Selpercatinib bei Tumoren mit RET-Mutation

PurposeCabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I.Patients and MethodsWe conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety.ResultsThe estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients.ConclusionCabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

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Active Surveillance in RET Gene Carriers Belonging to Families with Multiple Endocrine Neoplasia

Cancers ◽

10.3390/cancers13215554 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5554

Author(s):

Alessandro Prete ◽

Antonio Matrone ◽

Carla Gambale ◽

Valeria Bottici ◽

Virginia Cappagli ◽

...

Keyword(s):

Active Surveillance ◽

Thyroid Surgery ◽

Multiple Endocrine Neoplasia ◽

Ret Gene ◽

Ret Mutation ◽

Gene Carriers ◽

Endocrine Neoplasia ◽

Group A ◽

Group B

Multiple Endocrine Neoplasia 2 (MEN2) is a hereditary cancer syndrome for developing medullary thyroid cancer (MTC) due to germline mutations of RET gene. Subjects harboring a germline RET mutation without any clinical signs of MTC are defined as gene carriers (GCs), for whom guidelines propose a prophylactic thyroid surgery. We evaluate if active surveillance of GCs, pursuing early thyroid surgery, can be safely proposed and if it allows safely delaying thyroid surgery in children until adolescence/adulthood. We prospectively followed 189 GCs with moderate or high risk germline RET mutation. Surgery was planned in case of: elevated basal calcitonin (bCT) and/or stimulated CT (sCT); surgery preference of subjects (or parents, if subject less than 18 years old); other reasons for thyroid surgery. Accordingly, at RET screening, we sub-grouped GCs in subjects who promptly were submitted to thyroid surgery (Group A, n = 67) and who were not (Group B, n = 122). Group B was further sub-grouped in subjects who were submitted to surgery during their active surveillance (Group B1, n = 22) and who are still in follow-up (Group B2, n = 100). Group A subjects presented significantly more advanced age, bCT and sCT compared to Group B. Mutation RETV804M was the most common variant in both groups but it was significantly less frequent in Group A than B. Analyzing age, bCT, sCT and genetic landscape, Group B1 subjects differed from Group B2 only for sCT at last evaluation. Group A subjects presented more frequently MTC foci than Group B1. Moreover, Group A MTCs presented more aggressive features (size, T and N) than Group B1. Accordingly, at the end of follow-up, all Group B1 subjects presented clinical remission, while 6 and 12 Group A MTC patients had structural and biochemical persistent disease, respectively. Thank to active surveillance, only 13/63 subjects younger than 18 years at RET screening have been operated on during childhood and/or adolescence. In Group B1, three patients, while actively surveilled, had the possibility to reach the age of 18 (or older) and two patients the age of 15, before being submitted to thyroid surgery. In Group B2, 12 patients become older than 18 years and 17 older than 15 years. In conclusion, we demonstrated that an active surveillance pursuing an early thyroid surgery could be safely recommended in GCs. This patient-centered approach permits postponing thyroid surgery in children until their adolescence/adulthood. At the same time, we confirmed that genetic screening allows finding hidden MTC cases that otherwise would be diagnosed much later.

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A secondary RET mutation in the activation loop conferring resistance to vandetanib

Nature Communications ◽

10.1038/s41467-018-02994-7 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 27

Author(s):

Takashi Nakaoku ◽

Takashi Kohno ◽

Mitsugu Araki ◽

Seiji Niho ◽

Rakhee Chauhan ◽

...

Keyword(s):

Activation Loop ◽

Ret Mutation

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Medulläres Schilddrüsenkarzinom

DMW - Deutsche Medizinische Wochenschrift ◽

10.1055/a-1495-2991 ◽

2021 ◽

Vol 146 (23) ◽

pp. 1527-1532

Author(s):

Matthias Kroiss ◽

Viktoria Florentine Köhler ◽

Christine Spitzweg

Keyword(s):

Chirurgische Therapie ◽

Systemische Therapie ◽

Medulläres Schilddrüsenkarzinom ◽

Ras Gene ◽

Chirurgische Resektion ◽

Ret Mutation

Was ist neu? Diagnose und Prognose Calcitonin ist ein sensitiver und spezifischer Tumormarker zur Früherkennung und Verlaufskontrolle des MTC. Daneben kommt dem Ultraschall der Schilddrüse eine entscheidende Rolle zu. Rolle des RET-Proto-Onkogens Das medulläre Schilddrüsenkarzinom (MTC) nimmt seinen Ursprung aus den parafollikulären Calcitonin-produzierenden C-Zellen. Es macht nur ca. 3–8 % aller Schilddrüsenkarzinome aus. Aktivierende Mutationen im RET (rearranged during transfection)-Gen liegen bei etwa 25 % der Patienten in der Keimbahn vor, werden aber auch beim sporadischen MTC als somatische Mutationen in ca. 60 % der Fälle beobachtet. Bei metastasierter Erkrankung findet sich in 90 % eine RET-Mutation. RET-Mutationen gelten als Treibermutationen und schließen weitere Treibermutationen weitestgehend aus. Seltener sind somatische Mutationen der RAS-Gene. Chirurgische Therapie Die chirurgische Resektion ist bis heute der einzige kurative Therapieansatz. Entscheidend für eine frühzeitige Diagnosestellung ist die Bestimmung des Serum-Calcitonins bei Nachweis von Schilddrüsenknoten. Die chirurgische Therapie steht auch bei der Behandlung lokoregionärer Rezidive oder lokal angehbarer Metastasen im Zentrum. Systemtherapie Bei irresektabel fortgeschrittener und progredienter Erkrankung mit signifikanter Tumorlast kann eine systemische Therapie erforderlich werden. Neuerdings ist die Kenntnis einer RET-Mutation im Tumorgewebe therapeutisch relevant, da mit den selektiven RET-Inhibitoren Selpercatinib und zukünftig Pralsetinib neue, effektive und gut verträgliche Systemtherapien zur Verfügung stehen. Ihr Einsatz ist nach Vortherapie mit einem der Multityrosinkinase-Inhibitoren Vandetanib oder Cabozantinib zugelassen und wird derzeit in der Erstlinientherapie in klinischen Studien untersucht.

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Utility of RET Mutation Analysis in Multiple Endocrine Neoplasia Type 2

Archives of Pathology & Laboratory Medicine ◽

10.5858/1999-123-1047-uormai ◽

1999 ◽

Vol 123 (11) ◽

pp. 1047-1049 ◽

Cited By ~ 1

Author(s):

Walter W. Noll

Keyword(s):

Mutation Analysis ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Specific Test ◽

Ret Mutation ◽

Men 2 ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

The Individual

Abstract Objective.—To review the role of RET mutation analysis in the diagnosis of multiple endocrine neoplasia type 2 (MEN 2) and in presymptomatic screening for this disorder. Data Sources.—Review of the medical literature and current clinical practice. Conclusions.—RET mutation analysis is a sensitive and specific test for MEN 2. It plays a pivotal role in the diagnosis and management of patients and families with MEN 2 and in the individual who presents with an apparently sporadic medullary thyroid carcinoma or pheochromocytoma. These disorders may first come to the attention of either the anatomic or clinical pathologist, who has the opportunity to see that appropriate testing is done. As with any familial disease, professional genetic counseling is an important part of the care of these patients.

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