherapy eligibility in PDTC.

Abstract

Poorly differentiated thyroid carcinoma (PDTC) is a rare and aggressive
malignancy with a poor prognosis. Immunotherapy is typically guided by agnostic
biomarkers such as microsatellite instability-high or high tumor mutational
burden (TMB); however, these biomarkers are uncommon in PDTC. Therefore,
identifying alternative predictive biomarkers remains an urgent necessity. We
report the case of a 71-year-old woman who presented with life-threatening
locoregional disease and was ineligible for radioiodine or tyrosine kinase
inhibitors due to a prior subarachnoid hemorrhage. Molecular profiling of the
resected tumor revealed a high TMB (10 mut/Mb), somatic mutations in MSH2 and
ATM, and microsatellite stability (MSS). Immunohistochemistry demonstrated
complete loss of MSH2/MSH6 expression, while PD-L1 expression was 20% (tumor
proportion score). Based on these findings, pembrolizumab was initiated as
first-line therapy. The patient experienced clinical improvement and maintained
a sustained partial response for seven months, with excellent tolerability. This
case represents one of the few documented reports of PDTC with MSS exhibiting
marked responsiveness to immunotherapy. Our findings underscore that alternative
biomarkers, such as somatic mutations in DNA repair genes including MSH2 and
ATM, may predict unexpected responses to immune checkpoint blockade and inform
therapeutic decisions, even in the context of MSS and borderline TMB. Broader
implementation of molecular profiling is warranted to identify such
patients.

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