Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study

Annals of Oncology, Год журнала: 2022, Номер 33(4), С. 406 - 415

Опубликована: Янв. 10, 2022

Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis 23 response-assessable patients the ATC cohort phase II Rare Oncology Agnostic Research (ROAR) basket study. We report updated describing efficacy and safety full ROAR 36 ∼4 years additional study follow-up.ROAR (NCT02034110) is open-label, nonrandomized, evaluating rare cancers. The comprised unresectable or metastatic who received 150 mg twice daily 2 once orally until disease progression, unacceptable toxicity, death. primary endpoint investigator-assessed overall response rate (ORR) per Response Evaluation Criteria Solid Tumors version 1.1. Secondary endpoints were duration (DOR), progression-free survival (PFS), (OS), safety.At data cutoff (14 September 2020), median follow-up 11.1 months (range, 0.9-76.6 months). ORR 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; 12-month DOR 50%. Median PFS OS 6.7 14.5 months, respectively. respective rates 43.2% 51.7%, 24-month 31.5%. No new signals identified follow-up, adverse events consistent established tolerability trametinib.These results confirm substantial clinical benefit manageable toxicity ATC. Dabrafenib notably improved long-term represents a meaningful option this rare, aggressive cancer.

Язык: Английский

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Papillary Thyroid Cancer Prognosis: An Evolving Field

Cancers, Год журнала: 2021, Номер 13(21), С. 5567 - 5567

Опубликована: Ноя. 7, 2021

Over the last few years, a great advance has been made in comprehension of molecular pathogenesis underlying thyroid cancer progression, particularly for papillary (PTC), which represents most common malignancy. Putative driver mutations have identified more than 98% PTC, and new PTC classification into subtypes proposed order to resolve clinical uncertainties still present management patients. Additionally, prognostic stratification systems profoundly modified over decade, with view refine patients' staging being able choose approach tailored on single patient's needs. Here, we will briefly discuss recent changes nodules, review current patients by analyzing promising clinicopathological features (i.e., gender, auto-immunity, multifocality, histological variants, vascular invasion) as well markers BRAF/TERT promoter mutations, miRNAs, components plasminogen activating system) potentially capable ameliorating prognosis

Язык: Английский

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Immune Landscape of Thyroid Cancers: New Insights

Frontiers in Endocrinology, Год журнала: 2021, Номер 11

Опубликована: Апрель 27, 2021

Immune system plays a key role in cancer prevention as well its initiation and progression. During multistep development of tumors, cells must acquire the capability to evade immune destruction. Both vitro vivo studies showed that thyroid tumor can avoid response by promoting an immunosuppressive microenvironment. The recruitment such TAMs (tumor-associated macrophages), TAMCs mast cells), MDSC (myeloid-derived suppressor TANs neutrophils) Tregs (regulatory T cells) and/or expression negative checkpoints, like PD-L1 (programmed death-ligand 1), CTLA-4 (cytotoxic T-lymphocyte associated protein 4), enzymes, IDO1 (indoleamine 2,3-dioxygenase are just some mechanisms exploit escape Some authors systematically characterized cell populations soluble mediators (chemokines, cytokines, angiogenic factors) constitute Their purpose was verify involvement growth progression, highlighting differences infiltrate among histotypes. More recently, have provided more comprehensive view relationships between involved carcinogenesis. Cancer Genome Atlas (TCGA) delivered large amount data allowed combine information on inflammatory microenvironment with gene data, genetic clinical-pathological characteristics, differentiation degree papillary carcinoma (PTC). Moreover, using new sensitive highly multiplex analysis, NanoString Technology, it possible divide tumors two main clusters based immune-related genes. Starting from these results, performed phenotype analysis classify cancers hot, cold, or intermediate depending infiltration patterns aim this review is provide updated knowledge landscape tumors. Understanding interactions crucial effectively direct immunotherapeutic approaches treatment cancer, particularly for those not responsive conventional therapies.

Язык: Английский

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KRAS-driven model of Gorham-Stout disease effectively treated with trametinib

JCI Insight, Год журнала: 2021, Номер unknown

Опубликована: Июнь 22, 2021

Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose and can have life-threatening complications, such as chylothorax. The etiology of poorly understood, current treatments for this are inadequate most patients. To explore the pathogenesis GSD, we performed targeted high-throughput sequencing samples from patient identified an activating somatic mutation KRAS (p.G12V). characterize effect hyperactive signaling on development, expressed active form (p.G12D) murine (iLECKras mice). We found that iLECKras mice developed which hallmark GSD. also valve development maintenance was altered mice. Because chylothorax died before they had significant bone disease, analyzed trametinib (an FDA-approved MEK1/2 inhibitor) regression Notably, suppressed phenotype Together, our results demonstrate mutations be associated reveal stimulates formation impairs valves. These findings provide insight into suggest could effective treatment

Язык: Английский

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Molecular diagnosis and targeted treatment of advanced follicular cell-derived thyroid cancer in the precision medicine era

Cancer Treatment Reviews, Год журнала: 2022, Номер 106, С. 102380 - 102380

Опубликована: Март 15, 2022

Most malignant thyroid tumours are initially treated with surgery or a combination of and radioactive iodine (RAI) therapy. However, in patients metastatic disease, many become refractory to RAI, these require alternative treatments, such as locoregional therapies and/or systemic treatment multikinase inhibitors. Improvements our understanding the genetic alterations that occur cancer have led discovery several targeted clinical efficacy. These include NTRK (neurotrophic tyrosine receptor kinase) gene fusions, tropomyosin kinase inhibitors larotrectinib entrectinib both approved by European Medicines Agency other markets worldwide. Inhibitors aberrant proteins resulting from RET (rearranged during transfection) BRAF (B-Raf proto-oncogene) also shown promising efficacy, so far received approval US Food Drug Administration. Selpercatinib, inhibitor, was for use Europe early 2021. With multiple actionable targets, it is imperative effective testing strategies integrated into diagnostic armamentarium ensure who could potentially benefit treatments identified. In this review, we offer recommendations on optimal detecting potential be molecular We discuss future cancers, including immune checkpoint inhibitors, new generations being developed counter acquired tumour resistance.

Язык: Английский

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Novel Therapeutics in Radioactive Iodine-Resistant Thyroid Cancer

Frontiers in Endocrinology, Год журнала: 2021, Номер 12

Опубликована: Июль 15, 2021

Iodine-resistant cancers account for the vast majority of thyroid related mortality and, until recently, there were limited therapeutic options. However, over last decade our understanding molecular foundation function and carcinogenesis has driven development many novel therapeutics. These include FDA approved tyrosine kinase inhibitors small VEGFR, BRAF, MEK, NTRK RET, which collectively have significantly changed prognostic outlook this patient population. Some therapeutics can re-sensitize de-differentiated to iodine, allowing radioactive iodine treatment improved disease control. Remarkably, is now an BRAF-mutated patients with anaplastic cancer, previously considered invariably rapidly fatal. The landscape iodine-resistant cancer changing new targets, therapeutics, clinical trials, treatments. We provide up-to-date review options in cancer.

Язык: Английский

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The central role of a two‐way positive feedback pathway in molecular targeted therapies‐mediated pyroptosis in anaplastic thyroid cancer

Clinical and Translational Medicine, Год журнала: 2022, Номер 12(2)

Опубликована: Фев. 1, 2022

Язык: Английский

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Target Therapy in Thyroid Cancer: Current Challenge in Clinical Use of Tyrosine Kinase Inhibitors and Management of Side Effects

Frontiers in Endocrinology, Год журнала: 2022, Номер 13

Опубликована: Июль 8, 2022

Thyroid cancer (TC) is the most common endocrine malignancy. TC classified as differentiated (DTC), which includes papillary and follicular subtypes Hürthle cell variants, medullary (MTC), anaplastic (ATC), poorly (PDTC). The standard of care in DTC consists surgery together with radioactive iodine ( 131 I) therapy thyroid hormone, but patients MTC do not benefit from I therapy. Patients advanced resistant to treatment (RAI-R) have no chance cure, well affected by ATC progressive MTC, conventional plays only a palliative role, representing, until few years ago, an urgent unmet need. In last decade, better understanding molecular pathways involved tumorigenesis specific histopathological has led develop tyrosine kinase inhibitors (TKIs). TKIs represent valid disease were tested all TC, highlighting need improve progression-free survival. However, treatments using these novel therapeutics are often accompanied side effects that required optimal management minimize their toxicities thereby enable who show continue obtain maximal clinical efficacy. goal this overview provide update on current use main drugs recently studied for adverse events.

Язык: Английский

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Peptide Receptor Radionuclide Therapy in Thyroid Cancer

Frontiers in Endocrinology, Год журнала: 2022, Номер 13

Опубликована: Май 30, 2022

The treatment options that are currently available for management of metastatic, progressive radioactive iodine (RAI)-refractory differentiated thyroid cancers (DTCs), and medullary (MTCs) limited. While there several systemic targeted therapies, such as tyrosine kinase inhibitors, being evaluated implemented in the these cancers, therapies associated with serious, sometimes life-threatening, adverse events. Peptide receptor radionuclide therapy (PRRT) has potential to be an effective safe modality treating patients somatostatin (SSTR)+ RAI-refractory DTCs MTCs. MTCs certain sub-types DTCs, Hürthle cell which less responsive conventional modalities treatment, have demonstrated a favorable response PRRT. current literature offers hope utilization PRRT cancer, areas this field remain investigated further, especially head-to-head comparisons other therapies. In review, we provide comprehensive outlook on translational clinical data use various PRRTs, including diagnostic utility analogs, theranostic properties PRRT, future research.

Язык: Английский

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Current and future of immunotherapy for thyroid cancer based on bibliometrics and clinical trials

Discover Oncology, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 25, 2024

Thyroid cancer is a leading endocrine malignancy, with anaplastic and medullary subtypes posing treatment challenges. Existing therapies have limited efficacy, highlighting need for innovative approaches.

Язык: Английский

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