FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale.

Abstract

Background:

Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.

Materials and Methods:

Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.

Results:

PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.

Conclusion:

High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.

• Authors: Pia Adam, Stefan Kircher, Iuliu Sbiera, Viktoria Florentine Koehler, Elke Berg, Thomas Knösel, Benjamin Sandner, Wiebke Kristin Fenske, Hendrik Bläker, Constantin Smaxwil, Andreas Zielke, Bence Sipos, Stephanie Allelein, Matthias Schott, Christine Dierks, Christine Spitzweg, Martin Fassnacht, Matthias Kroiss
• Journal: Frontiers in endocrinology (Front Endocrinol (Lausanne)) Vol. 12 Pg. 712107 ( 2021) ISSN: 1664-2392 [Print] Switzerland
• PMID: 34475850 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Adam, Kircher, Sbiera, Koehler, Berg, Knösel, Sandner, Fenske, Bläker, Smaxwil, Zielke, Sipos, Allelein, Schott, Dierks, Spitzweg, Fassnacht and Kroiss.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Antineoplastic Agents, Immunological
• B7-H1 Antigen
• CD274 protein, human
• Phenylurea Compounds
• Quinolines
• RNA, Messenger
• Receptors, Fibroblast Growth Factor
• pembrolizumab
• lenvatinib

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents
• Antineoplastic Agents, Immunological
• B7-H1 Antigen (analysis, antagonists & inhibitors)
• Drug Evaluation, Preclinical (methods)
• Female
• Germany
• Humans
• Male
• Middle Aged
• Phenylurea Compounds (pharmacology)
• Quinolines (pharmacology)
• RNA, Messenger (analysis)
• Receptors, Fibroblast Growth Factor (antagonists & inhibitors, genetics)
• Thyroid Carcinoma, Anaplastic (chemistry, drug therapy, pathology)
• Thyroid Neoplasms (chemistry, drug therapy, pathology)