Genotype-phenotype correlation in multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 is an autosomal-dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the rearranged during transfection proto-oncogene, which encodes the receptor tyrosine kinase, on chromosome 10. It has a strong penetrance of medullary thyroid carcinomas and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Multiple endocrine neoplasia type 2 is divided into three varieties depending on its clinical features: multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma. The specific rearranged during transfection mutation may suggest a predilection toward a particular phenotype and clinical course of medullary thyroid carcinoma, with strong genotype-phenotype correlations. Offering rearranged during transfection testing is the best practice for the clinical management of patients at risk of developing multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2 has become a classic model for the integration of molecular medicine into patient care. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on the classification of rearranged during transfection mutations into risk levels according to genotype-phenotype correlations. Earlier identification of patients with hereditary medullary thyroid carcinoma can change the presentation from clinical tumor to preclinical disease, resulting in a high cure rate of affected patients and a much better prognoses

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

SIMPLE SUMMARY: Lately, a more personalized approach in the management of advanced thyroid cancer patients has improved the outcomes, and several novel molecularly guided therapies, including selective RET inhibitors (sRETis), have demonstrated promising efficacy in clinical trials. RET (rearranged during transfection) variants are the most prevalent oncogenic event in medullary thyroid cancer (MTC). We here found RET oncogene variants in 44/48 prospectively collected MTC tumor samples from patients treated with more unselective kinase inhibitors vandetanib and/or cabozantinib. Our study shows that RET variants were highly prevalent in patients with advanced MTC, and the treatment results in RET-positive cases were similar to those reported in unselected cohorts. ABSTRACT: 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

Risk profile of the RET A883F germline mutation: an international collaborative study

Context: The A883F germline mutation of the REarranged during Transfection proto-oncogene causes multiple endocrine neoplasia 2B. In the revised American Thyroid Association (ATA) guidelines for the management of medullary thyroid carcinoma (MTC) the A883F mutation has been reclassified from the highest to high risk level, although no well-defined risk profile for this mutation exists. Objective: To create a risk profile for the A883F mutation for appropriate classification in the ATA risk levels. Design: Retrospective analysis. Setting: International collaboration. Patients: Included were 13 A883F carriers. Intervention: The intervention was thyroidectomy. Main Outcome Measures: Earliest age of MTC, regional lymph node metastases, distant metastases, age-related penetrance of MTC and pheochromocytoma (PHEO), overall and disease-specific survival and biochemical cure rate. Results: One and three carriers were diagnosed at age 7-9 years (median 7.5) with a normal thyroid and C-cell hyperplasia, respectively. Nine carriers had MTC diagnosed at age 10-39 years (median 19). The earliest age of MTC, regional lymph node and distant metastasis were 10, 20, 20 years, respectively. Fifty percent penetrance of MTC and PHEO was achieved by age 19 and 34 years, respectively. Five- and 10-year survival (both overall and disease-specific) were 88% and 88%, respectively. Biochemical cure for MTC at latest follow-up was achieved in 63% (5/8 carriers) with pertinent data. Conclusions: MTC of A883F carriers seems to have a more indolent natural course compared to that of M918T carriers. Our results support the classification of the A883F mutation in the ATA high risk level

Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma

The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association

Importance of Ultrasound Examination for the Follow-up of Medullary Thyroid Carcinoma: Comparison with Other Localization Methods

Ultrasound examinations for the follow-up of 41 patients with histologically proven medullary thyroid carcinoma (MTC) were done regularly at three- to six-month intervals. In patients with elevated serum calcitonin (CT) levels, other localization methods such as computed tomography, selective venous catheterization with measurement of CT levels, and fine-needle aspiration were performed. Thirty-four tumor recurrences in the neck were suspected by ultrasound examination in 23 patients with postoperatively elevated CT levels. The smallest occult MTC nodule had a diameter of 8 mm. One nodule was hyperechogenic with hypoechoic lesions, one was isoechoic with a halo, and all others were hypoechoic. Seventeen of 21 results of computed tomography, nine of 12 fine-needle biopsies, and nine of 16 selective venous catheterizations correlated with the ultrasound findings. Tumor tissue suspected by ultrasound was histologically proven in 25 of 29 cases. In comparison with other localization methods, ultrasound is the most practicable and reliable method for identification of MTC tissue in the neck

Amino alcohol- (NPS-2143) and quinazolinone-derived calcilytics (ATF936 and AXT914) differentially mitigate excessive signalling of calcium-sensing receptor mutants causing bartter syndrome type 5 and autosomal dominant hypocalcemia

Introduction Activating calcium sensing receptor (CaSR) mutations cause autosomal dominant hypocalcemia (ADH) characterized by low serum calcium, inappropriately low PTH and relative hypercalciuria. Four activating CaSR mutations cause additional renal wasting of sodium, chloride and other salts, a condition called Bartter syndrome (BS) type 5. Until today there is no specific medical treatment for BS type 5 and ADH. We investigated the effects of different allosteric CaSR antagonists (calcilytics) on activating CaSR mutants. Methods All 4 known mutations causing BS type 5 and five ADH mutations were expressed in HEK 293T cells and receptor signalling was studied by measurement of intracellular free calcium in response to extracellular calcium ([Ca2+]o). To investigate the effect of calcilytics, cells were stimulated with 3 mM [Ca2+]o in the presence or absence of NPS-2143, ATF936 or AXT914. Results All BS type 5 and ADH mutants showed enhanced signalling activity to [Ca2+]o with left shifted dose response curves. In contrast to the amino alcohol NPS-2143, which was only partially effective, the quinazolinone calcilytics ATF936 and AXT914 significantly mitigated excessive cytosolic calcium signalling of all BS type 5 and ADH mutants studied. When these mutants were co-expressed with wild-type CaSR to approximate heterozygosity in patients, ATF936 and AXT914 were also effective on all mutants. Conclusion The calcilytics ATF936 and AXT914 are capable of attenuating enhanced cytosolic calcium signalling activity of CaSR mutations causing BS type 5 and ADH. Quinazolinone calcilytics might therefore offer a novel treatment option for patients with activating CaSR mutations

Medullary thyroid cancer with ectopic Cushing's syndrome: A multicentre case series

OBJECTIVE Ectopic Cushing's syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. DESIGN Retrospective cohort study in three German and one Swiss referral centres. PATIENTS Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. MEASUREMENTS The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. RESULTS The median age at diagnosis of ECS was 59 years (range: 35-81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0-193). Median serum morning cortisol was 49 µg/dl (range: 17-141, normal range: 6.2-18). Eight (73%) patients received treatment for~ECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval 95{\%} CI: 64-111) than matched controls (190 months, 95{\%} CI: 95-285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. CONCLUSION This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case