RET M918T

We previously showed that the multi-kinase inhibitors vandetanib and cabozantinib increase the mitochondrial membrane potential (Δψm) in RET-mutated thyroid tumor cells and that this effect can be exploited to increase mitochondrial enrichment of Δψm-sensitive agents in the tumor cells...The quality of life of one patient significantly improved over a year until the tumor relapsed. This combination of selpercatinib with MitoQ may have therapeutic potential for patients with RET-mutated tumors and intolerant to regular selpercatinib doses.

Bypass resistance may be the most frequent mechanism of progression under RETi. A more aggressive histology may arise following RETi and warrants further investigation.

IMTCGS grading was associated with DSS independently of other clinical, pathological, and molecular factors. Moreover, MTC grading was associated with RET and RAS patterns, which explains, at least in part, the molecular basis of the aggressive behavior of high-grade MTC.

Our work suggests that papillary-like nuclear features in MTC may be associated with high-grade tumors. These findings may be cytologically indicative of high-grade tumors other than necrosis or mitosis.

Multi tyrosine kinase inhibitors (mTKIs) cabozantinib and vandetanib are good first line options, even vandetanib prescription is currently limited to RET mutated patients. Selective RET inhibitors such as pralsetinib could be a preferred upfront treatment in case of RET mutated MTC presenting common or gatekeeper RET mutations (e.g. M918T; V804L/M). Selpercatinib, otherwise, can be prescribed as the second line after disease progression to mTKIs. The best option for subsequent lines is to consider inclusion in clinical trials or alternatively other mTKIs such as sunitinib, sorafenib, lenvatinib, or pazopanib could be evaluated. New perspectives include next-generation RET inhibitors able to overcome resistance mechanisms responsible for disease progression to standard mTKIs and RET inhibitors, and immunotherapy for MTC presenting with high tumor mutational burden.

RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage . RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased overall and disease-specific survival in MTC but its prognostic value needs to be confirmed in future studies.

Other factors might however impact the natural history of the disease, such as RET polymorphisms, epigenetic factors, environmental factors, MET (mesenchymal-epithelial transition) alterations, or even other genetic alterations such as RAS family (HRAS, KRAS, NRAS) genetic alterations. This review will detail the molecular bases of MTC, focusing on RET pathways, and the potential mechanisms that explain the phenotypic intra- and interfamilial heterogeneity.

In weighted comparison, selpercatinib demonstrated a significant improvement in ORR, PFS and OS versus cabozantinib. A limited number of covariates were available for adjusting selpercatinib data. Hence, there is a risk of unmeasured confounding that could influence these findings.

He began treatment with vandetanib, a multityrosine kinase inhibitor, which resulted in decreased tumor burden as well as clinical and biochemical resolution of ECS. Due to progressive structural disease 10 months later, he was switched to the selective RET inhibitor selpercatinib, which was followed by a rapid reduction of cortisol nearing the threshold of adrenal insufficiency...Selective RET inhibitors may emerge as preferred targeted treatment options due to better efficacy and toxicity profiles compared to multikinase inhibitors. Clinicians should monitor for adrenal insufficiency following treatment of paraneoplastic ECS with selective RET inhibitors.

RET-mutant MTC correlates with better OS, as previous studies have demonstrated with RET M918T carriers. NGS, FISH and IHC comparison is underway.

We treated both mouse models with multikinase inhibitors (MKI) (cabozantinib, lenvatinib and axitinib) or with a selective RET inhibitor (BLU667)...Such immune reaction affected the gene expression of both cancer (human) and stroma (mouse) cells. Conclusions These results pave the way for a rational combination of RET inhibitors and immunotherapy in the two scenarios, as primary therapy to reduce the minimal residual disease and at time of resistance to selective RET inhibition.

No abstract available

Due to concern about ability to tolerate thyroidectomy, the patient was begun on selpercatinib, an oral chemotherapeutic agent specifically for tumors with disruption of RET gene...Now, 3 months out from pamidronate and her hypercalcemia has not recurred. Hypercalcemia in pediatric patients with low PTH should prompt further workup including PTHrP measurement. In this case, we report a case of a child with MEN 2A and metastasized MTC with hypercalcemia attributable to PTHrp secretion.

The V804M RET variant has been often associated with MTC or MEN2A phenotypes [1]. However, the variable expression of this variant may lead to a mild clinical phenotype or even absence of MTC/MEN2A manifestations. Hence, active surveillance as opposed to radical surgery like prophylactic thyroidectomy would be more beneficial in patients with no clinical or biochemical evidence of disease.

Vandetanib and octreotide were previously trialed but discontinued due to financial constraints... Severe hypokalemia causes autophagic degradation of aquaporin-2 channels in the renal tubules and is an under-recognized cause of NDI. Profound hypercortisolism in ectopic-CS may result in cortisol-mediated overactivation of mineralocorticoid receptors that can cause renal potassium loss leading to NDI. Only 0.6% of MTCs are associated with ectopic-CS (PMID: 16029131).

1)This is the largest study comprising 61 patients after screening 24 family members in India. 2)Synchronous presentation of MEN2 with PCC and MTC is 67% vs 17% in western literature in Index patients.3)MEN2 syndrome should be suspected in patients with MTC and young-onset PCC and all first-degree relatives of index patients with this syndrome*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins.

Due to concern about ability to tolerate thyroidectomy, the patient was begun on selpercatinib, an oral chemotherapeutic agent specifically for tumors with disruption of RET gene...Now, 3 months out from pamidronate and her hypercalcemia has not recurred. Hypercalcemia in pediatric patients with low PTH should prompt further workup including PTHrP measurement. In this case, we report a case of a child with MEN 2A and metastasized MTC with hypercalcemia attributable to PTHrp secretion.

In addition to well-characterized extra-endocrine manifestations of MEN2B, patients with this syndrome may also have neurological, gastrointestinal, and genitourinary issues. Recognition of these features of MEN2B may facilitate earlier diagnosis of patients with this rare syndrome.

In the entire cohort and in sporadic cases, RET mutation correlates with high-grade, aggressive primary tumor characteristics, and decreased DMFS and LRRFS, but in contrast to grade does not impact DSS. RET p.M918T is associated with high-grade and aggressive primary tumors but does not impact outcome.

Patient was started on Selpercatinib 160 mg twice daily as well as Levothyroxine 25 mcg daily (TSH had increased to 4.5 uIU/mL (0.358‐3.740 uIU/mL)). More recently, RET inhibitors, like Selpercatinib, have shown promising results with significantly less side effects. These may prove to be an effective bridge to surgery for initially unresectable tumors.

Our study showed that sMTC patients harboring somatic RET mutations had similar clinical outcomes as those with RAS alterations and RET/RAS WT tumors. In the era of NGS testing for advanced sMTC for clinical indications, somatic RET alterations, including the novel RET deletions described here, do not appear to portend a worse overall survival.

Pts received RETi after a median number of 1 treatment line (range 0‐6) and 83% had received vandetanib (V) prior to RETi... By‐pass resistance MA may be the most frequent mechanism of progression under RETi. More aggressive histology may arise following proghression; further explorations are warranted.

Two FDA-approved RET inhibitors-pralsetinib and selpercatinib have been implied for the treatment of patients with RET S891L mutant UCEC and the treatment of patients with metastatic RET-fusion positive THCA and non-small cell lung cancer (NSCLC) at therapeutic level 1. At last, patients with higher expression and sequence variant frequency have a worse prognosis, such as sarcoma patients. This work provided a profound and comprehensive analysis of RET and co-occurred alterations, RET mRNA expression and the clinical significance in pan cancer, offering new insights into targeted therapy for patients with RET anomalies.

In patients with MTC, AE, necrosis and high MI were associated with poor OS, thus validating the prognostic value of IMTCGS in an independent cohort. Ten of the high grade and seven of the low grade RET_M918T mutated cases experienced relapse, suggesting that this biological trait may represent an independent biological prognostic factor from IMTCGS. Analysis of a larger panel is necessary to confirm these data.

The Ki-67 index was correlated with neither PD-L1 expression nor major genetic alterations. Our results indicate that immunotherapy targeting PD-L1/PD-1 might be more effective for patients with sporadic medullary thyroid carcinoma harboring HRAS mutations.

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.

Pre-operative ctDNA in medullary thyroid cancer is not useful for diagnostic purposes, but it can be useful for predicting the outcome of the disease. In our series, post-operative ctDNA showed a potential for monitoring the response to therapies, but further studies are required to confirm our results.

The preclinical data presented herein demonstrate the potential of using genetically engineered T cells targeting CEA, calcitonin, and/or RET M918T to treat metastatic MTC.

MTC rarely shows a tumor capsule, which seems to correlate with a better prognosis and absence of nodal metastases, regardless of RET or RAS mutational status. Among encapsulated MTCs (E-MTC), Ctn levels and tumor size are not predictive of persistence of disease after surgery.

Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. APS03118 is a novel highly selective next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFMs-mediated resistance. A first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022.

For the treatment of advanced/metastatic MTC, no specific preference of sequencing systemic agents was observed in the first- and second-line settings. Considering the recent approval of selective RET inhibitors for patients with RET-mutant MTC, future research should investigate how treatment patterns evolve for these patients.

Although different circulating biomarkers contributed to MTC have been discovered, a few of them could be used in clinical diagnosis. In many cases, the application of each marker may not be useful lonely; therefore, a combination of two or more biomarkers could open a new avenue in the diagnosis, prognosis and prediction of MTC.

The patient responded partially to vandetanib and the disease has shown no progression in 25 months...The mother was uninformed about the genetic characteristics of MEN2B, delaying the detection of MTC in her children. The present study reaffirms the importance of family history and screening.

Irrespective of the driving mutation, SSVs in RET occured in high frequency in MTC. The identification of RET SSVs in MTC might represent a novel diagnostic feature for this tumor and may represent an opportunity for better understanding its pathogenesis. Additional work is needed to explore any potential options for targeted therapy for MTC with RET SSVs.

In advanced breast cancer, 28% with PIK3CA mutations received Alpelisib. Erdafitinib was used in 60% of bladder cancer patients with FGFR3 mutation. All patients with NTRK3 fusion received Larotrectinib...Off-label use of targeted therapy was uncommon, occurring in <1% of patients; examples include Binimetinib+Encorafinib for BRAF V600E (lung), Vendatinib for RET M918T (lung), Afatinib and Neratinib for ERBB2 S310F (lung and breast), and Olaparib for BRCA1 mutated colorectal cancer... We demonstrate that automated data mining can provide insights into the genomic and therapeutic landscape of a real-world patient population. Across all tumor types, most patients are being given appropriate targeted therapies as per guidelines or, more rarely, offlabel. Early-stage patients were less likely to have been treated with targeted therapies, and genetic testing results may become actionable as their disease progresses and new drugs are approved.

RET mutation detection is a promising/golden screening test and provides an accurate presymptomatic diagnostic test for at-risk carriers (the siblings and offspring of the patients) to consider prophylactic thyroidectomy. Thus, according to the ATA recommendations, the screening of the RET proto-oncogene is indicated for patients with MTC.