Genomic landscape of 891 RET fusions detected across diverse solid tumor types

Parimi, Vamsi; Tolba, Khaled A.; Danziger, Natalie; Kuang, Zheng; Sun, Daokun; Lin, Douglas I.; Hiemenz, Matthew; Schrock, Alexa B.; Ross, Jeffrey S.; Oxnard, Geoffrey R.; Huang, Richard S.P.

doi:10.1038/s41698-023-00347-2

Cited by 26 publications

(14 citation statements)

References 48 publications

(53 reference statements)

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“…With the utilization of next‐generation sequencing (NGS) technology, over 50 distinct fusion partners have been identified, indicating a diverse and varied distribution in their occurrence. This demonstrates a clear long‐tail effect in the incidence distribution of RET fusion events 21 …”

Section: The Biological Basis Of the Ret Genementioning

confidence: 83%

“…This demonstrates a clear long-tail effect in the incidence distribution of RET fusion events. 21 Activating point alterations represent another significant oncogenic mutation associated with inherited diseases such as multiple endocrine neoplasia 2A (MEN2A), multiple endocrine neoplasia 2B (MEN2B), and familial medullary thyroid carcinomas. These mutations are distributed across exons 7 to 16, predominantly occurring in the cysteine-rich domain and tyrosine kinase domains.…”

Section: Ret Gene Alterations and Their Mechanism Of Carcinogenesismentioning

confidence: 99%

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Expert consensus on the diagnosis and treatment of RET gene fusion non‐small cell lung cancer in China

Pu,

Xu,

Wang

et al. 2023

Thoracic Cancer

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The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell‐surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non‐small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second‐generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first‐generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET‐targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next‐generation sequencing (NGS), reverse transcription‐polymerase chain reaction (RT‐PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.

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Section: The Biological Basis Of the Ret Genementioning

confidence: 83%

Section: Ret Gene Alterations and Their Mechanism Of Carcinogenesismentioning

confidence: 99%

Expert consensus on the diagnosis and treatment of RET gene fusion non‐small cell lung cancer in China

Pu,

Xu,

Wang

et al. 2023

Thoracic Cancer

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“…A retrospective multi-center study has recently investigated clinic-biological features and treatment outcomes of patients with any-stage RET + NSCLC from 31 centers, 30 European and one from Argentina. The most frequent fusion partner was KIF5B followed by CCDC6; no cases were detected with ANK3::RET fusion ( 34 ). RET translocations/fusion genes are predominantly reported in papillary thyroid carcinoma and NSCLC, less in other solid tumors, such as colorectal carcinoma, salivary gland carcinoma, serous ovarian carcinoma, pancreatic and breast carcinoma, in global multicenter networks and reviews; ANK3::RET fusion was seen only in a papillary thyroid cancer ( 12 , 17 , 34 , 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…The most frequent fusion partner was KIF5B followed by CCDC6; no cases were detected with ANK3::RET fusion ( 34 ). RET translocations/fusion genes are predominantly reported in papillary thyroid carcinoma and NSCLC, less in other solid tumors, such as colorectal carcinoma, salivary gland carcinoma, serous ovarian carcinoma, pancreatic and breast carcinoma, in global multicenter networks and reviews; ANK3::RET fusion was seen only in a papillary thyroid cancer ( 12 , 17 , 34 , 35 ). The study of Parimi et al, reported the clinicopathologic and genomic landscape of a large cohort of RET fusion positive solid tumors (523 patients with NSCLC and 368 with other solid tumors), including the discovery of 61 novel fusions, detected by a DNA tissue-based NGS assay; no case of ANK3::RET rearrangement was detected in all African, Central and South American, East Asian, and South Asian patients ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Case report: First evidence of impressive efficacy of modulated dose selpercatinib in a young Caucasian with ANK3-RET fusion-positive NSCLC

De Carlo,

Bertoli,

Schiappacassi

et al. 2024

Front. Oncol.

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Over the past decade, molecular characterization has led to change the management of advanced non-small cell lung cancer (NSCLC) harboring driver mutations. Rearranged during transfection (RET) gene fusions, occurring in 1% to 2% of NSCLC, have emerged as an oncogenic druggable target. Systemic targeted therapies with highly selective RET inhibitors (RETi), selpercatinib and pralsetinib, represent a recent clinical breakthrough. While the development of RETi has improved survival, with their increasing use, it is crucial to be aware of the risks of rare but serious adverse events (AEs). A particular challenge for clinicians in applying targeted therapies is not only diagnosing but also interpreting rare mutations. Herein, we report a case of a 43-year-old Caucasian advanced NSCLC patient diagnosed with a rare RET gene fusion, ANK3::RET, identified with Next Generation Sequencing (NGS). Selpercatinib has been initiated at the recommended initial dose after one incomplete chemotherapy cycle due to a severe infusion reaction, but it subsequently required a dose adjustment following grade 3 (G3) AEs. During treatment, we used a particular selpercatinib dosage (160 mg in the morning and 80 mg in the evening) with good tolerance and without compromising effectiveness. Our finding broadens the range of RET fusion types in not-Asian NSCLC. To the best of our knowledge, our case demonstrates, for the first time, a clinical and radiological response to frontline highly selective RETi selpercatinib, expanding the spectrum of potential oncogenic RET fusion partners in newly diagnosed NSCLC patients. Furthermore, to our knowledge, this is the first case describing a RET fusion-positive (RET+) NSCLC patient treated with a modified selpercatinib dosage outside the drug data sheet and demonstrating a safe and effective use.

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“…Ideally, each tumor type in the experimental arm would have corresponding control patients, and the trial would be powered for this comparison. In reality, the number of patients with a specific tumor type in the trial is too small for this to be feasible, especially when the overall prevalence of genetic alterations, such as RET or NTRK fusions, 42 , 43 is already low. If patients with an alteration-positive tumor have improved prognoses versus those who are alteration-negative, the apparent increased efficacy seen in tumor-agnostic trials could be partly or wholly due to the prognostic effect of the alteration (ie, confounding) and not the treatment.…”

Section: Discussionmentioning

confidence: 99%

Characteristics and Survival Outcomes of Patients With Metastatic RET Fusion–Positive Solid Tumors Receiving Non-RET Inhibitor Standards of Care in a Real-World Setting

Hackshaw,

Fajardo,

Dafni

et al. 2024

JCO Precis Oncol

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PURPOSE RET fusions are oncogenic drivers across different solid tumors. However, the genomic landscape and natural history of patients with RET fusion–positive solid tumors are not well known. We describe the clinical characteristics of RET tyrosine kinase inhibitor (TKI)-naïve patients with RET fusion–positive solid tumors (excluding non–small-cell lung cancer [NSCLC]), treated in a real-world setting and assess the prognostic effect of RET fusions. METHODS Data for RET TKI-naïve patients with metastatic solid tumors (excluding NSCLC) who had ≥one Foundation Medicine comprehensive genomic profiling test (January 1, 2011-March 31, 2022) were obtained from a deidentified nationwide (US-based) clinicogenomic database. The primary objective of this study was to compare the overall survival (OS) of patients with RET fusion–positive tumors versus matched patients with RET wild-type ( RET-WT) tumors. Patients with RET-WT solid tumors were matched (4:1) to patients with RET fusion–positive tumors on the basis of preselected covariates. RESULTS The study population included 26 patients in the RET fusion–positive cohort, 7,220 patients in the RET-WT cohort (before matching), and 104 patients in the matched RET-WT cohort. Co-occurring genomic alterations were rare in the RET fusion–positive cohort. Median OS was consistently lower in patients with RET fusion–positive tumors versus those with RET-WT tumors, using three different analyses (hazard ratios, 2.0, 1.7, and 2.2). CONCLUSION These data suggest that RET fusions represent a negative prognostic factor in patients with metastatic solid tumors and highlight the need for wider genomic testing and use of RET-specific TKIs that could improve patient outcomes. Our study also highlights the value of real-world data when studying rare cancers or cancers with rare genomic alterations.

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Genomic landscape of 891 RET fusions detected across diverse solid tumor types

Cited by 26 publications

References 48 publications

Expert consensus on the diagnosis and treatment of RET gene fusion non‐small cell lung cancer in China

Expert consensus on the diagnosis and treatment of RET gene fusion non‐small cell lung cancer in China

Case report: First evidence of impressive efficacy of modulated dose selpercatinib in a young Caucasian with ANK3-RET fusion-positive NSCLC

Characteristics and Survival Outcomes of Patients With Metastatic RET Fusion–Positive Solid Tumors Receiving Non-RET Inhibitor Standards of Care in a Real-World Setting

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