RET (Ret Proto-Oncogene)

In this cohort study that includes 245,394 genotyped participants in the All of Us Research Program (AoU), the prevalence was 1:2,172 for multiple endocrine neoplasia type 2 (MEN2) and 1:8,764 for PTEN hamartoma syndrome (PHTS). The prevalence of MEN2 and PHPS is ∼10-20 times higher than currently estimated for the general population.

EGFR mutations, especially rare variants (G724A, L747P, Q701 L, G719C, V769 L and S768I), exhibited significant enrichment in the non-AM group (P<0.001)...Meanwhile, patients with adrenal metastases harboring ALK or KRAS mutations have a poor prognosis and require more aggressive treatment. The TNF and TGF-β pathways might be associated with adrenal metastasis.

RET pathogenic variant (p.Cys634Trp) associated with MEN2A syndrome was the most prevalent in Romanian population with PPGLs and could be considered as a founder effect. Patients with hereditary disease are diagnosed at a younger age and develop bilateral tumors more frequently compared to sporadic cases.

In summary that increased breast cancer risk with the G allele in NRTN gene IVSI-663 polymorphism, as well as the increased serum NRTN and FAK levels, will contribute to the diagnosis, prognosis and determination of new treatment strategies.

To the best of our knowledge, this is the first clinical case report in the literature describing the benefit of anlotinib and sintilimab treatment for non-small cell lung cancer with RET fusion and high PD-L1 expression. This study explores the biomarker selection for targeted therapy and combined immunotherapy in NSCLC patients.

P2, N=175, Active, not recruiting, German Cancer Research Center | Recruiting --> Active, not recruiting

No abstract available

Understanding these mechanisms is crucial for identifying therapeutic opportunities to overcome resistance. Successful treatment targeting bypass oncogenes has been reported in several instances, at least for short-term outcomes; in contrast, although several compounds have been reported to overcome on-target RET alterations, none have yet been translated into routine clinical practice and this remains an area of urgent clinical need.

Proteins were precipitated with acetonitrile, and selpercatinib and the internal standard (gefitinib) were separated via HPLC-UV. Thus, this study establishes a simple and sensitive method for quantifying selpercatinib in human plasma. Future studies will analyze plasma samples from patients treated with selpercatinib and utilize this method to explore the relationships among plasma concentration, efficacy, and adverse events to define the therapeutic concentration range.

Patients were treated with selpercatinib (n = 13) or pralsetinib (n = 10), 57% (13/23) within a clinical trial. In patients with advanced hMTC, selective RETis appear safe and effective with outcomes similar to clinical trial cohorts, which mostly comprised patients with sMTC. Duration of response and AE profile was similar to sMTC, although longer follow-up and larger patient numbers are needed to confirm this.

Pralsetinib and selpercatinib have been approved as specific tyrosine kinase inhibitors (TKIs) for the treatment of patients with non-small cell lung cancer (NSCLC) harboring rearranged during transfection (RET) fusion and mutation. In this case, invasive aspergillosis that appeared concurrent with RET-TKI targeted therapy is proposed to be an additional adverse drug reaction (ADR) that was not mentioned in previous reports. Here, we describe the process of clinical diagnosis and treatment of invasive aspergillosis and attempt to explore its possible pathogenesis in association with RET-TKI targeted therapy, with the aim of providing clinicians a more in-depth understanding of the ADR associated with RET-TKIs, as well as to prevent serious outcomes caused by reduction or discontinuation of antitumor therapy.

It is paramount to stay vigilant concerning the potential emergence of three newly identified AEs. Significant differences were found in selpercatinib-related AEs concerning reporter continent, sex, weight, dose, frequency, and onset time, which deserved clinical attention. These findings contribute to a broader understanding of the AE profiles of selpercatinib.

P1, N=36, Recruiting, Transgene | Trial completion date: Mar 2025 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

Emergence of RTK fusions is one of the mechanisms of bypass resistance of EGFR TKI. Dual inhibition of EGFR-RTK was safe and efficacious in patients with targetable RTK fusion post progression on EGFR TKIs.

SGIC is a histopathologically and molecularly heterogeneous lesion with an overall excellent prognosis. The presence of invasive lesions, as well as lymph node or distant metastasis, has emerged as one of the most critical prognostic factors in SGIC patients.

Survival outcomes observed in our cohort mirror those reported in the literature and highlight the need for improved therapy options, especially in those presenting with metastatic disease. Our data reaffirmed a lack of survival benefit with adjuvant radiotherapy for MTC with a high rate of systemic relapse and future research should focus on evolving mechanisms of resistance to novel tyrosine kinase inhibitors.

Interestingly, after ablation, distention also increased the frequency of non-voiding contractions, a poorly understood phenotype of several urologic diseases. These genetic strategies comprise critical new tools to advance the study of mechanoreceptors in bladder function and urologic disease pathophysiology.

In this context, peptide receptor radionuclide therapy (PRRT) may be a treatment option, but its clinical utility remains under investigation. The aim of this review is to evaluate the evidence of PRRT in MTC and discuss its limitations in the RET inhibitor era.

Through highly sensitive and selective technologies we show Gfral expression is overwhelmingly restricted to the brainstem and expect that GDF15 and GFRAL-based therapies in development for cancer cachexia will specifically target AP/NTS cells.

P2, N=124, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jan 2025 --> Dec 2025 | Trial primary completion date: Jan 2025 --> Jun 2025

Thus, the patient was considered to have multiple primary lung cancers. In such cases, whole-exome sequencing can distinguish whether the nodules have the exact origin.

Nodules with RAS mutations (NRAS, KRAS, HRAS) and TP53 inactivating mutations were considered to be in the intermediate-risk group, while those with non-pathogenic mutations (negative and variants of uncertain significance) were placed in the low-risk group. When combined with cytopathology, NGS increases the sensitivity of diagnosing benign and malignant thyroid nodules, and the reference is useful for patient risk stratification.

Our pharmacovigilance analysis of real-world data from the FEARS database revealed the safety signals and potential risks of pralsetinib usage. These results can provide valuable evidence for further clinical application of pralsetinib and are important in enhancing clinical medication safety.

P3, N=121, Recruiting, Hoffmann-La Roche | Trial completion date: Apr 2035 --> Sep 2033 | Trial primary completion date: Jun 2029 --> Aug 2032

This case series highlights the following key message: awareness of the dermatologic findings in MTC/MEN2 patients is essential since lesions such as cutaneous lichen amyloidosis might represent the skin signature of the endocrine condition even before the actual endocrine manifestations. These data add to the limited published reports with respect to this particular presentation, noting the fact that RET-C634 is the most frequent pathogenic variant in MEN2-associated lichen amyloidosis; females are more often affected; the interscapular region is the preferred site; the age of diagnosis might be within the third decade of life, while we reported one of the youngest patients with the lesion. The same RET pathogenic variant is not associated with the same dermatologic features as shown in the vignette. The same RET mutation does not mean that all family members will present the same skin anomaly.

Some of these targeted therapies have already been approved by the Food and Drug Administration (FDA), and many others are currently undergoing clinical trials. This review summarizes recent advances in NSCLC treatment with molecular targets, highlighting progress, challenges, and their impact on patient prognosis.

Conclusion  ERBB2 mutations and RET fusions are early genomic events in LUAD, while TP53 and CDKN2A mutations and ALK fusions occur later. Genomic intratumor heterogeneity likely arises early, before invasive characteristics develop.

These cases highlight the potential efficacy of selpercatinib in treating intracranial metastases in RET fusion-positive patients with NSCLC after pralsetinib-refractory progression. The key takeaway is that selpercatinib may offer a viable treatment option in such scenarios, although more extensive studies are needed to determine its role as a monotherapy or in combination with other treatments.

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.

Patients diagnosed with PTC harboring RET fusion presented with distinctive clinical characteristics and sonographic patterns, underscoring the unique diagnostic value of ultrasound examination. It can provide a preoperative non-invasive primary screening method for RET-fusion diagnosis, thus facilitating targeted patients with purposeful molecular sequencing to improve treatment outcomes.

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.

Blood-based LB performed by NGS is a non-invasive viable alternative tool for molecular genotyping and identifiy tumor-derived somatic alterations to increase the number of pts elegible to target therapy and guide personalized medicine.

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.

Although further research is needed to firmly establish a possible association, this case also highlights the necessity of exploring genetic backgrounds when patients present with clinical manifestations not readily explained by a single endocrine disorder. Investigating potential genetic associations is crucial since a positive genetic test allows for the testing of relatives, genetic counseling, and proper surveillance of individuals at risk.

Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers...It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.

IF-PTC from the isthmus is molecularly different compared with IF-PTC from the lobes. More data are needed to know if a change in surgical therapy is warranted in isthmic thyroid cancers relative to lobar cancers and if this molecular data should influence isthmic thyroid cancer management and monitoring.

Genomic profiling yields clinically actionable information for approved therapies and evidence of resistance, and it may uncover rational therapeutic opportunities regardless of tumor type.

AFP, the targeted, breakpoint/fusion partner agnostic panel, outperformed 3 other established panels using real-world, fusion-driven thyroid cancers by an average detection frequency of 39%. Such findings demonstrate the importance in sequencing panel selection for fusion-driven thyroid cancer detection, and the potential downstream consequences for diagnostic utility and therapeutic intervention.

Given the importance of timely, comprehensive molecular test results to inform appropriate treatment decisions in NSCLC and CRC, these results suggest that the rapid in-house GeneXus NGS system can reduce TAT with comparable failure rates and alteration detection rates compared to other testing methods. Further studies evaluating the impact of the rapid OPA compared to other methods on patient care, as well as the economics of different molecular tests, are ongoing.

The routine use of RNA-based CGP analysis allows for the comprehensive detection of oncogenic fusions in patients with cancer. The diversity of tumor types in which actionable fusions were detected supports the broader utilization of CGP to potentially increase targeted therapy usage and improve outcomes across cancer subtypes.