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Molecular features of aggressive thyroid cancer.

ABSTRACT: Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have a worse prognosis with respect to well differentiated TC, and the loss of the capability of up-taking ¹³¹I is one of the main features characterizing aggressive TC. The knowledge of the genomic landscape of TC can help clinicians to discover the responsible alterations underlying more advance diseases and to address more tailored therapy. In fact, to date, the antiangiogenic multi-targeted kinase inhibitor (aaMKIs) sorafenib, lenvatinib, and cabozantinib, have been approved for the therapy of aggressive radioiodine (RAI)-resistant papillary TC (PTC) or follicular TC (FTC). Several other compounds, including immunotherapies, have been introduced and, in part, approved for the treatment of TC harboring specific mutations. For example, selpercatinib and pralsetinib inhibit mutant RET in medullary thyroid cancer but they can also block the RET fusion proteins-mediated signaling found in PTC. Entrectinib and larotrectinib, can be used in patients with progressive RAI-resistant TC harboring TRK fusion proteins. In addition FDA authorized the association of dabrafenib (BRAF^V600E inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAF^V600E-mutated ATC. These drugs not only can limit the cancer spread, but in some circumstance they are able to induce the re-differentiation of aggressive tumors, which can be again submitted to new attempts of RAI therapy. In this review we explore the current knowledge on the genetic landscape of TC and its implication on the development of new precise therapeutic strategies.

SUBMITTER: Elia G

PROVIDER: S-EPMC9807782 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Molecular features of aggressive thyroid cancer.

Elia Giusy G Patrizio Armando A Ragusa Francesca F Paparo Sabrina Rosaria SR Mazzi Valeria V Balestri Eugenia E Botrini Chiara C Rugani Licia L Benvenga Salvatore S Materazzi Gabriele G Spinelli Claudio C Antonelli Alessandro A Fallahi Poupak P Ferrari Silvia Martina SM

Frontiers in oncology 20221220

Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have a worse prognosis with respect to well differentiated TC, and the loss of the capability of up-taking <sup>131</sup>I is one of the main features characterizing aggressive TC. The knowledge of the genomic landscape of TC can help clinicians to discover the responsible alterations underlying more advance diseases and to address more tailored therapy. In fact, to date, the antiangiogenic multi-targeted kinase inhi ...[more]

PMID: 36605433

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Project description:Differentiated thyroid carcinomas (DTCs) that arise from follicular cells account >90% of thyroid cancer (TC) [papillary thyroid cancer (PTC) 90%, follicular thyroid cancer (FTC) 10%], while medullary thyroid cancer (MTC) accounts <5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC, and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts toward the development of new drugs. Several genetic alterations in different molecular pathways in TC have been shown in the past few decades, associated with TC development and progression. Rearranged during transfection (RET)/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the aforementioned molecular pathways involved in growth, angiogenesis, local, and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC, and anaplastic thyroid cancer, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds and to personalize the therapy in each TC patient.

Project description:BackgroundIn clinical practice, thyroid tumor size plays a critical role in the staging of thyroid malignancies and in the selection of nodules that should undergo ultrasound-guided fine-needle aspiration. Thyroid tumor size is influenced by the elapsed time since the beginning of oncogenesis and by the presence of somatic mutations driving growth, such as BRAFV600E mutations, associated with aggressive phenotypes, and RAS-like mutations, associated with more indolent behavior. Although large nodules are often considered to be more alarming, the true impact of tumor size on prognosis remains controversial. The aim of this study was to assess the relationship between mutational status, tumor size and aggressiveness, with emphasis on BRAFV600E and RAS-like mutations.MethodWe conducted a multicentric retrospective chart review in Montréal, Canada, of all patients who underwent thyroid surgery between January 2016 and December 2020, with well-differentiated thyroid cancer on final pathology, and who had undergone molecular testing revealing the presence of BRAFV600E mutations or RAS-like mutations (NRAS, HRAS or KRAS).ResultsWe included 214 cases. There were 117 (54.7%) cases of BRAFV600E and 97 (45.3%) cases of RAS-like mutations. The BRAFV600E group was statistically associated with a smaller mean tumor size when compared with the RAS group of 1.55 cm and 2.04 cm, respectively. In a multivariate model, tumors with BRAFV600E mutations were also more likely to display aggressive pathological features, including extra-thyroidal extension, lymph node metastasis, columnar cell features, tall cell histology, or hobnail histology (OR 26.69; 95% CI 11.15-70.81). In contrast, tumor size was not associated with pathologic aggressive features on multivariate analysis (OR 0.81; 95% CI 0.54-1.22).ConclusionThis study demonstrates that thyroid tumors expressing BRAFV600E mutations correlate with aggressive pathologic features more than tumors expressing RAS-like mutations. When comparing tumors with BRAFV600E and RAS-like mutations, the former were found to be smaller. As a result of this finding, this study suggests that molecular alterations may better predict aggressive pathologic features than the size of the tumor.

Project description:ObjectiveTo investigate the association between the presence of female-specific tumors and aggressive clinicopathological features in papillary thyroid cancer (PTC).MethodsThis study retrospectively analyzed 9,822 female cases between June 2008 and December 2017. Odds ratios and corresponding 95% confidence intervals were calculated. Findings were stratified by age and body mass index (BMI) in different models.Results1443/9822 (14.7%) patients with PTC had a female-specific tumor. Presence of a benign breast mass was an independent risk factor for a primary PTC lesion > 1 cm in diameter (adjusted OR = 1.446, 95% CI 1.136-1.840, P = 0.003), but a protective factor against extrathyroidal extension of PTC (adjusted OR = 0.650, 95%CI 0.500-0.845, P = 0.001). Presence of a benign uterine mass was an independent risk factor for multifocal PTC (adjusted OR = 1.305, 95%CI 1.113-1.531, P = 0.001). Analyses stratified by age and BMI revealed the presence of a benign breast mass was an independent risk factor for a primary PTC lesion > 1 cm in diameter in patients aged <36 years (adjusted OR = 1.711, 95% CI 1.063-2.754, P = 0.027), and a protective factor against extrathyroidal extension of PTC in patients aged ≥36 - <42 years (OR adjusted = 0.533, 95% CI 0.302-0.941, P = 0.030) or with a BMI ≥ 23.4 kg/m2 (BMI ≥ 23.4 to < 25.7 kg/m2, adjusted OR = 0.441, 95% CI 0.246-0.792, P = 0.006; BMI ≥25.7 kg/m2, adjusted OR = 0.558, 95% CI 0.315-0.998, P 2 = 0.045). Presence of a benign uterine mass was an independent risk factor for multifocal PTC in patients aged ≥49 years (adjusted OR = 1.397, 95% CI 1.088-1.793, P = 0.009) or with a BMI <21.5 kg/m2 (OR adjusted = 1.745, 95% CI 1.214-2.509, P = 0.003).ConclusionThe presence of a benign breast mass was an independent risk factor for a primary PTC lesion > 1 cm in diameter and a protective factor against extrathyroidal extension of PTC, while the presence of a benign uterine mass was an independent risk factor for multifocal PTC. Data from this study may help surgeons propose more personalized treatment plans when encountering patients with PTC and female-specific benign tumors.

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Molecular features of aggressive thyroid cancer.

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Molecular features of aggressive thyroid cancer.

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