Long-term control of hypercortisolism by vandetanib in a medullary thyroid carcinoma with a somatic RET mutation

Anne-Cécile Paepegaey1,2, Béatrix Cochand-Priollet2,3, Estelle Louiset4, Pierre-Olivier Sarfati5, Marco Alifano2,6, Nelly Burnichon2, 7, 8, Marie Bienvenu-Perrard9, Najiba Lahlou2,10, Léopoldine Bricaire1, Lionel Groussin1,2.

Abstract

Context: Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing’s syndrome have a poor prognosis, partially due to the difficulties to control hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an antisecretory action on ACTH. However, there is a lack of long-term follow-up studies.
Case description: We report the case of a 58 year-old man with MTC-related Cushing’s syndrome resistant to a combination of several anticortisolic drugs. Vandetanib, an oral multi- TKI that targets RET in particular, was initiated and a rapid reversal of the hypercortisolim was observed without any change in tumor size. Vandetanib was briefly interrupted twice, once during 45 days because of side effects and a second time during 10 days to schedule surgical debulking. Each time plasma cortisol and calcitonin levels increased after TKI withdrawal and were rapidly lowered by vandetanib reintroduction. As described in other cases of Cushing’s syndrome caused by MTC, a marked ACTH increase after desmopressin stimulation was observed before vandetanib therapy. In contrast, a blunted ACTH response to desmopressin was documented throughout the course of vandetanib treatment. This modulation of the tumoral ACTH production is a strong argument in favor of a TKI antisecretory action. A left thyroid lobectomy and a modified neck dissection were performed one year after the initiation of vandetanib to reduce the tumor mass. An activating M918T RET (c.2753T>C) somatic mutation was identified in a lymph node metastasis. Three years and eight months after vandetanib initiation, there was no sign of recurrence of hypercortisolism.
Conclusion: This case illustrates the long-term effectiveness of vandetanib in maintaining the control of hypercortisolism in MTC-related Cushing’s syndrome.

Key terms: hypercortisolism; Cushing’s syndrome; vandetanib; RET; medullary thyroid carcinoma.

Introduction

Medullary thyroid carcinoma (MTC) accounts for 4% of all thyroid cancers. Around 25% of MTC are hereditary and 75% are sporadic (1). MTCs produce tumor-specific biomarkers such as calcitonin. It can also secrete other peptides like corticotropin-releasing hormone (CRH) or adrenocorticotropin hormone (ACTH) leading to ectopic Cushing’s syndrome (CS) in about 1-2% of patients with MTC (1). The presence of CS significantly worsens the prognosis. In these cases, survival at one year is only 20% with half of the patients dying of complications associated with hypercortisolism (1). Indeed, the control of CS with usual anticortisolic drugs is often unsuccessful and bilateral adrenalectomy is frequently needed (1). Here we describe the first case of long-term control of an MTC-related CS by vandetanib, an oral TKI.
A 58 year-old man was hospitalized for diarrhea, muscle weakness and a melancholic depression. A diagnosis of metastatic MTC was made with common sites of metastasis: cervical and mediastinal lymph nodes, lung, liver and bone. The initial plasma calcitonin level was 6900 ng/l (normal <10 ng/l). There was no family history of MTC and the RET proto-oncogene germline mutation screening was negative. The clinical presentation led to the diagnosis of an associated ACTH-dependent CS. Dynamic tests were concordant with paraneoplastic CS: absence of ACTH response to CRH stimulation and unsuppressed cortisol after high-dose of dexamethasone. The desmopressin test resulted in a marked ACTH increase, as it can be observed in ectopic CS (Figure 1A and 1B).
A sequential combination therapy with four anticortisolic drugs (metyrapone, mitotane, somatostatin analogues and ketoconazole) had proved ineffective to normalize plasma cortisol (Figure 1A). As previously reported (initial follow-up of 2.5 months), vandetanib was then initiated (300 mg once daily) (2). A rapid reduction of plasma cortisol and calcitonin was observed within a few days, independently of any antitumor effect. The disappearance of the ACTH stimulation by desmopressin under vandetanib suggested an antisecretory action on ACTH. Cortisol substitution therapy was necessary to compensate for the secondary adrenal insufficiency.
The subsequent follow-up allowed us to gain further insight into the cortisol- lowering mechanism of action of vandetanib. The TKI was interrupted once after ten months of treatment due to the apparition of seizures with no obvious etiology. We observed a rapid rise of serum cortisol and calcitonin levels and, for the second time, a marked ACTH response to desmopressin was documented (Figure 1A and 1B). As a consequence, therapy with vandetanib was resumed and resulted again in a rapid lowering of cortisol and calcitonin levels. The reversible suppressive action of vandetanib on ACTH secretion (documented by several desmopressin tests throughout the follow-up (Figure 1B)) and stable disease without any tumor reduction after seventeen months of TKI treatment led us to plan surgical debulking. Vandetanib was interrupted a second time, one week before and after the surgery. A neck dissection combined with a sternotomy was performed to remove the cervical and mediastinal lymph node metastases (Figure 1C). Because the disease was already known to be metastatic, we decided to limit the thyroid surgery to a left lobectomy (because of a suspicious nodule on ultrasound) to preserve thyroid function and avoid hypoparathyroidism, which could have complicated the vandetanib therapy. Pathological examination confirmed metastatic disease to the lymph nodes with positive immunostaining for calcitonin and ACTH (Figure 1D). A primary MTC could not be identified in the left thyroid lobe (the nodule was an adenoma). As the remaining lobe was free of suspicious cytological findings, the possibility of a MTC arising from ectopic thyroid tissue could not be ruled out. Moreover, next-generation sequencing revealed a RET somatic mutation in one mediastinal lymph node metastasis. A c.2753T>C RET mutation has been identified in the tumor DNA (mutant allele frequency of 44 %) and was not found in the germline. This mutation (p.M918T) is the most frequent RET mutation in sporadic MTCs (95%) (Figure 1D) (3).
In the perioperative period, cortisol levels began to increase again. Vandetanib was resumed and, until the time of publication, it has remained effective to control hypercortisolism and calcitonin levels (Figure 1A). The patient has now been on vandetanib therapy for 3 years and 8 months without noticeable lesions and with good control of the calcitonin levels at 132 ng/l.

Discussion

MTC-related Cushing’s syndrome is difficult to manage as hypercortisolism is usually resistant to cortisol-lowering drugs. In addition to the present case, reversal of CS in MTC by vandetanib has been reported in two other cases (4, 5). The first case was a 17-year- old boy with Multiple Endocrine Neoplasia type 2B due to a germline M918T RET mutation. He had metastatic MTC complicated by ectopic CS. Vandetanib was effective in controlling hypercortisolism one month after initiation of therapy and during the next 26 months, when the TKI was discontinued due to tumor progression (4). The second case was a 37-year-old woman with a sporadic MTC (with unknown somatic RET mutational status). Reversal of the CS was documented one month after initiation of vandetanib therapy. The biochemical response was still present at the time of the publication (8 months) (5). In these three cases, cortisol and calcitonin levels decreased rapidly on vandetanib, and independently of any tumor mass reduction. This rapid antisecretory effect, which is dissociated from tumor- reducing effect, reinforces the hypothesis of an antisecretory action on ACTH by vandetanib on MTC cells. A possible explanation could be a direct inhibition of RET by vandetanib. RET was mutated in at least two of the three cases. Sporadic MTC is characterized by the presence of a somatic RET mutation in 41% of cases (3). Ectopic CS is very uncommon in MTC suggesting additional molecular alterations leading to aberrant ACTH expression. The antisecretory effect of vandetanib in MTC-related CS suggests that under certain circumstances RET (or other targets of the TKI) may drive ACTH secretion. This kind of regulation has been demonstrated in vitro between oncogenic RET and calcitonin secretion, after RET kinase inhibition (6). The RET kinase seems to control signaling pathways which regulate peptide secretion. Moreover this effect seems to be reversible, as suggested by the rapid increase of cortisol and calcitonin after vandetanib withdrawal. Our case is the first report of a prolonged control (3 years and 8 months until the time of this publication) of MTC-related CS by vandetanib, without secondary resistance. Resistance occurring during vandetanib therapy has been described; one reported mechanism seems to consist in the acquisition of a secondary RET mutation at codon 804 (7).
Two other TKIs have been used for the therapy of paraneoplastic CS associated with MTC. Sorafenib has been demonstrated to reverse hypercortisolism in 7 days in a sporadic MTC (somatic RET mutational status unknown), for a period of 15 months until tumor progression (8). One hypothesis offered by the authors is a decrease of ACTH synthesis by inhibition of the MAPK pathway due to targeting of BRAF by sorafenib. The suppressive effect of sorafenib on ACTH and cortisol secretion was also reversible after discontinuation of sorafenib (8). Sunitib has also been shown to control MTC-associated CS, with a short follow-up of 5 months (9).
Another interesting aspect of the present case is the absence of MTC in the thyroid on pathological examination. Perhaps an ectopic MTC could be the explanation, as previously suggested in another case associated with TPX-0046 CS (10). In conclusion, our case demonstrates that vandetanib may be a potent therapeutic tool for long-term control of CS associated with some MTC.

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