Abstract
BackgroundTreatment 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 MethodsPrimary 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.ResultsPD-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.ConclusionHigh 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.
Highlights
Anaplastic (ATC) and poorly differentiated thyroid carcinoma (PDTC) are orphan diseases which account for 1-2% and 2-15% % among all thyroid malignancies [1, 2]
93 patients (40 male, 53 female) with histological evidence of ATC and 47 patients (17 male, 30 female) with poorly differentiated thyroid carcinoma treated at five German tertiary care centers were included
Disease was restricted to the thyroid gland at diagnosis in one single ATC patient whereas 52% had distant metastasis. 15 PDTC patients had distant metastases at first diagnosis, four of whom were
Summary
Anaplastic (ATC) and poorly differentiated thyroid carcinoma (PDTC) are orphan diseases which account for 1-2% and 2-15% % among all thyroid malignancies [1, 2]. While treatment of DTC is well established and 5-year survival rates are above 90% [3], the management of PDTC and ATC is unsatisfactory and prognosis generally poor with a median overall survival of only six months for ATC patients [4, 5]. Lenvatinib (LEN) is a multi-tyrosine kinase inhibitor (TKI) of VEGFR1-3, FGFR1-4, PDGFR-a, RET and c-kit and approved for the treatment of progressive radioiodine refractory DTC and radioiodine refractory PDTC [14]. 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
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