Kinase-inhibitors for iodine-refractory differentiated thyroid cancer: still far from a structured therapeutic algorithm

Marotta, Vincenzo; Chiofalo, Maria Grazia; Gennaro, Francesca Di; Daponte, Antonio; Sandomenico, Fabio; Vallone, Paolo; Costigliola, Luciana; Botti, Gerardo; Ionna, Franco; Pezzullo, Luciano

doi:10.1016/j.critrevonc.2021.103353

Cited by 9 publications

(8 citation statements)

References 92 publications

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“…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). Nevertheless, important practical issues in the use of tyrosine kinase inhibitors are still unsolved (15,16).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…To date, four KIs have been approved for these settings: sorafenib (for iodine-refractory DTC), lenvatinib (for iodine-refractory DTC), vandetanib (for MTC), cabozantinib (for MTC and as a second line for iodine-refractory DTC) [ 95 , 96 ].…”

Section: Management Of Advanced Diseasementioning

confidence: 99%

Cell-Free DNA Analysis within the Challenges of Thyroid Cancer Management

Marotta

Cennamo

Civita

et al. 2022

Cancers

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Thyroid cancer is the most frequent endocrine malignancy with an increasing incidence trend during the past forty years and a concomitant rise in cancer-related mortality. The circulating cell-free DNA (cfDNA) analysis is a patient’s friendly and repeatable procedure allowing to obtain surrogate information about the genetics and epigenetics of the tumor. The aim of the present review was to address the suitability of cfDNA testing in different forms of thyroid cancer, and the potential clinical applications, as referred to the clinical weaknesses. Despite being limited by the absence of standardization and by reproducibility and validity issues, cfDNA assessment has great potential for the improvement of thyroid cancer management. cfDNA may support the pre-surgical definition of thyroid nodules by complementing invasive thyroid fine needle aspiration cytology. In addition, it may empower risk stratification and could be used as a biomarker for monitoring the post-surgical disease status, both during active surveillance and in the case of anti-tumor treatment.

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“…MKIs target different signaling pathways and oncogenes, which are affected by the TC and involved in proliferation, survival, motility, migration, invasion, etc. RTKs are enzymes that phosphorylate proteins important in intracellular signaling pathways [31,39], and the inhibition of these tyrosine kinases associated with cellular receptors leads to the inhibition of tumor growth [13,40].…”

Section: Multikinase Inhibitorsmentioning

confidence: 99%

“…Mutations at any level of the pathways can lead to constitutive activation, overexpression, or other oncogenic effects [8,12]. Treatment strategies of TC rely on both anti-proliferative and anti-angiogenic properties, as tyrosine kinases (TKs) are important in these two areas of the TC development of factors involved in proliferation, survival, cell cycle, and intracellular growth pathways, as well as angiogenic factors, i.e., those leading to neo-angiogenesis [13][14][15]. However, although first breakthroughs in the form of marketable drugs have been achieved, the field of developing TKI against refractory DTC is still evolving [13,16].…”

Section: Introductionmentioning

confidence: 99%

Kinase-Inhibitors in Iodine-Refractory Differentiated Thyroid Cancer—Focus on Occurrence, Mechanisms, and Management of Treatment-Related Hypertension

Kaae

Kreißl

Krüger

et al. 2021

IJMS

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Differentiated thyroid cancer (DTC) usually has a good prognosis when treated conventionally with thyroidectomy, radioactive iodine (RAI) and thyroid-stimulating hormone suppression, but some tumors develop a resistance to RAI therapy, requiring alternative treatments. Sorafenib, lenvatinib and cabozantinib are multikinase inhibitors (MKIs) approved for the treatment of RAI-refractory DTC. The drugs have been shown to improve progression-free survival (PFS) and overall survival (OS) via the inhibition of different receptor tyrosine kinases (RTKs) that are involved in tumorigenesis and angiogenesis. Both sorafenib and lenvatinib have been approved irrespective of the line of therapy for the treatment of RAI-refractory DTC, whereas cabozantinib has only been approved as a second-line treatment. Adverse effects (AEs) such as hypertension are often seen with MKI treatment, but are generally well manageable. In this review, current clinical studies will be discussed, and the toxicity and safety of sorafenib, lenvatinib and cabozantinib treatment will be evaluated, with a focus on AE hypertension and its treatment options. In short, treatment-emergent hypertension (TE-HTN) occurs with all three drugs, but is usually well manageable and leads only to a few dose modifications or even discontinuations. This is emphasized by the fact that lenvatinib is widely considered the first-line drug of choice, despite its higher rate of TE-HTN.

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Kinase-inhibitors for iodine-refractory differentiated thyroid cancer: still far from a structured therapeutic algorithm

Cited by 9 publications

References 92 publications

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

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

Cell-Free DNA Analysis within the Challenges of Thyroid Cancer Management

Kinase-Inhibitors in Iodine-Refractory Differentiated Thyroid Cancer—Focus on Occurrence, Mechanisms, and Management of Treatment-Related Hypertension

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