Sporadic and Familial Medullary Thyroid Carcinoma: A Retrospective Single Center Study on Presentation and Outcome.

BACKGROUND: Medullary Thyroid Carcinoma (MTC) is a neuroendocrine tumor that arises from the thyroid C-cells. Most cases are sporadic (sMTC) while, approximately 25%, are hereditary (hMTC) due to germline mutations of REarranged during Transfection (RET) gene mutations and manifest in the framework of multiple endocrine neoplasia (MEN) 2A or 2B, or as pure familial MTC syndrome (FMTC). OBJECTIVE: The aim of this study is to evaluate the clinical, histopathological, biochemical and outcome differences between sMTC and hMTC. METHODS: Retrospective analysis of a consecutive series of 102 patients with histologically proven MTC diagnosed in the period between 2000 and 2022. For the analysis patients with MTC diagnosed during screening through genetic test were excluded. RESULTS: Patients with hMTC had higher incidence of multifocal and bilateral MTC and younger age at diagnosis. We did not found differences on tumor stage at diagnosis between sMTC and hMTC, such as time to progression and rate of persistent and recurrent disease. 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. CONCLUSION: Patients with hMTC and sMTC had similar histopathological characteristics and clinical outcome.

Cost-effectiveness analysis of selpercatinib versus chemotherapy and pembrolizumab in the first-line treatment of rearranged during transfection fusion-positive non-small cell lung cancer in the United States.

BACKGROUND: Although selpercatinib has shown clinical benefits for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), its cost-effectiveness requires further evaluation. AIM: This study aimed to evaluate the cost-effectiveness of selpercatinib versus chemotherapy and pembrolizumab in the first-line treatment of RET fusion-positive NSCLC from the perspective of the United States (US) payer. METHOD: A partitioned survival model was developed based on data from the LIBRETTO-431 trial. Cost and utility values for the health state were obtained from database data or published literature. The measured outcomes included quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis and probabilistic sensitivity analyses (PSA) were conducted to assess the uncertainty of the model. RESULTS: Selpercatinib increased QALYs in patients with RET fusion-positive NSCLC by 0.90 compared to chemotherapy plus pembrolizumab, with an additional cost of $542,517.45, resulting in an ICER of $603,286.49/QALY, which exceeded the willingness-to-pay (WTP) threshold ($150,000) in the US. One-way sensitivity analysis suggested that the utility of progressed disease, the utility of progression-free survival, the price of selpercatinib, the discount, the price of pemetrexed, and the price of pembrolizumab had the greatest influence on the cost- effectiveness analysis process. In the PSA, 99.9% of the scatter points were distributed above the US WTP threshold of $150,000. CONCLUSION: From the perspective of the US payer, selpercatinib is not cost-effective compared to chemotherapy and pembrolizumab for first-line treatment in patients with RET fusion-positive NSCLC.

Cheminformatics-based identification of phosphorylated RET tyrosine kinase inhibitors for human cancer.

Background: Rearranged during transfection (RET), an oncogenic protein, is associated with various cancers, including non-small-cell lung cancer (NSCLC), papillary thyroid cancer (PTC), pancreatic cancer, medullary thyroid cancer (MTC), breast cancer, and colorectal cancer. Dysregulation of RET contributes to cancer development, highlighting the importance of identifying lead compounds targeting this protein due to its pivotal role in cancer progression. Therefore, this study aims to discover effective lead compounds targeting RET across different cancer types and evaluate their potential to inhibit cancer progression. Methods: This study used a range of computational techniques, including Phase database creation, high-throughput virtual screening (HTVS), molecular docking, molecular mechanics with generalized Born surface area (MM-GBSA) solvation, assessment of pharmacokinetic (PK) properties, and molecular dynamics (MD) simulations, to identify potential lead compounds targeting RET. Results: Initially, a high-throughput virtual screening of the ZINC database identified 2,550 compounds from a pool of 170,269. Subsequent molecular docking studies revealed 10 compounds with promising negative binding scores ranging from -8.458 to -7.791 kcal/mol. MM-GBSA analysis further confirmed the potential of four compounds to exhibit negative binding scores. MD simulations demonstrated the stability of CID 95842900, CID 137030374, CID 124958150, and CID 110126793 with the target receptors. Conclusion: These findings suggest that these selected four compounds have the potential to inhibit phosphorylated RET (pRET) tyrosine kinase activity and may represent promising candidates for the treatment of various cancers.

Target-Driven Tissue-Agnostic Drug Approvals-A New Path of Drug Development.

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAFV600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.

Fundamentals and recent advances in the evaluation and management of medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a rare primary neuroendocrine thyroid carcinoma that is distinct from other thyroid or neuroendocrine cancers. Most cases of MTC are sporadic, although MTC exhibits a high degree of heritability as part of the multiple endocrine neoplasia syndromes. REarranged during Transfection (RET) mutations are the primary oncogenic drivers and advances in molecular profiling have revealed that MTC is enriched in druggable alterations. Surgery at an early stage is the only chance for cure, but many patients present with or develop metastases. C-cell-specific calcitonin trajectory and structural doubling times are critical biomarkers to inform prognosis, extent of surgery, likelihood of residual disease, and need for additional therapy. Recent advances in the role of active surveillance, regionally directed therapies for localized disease, and systemic therapy with multi-kinase and RET-specific inhibitors for progressive/metastatic disease have significantly improved outcomes for patients with MTC.

Patient-reported outcomes with selpercatinib treatment in patients with RET-driven cancers in the phase I/II LIBRETTO-001 trial.

BACKGROUND: This post-hoc retrospective study describes long-term patient-reported outcomes (PROs) for REarranged during Transfection (RET)-altered non-small-cell lung cancer (NSCLC), medullary thyroid cancer (MTC), non-MTC thyroid cancer (TC), and tumor agnostic (TA) patients (Data cut-off: January 2023) from the LIBRETTO-001 trial. PATIENTS AND METHODS: Patients completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30). Patients with MTC also completed a modified version of the Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). The proportion of patients with improved, stable, or worsened status after baseline was reported. PROs were summarized at 3 years (cycle 37) post-baseline for the NSCLC and MTC cohorts, and at 2 years (cycle 25) post-baseline for the TC and TA cohorts. Time-to-event outcomes (time to first improvement or worsening and duration of improvement) were reported. RESULTS: The baseline assessment was completed by 200 (63.3%), 209 (70.8%), 50 (76.9%), and 38 (73.1%) patients in the NSCLC, MTC, TC, and TA cohorts, respectively. The total compliance rate was 80%, 82%, 70%, and 85%, respectively. Approximately 75% (NSCLC), 81% (MTC), 75% (TC), and 40% (TA) of patients across all cohorts reported improved or stable QLQ-C30 scores at year 3 (NSCLC and MTC) or year 2 (TC and TA) with continuous selpercatinib use. Across cohorts, the median time to first improvement ranged from 2.0 to 19.4 months, the median duration of improvement ranged from 1.9 to 28.2 months, and the median time to first worsening ranged from 5.6 to 44.2 months. The total compliance rate for the mSTIDAT was 83.7% and the proportion of patients with MTC who reported diarrhea on the mSTIDAT was reduced from 80.8% at baseline to 35.6% at year 3. CONCLUSIONS: A majority of patients with RET-driven cancers improved or remained stable on most QLQ-C30 domains, demonstrating favorable health-related quality of life as measured by the QLQ-C30 during long-term treatment with selpercatinib.

Sustained Clinical Response to 4th-Line Therapy with Selpercatinib in RET Fusion-Positive Combined Small Cell Lung Cancer.

Objective: Combined small cell lung cancer (C-SCLC) is a relatively rare subtype of small cell lung cancer (SCLC) which combines SCLC and any component of non-small cell carcinoma (NSCLC). Patients diagnosed with C-SCLC are currently recommended to receive the same treatment as SCLC cases in the absence of clear evidence suggesting different strategies. The genomic profiling of C-SCLC is rarely studied. Herein, we report a case of extensive-stage C-SCLC harboring the KIF5B-RET fusion before first-line therapy and with persistent sensitivity to fourth-line selpercatinib treatment is reported. Materials and Methods: Molecular and pathological features were evaluated using transbronchial lung biopsy, immunohistochemical (IHC) staining and next-generation sequencing (NGS). Results: NGS revealed the KIF5B-RET fusion in the C-SCLC tumor. The patient had a progression-free survival (PFS) surpassing 14 months after selpercatinib treatment, with ongoing clinical response in 4th-line treatment. Conclusion: This case highlights the importance of comprehensive molecular testing in C-SCLC for selecting the optimal treatment. Although RET fusion is rare in patients with C-SCLC, its identification and treatment with selective RET inhibitors may contribute to clinical benefits.

Glial cell line-derived neurotrophic factor and its role in attenuating renal fibrosis: a review.

Chronic kidney disease is estimated to affect approximately 10 to 15% of the Chinese population. Renal fibrosis is characterized by progressive extracellular matrix deposition in the kidney parenchyma with eventual tissue scarring and inevitable deterioration of renal function. Vascular rarefaction, glomerulosclerosis, interstitial inflammation, and fibrogenesis are associated with or contribute to renal fibrosis. Recent studies have revealed that glial cell-derived neurotrophic factor (GDNF) is involved in kidney morphogenesis and amelioration of renal injury. Ideal therapies targeting the pathogenesis of renal fibrosis should have the potential to inhibit glomerular and tubulointerstitial fibrosis by targeting multiple pathological events. GDNF plays a unique role in both renal development and improvement of renal fibrosis, and GDNF kidney receptors and signaling pathways can ameliorate renal apoptosis and inflammation. Our work contributes to the establishment of GDNF as an emerging therapy that can increase the effectiveness of currently used interventions to improve renal fibrosis. This literature review focuses on the important role of GDNF in renal development and its relationship with renal fibrosis.

[Chinese expert consensus on the diagnosis and treatment of advanced RET fusion-positive non-small cell lung cancer (2023 edition)].

Lung cancer is the most common cancer and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer. Mutations of driver genes have major impacts on incidence and progression of lung cancer. Advances in molecular biology research and clinical research have promoted the discovery of rare tumor driver genes, as well as the development and application of new targeted drugs. Nearly 1% to 2% of NSCLCs harbor RET fusions, and this patient population may not respond well to traditional treatments like chemotherapy or radiation therapy. After the new highly selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) entered clinical application, the diagnosis and treatment of RET fusion positive NSCLC has made breakthrough progress. At present, there is a lack of guiding consensus on the standardized diagnosis and treatment of RET fusion-positive NSCLC in China. The Society of Cancer Precision of Chinese Anti-Cancer Association and Lung Cancer Expert Group of Chinese Medical Journal, invited 38 experts form respiratory medicine, medical oncology, oncology radiotherapy and pathology to form a consensus development group. Based on the existing research evidence, combined with China's clinical practice experience, a standardized process for the diagnosis and treatment of advanced RET fusion-positive NSCLC is proposed, including suitable populations and methods for RET gene fusion, treatment drug selection, treatment of resistance to highly selective RET inhibitors, and management of adverse reactions to treatment, with a view to providing guidance for clinicians.

First-line versus second-line use of pralsetinib in treatment of rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer: a cost-effectiveness analysis.

Background: The ARROW study demonstrated favorable clinical efficacy and safety of pralsetinib (PRL) in treating rearranged during transfection (RET) fusion positive non-small cell lung cancer (NSCLC) in clinical trials. However, due to the high cost of PRL, evaluating its cost-effective characteristics is crucial. Currently, there has been no cost-effectiveness analysis specifically for PRL. Therefore, the aim of this study was to assess the cost-effectiveness characteristics of using PRL as a first-line therapy versus reserving it until the second-line versus solely relying on chemotherapy from the perspective of payers in the United States. Methods: A Markov model was developed to evaluate the 3 above mentioned PRL-based treatment strategies. Clinical data from the ARROW trial were incorporated into the model, and costs and utilities values were obtained through previously published literature and public databases, with both being discounted at 3% per year. To ensure the robustness of the model, both probabilistic and univariate sensitivity analyses were performed. The primary endpoints included quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER). Results: Compared to chemotherapy, the use of PRL in the first-line therapy resulted in an additional 0.07 QALYs at a cost of $133,561, with an ICER of $1,353,849.65 per QALY. Similarly, when used in the second-line setting, PRL led to an additional 0.09 QALYs at a cost of $92,797, with an ICER of $559,232.70 per QALY. The ICER value in the first-line or in the second-line therapy strategy was higher than the US willingness-to-pay (WTP) threshold of $150,000 per QALY. Univariable sensitivity analyses revealed that the cost of PRL and the utility of progressed disease had the most significant impact on the ICER. To be considered cost-effective at a WTP threshold of $150,000 per QALY, the cost of PRL would need to be reduced by 71.34% in first-line treatment or 84.49% in second-line treatment. Conclusions: Based on current pricing, neither PRL as first-line nor second-line therapy was found to be cost-effective for patients with RET fusion-positive advanced NSCLC compared to chemotherapy. Reserving PRL until second-line therapy may be a compromise approach to maintaining control over healthcare expenses yet still achieving favorable clinical outcomes.

Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A in Denmark 1930­2021: A Nationwide Population-Based Retrospective Study

Studies of primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 2A (MEN 2A) shows divergence in frequency, disease definition, reporting of clinical characteristics and traces of selection bias. This is a nationwide population-based retrospective study of PHPT in MEN 2A, suggesting a representative frequency, with complete reporting and a strict PHPT definition. The Danish MEN 2A cohort 1930-2021 was used. Of 204 MEN 2A cases, 16 had PHPT, resulting in a frequency of 8% (CI, 5-12). Age-related penetrance at 50 years was 8% (CI, 4-15). PHPT was seen in the American Thyroid Association moderate (ATA-MOD) and high (ATA-H) risk groups in 62% and 38% of carriers, respectively. Median age at PHPT diagnosis was 45 years (range, 21-79). A total of 75% were asymptomatic and 25% were symptomatic. Thirteen underwent parathyroid surgery, resulting in a cure of 69%, persistence in 8% and recurrence in 23%. In this first study with a clear PHPT definition and no selection bias, we found a lower frequency of PHPT and age-related penetrance, but a higher age at PHPT diagnosis than often cited. This might be affected by the Danish RET p.Cys611Tyr founder effect. Our study corroborates that PHPT in MEN 2A is often mild, asymptomatic and is associated with both ATA-MOD and ATA-H variants. Likelihood of cure is high, but recurrence is not infrequent and can occur decades after surgery.

1-Methyl-3-((4-(quinolin-4-yloxy)phenyl)amino)-1H-pyrazole-4-carboxamide derivatives as new rearranged during Transfection (RET) kinase inhibitors capable of suppressing resistant mutants in solvent-front regions.

REarranged during Transfection (RET) is a validated target for anticancer drug discovery and two selective RET inhibitors were approved by US FDA in 2020. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) becomes a major challenge for selective RET inhibitor therapies. Herein, we report a structure-based design of 1-methyl-3-((4-(quinolin-4-yloxy)phenyl)amino)-1H-pyrazole-4-carboxamide derivatives as new RET kinase inhibitors which are capable of suppressing the RETG810 C/R resistant mutants. One of the representative compounds, 8q, potently suppressed wild-type RET kinase with an IC50 value of 13.7 nM. It also strongly inhibited the proliferation of BaF3 cells stably expressing various oncogenic fusions of RET kinase with solvent-front mutations, e.g. CCDC6-RETG810C, CCDC6-RETG810R, KIF5B-RETG810C and KIF5B-RETG810R, with IC50 values of 15.4, 53.2, 54.2 and 120.0 nM, respectively. Furthermore, 8q dose-dependently inhibited the activation of RET and downstream signals and obviously triggered apoptosis in Ba/F3-CCDC6-RETG810 C/R cells. The compound also exhibited significant anti-tumor efficacy with a tumor growth inhibition (TGI) value of 66.9% at 30 mg/kg/day via i. p. in a Ba/F3-CCDC6-RETG810C xenograft mouse model. Compound 8q may be utilized as a lead compound for drug discovery combating acquired resistance against selective RET inhibitor therapies.

GDNF regulates lipid metabolism and glioma growth through RET/ERK/HIF­1/SREBP­1.

Cancer cells rewire their metabolism to meet the demands of growth and survival and this metabolic reprogramming has been recognized as an emerging hallmark of cancer. However, the respective mechanisms remain elusive and the contribution of aberrant lipid metabolism to the malignant phenotypes of glioma are unclear. The present study demonstrated that glial­derived neurotrophic factor (GDNF) is highly expressed in glioma and associated with poor clinical outcomes. In addition, there was a significant correlation between GDNF/rearranged during transfection (RET)/ERK signaling and sterol regulatory element­binding protein­1 (SREBP­1) expression in glioma cells. Pharmacological or genetic inhibition of GDNF­induced RET/ERK activity downregulated SREBP­1 expression and SREBP­1­mediated transcription of lipogenic genes. Additionally, GDNF regulated SREBP­1 activity by promoting hypoxia­inducible factor­1α (HIF­1α) mediated glucose absorption and hexosamine biosynthetic pathway mediated SREBP cleavage­activating protein N­glycosylation. In addition, the inhibition of SREBP­1 reduced the in vitro GDNF­induced glioma cell proliferation. The results elucidated the complex relationship between GDNF/RET/ERK signaling and dysregulated glycolipid­metabolism, which shows great potential to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors-A Retrospective Multi-Center Registry Analysis.

BACKGROUND: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. METHODS: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. RESULTS: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32-NR (not reached); n = 36), and the median PFS was 21 months (12-39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13-79; n = 22), and the median PFS was 3.5 months (2-14; n = 22) in RET-positive cases. CONCLUSIONS: 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.

Clinicopathologic characteristics and diagnostic methods of RET rearrangement in Chinese non-small cell lung cancer patients.

Background: Rearranged during transfection (RET) rearrangement has been identified as one of the crucial oncogenic drivers in non-small cell lung cancer (NSCLC). Recently, two highly selective RET inhibitors have been approved by the US Food and Drug Administration and demonstrated remarkable responses. However, the clinical characteristics, outcomes and optimal diagnostic method of RET-rearrangements are not well understood. This study sought to evaluate the prevalence and characteristics of RET rearrangement, identify an effective diagnostic method for it, and correlate its presence with outcomes. Methods: A total of 9,431 Chinese NSCLCs from two cancer centers who have undertaken targeted DNA-NGS were enrolled and 167 RET-positive cases were screened. Non-canonical RET rearrangements were confirmed by targeted RNA-NGS. If material was sufficient, positive cases were analyzed by fluorescence in situ hybridization (FISH) (n=30) and immunohistochemistry (IHC) (n=57). Clinicopathologic characteristics, molecular profiling and treatment outcomes of RET rearrangement were evaluated. Results: The prevalence of RET rearrangement was 1.52% (138/9,101) in unfiltered cases and 8.79% (29/330) in EGFR/KRAS/BRAF/ALK-negative cases. RET rearrangement was common in females, never smokers, and lung adenocarcinoma patients. Additionally, 40.3% of stage IV RET-rearranged NSCLC patients developed brain metastases. TP53 was the most common concurrent mutation, and 8 patients harbored concurrent driver oncogenic alterations, including EGFR (N=5), KRAS (N=2), and ALK (N=1). Non-canonical fusion partners were identified in 13.8% (23/167) of cases by DNA-based NGS, and RNA-based NGS identified 3 new partners (EPS8, GOLGA5, and TNIP1). The concordance of FISH and NGS was 83.3% (25/30), while the concordance of IHC and NGS was only 28.1% (16/57). Both IHC and FISH demonstrated lower sensitivity for NCOA4-/other-RET fusions. The CCDC6-RET subgroup had significantly longer progression-free survival than the KIF5B-RET subgroup, both after chemotherapy (23 vs. 9.7 months; P=0.014). Conclusions: RET rearrangement occurs in 1.52% of Chinese NSCLCs and has identifiable clinicopathologic characteristics. RET IHC has a low sensitivity, disavowing its use in routine practice. While NGS and FISH has good performance in identifying RET rearrangement. Both IHC and FISH demonstrated lower sensitivity for NCOA4-/others-RET fusions. Clinical benefit with chemotherapy is different between CCDC6-RET and KIF5B-RET fusion patients, optimal treatment should be considered when selecting therapies for patients with RET-rearranged lung cancers.

Pralsetinib for the treatment of a RET-positive advanced non-small-cell lung cancer patient harboring both ANK-RET and CCDC6-RET fusions with coronary heart disease: a case report.

Background: Rearranged during transfection (RET) is one of the rare driver genes of non-small-cell lung cancer (NSCLC), having a gene fusion incidence of 1-2% in NSCLC. Before the emergence of specific RET inhibitors, multikinase inhibitors such as cabozantinib and vandetanib were tried for RET fusion-positive NSCLC, but their efficacies were poor, and the U.S. Food and Drug Administration did not approve the application of these drugs for such patients. In the phase I/II ARROW clinical trial, pralsetinib significantly improved the overall remission rate and disease progression-free survival (PFS) of RET fusion-positive NSCLC patients. In the clinic, it is necessary to conduct adequate molecular screening of patients to guide drug choices. With the wide application of second-generation sequencing technology in clinical practice, many RET fusion partners have been discovered. It is rare for one patient with two RET fusions. Case Description: This paper reports a rare case of RET dual fusion in an advanced NSCLC patient who had coronary heart disease. After the failure of first-line treatment with platinum-based chemotherapy and post-line treatment with small-molecule targeted therapy of anlotinib and alectinib, the application of pralsetinib (400 mg, qd) reduced the tumor volume by 79% and achieved partial remission (based on the evaluation criteria of the World Health Organization) or reduced tumor volume by 17% (based on the Response Evaluation Criteria in Solid Tumors). It had an overall manageable safety profile. Conclusions: This patient with two different RET fusions was sensitive to pralsetinib. Patients with well-controlled coronary heart disease and recurrent myocardial infarction might benefit from pralsetinib. The pathogenesis of RET-dual-fusion NSCLC and its clinical impact need to be further studied to provide a theoretical basis for personalized treatment.

Identifification of a novel LDLR-RET Fusion in Lung Adenocarcinoma.

BACKGROUND: REarranged during Transfection (RET) gene fusion is one of the common oncogenic variants detectable in non-small cell lung cancer (NSCLC). The feature of most oncogenic RET gene fusion cases is that RET tyrosine kinase domain is retained in fusions and the partner gene includes a coiled-coil or LIS1 homology domain. However, only a few studies reported about the exceptional form of RET fusion in NSCLC so far. METHODS: Targeted next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) were performed on resected cancerous tissue. RESULTS: A rare form of RET fusion was identified in a 45 year-old Chinese female patient, in which exon 1-4 of LDLR fused with exon 12-21 of RET. The result was validated by FISH. CONCLUSIONS: This novel form of RET fusion in NSCLC is reported for the first time worldwide, offering a new treatment option for the patient with the possibility of using RET-selective inhibitors.