RET rearrangement

P2, N=109, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2023 --> Sep 2024

A significantly higher proportion of ATCs expressed p53 and PD-L1, and a lower proportion expressed PAX-8 and TTF-1, than the coexisting DTCs. Our findings provide more reliable evidence that ATCs and PDTCs are derived from DTCs.

P2, N=88, Not yet recruiting, SWOG Cancer Research Network | Initiation date: Feb 2024 --> May 2024

There is a lower rate of BRAF V600E protein positivity in PTC combined with HT patients, as well as a higher rate of RET gene rearrangements positive in PTC combined with HT patients. There is a correlation between multifocality and BRAF V600E protein expression.

P2, N=125, Active, not recruiting, National Cancer Institute (NCI)

P1/2, N=589, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

Given its short turnaround time of about 3 h, it is a time-efficient upfront screening tool in FFPE samples, supporting rapid clinical decision making. Moreover, expression-imbalance-based detection of potentially novel fusions may be easily verified with other routine technologies without delaying treatment initiation.

The anti-PD-1 inhibitor-based combinational therapy elicited exciting anti-tumor efficacy and prolonged patient survival with manageable adverse effects in NSCLC patients harboring oncogenic alterations. The PD-L1 status and LIPI could be used as a biomarker predicting response to anti-PD-1 inhibitor-based combinational treatment in these patients.

The size of the tumor has a significant correlation with its aggressive characteristics. PTMC with a diameter of ≤5 mm should be distinguished and targeted as a unique subset for specialized treatment.

P2, N=20, Active, not recruiting, Washington University School of Medicine | Trial completion date: Dec 2023 --> Dec 2024

This provides insights into proper curative surgery timing in the management of patients with gene fusions. However, these findings must be treated with caution and validated in future multi-center studies with larger sample size.

Following the modest success of repurposed RET-active multikinase inhibitors, the first selective RET inhibitors (SRIs), selpercatinib and pralsetinib, received regulatory approval in 2020. The ideal next-generation SRIs will be active against on-target acquired resistance alterations, including those that emerge in the CNS, and will have improved safety and tolerability relative to first-generation SRIs. In this review, we will provide an update on these candidates and their potential to meet the unmet clinical need for patients who progress on first-generation SRIs.

In this study, we investigated PLM-101, a novel dual-target inhibitor of RET/YES1, which exhibits notable anti-cancer activities against CCDC6-RET-positive cancer cells and anti-metastatic effects against YES1-positive cancer cells. Our findings shed light on the significance of the YES1-Cortactin-actin remodeling pathway in the metastasis of lung cancer cells, establishing YES1 as a promising target for suppression of metastasis. This paper unveils a novel inhibitor that effectively targets both RET and YES1, thereby demonstrating its potential to impede the growth and metastasis of RET rearrangement lung cancer.

We present two cases of iT-LBP associated with HCC in novel settings-in post-liver transplant patients and in recurrent/metastatic sites of HCC. In addition, a comprehensive literature review of clinical, histological, and immunophenotypic characteristics of reported cases of iT-LBP is presented.

Furthermore, the LPCs derived from RET iPSCs exhibited a positive response to the RET inhibitor pralsetinib, evidenced by the downregulation of the cancer markers. This study provides a novel patient-derived off-the-shelf iPSC model of RET-driven NSCLC, paving the way for exploring the molecular mechanisms involved in RET-driven NSCLC to study disease progression and to uncover potential therapeutic targets.

Across studies, there was heterogeneity in treatment and patient characteristics and a lack of reporting on many important predictive and prognostic factors, including treatment regimens, patients' line of therapy, and tumor PD-L1 expression, which may explain the wide variation in objective response rate, progression-free survival, and overall survival across studies. Therefore, additional studies prospectively evaluating clinical outcomes of PD-1/PD-L1 inhibitors among patients with advanced or metastatic NSCLC whose tumors harbor emerging predictive or prognostic biomarkers are needed to determine whether this class of immunotherapy can provide additional survival benefits for these patients.

Small cell transformation was one mechanism by which EGFR-mutation NSCLC acquired resistance after tyrosine kinase inhibitors (TKIs) treatment. In addition, the APOBEC family of cytidine deaminases appeared amplification. Although RET rearrangement still existed, using another RET TKIs was ineffective, and etoposide plus platinum might be an effective rescue treatment.

Studies have shown that this mutation leads to activation of PKA, which, in turn, can induce FTC. In this comprehensive review, we aim to elucidate the intricate molecular mechanisms underlying thyroid tumorigenesis, specifically focusing on the deleterious consequences resulting from the deactivation of the PRKAR1A gene.

In contrast to some prior literature, this study reports detection of a wide variety of rearrangements in ctDNA. The prevalence of driver rearrangements in tissue and LBx was comparable when TF ≥1%. LBx presents a viable alternative when TBx is not available, and there may be less value in confirmatory testing when TF is sufficient.

P1/2, N=160, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting | Trial completion date: Aug 2025 --> Nov 2025 | Initiation date: Aug 2023 --> Oct 2023 | Trial primary completion date: Aug 2025 --> Nov 2025

Amplification of wild-type RET represents a novel, targetable molecular subset of cancer.

Molecular hyperselection and comprehensive genomic profiling have a potential usefulness in elderly patients with RAS/BRAF wild-type, pMMR/MSS mCRC, eligible for upfront EGFR inhibition.

This study suggests that the efficacy of combining pembrolizumab with pemetrexed and platinum-based chemotherapy differs according to the histo-molecular biomarkers, which may help to identify patients liable to benefit from CIT.

The clinical characteristics of primary AML with 11q23/KMT2A rearrangements are heterogeneous. Patients did not receive HSCT had poorer survival, particularly with the presence of t(6;11). Allo-HSCT could significantly improve the survival of such patients.

IO based treatments seem not detrimental for patients harboring novel driver alteration. Adding CT could improve modest responses to IO alone. Confirmation on larger datasets is required.

MET alterations in NSCLC typically occur in the absence of other oncogenic driver mutations and are associated with poor survival outcomes. Notably, METi therapies are associated with improved survival outcomes in patients with MET-dysregulated NSCLC.

Pathologists must be aware of these requirements to optimally triage tissue. Advances in colorectal cancer molecular diagnostics will continue to drive refinements in colorectal cancer personalized therapy.

P2, N=88, Not yet recruiting, SWOG Cancer Research Network

Among the 19 HTG-assay false negative samples, the preanalytical conditions were identified as the major factors impacting the assay efficiency. Overall, the HTG EdgeSeq assay offers comparable sensitivities and specificity than other RNA sequencing techniques, with the advantage that it can be used on very small and old samples collected multicentrically.

She responded to selpercatinib treatment with the elimination of supplemental oxygen need, marked reduction in pulmonary nodules and mediastinal lymphadenopathy, and biomarker decline. The response was maintained despite 2 dose reductions for possibly related weight gain.

Conclusions The combination of GGTT and osimertinib improves TTF and OS in EGFR mutation positive NSCLC patients failing osimertinib. Future prospective comparative study is warranted.

P2, N=20, Active, not recruiting, Washington University School of Medicine | Trial completion date: Jun 2023 --> Dec 2023

Here, we review the background of RET as a potential therapeutic target in neuroblastoma tumors and the results of recent preclinical studies and clinical trials evaluating the safety and efficacy of RET inhibition in adults and children. We also present a novel approach to drug discovery leveraging the chemical phenomenon of atropisomerism to develop specific RET inhibitors and present preliminary data demonstrating the efficacy of a novel RET inhibitor against neuroblastoma tumor cells.

In light of these findings, malignant struma ovarii might yield a clue to cervical thyroid carcinoma, and the molecular analysis could provide valuable information for understanding the underlying mechanism, tumor clinicopathological behaviors, and prognosis.

We conclude that resistance to low concentrations of BPA cytotoxic effects on mutated thyroid cells is due, at least in part, to DNA damage. Even doses of BPA that are considered acceptable can be genotoxic for normal thyroid cells but affect less thyroid mutated cells that can therefore be selected for and contribute to the emergence of thyroid tumors.

Treatment of stage III NSCLC has always been controversial and challenging: Multidisciplinary approach is mandatory and defining resectability is a critical issue. Chemo-radiotherapy followed by maintenance Durvalumab is now the standard of treatment. Herein, we provide a comprehensive overview of the key challenges and open questions that we are currently facing in clinical practice, in unresectable stage III and in early-stage NSCLC, identifying the knowledge gaps and the possible solutions.

There was no correlation between the presence of gene rearrangement and recurrence-free survival.Features associated with persistent/recurrent disease included pediatric population (p = 0.030), gene-rearranged tumors (p = 0.020), microscopic extrathyroidal extension (p=0.009), metastases at presentation (p=0.007) and Stage II disease (p=0.015).We conclude DS-PTC represents 1.9% of papillary thyroid carcinomas and actionable gene rearrangements are extremely common in DS-PTC. DS-PTC can be divided into two distinct molecular subtypes and all BRAF negative tumors (1.5% of papillary thyroid carcinomas) are driven by potentially actionable oncogenic fusions.

There were no instances of MSI in 56 non-colorectal tumors carrying ALK, ROS1, RET or NTRK1 rearrangements. An analysis of tyrosine kinase gene translocations is particularly feasible in KRAS/NRAS/BRAF wild-type microsatellite-unstable CRCs, although other categories of tumors with MSI also demonstrate moderate occurrence of these events.

P1/2, N=280, Recruiting, DualityBio Inc. | Not yet recruiting --> Recruiting

P2, N=56, Not yet recruiting, SWOG Cancer Research Network

The present study further supports that breast myoid hamartoma may be pathogenetically related to other benign fibroadipose/myomatous lesions sharing the same HMGA2 gene rearrangement. The expression of HMGA2 in myofibroblastoma and fibroadenoma with myoid metaplasia also indicates that these 2 lesions should be included among the lesions with HMGA2 rearrangement gene.

P2, N=0, Withdrawn, University of Washington | N=30 --> 0 | Not yet recruiting --> Withdrawn