RET mutation

This case highlights the importance of comprehensive genetic testing in patients with pheochromocytoma and paraganglioma, particularly when hereditary syndromes are suspected. Genetic insights ensure precise management, allowing for tailored treatment and improved outcomes in patients with hereditary pheochromocytoma and paraganglioma.

Therefore, a good understanding regarding the genetic and epigenetic modifications is not only essential for the diagnosis and prognosis of TC, but also for the development of novel therapeutics. In this review, most of the major TC-related genetic and epigenetic modifications and their potential as biomarkers for TC diagnosis and prognosis have been extensively discussed.

Our data demonstrate that British Thyroid Association U-score has limited value for medullary thyroid cancer detection in this high-risk group and cannot be used for risk stratification or surveillance. As a rarer thyroid cancer subtype, medullary thyroid cancer and the high-risk multiple endocrine neoplasia 2 population are under-represented in British Thyroid Association 2014 guidance and deserve consideration in future editions.

NGS technology can comprehensively analyze the genetic mutations in PTC patients, which provides important prompts for the occurrence, development, diagnosis and treatment of PTC. In addition, BRAF V600E mutation, RET fusion and TERT mutation are associated with a number of high-risk clinicopathological features. Detection of genetic mutations in PTC patients by NGS is of great significance.

Our study provides an example of implementation of molecular profiling in an academic pre-screening program. Further analysis will investigate treatment matching rates, drug access schemes, and their impact on treatment efficacy and survival.

4 pts received TT at recurrence, within clinical trials: one with grade 3 meningioma and ALK rearrangement treated with alectinib, one with PTCH1 mutant medulloblastoma treated with vismodegib, and two with high TMB treated with nivolumab/ipilumumab. The incidence of targettable molecular alterations in adult CNS tumor patients was lower than in GBM. Nevertheless, in a few selected cases TT have the potential to increase treatment options at recurrence and improve outcomes.

P4, N=100, Not yet recruiting, Anhui Chest Hospital; Anhui Chest Hospital

P1, N=388, Recruiting, Shanghai Chest Hospital; CSPC Megalith Biopharmaceutical Co., Ltd

P2, N=100, Active, not recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Recruiting --> Active, not recruiting | Trial completion date: Nov 2025 --> Mar 2028 | Trial primary completion date: Nov 2022 --> Mar 2025

The earlier diagnosis of MTC significantly improves survival and prompts better management of MEN2A. In this editorial, we will discuss the significance of molecular diagnostic approaches in detecting RET oncogene mutations in MEN2A.

The development of multi-kinase inhibitors cabonzantinib and vandetanib, and RET-targeted inhibitors selpercatinib, has completely changed the therapeutic arsenal for advanced disease, but their prescription is reserved to progressive disease with high tumor volume or to symptomatic disease inaccessible to local treatment in expert centers from the ENDOCAN-TUTHYREF network. Active surveillance is the alternative of choice for slowly progressing disease.

The prognosis of papillary thyroid carcinoma (PTC) is highly dependent on gene mutations and pathologic features.The common gene mutations in PTC include BRAF V600E,RET/PTC rearrangement,and RAS mutations.These mutations have been suggested to be associated with an increased risk of recurrence,poorer efficacy of postoperative radioactive iodine therapy,and reduced survival.The pathologic subtypes of PTC include classic,follicular,tall cell,hobnail,columnar cell,diffuse sclerosing,solid/trabecular,oncocytic,Warthin-like,clear cell,and spindle cell subtypes,which have different aggressiveness and linked with varied clinical prognosis.Therefore,detecting the gene mutations and pathologic subtypes of PTC is of great importance for therapeutic regimen selection and prognosis evaluation.Ultrasound imaging with non-invasiveness,convenience,and high resolution has become the primary examination method for the diagnosis and treatment of thyroid cancer.This paper reviews the correlations of gene mutations and pathologic subtypes with the ultrasound features of PTC,aiming to give new insights into the application of ultrasound imaging in predicting gene mutations and pathologic subtypes of PTC before surgery as well as provide new ideas for accurate assessment of preoperative prognosis.

Extrathyroidal extension was identified as the strongest prognostic factor for RFS and DSS. Older age and larger tumor size were associated with decreased DSS, while RET mutation and lymph node metastasis significantly impacted RFS.

However, for papillary thyroid carcinoma, sensitivity in Bethesda categories V and VI was 86% in non-AIT patients but decreased to 61.5% in AIT patients. These findings emphasize the importance of considering surgical intervention in pediatric patients with Bethesda III-VI cytology, particularly in those with AIT.

In addition, despite improved genotype/phenotype correlation in MEN2, we highlight that not all cases are 'typical' which emphasises the need for all MEN2 patients to be cared for in a centre of expertise and experience. Some of our case study patients or parents also took this opportunity to personally tell us more about their lives with MEN2, illustrating the need for more research into the psychosocial impact of these hereditary diseases.

Neoadjuvant use of tyrosine kinase inhibitors seems extremely effective in downstaging surgically unresectable differentiated thyroid cancers to achieve R0 resection while avoiding unnecessary surgical morbidities. A multidisciplinary approach with early genomic profiling to guide personalized neoadjuvant use of tyrosine kinase inhibitors is essential. Prospective studies are urgently needed to define the potential role of neoadjuvant tyrosine kinase inhibitors in advanced thyroid cancer management.

Long-term treatment with selpercatinib is feasible. AEs are manageable with dose modifications, allowing most patients to continue safely on therapy.

Together, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to differences in tumour progression and disease aggressiveness.

Importantly, in PK/PD studies, 39 exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound 3. Robust and sustained degradation of total-RET (tRET) protein and inhibition of phospho-RET (pRET) signaling were observed in TPC-1 xenograft tumors driven by RET and the RET/G810R mutant following a single dose of LDD 39 at 15 and 75 mg/kg, respectively.

At univariate analysis, factors associated with persistent and recurrent disease during follow-up in patients with sMTC were tumor size, extrathyroidal extension, presence of lymph node metastases at diagnosis, pre- and post-operative calcitonin, post-operative CEA; in patients with hMTC, features associated with persistent and recurrent disease were lymph node metastases, post-operative calcitonin and pre- and post-operative CEA values. Patients with hMTC and sMTC had similar histopathological characteristics and clinical outcome.

Improving our understanding of the genotype-phenotype correlations would allow individualizing the management and follow-up of patients with MEN 2. The aim of this brief review is to discuss the main genotype-phenotype correlations in MEN 2 and the potential factors that might influence these correlations.

However, ethnicity has not been found to be associated with this driver mutation, unlike, for example, EGFR-mutated lung adenocarcinoma and its association with Asian women. In this case series we describe three patients identified as having a RET mutated lung adenocarcinoma, all of whom were originally from Honduras, presenting over the course of three years (3/2022, 5/2023, 6/2020).

No abstract available

P1/2, N=125, Recruiting, Kahr Medical | Trial completion date: Dec 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

The diagnosis of MEN2B is made with the confirmation of the autosomal dominant genetic mutation or a mutation of the RET gene. In the absence of these mutations, the majority of clinical manifestations should be present.

P1, N=110, Active, not recruiting, Eli Lilly and Company | Trial primary completion date: Jun 2025 --> Sep 2024

Our results regarding the proportion of samples with actionable mutations demonstrate the value of NGS testing for NSCLC patients in a real-world clinical diagnostic setting.

This mutation does not directly alter the catalytic region, which may explain its association with later onset disease. This case highlights the increasing availability of genetic risk information and the need for correlation to disease penetrance and phenotypes.

Objective: In 2022, the OncomineTM Dx Target Test (ODxTT) was approved in Japan as a companion diagnostic for selecting patients eligible for selpercatinib for advanced thyroid cancer, introducing a multigene test for thyroid cancer... A total of 571 patients were enrolled. There were 357 women (62.5%) and 214 men (37.5%) with a mean age of 65.9 ± 14.2 years. Four hundred and 18 (73.2%) were papillary carcinoma (PTC), 56 (9.8%) follicular carcinoma (FTC), 31 (5.4%) poorly differentiated carcinoma (PDTC), 38 (6.7%) anaplastic carcinoma (ATC), 21 (3.7%) medullary carcinoma (MTC), and 7 (1.2%) others.

The patient recovered well after surgery, demonstrating the potential efficacy of neoadjuvant pralsetinib in locally advanced RET-rearranged lung adenocarcinoma. However, further clinical validation is required to establish the role of neoadjuvant targeted therapy and postoperative adjuvant therapy in this patient population.

This multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment...Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options...Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects.

OSMR p. G513D may play a role in modifying the evolutionary processes of CLA in subjects co-harboring RET mutations (further studies are necessary to sustain this aspect). Awareness in CLA-positive patients is essential, including the decision of RET testing in selected cases.

SEZ6 may serve as a novel biomarker for MTCs. Although SEZ6 lacks any prognostic values in MTC, its positivity in 91% to 93% of MTCs, including MTCs without RET and RAS mutations, renders SEZ6-targetted antibody-drug conjugate therapy a promising targeted therapy for MTCs.

Herein, we present our investigation into the side chains of imidazopyridazine hinge binders that are capable of inducing protein-ligand interaction patterns from the gatekeeper to the waterfront regions. Extending the substituents at the second and sixth positions enhanced the IC50 up to < 0.5 nM for diverse RET alterations.

In patients receiving an early diagnosis of MEN2 via family screening, prophylactic thyroidectomy taking into account the RET mutation risk group can achieve a long-term cure of MTC with undetectable serum Ctn levels.

P=N/A, N=186, Recruiting, Yongchang Zhang | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=130, Recruiting, National Cancer Institute (NCI) | N=90 --> 130

Known under low incidence – mutations require research for 0.4% to 1.1 in pulmonary adenocarcinomas, IDH1/2 inhibitors prescription due to high prevalence of lung carcinoma worldwide. Mutations in IDH1/2 gene may be branching drivers leading to lower subclonality evolution with predictable benefit of IDH1/2 inhibitors.The accumulation of more known cases with IDH1/2 mutations is necessary to elucidate clinicopathological characteristics/clinical evolution after target therapy, in order to reforce the new interpretation of malignant tumours postponed survival through conversion of cell cycle.

In this study, an increase in M classification cases was found in the RET rearrangements group. However, genetic mutations were not associated with the clinical stage, and no factors that could be incorporated into the treatment algorithm were identified.

The case presented contributes to the better understanding of this SOT tumor entity and to indicates its malignant evolution, together with its biological behavior and its histologic, clinical, and radiographic features. Also, it aims to stress the importance of deeper genetic analyses in rare diseases to uncover mutations that help to select a personalized treatment.

EGFR inhibition with afatinib or cetuximab in combination with RET TKIs was effective in addressing drug persistence. Consistently, knocking out EGFR or RET led to high sensitivity to RET or EGFR inhibitor respectively. Here, we have provided a comprehensive analysis of adaptive and acquired resistance against RET-rearranged NSCLC.