RET rearrangement

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.

Most treatment-emergent adverse events were mild-to-moderate in severity. The study closed before the planned number of patients were enrolled in all cohorts. Sitravatinib had a manageable safety profile with modest signals of clinical activity in patients with molecularly selected solid tumors.Clinical trial registration: www.clinicaltrials.gov identifier is NCT02219711.

It is feasible to yield actionable molecular testing results from cytology specimens within 2 to 3 hours of the patient's diagnostic procedure, and aspirate smears can be triaged for this use at the time of the rapid on-site evaluation. Targetable genetic alterations can be detected from destained cytology aspirate smear slides and unstained FFPE cell blocks with high accuracy, precision, and analytical sensitivity and specificity. The cost of each cartridge ranges from $127 to $462 and is covered by the average national reimbursement schemes.

The AVENIO CGP Assay demonstrated high agreement with 2 established CGP tests, F1CDx and PGDx, in variant reporting, and closely aligned with F1CDx in HRDsig analysis across various tissue types. These results highlight the assay's reliability and demonstrate its utility in translational research.

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

Overall, both existing literature and our data suggest that RET-FISH testing can be used for rapid screening of RET rearrangements in NSCLC. Nevertheless, using an orthogonal technique such as RNA-seq to confirm RET-FISH-positive cases is essential for ensuring that only patients likely to benefit from RET-target therapy receive the treatment.

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.

This study encapsulates the research endeavors and treatment advancements of RET rearrangement solid tumors within the Chinese healthcare landscape, specifically highlighting the diverse real-world therapeutic approaches and their effectiveness in managing advanced RET rearrangement NSCLC among Chinese patients. Notably, targeted RET inhibitors like Pralsetinib have emerged as potent therapeutic agents, exhibiting remarkable efficacy and a manageable safety profile in this patient cohort. These findings underscore the potential of Pralsetinib and similar targeted therapies as novel treatment options for individuals with RET fusion-positive NSCLC.

P2, N=88, Recruiting, SWOG Cancer Research Network | Not yet recruiting --> Recruiting

The finding of synchronous mutations is a rare occurrence suggesting for intratumoral heterogeneity (ITH) even in PTC. Patients with multiple mutations have a clinical worse prognosis, generally characterized by an aggressive thyroid cancer, which may influence the surgical treatment, chemotherapy, and BRAF V600E mutation-targeting therapy.

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.

The patient is alive 24 years after resection with no additional recurrences. Bronchial SP needs to be recognized and distinguished from other benign and malignant salivary gland and pulmonary neoplasms so that patients can receive appropriate treatment and follow-up.

P2, N=56, Recruiting, SWOG Cancer Research Network | Not yet recruiting --> Recruiting

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.

We conclude that FFPE-TLC sequencing enables the detection of tumor-specific SVs caused by chromosomal rearrangements and LINE retrotranspositions in FFPE tissue. Therefore, FFPE-TLC sequencing facilitates the investigation of the biological and clinical impact of SVs using FFPE material from (retrospective) cohorts of cancer patients and has potential clinical applicability to detect SV biomarkers in the routine molecular diagnostics setting.

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.

This suggests that additional factors beyond the immune environment may also influence immunotherapy responses in LUAS, highlighting the need for further investigation. Table 1: Genomic/Immune landscape of LUAS, AC, SCC along with LUAS primary and metastatic sites Adenosquamous (LUAS, n =374) Squamous (SCC, n = 9635) Adenocarcinoma (AC, n = 25665) p-value (SCC vs LUAS) p-value (AC vs LUAS) Overall Actional Alteration Prevalence EGFR, ALK, ROS1, RET fusions /rearrangements, METex14, BRAF V600E, KRAS G12C, NTRK fusions, HER2 110 (29.4%) 343 (3.67%) 9267 (36.22%) 1%) 228 (65.5%) 5293 (59.8%) 12789 (53.7%) 0.033 50%) 110 (31.6%) 2119 (26.3%) 6218 (31.2%) 0.0293 0.1843 PD-L1 low (1-49%) 112/348 (33.9%) 3009/8045 (37.8%) 6177/20023 (30.8%) 0.048 0.512 No PDL1 (0%) 126/348 (36.2%) 2917/8045 (35.9%) 7628/20023 (38.1%) 0.984 0.3621 TMB High ( > 10 Mut/MB) 112 (30.6%) 3488 (38.47%) 8159 (32.94%) 0.002 0.344 Tumor microenvironment LUAS Median cell fraction (%) SCC Median cell fraction (%) AC Median cell fraction (%) p-value (SCC vs LUAS) p-value (AC vs LUAS) Monocytes 0.02 0.06 0.10 0.138 0.017 T cells CD4 0.04 0.07 0.11 0.274 0.130 Neutrophils 5.57 5.23 4.85 0.165 0.020 NK cells 2.68 2.49 2.94 0.005 <0.001 T cells CD8 0.39 0.11 0.27 <0.001 0.164 Macrophages M2 6.08 4.65 6.19 <0.001 0.172 Macrophages M1 4.57 2.64 5.12 <0.001 0.005 B cells 4.08 4.19 3.87 0.092 0.160 Dendritic cells 0.61 1.07 0.54 <0.001 0.049 Tregs 2.92 1.75 2.76 <0.001 0.365 Immune-related genes LUAS Median Gene expression median ((Log2 (TPM+1)) SCC Median Gene expression median ((Log2 (TPM+1)) AC Median Gene expression median ((Log2 (TPM+1)) p-value (SCC vs LUAS) p-value (AC vs LUAS) PDCD1LG2 1.447 1.319 1.284 0.009 <0.001 PDCD1 0.817 0.711 0.790 0.003 0.251 CTLA4 1.914 1.629 1.638 <0.001 0.001 CD86 3.534 3.218 3.482 <0.001 0.337 ID01 2.850 2.300 2.241 <0.001 <0.01 CD274 3.210 3.122 3.031 0.717 0.132 CD80 2.888 2.569 2.798 <0.001 0.453 HAVCR2 4.511 3.999 4.499 <0.001 0.739 LAG3 1.037 1.043 0.865 0.466 0.001 IFNG 0.841 0.697 0.691 0.026 0.025

Notably, individuals with exclusive reciprocal rearrangements of RET or ROS1 might be less prone to co-mutations in TP53, ATM, and ARID1A, than are those with detectable activating rearrangements. This emphasizes the significance of evaluating co-mutations in DNA repair genes alongside fusions to refine treatment approaches.

For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

Coexisting RET/PTC and TERT promoter mutation identify PTC as a unique clinical entity with high mortality, providing new implications for genetic-based prognostication and potential therapeutic targeting of RET and MEK guided by RET/PTC and TERT status.

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.