TY  - JOUR
A1  - Adam, Pia
A1  - Kircher, Stefan
A1  - Sbiera, Iuliu
A1  - Koehler, Viktoria Florentine
A1  - Berg, Elke
A1  - Knösel, Thomas
A1  - Sandner, Benjamin
A1  - Fenske, Wiebke Kristin
A1  - Bläker, Hendrik
A1  - Smaxwil, Constantin
A1  - Zielke, Andreas
A1  - Sipos, Bence
A1  - Allelein, Stephanie
A1  - Schott, Matthias
A1  - Dierks, Christine
A1  - Spitzweg, Christine
A1  - Fassnacht, Martin
A1  - Kroiss, Matthias
T1  - FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale
JF  - Frontiers in Endocrinology
N2  - 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.
KW  - tyrosine kinase inhibitor (TKI)
KW  - immune checkpoint inhibitor (ICI)
KW  - immunohistochemistry
KW  - immunotherapy
KW  - PD-L1
KW  - FGFR
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244653
SN  - 1664-2392
VL  - 12
ER  - 
TY  - JOUR
A1  - Koehler, Viktoria Florentine
A1  - Adam, Pia
A1  - Fuss, Carmina Teresa
A1  - Jiang, Linmiao
A1  - Berg, Elke
A1  - Frank-Raue, Karin
A1  - Raue, Friedhelm
A1  - Hoster, Eva
A1  - Knösel, Thomas
A1  - Schildhaus, Hans-Ulrich
A1  - Negele, Thomas
A1  - Siebolts, Udo
A1  - Lorenz, Kerstin
A1  - Allelein, Stephanie
A1  - Schott, Matthias
A1  - Spitzweg, Christine
A1  - Kroiss, Matthias
T1  - Treatment of RET-positive advanced medullary thyroid cancer with multi-tyrosine kinase inhibitors — a retrospective multi-center registry analysis
JF  - Cancers
N2  - Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.
KW  - medullary thyroid cancer
KW  - rearranged during transfection
KW  - variant
KW  - multi-tyrosine kinase inhibitor
KW  - survival
KW  - treatment outcome
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281776
SN  - 2072-6694
VL  - 14
IS  - 14
ER  -