Abstract
Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies.
Introduction
Medullary thyroid carcinoma (MTC) is a malignant tumor originating in parafollicular or C cells of the thyroid. The main secretory product of MTC is calcitonin, a specific and highly sensitive biomarker that is produced by normal and neoplastic C cells. Neoplastic C cells also produce the carcinoembryonic antigen (CEA). These molecules are widely used markers for the diagnosis, prognosis, and follow-up of MTC patients.
The overall frequency of MTC is not well established, but it has recently shown an increase from 0.14 to 0.21 per 100,000 population between 1983 and 2012 in the USA (Randle et al. 2017). The prevalence is ~2% of all thyroid malignancies, 0.4–1.4% of all thyroid nodules, and it is detected in ~0.14% thyroids of subjects submitted to autopsy (Valle & Kloos 2011, Tuttle et al. 2014, Lim et al. 2017). The clinical presentation is mainly in the fourth and fifth decades of life with a small, but statistically significant, increase in diagnosis at a mean age from 50 to 54 years (Randle et al. 2017). MTC accounts for 13.4% of the total deaths attributable to thyroid cancer (Modigliani et al. 1998).
Approximately 35% of patients with MTC who present with a palpable thyroid nodule have cervical metastases, and ~13% have distant metastases (Kebebew et al. 2005, Roman et al. 2006). The reported 10-year disease-specific mortality rate for MTC varies from 13.5 to 38% (Girelli et al. 1998, Kuo et al. 2018). The tumor stage at the time of diagnosis and the possibility of a complete surgical resection mostly determine the likelihood of attaining a cure for MTC. The classical main prognostic factors are age, tumor size, local and distant metastases, somatic M918T mutations, calcitonin, and CEA doubling times (Meijer et al. 2010).
MTC presents as sporadic (75–80%) or inherited tumors (20–25%). Hereditary MTC appears as part of the MEN 2 syndrome. MTC is extremely rare in children, making the probability of a hereditary form very high. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations are frequently present in sporadic disease (Eng et al. 1995, Mulligan 2018). RET encodes a transmembrane receptor, and point-activating RET mutations promote continuous phosphorylation of a distinct set of tyrosine residues, triggering intracellular signaling pathways responsible for cell survival, differentiation, and proliferation (Fig. 1).
Illustration of the activated pathways and genetic aberrations involved in medullary thyroid cancer, as well as the molecular targeted-related compounds. AKT, v-akt murine thymoma viral oncogene homolog; BRAF, serine/threonine-protein kinase B-Raf; c-Kit, tyrosine-protein kinase Kit; c-MET, hepatocyte growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGFR, fibroblast growth factor receptor; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; P38, mitogen-activated protein kinase; PDK-1, pyruvate dehydrogenase kinase isozyme 1; PI3K, phosphatidylinositol-3 kinase; PIP2, phosphatidylinositol (4,5) biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homolog; RAS, rat sarcoma viral oncogene homolog; RET, rearranged during transfection; VEGFR, vascular endothelial growth factor receptor.
Citation: Endocrine-Related Cancer 26, 9; 10.1530/ERC-18-0574
Illustration of the activated pathways and genetic aberrations involved in medullary thyroid cancer, as well as the molecular targeted-related compounds. AKT, v-akt murine thymoma viral oncogene homolog; BRAF, serine/threonine-protein kinase B-Raf; c-Kit, tyrosine-protein kinase Kit; c-MET, hepatocyte growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGFR, fibroblast growth factor receptor; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; P38, mitogen-activated protein kinase; PDK-1, pyruvate dehydrogenase kinase isozyme 1; PI3K, phosphatidylinositol-3 kinase; PIP2, phosphatidylinositol (4,5) biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homolog; RAS, rat sarcoma viral oncogene homolog; RET, rearranged during transfection; VEGFR, vascular endothelial growth factor receptor.
Citation: Endocrine-Related Cancer 26, 9; 10.1530/ERC-18-0574
Illustration of the activated pathways and genetic aberrations involved in medullary thyroid cancer, as well as the molecular targeted-related compounds. AKT, v-akt murine thymoma viral oncogene homolog; BRAF, serine/threonine-protein kinase B-Raf; c-Kit, tyrosine-protein kinase Kit; c-MET, hepatocyte growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGFR, fibroblast growth factor receptor; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; P38, mitogen-activated protein kinase; PDK-1, pyruvate dehydrogenase kinase isozyme 1; PI3K, phosphatidylinositol-3 kinase; PIP2, phosphatidylinositol (4,5) biphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homolog; RAS, rat sarcoma viral oncogene homolog; RET, rearranged during transfection; VEGFR, vascular endothelial growth factor receptor.
Citation: Endocrine-Related Cancer 26, 9; 10.1530/ERC-18-0574
Clinical presentation and genotype-related phenotypes
Hereditary MTC is usually associated with C-cell hyperplasia, multicentric, and bilateral (Schmid 2015), while the diagnosis of sporadic forms tends to be late, generally in the fifth or sixth decade of life (Heshmati et al. 1997). Lymph node metastases occur in at least 35% of MTC patients at diagnosis, while distant metastases occur in approximately 20% of cases. A minority of patients with MTC present systemic manifestations that include diarrhea, flushing, or painful bone metastases (Kebebew et al. 2000, Elisei et al. 2008, Hannah-Shmouni et al. 2016).
Hereditary MTC is inherited as an autosomal dominant syndrome that involves other endocrine neoplasias, with a variable degree of expressivity and an age-related penetrance, named multiple endocrine neoplasia type 2 (MEN 2). Interestingly, MEN 2 syndrome is classically defined by the occurrence of multicentric tumor formation in organs in which the RET proto-oncogene is expressed. This idea emerged because thyroid C cells have long been considered to be derived from neural crest cells. However, recent lineage-tracing experiments in mouse embryos have demonstrated that thyroid C-cell precursors are derived from anterior endoderm, specifically from the pharyngeal pouches from which the ultimobranchial bodies develop (Johansson et al. 2015). These surprising results may disprove the current concept of a neural crest origin of thyroid C cells and would have implications for understanding coincidental tumorigenesis of MTC, pheochromocytoma (PHEO) and hyperparathyroidism (HPT), revealing new paths for investigation of the involved molecular mechanisms (Nilsson & Williams 2016).
The MEN 2 syndrome is classified according to the involved organs as multiple endocrine neoplasia type 2A (MEN 2A) and multiple endocrine neoplasia type 2B (MEN 2B) (Pelizzo et al. 2007, Wells et al. 2015). MEN 2A constitutes approximately 70–80% of all MEN 2 cases and classically includes four subtypes: classical MEN 2A, MEN 2A associated with cutaneous lichen amyloidosis (CLA), MEN 2A and Hirschsprung’s disease (HD), and familial medullary thyroid carcinoma (FMTC). Classical MEN 2A is characterized by the presence of MTC (95%), PHEO (30–50%) and HPT (10–20%). MEN 2A with CLA, a pruriginous lesion in the scapular region characterized by amyloid deposition, and MEN 2A with HD, caused by the absence of autonomic ganglia in the terminal hindgut that results in colonic dilatation, obstipation, and constipation are rare variants of the disease (Gagel et al. 1989, Decker et al. 1998). Previously, considered a freestanding syndrome, FMTC, characterized by the presence of an inheritable MTC with no association with other endocrine neoplasia, is now regarded as a variant of the MEN 2A spectrum, in which the clinical presentation of MTC occurs later, and the prognosis is more favorable in comparison to the other forms of MTC. The reclassification into MEN 2A resulted from the concern that premature categorization of a family with FMTC could lead to a failure to identify a PHEO.
The clinical course of MTC in patients with MEN 2A is variable, and the disease progression is associated with codon-specific mutations in the RET proto-oncogene (Eng et al. 1996a , Machens et al. 2003). Approximately 98% of MEN 2A is associated with RET mutations in the cysteine-rich extracellular domain, particularly in exons 10 and 11, codons 609, 611, 618, 620, and 634, which is responsible for at least 85% of MEN 2A cases and correlated with the presence of PHEO, HPT, and CLA (Eng et al. 1996b , Raue & Frank-Raue 2009, Scapineli et al. 2016, Maciel et al. 2019). Amino acid change in the intracellular domain of RET in exon 13 (codons 768,790 and 791), exon 14 (codons 804 and 844) and exon 15 (codon 891) are less frequent. Mutations in exon 8 (codon 533) is rare, but they have been described in a large Brazilian family (Da Silva et al. 2003) and are most prevalent in familial cases in the Greek population (Sarika et al. 2015, Maciel et al. 2019). In 2–5% of cases of apparently hereditary MTC, no RET mutations are found (Leboulleux et al. 2004). Of note, whole exome sequencing has recently identified a germline MET mutation in two siblings with hereditary WT RET MTC (Sponziello et al. 2018).
A distinct MTC biological behavior, characterized by reduced aggressiveness and an older mean age at diagnosis, has been described for MEN 2A associated with mutations in noncysteine codons comparatively to mutations in cysteine codons (Raue & Frank-Raue 2009), and mutations in codon 611 tend to give rise to slow tumor progression than mutations in codons 618 and 620 (Machens et al. 2018). On the other hand, more advanced stage and increasing risk of metastases correlated with mutations in codon position (609→620) near the juxtamembrane domain (Frank-Raue et al. 2011). Interestingly, specific nucleotide and amino acid exchanges seem to have an impact on tumor behavior and aggressiveness in patients harboring codon 634 mutations (Punales et al. 2003). Of interest, a case of aggressive sporadic MTC with a somatic RET C634R mutation and germline synonymous C630C mutation was reported. Expression analysis has shown increased levels of RET transcript in C630C/C634R compared with that observed in 7 MTCs harboring only C634 mutations, suggesting that synonymous mutations can contribute to cancer progression (Pecce et al. 2018).
The MEN 2B accounts for approximately 5% of the cases of MEN 2 and is characterized by a single phenotype, which includes diffuse ganglioneuromatosis of the tongue, lips, eyes, and gastrointestinal tract, Marfanoid habitus, and alacrimia. MEN 2B patients present with MTC (90%), PHEO (45%), ganglioneuromatosis (100%), and Marfanoid habitus (65%). MTC in the setting of MEN 2B develops earlier and has a more aggressive course compared with MTC in other MEN 2 subtypes (Brandi et al. 2001, Makri et al. 2018). A specific mutation in RET exon 16, M918T, is almost invariably associated with MEN 2B and usually presents MTC development a few years after birth. Other mutations rarely associated with MEN 2B have been reported at codon 883 of exon 15; however, MTC in A883F carriers seems to present a more indolent course in comparison to M918T carriers (Mathiesen et al. 2017). Double RET mutations involving codons 804/806, 804/778 or 804/904 have also been described (Kasprzak et al. 2001, Menko et al. 2002, Kihara et al. 2014). A recent large, multicenter study has shown that over 80% of the cases of MEN 2B are de novo RET mutations, implying that the majority of children will be diagnosed after the recommended age of thyroidectomy. These observations highlight the importance to educate pediatricians and other health care providers to recognize the early nonendocrine manifestations of the disease (Castinetti et al. 2019).
Sporadic MTC
The molecular mechanisms involved in sporadic MTC have not yet been clarified. Approximately 23–66% of sporadic MTC presents the somatic RET M918T mutation. Also, mutations in codons 618, 603, 634, 768, 804, and 883 and partial deletion of the RET gene have been described in a few tumors (Dvorakova et al. 2008, Elisei et al. 2008, Romei et al. 2016). However, the mutations are not uniform throughout the tumor, suggesting that sporadic MTC might have a polyclonal origin or that these mutations are secondary events of MTC tumorigenesis (Eng et al. 1996b , Romei et al. 2018).
In addition to gain-of-function RET mutations, several RET variants have been associated with an increased risk of development or progression of MTC (Ceolin et al. 2012a ,b). Nevertheless, the mechanism by which these variants modulate MTC pathogenesis remains unclear. The exchange of bases in the DNA molecule may create an alternative splicing site, leading to the synthesis of a truncated protein, erroneous ligand binding, micro-RNA binding, or a change in mRNA structure and stability as well as in the number of copies (Borrego et al. 1999). It is also possible that this neutral variant is in linkage disequilibrium (LD) with an as yet unknown functional variant. Indeed, it has been shown that the S836S polymorphism is in LD with the intronic IVS1-126G>T variant found to be overrepresented in a cohort of sporadic MTC patients (Fernandez et al. 2006). LD between RET S836S and 3′untranslated region (UTR) variants has also been demonstrated. Of note, the RET mRNA sequence carrying the S836S/3′UTR haplotype presents higher structural and thermodynamic stability, suggesting a functional involvement of the 3′UTR variant allele in the posttranscriptional control of RET (Ceolin et al. 2016). Sporadic MTC patients present higher DNA methylation levels compared to those with the inherited form or control individuals, which might suggest an epigenetic contribution to MTC tumorigenesis (Ceolin et al. 2018). Moreover, epigenetic-related gene profiling shows significant increases of histone methyltransferases genes, which are involved in transcriptional regulation of gene expression, in patients with aggressive MTC (Sponziello et al. 2014).
Diagnosis and prognostic markers
The clinical presentation of MTC traditionally consists of a palpable thyroid nodule, which may be solitary or appears in the context of a multinodular goiter. Subsequently, the diagnosis is performed through the typical diagnostic work-up of thyroid nodules (Haugen et al. 2016). The routine use of serum calcitonin in the evaluation of thyroid nodules is not a consensus. The European Thyroid Society recommends it, but not the Brazilian Society of Endocrinology (Schlumberger et al. 2012, Maia et al. 2014), while the current guidelines of the American Thyroid Association state that there is no evidence to recommend for or against calcitonin measurements in nodule evaluations (Haugen et al. 2016). There was an agreement that, in certain situations, such as patients considered for less than total thyroidectomy or with suspicious cytology not consistent with papillary thyroid cancer, serum calcitonin measurement should be considered. In these situations, serum calcitonin presents a positive predictive value of 100% if >100 pg/mL and 5% if between 10 and 100 pg/mL (Wells et al. 2015, Tormey et al. 2017, Turk et al. 2017). Besides, calcitonin measurement in the fine-needle aspiration (FNA) washout might be an additional tool when FNA biopsy findings are inconclusive or undetermined (Trimboli et al. 2014). Nevertheless, one should keep in mind that false-positive results have been reported in selected cases (Massaro et al. 2009, Trimboli et al. 2012).
Calcitonin is the most important MTC marker, as it is useful for diagnosis, surgical planning, follow-up, and prognosis. When compared to FNA biopsy for MTC diagnosis, calcitonin presents higher sensibility (nearly 100%) and specificity (95%) (Bugalho et al. 2005). High levels of calcitonin may also occur in other medical conditions such as chronic kidney failure, hyperparathyroidism, neuroendocrine neoplasms, lung and prostate tumors and autoimmune thyroiditis (Karanikas et al. 2004, Rosario & Calsolari 2016). Preoperative basal serum calcitonin correlates with the tumor size and extent of lymph node metastasis. Levels higher than 20, 50, 200, and 500 pg/mL were associated, respectively, with metastases to lymph nodes in the ipsilateral central and ipsilateral lateral neck, the contralateral central neck, the contralateral lateral neck, and the upper mediastinum. A biochemical cure is very unlikely in patients with preoperative serum calcitonin levels higher than 1000 pg/mL (Machens & Dralle 2010, Wells et al. 2015).
The diagnosis of hereditary MTC usually occurs in advanced stages on index cases, taking into account the development at early ages and the asymptomatic nature of the disease in the initial stages. However, the diagnosis is made in early stages or even in a premalignant phase in family members, due to the broad recommendation of genetic screening in all MEN 2 patients. Indeed, the molecular test of proband’s relatives is of paramount importance since the earlier diagnosis and treatment increase the likelihood of cure of MTC (Skinner et al. 2005, Punales et al. 2008). Depending on the RET mutation, the MTC risk is classified as highest (M918T), high (C634F/G/R/S/W/Y and A883F) or moderate (all others), changing the time for initiating calcitonin level measurements and prophylactic thyroidectomy. Biochemical calcitonin monitoring might demarcate a ‘window of opportunity’ for pre-emptive thyroidectomy without central node dissection. For individuals harboring highest risk mutations, thyroidectomy should be performed early in life. For carriers of high-risk mutations, the thyroid surgery should be recommended before 5 years of age, whereas those carrying moderate risk mutations might be followed every 6–12 months until serum calcitonin levels became elevated (Wells et al. 2015). Of interest, recent studies indicate that some mutations, classified as moderate risk by the ATA (codons 768, 790, 804), have a more indolent clinical course with a 5-year-long expectant observation period under the premise that calcitonin levels remain within reference limits (Wells et al. 2015, Machens et al. 2018). Moreover, in a series of MEN 2A gene-carrier patients followed in a referral center in Italy, basal calcitonin levels below 60 pg/mL were always associated to an intrathyroidal MTC (Elisei et al. 2012). These observations might suggest that the ideal timing for prophylactic thyroid surgery could be individualized, taking into account patient age, type of mutation, biomarkers and imaging exams. Stimulation calcitonin tests might be useful in the decision-making process regarding prophylactic surgery (Elisei et al. 2012, Jarzab et al. 2013). Nevertheless, although extensively used in the past, recent studies found a similar accuracy between basal and stimulated calcitonin levels, indicating that the new serum calcitonin assays with improved functional sensitivity decrease the significance of stimulation tests (Elisei et al. 2012, Mian et al. 2014).
Therapeutic strategies
Surgery is the only curative treatment for MTC. Total thyroidectomy with central lymph node dissection is the procedure of choice and, depending on the serum calcitonin levels, and preoperative cervical US imaging, a more extensive surgery with lateral neck dissection should be considered (Maia et al. 2014, Wells et al. 2015, Wells 2018). Patients with intrathyroidal tumor have a 10-year survival rate of 95.6%, whereas patients with regional stage disease or distant metastasis at diagnosis present overall survival rates of 75.5 and 40%, respectively (Roman et al. 2006). Interestingly, the absolute number of lymph node metstases seems to impact on the chances of biochemical cure after additional surgical intervention. Scollo et al. found higher rates of calcitonin normalization in patients with less than 10 metastatic lymph nodes, as compared with those present a large number (57 vs 4%) (Scollo et al. 2003). Recently, Sosa et al. (2017) proposed a more accurate TNM risk stratification and potential treatment selection, lowering the risk of overtreatment for patients with stage I MTC. Based on the proposed new TNM grouping, the 5-year overall survival was 94% for stage I, 86% for stage II, 69% for stage III and 35% for stage IV (Sosa et al. 2017). Patients with persistent or recurrent MTC localized to the neck are candidates for repeat neck operations. However, in the presence of widespread regional or metastatic disease, extensive surgery is not associated with a higher cure rate, and less aggressive procedures should be considered (Randle et al. 2017, Wells 2018). Patients with incidental, sporadic MTC and no evidence of residual disease might be safely observed after less extensive resections (Randle et al. 2017).
The presence and volume of residual disease should be assessed through calcitonin measurements to define the appropriate treatment and follow-up strategy after thyroid surgery. Distant metastases should be investigated if serum calcitonin levels are above 500 pg/mL preoperative or 150 pg/mL post-total thyroidectomy. Neck and/or chest CT, liver MRI, bone scintigraphy, and, eventually, [18F]-fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT) or 18F-dihydroxyphenylalanine (18F-DOPA PET/CT) might be used (Maia et al. 2014, Wells et al. 2015). The 18F-DOPA PET/CT appears to be particularly useful in detecting lesions in patients with recurrent MTC and negative imaging studies (Romero-Lluch et al. 2017). The sensitivities of these tests for detecting metastatic disease vary from 50 to 80%, with a lower likelihood of identifying metastatic disease in those individuals with discrete calcitonin elevation (Giraudet et al. 2007, Wells et al. 2015). Of interest, a recent study, which evaluated the performance of 68Ga-PET/CT in detecting MTC lesions, indicates that it is highly sensitive in identifying bone lesions and could be a substitute for a bone scan and MRI (Castroneves et al. 2018).
In the postoperative period, calcitonin and CEA may require weeks to reach their lowest levels, so the measurement should be performed at least 2–3 months after surgery. Since serum calcitonin and CEA levels may either persist steadily high for years or rapidly increases, the calculations of their doubling times (DT; available at the ATA website https://www.thyroid.org/professionals/calculators/thyroid-cancer-carcinoma/) are more accurate to evaluate the disease progression. The 5-year and 10-year survival rates are 25 and 8%, respectively, when the doubling time is less than 6 months, and 92 and 37%, respectively, when the doubling time ranges from 6 months to 2 years. The calcitonin doubling time correlates with the survival and tumor recurrence rates, providing a better predictor of survival, whereas the CEA doubling time seems to be more useful for predicting prognosis (Meijer et al. 2010).
Recently, it has been shown that dynamic risk stratification is an excellent and useful tool to acquire prognostic information and can be used to modify the initial risk estimates by the classical TNM staging. The 5-year and 10-year recurrence rates vary from less than 1–8.5% in patients who achieve an excellent response, defined as an undetectable calcitonin level after surgery. Furthermore, the nomenclature excellent, biochemical incomplete and structural incomplete response, which has been successfully used to characterize the response to therapy and predict the clinical outcome in differentiated thyroid cancer, has also been shown to be useful in MTC (Lindsey et al. 2015, Kwon et al. 2016, Choi et al. 2018).
Other potential prognostic markers have been studied in recent years. Classically used as a marker for pancreatic neoplasms, higher levels of carbohydrate antigen (CA19.9) have been reported in patients with very aggressive MTC disease, low calcitonin levels, and increased CEA levels (Milman et al. 2011, Elisei et al. 2013a ). Based on an evaluation of serum CA19.9 levels in patients with advanced structural recurrent/persistent MTC, an elevated serum CA 19.9 value appears to be a predictive factor for poor prognosis and identifies those cases with a higher risk of short-term mortality (Elisei et al. 2015). CA19.9 has also been shown to be associated with an advanced disease stage in a small pilot study (Milman et al. 2015). However, in a study conducted by our group, immunohistochemical analysis of CA19.9 was not associated with age, sex, calcitonin, CEA, or local or distant metastases (CVF Vargas, L Ceolin, AF Benine, MS Graudenz & AL Maia unpublished observations).
General therapeutic approach in metastatic MTC
When evaluating a patient with advanced MTC, the following questions should be considered during decision-making: Is the patient symptomatic or asymptomatic? Is the locoregional disease controlled? Where are the metastases located? Are there lesions that require intervention due to imminent risk or associated symptoms? What is the speed of metastatic disease progression? Unfortunately, it is not always possible to get a definitive answer for some of these questions.
For patients with locally advanced disease that is not amenable to surgery or those who present distant metastasis, there is no effective therapeutic, curative option. Chemotherapy and external beam radiation therapy for the metastatic cervical recurrent disease have limited response rates (Brierley & Tsang 1996, Nocera et al. 2000). The response rate to cytotoxic chemotherapy seems to be approximately 20%, with most studies performed on limited numbers of patients and without robust evaluation criteria such as RECIST (Hadoux & Schlumberger 2017). External beam radiation therapy (EBRT) may be recommended to improve locoregional control in patients at high risk of cervical relapse. Few studies have shown an improvement in locoregional control but no survival benefit, confirming that although neck disease can be controlled in high-risk patients, the progression of distant disease and subsequent death are still a significant problem (Schwartz et al. 2008, Martinez et al. 2010, Brierley & Sherman 2012, Call et al. 2013).
Upon planning the therapeutic strategy, it is essential to keep in mind that some patients with metastatic MTC present indolent disease and good long-term prognosis, whereas others develop a progressive disease that requires close evaluation for immediate treatment. The schematic flowchart (Fig. 2) summarizes a therapeutic strategy to metastatic MTC. Expectant management can be appropriated for asymptomatic individuals with indolent, low-burden disease, whereas urgent therapy might be indicated in the presence of lesions which are associated with a high risk of serious complications, such as large brain metastases, a spinal cord compression or a lesion growing into an airway or bone metastases with an imminent risk of fracture. Embolization or cryoablation may be beneficial in selected cases to decrease the tumor burden, pain, or refractory diarrhea associated with liver metastases (Fromigue et al. 2006). Localized EBRT and/or bisphosphonates administration should be considered for painful bone metastases or prevention of skeletal-related events (Beuselinck et al. 2012, Farooki et al. 2012).
Schematic flowchart for the management of patients with metastatic medullary thyroid carcinoma (MTC). 1Progressive disease: ≥20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more new lesions; 2Partial response: ≥30% decrease in the sum of the longest diameters of target lesions compared with baseline; 3Stable disease: neither partial response nor progressive disease (RECIST 1.1).
Citation: Endocrine-Related Cancer 26, 9; 10.1530/ERC-18-0574
Schematic flowchart for the management of patients with metastatic medullary thyroid carcinoma (MTC). 1Progressive disease: ≥20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more new lesions; 2Partial response: ≥30% decrease in the sum of the longest diameters of target lesions compared with baseline; 3Stable disease: neither partial response nor progressive disease (RECIST 1.1).
Citation: Endocrine-Related Cancer 26, 9; 10.1530/ERC-18-0574
Schematic flowchart for the management of patients with metastatic medullary thyroid carcinoma (MTC). 1Progressive disease: ≥20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more new lesions; 2Partial response: ≥30% decrease in the sum of the longest diameters of target lesions compared with baseline; 3Stable disease: neither partial response nor progressive disease (RECIST 1.1).
Citation: Endocrine-Related Cancer 26, 9; 10.1530/ERC-18-0574
Patients with advanced MTC may experience paraneoplastic debilitating diarrhea due to hypersecretion of calcitonin, VIP (Cox et al. 1979), or increases on intestinal motility (Rambaud et al. 1988). Antimotility agents (loperamide or codeine) may be initially used as first-line therapy. Further options for unsuccessful cases include somatostatin analogs (Mahler et al. 1990, Zatelli et al. 2006). For those patients with extensive liver metastases, surgical resection, percutaneous radiofrequency ablation, or arterial chemoembolization might be considered in an attempt to reduce the calcitonin levels (Fromigue et al. 2006). The most common ectopic hormones, CRH or ACTH, can rarely cause paraneoplastic Cushing’s syndrome (0.7% cases), accounting for up to 2–6% of ectopic Cushing’s syndrome cases (Barbosa et al. 2005). Until recently, the management of this challenging situation, associated to extreme morbidity and mortality, was limited to surgical removal of metastatic disease, medical therapy with anti-adrenal compounds or bilateral adrenalectomy. Nevertheless, recent reports indicate successful treatment of MTC-related Cushing syndrome with TKIs (Barroso-Sousa et al. 2014, Nella et al. 2014).
Systemic therapy for advanced MTC
General overview
Cumulative knowledge regarding the distinct signaling pathways and multiple genetic abnormalities involved in the pathogenesis of cancer has allowed the development of targeted molecular therapies. Protein kinases are characterized by their ability to catalyze the phosphorylation of tyrosine amino acid residues in proteins, activating the various intracellular signaling pathways, cell proliferation, differentiation, migration, and anti-apoptosis. Therefore, tyrosine kinase inhibitors (TKIs) may provide a therapeutic benefit in cancer by blocking tyrosine kinase-dependent oncogenic pathways. TKIs can be specific to inhibit one or several tyrosine kinase receptors (multikinase inhibitors, MKIs) (Lemmon & Schlessinger 2010, Broekman et al. 2011).
Signaling pathways implicated in medullary thyroid cancer
Uncontrolled tyrosine kinase receptor activation is one of the primary mechanisms of cancer development and progression. In normal thyroid C cells, signaling pathways such as RET, RAS/MAPK, PI3K, c-MET, and mTOR modulate a wide range of intracellular processes, including cell proliferation, differentiation, migration, and apoptosis. Diverse molecular-driven alterations in these signaling pathways are involved in thyroid carcinogenesis (Santarpia et al. 2010, Mulligan 2014). The role of RET tyrosine kinase receptor in MTC pathogenesis has been well documented. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (c-MET), as well as their tyrosine kinase receptors, are overexpressed in MTC and play critical roles in pathogenesis, progression, and disease recurrence (Papotti et al. 2000, Capp et al. 2010).
RET pathway
Hereditary MTC is caused by gain-of-function mutations of the RET receptor that lead to constitutive RET kinase activity. In this oncogenic mechanism, MEN 2A-related mutations activate RET by inducing disulfide-linked homodimerization, in which a cysteine residue is mutated to a noncysteine residue, and a partner cysteine that is involved in the formation of a disulfide bond become free and form an aberrant intermolecular disulfide bond between two mutants RET. In MEN 2B mutations, which occur in the tyrosine kinase 2 domain, RET is activated in monomeric form, probably due to a conformational change in the catalytic core of the kinase domain. These mutations increased ATP-binding and kinase activity, allowing robust activation of downstream signals (Mulligan 2018).
The RET gene was identified in 1985 by Takahashi and cols, mapping on 10q11.2 and containing 21 exons spanning a region of 55,000 bp (Takahashi et al. 1985). RET is a member of the cadherin superfamily and encodes a tyrosine kinase receptor, which is a cell-surface molecule that transduces signals for cell growth, proliferation, differentiation, migration, survival, and apoptosis. RET proteins are derived from a single polypeptide core of 120 kDa and modified to 150 kDa and 170 kDa by post-translational glycosylation. Only the fully mature glycosylated 170-kDa RET protein isoform is present on the cell surface, whereas the immature 150-kDa isoform is confined to the Golgi (Takahashi et al. 1991, 1993). Alternative splicing of the RET gene results in the RET51, RET43 and RET9 isoforms, which differ at their carboxyl termini (Tahira et al. 1990, Myers et al. 1995, Carter et al. 2001).
The RET receptor comprises three domains: an extracellular, a transmembrane, and an intracellular domain. The extracellular domain includes regions that are homologous to the cadherin family of cell adhesion (cadherin-like) molecules that induce and stabilize conformational changes needed for interactions with the ligands and coreceptors and a large region enriched in cysteine residues (cysteine-rich region), which is responsible for the tertiary structure and formation of dimers. The intracellular domain contains two tyrosine kinase domains (TK1 and TK2) that are separated by 28 amino acids. These subdomains contain the tyrosine residues are phosphorylated during receptor activation and are involved in the activation of the signaling pathways (Takahashi et al. 1988). The tyrosine residues 905, 1015, 1062 are conserved in all three RET isoforms, but the tyrosine residue 1096 is present only in the long (RET 51) isoform.
RET is a receptor tyrosine kinase essential for the normal development and maturation of different tissues. Under normal conditions, RET is activated by a group of proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), including GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN). RET does not directly bind to GFLs, requiring an additional coreceptor, a GDNF family receptor-α (GFRα). The GFL–GFRα complex binds to RET, inducing RET dimerization and a subsequent autophosphorylation on multiple tyrosine residues within the intracellular tyrosine kinase domain (Airaksinen & Saarma 2002).
Studies using transgenic mouse models have demonstrated that Ret oncogenes can drive MTC development. Mice expressing Ret-C634R or Ret-M918T under the control of the calcitonin gene promoter developed MTC (Michiels et al. 1997, Acton et al. 2000). Additionally, transgenic mice carrying Ret-C634R under the control of a ubiquitous viral promoter developed MTC, suggesting that murine C cells are highly susceptible to RET-mediated transformation (Kawai et al. 2000). However, knock-in of the M918T mutation into the mouse endogenous Ret gene caused CCH but not MTC, suggesting that, in the background of a normally expressed Ret-mutant allele, the accumulation of secondary genetic alterations is required for the development of MTC (Smith-Hicks et al. 2000).
Interestingly, RET protein has been shown to induce cell death in the absence of their ligands (GFL-GFRα), while in the presence of their ligands a completely different signal is transduced. In the absence of ligand, RET exerts pro-apoptotic activity, and the addition of GDNF is then sufficient to block RET apoptotic activity. This finding implies that a single mutation may simultaneously induce increased mitogenic signaling and reduce pro-apoptotic activity (Bordeaux et al. 2000).
RAS pathway
RAS gene mutations have been found in 0–68% RET-negative MTC (Moura et al. 2011, 2015, Ciampi et al. 2013), and a recent meta-analysis has shown that the RAS mutation appears to lack significant prognostic value in predicting tumor aggressiveness (Vuong et al. 2018). In our center, we identified a mutation in exon 2 of H-RAS in 3.8% of patients with sporadic MTC, 70% of whom were positive for somatic M918T in RET (CV Ferreira & AL Maia unpublished observations). The oncogenic RAS mutations and mutations in other components of the RAS/MAPK signaling pathway appear to be mutually exclusive events in most tumors, indicating that the deregulation of Ras-dependent signaling is an essential requirement for tumorigenesis (Moura et al. 2011, Ciampi et al. 2013, Nikiforova et al. 2013).
RAS genes (H-RAS, chromosome 11; K-RAS, chromosome 12 and N-RAS, chromosome 1) encode highly related G-proteins that play a central role in intracellular signal transduction by activation of the MAPK and other signaling pathways, such as PI3K/AKT (Santarpia et al. 2010, Fernandez-Medarde & Santos 2011). The H-RAS, K-RAS, and N-RAS genes all have a similar exonic structure, and therefore, all probably derive from a common, spliced ancestral gene (Shimizu et al. 1983).
The molecular mechanism proposed for RAS-derived tumorigenesis is the constitutive activation of distinct pathways that are linked to the functional control of a vast assortment of cellular outcomes, including cell cycle progression, growth, migration, cytoskeletal changes, apoptosis, and senescence (Santarpia et al. 2010, Fernandez-Medarde & Santos 2011). The ras-mutated protein mediates its effects on cellular proliferation in part by activation of a cascade of kinases: RAF (A-RAF B-RAF and C-RAF), dual-specificity mitogen-activated protein kinases (MEK1/2), extracellular signal-regulated kinases (ERK1/2) and p38 mitogen-activated protein kinase. RAS also activates the PI3K pathway via direct interaction with the catalytic subunit of the protein. PI3K activation leads to the accumulation of the second messenger, phosphatidylinositol 3,4,5-trisphosphate (PIP3), resulting in pyruvate dehydrogenase kinase isozyme 1 (PDK1) and v-akt murine thymoma viral oncogene homolog (AKT) activation (Krasilnikov 2000, Vojtek and Der 1998).
MET pathway
Overexpression of MET and co-expression of HGF-MET has been reported in MTC tumors and has been associated with multifocality (Papotti et al. 2000, Ricarte-Filho et al. 2009). Silencing of the MET proto-oncogene has resulted in the impairment of the execution of the fully invasive growth program in vitro, lack of tumor growth and decreased generation of experimental metastases in vivo (Corso et al. 2008). Crosstalk has been demonstrated between MET and RET at transcriptional and signaling levels, leading to the promotion of thyroid cell transformation and invasive phenotypes (Cassinelli et al. 2009, Bentzien et al. 2013).
The MET proto-oncogene is located on chromosome 7q21-31 and encodes a single-pass tyrosine kinase protein. MET kinase is a cell-surface receptor for hepatocyte growth factor (HGF), a cytokine that conveys a unique combination of pro-migratory, anti-apoptotic, and mitogenic signals expressed in the epithelial cells of many organs during embryogenesis and in adulthood (liver, pancreas, prostate, kidney, muscle, and bone marrow) (Cooper & Spaulding 1984, Gonzatti-Haces et al. 1986, Park et al. 1986). In tumor cells, MET activation triggers a diverse series of signaling cascades resulting in cell growth, proliferation, invasion, and protection against apoptosis (Birchmeier et al. 2003, Liu et al. 2008). Signaling for growth and mitogenesis occurs via the RAS-MAPK signaling pathway and plays an essential role in the epithelial-to-mesenchymal transition that results from loss of intracellular adhesion via cadherins and integrins, with a change in cell shape (Boccaccio & Comoglio 2006).
mTOR pathway
The oncogenic RET activity in MTC seems to be partially modulated by overactivation of the PI3K/Akt/mTOR pathway (Drosten et al. 2004). Interestingly, studies have shown that mTOR has a higher activation in lymph node metastases than in primary MTC and that the expression of eiF4E has a strong correlation with the tumor stage, suggesting a role of mTOR in tumor progression (Kouvaraki et al. 2011, Tamburrino et al. 2012). Besides, mTOR activation appears to be an early event in C-cell transformation, playing a role early in the MTC tumorigenic process (Tamburrino et al. 2012).
The mTOR gene is located on chromosome 1p36.22 and contains 60 exons. mTOR encodes a serine/threonine kinase, in the family of phosphatidylinositol kinase-related kinases, which is involved in the regulation of cell proliferation, apoptosis, the cell cycle, angiogenesis, metabolism, and protein synthesis (Meric-Bernstam & Gonzalez-Angulo 2009). mTOR functions as part of 2 structurally and functionally distinct signaling complexes: mTOR complex 1 (mTORC1), which consists of mTOR, mammalian LST8 (mLST8), proline-rich Akt substrate 40 (PRAS40), and raptor; mTOR complex 2 (mTORC2), which includes mTOR, mLST8 (GβL), mSIN1, PRR5 (protor), and Rictor (Jacinto et al. 2006, Wullschleger et al. 2006, Martin et al. 2008).
The deregulation of mTOR pathway activation is observed in several types of cancer. The main pathway of mTOR activation is PI3K/Akt. Specific growth factors are responsible for stimulating RTKs that lead to PI3K/Akt activation. Once these receptors are stimulated, PI3K is recruited and catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3) and thus activates Akt. The control of Akt activation and, consequently of mTOR, is done by PTEN, a tumor suppressor that converts PIP3 to PIP2 thus inhibiting the activation of Akt (Sekulic et al. 2000, Meric-Bernstam & Gonzalez-Angulo 2009).
Molecular target therapy: multikinase inhibitors
The advances in knowledge of the molecular mechanisms and intracellular signaling pathways involved in MTC pathogenesis have allowed the development of target therapy, promoting noteworthy developments and new perspectives on metastatic MTC therapy.
Several multikinase inhibitors (MKI) compounds have been tested for MTC treatment, including motesanib (Schlumberger et al. 2009), sorafenib (Lam et al. 2010, de Castroneves et al. 2016), sunitinib (Carr et al. 2010), axitinib (Cohen et al. 2008), imatinib (de Groot et al. 2007), pazopanib (Bible et al. 2014), anlotinib (Sun et al. 2018), lenvatinib (Haugen et al. 2016), vandetanib (Wells et al. 2012), and cabozantinib (Elisei et al. 2013b ) (Fig. 1). Because patients with metastatic MTC may present indolent disease and long life expectancy, prospective trials use surrogates than overall survival (OS) to evaluate drug efficacy. The objective response rate (ORR) and the progression-free survival (PFS) are the most used outcomes since they show a better correlation with OS (Hadoux & Schlumberger 2017).
Vandetanib and cabozantinib are the only MKIs approved for advanced MTC treatment. The first approved compound, vandetanib, selectively targets RET, VEGF, and epidermal growth factor (EGF) receptors (Wedge et al. 2002). The efficacy of vandetanib was evaluated in 331 individuals with metastatic MTC who were randomized to receive vandetanib (300 mg) or placebo (Wells et al. 2012). The results showed a significant increase in PFS in the vandetanib-treated group (30.2 vs 19.2 months; HR = 0.46, 95% CI = 0.31–0.69) Vandetanib has also been successfully used to treat children with MEN 2B (Fox et al. 2013). The second approved compound, cabozantinib, is a c-MET, VEGFR2, and RET MKI. A randomized study of 330 individuals with documented MTC progression demonstrated a significant increase in PFS in the cabozantinib-treated group (11.2 vs 4.0 months; HR = 0.28, 95% CI = 0.19–0.40, P < 0.0001) (Elisei et al. 2013b ). The effect of vandetanib or cabozantinib on the survival of MTC patients remains unknown, but interim analyses have not revealed any differences between the two drug-treated and placebo groups (Wells et al. 2012, Elisei et al. 2013b ).
Lenvatinib, an MKI of the VEGFR-1, 2, and 3, FGFR-1–4, PDGFRa, RET, and KIT signaling networks, was evaluated in a phase 2 trial. Fifty-nine patients with unresectable progressive MTC were included in that study. The disease control rate was 80% (95% CI: 67–89%), which is the highest reported rate to date. Of interest, the objective response rate (ORR) was similar between patients with (35%) and without (36%) prior anti-VEGFR therapy, confirming the lack of cross-resistance among MKIs (Haugen et al. 2016).
Given that RET and RAS activate the PI3K/AKT/mTOR pathway, a small phase 2 trial was conducted to evaluate the efficacy of everolimus, an mTOR inhibitor approved for the treatment of neuroendocrine tumors and renal cell carcinoma, in patients with progressive metastatic or inoperable MTC (Schneider et al. 2015). Seven patients were enrolled, of whom five (71%) showed stable disease. The median PFS was 33 weeks, and no objective responses were observed. Similar findings were observed in another everolimus phase 2 trial that included 9 MTC patients (Lim et al. 2013), indicating that everolimus alone has limited activity against MTC. Nevertheless, promising data have been reported from a phase 2 trial in patients with progressive, advanced thyroid cancer who received everolimus in combination with sorafenib (Sherman et al. 2016). In another report, everolimus was prescribed in addition to vandetanib in a patient who presented disease progression and observed a 25% tumor reduction (Heilmann et al. 2016). The combination of RET kinase inhibitors and mTOR inhibitors might be an exciting dual targeting strategy, but it awaits further evaluation in clinical trials.
A limitation of MKI therapy is that the tumor cells might develop an escape mechanism, allowing the tumor to start to grow again after a variable period of treatment. This phenomenon is independent of the type of MKI used or tumor treated (Arao et al. 2011). Secondary mutations in the kinase domains that sterically block the binding of MKIs, usually downstream from the TKI target, or in parallel pathways that result in a mechanism to bypass the action of the drug, have been demonstrated in other tumors, but is still unclear in MTC (Viola et al. 2016, Liu et al. 2018). Interestingly, a suggestive case of an acquired RET V804M gatekeeper resistance mutation to vandetanib has been described (Subbiah et al. 2018b ). In such cases, a second MKI might be considered. Of note, the discontinuation of an MKI treatment could lead to a rapid increase in tumor growth and disease progression (Resteghini et al. 2017, Trimboli et al. 2018).
Mutational profile and response to multikinase inhibitor therapy
Several recent studies have indicated the potential clinical relevance of the identification of oncogenic driver alterations on molecular target therapeutic strategy. In the phase III trial of vandetanib, patients with sporadic MTC harboring a somatic RET M918T mutation had a higher response rate to vandetanib as compared with patients without this mutation (54.5 vs 32%), although the results were inconclusive due to the small sample size (Wells et al. 2012).
In the cabozantinib phase III trial, patients with RET mutation exhibited a longer PFS when compared with the placebo group (60 vs 20 weeks), with the subgroup of patients harboring RET M918T achieving the greatest PFS (61 vs 17 weeks). Patients with RAS mutations treated with cabozantinib also exhibited a longer PFS when compared with those treated with placebo (Sherman et al. 2016). Subsequent exploratory analyses have shown a statistically nonsignificant increase in the OS on the group who received cabozantinib as compared with placebo. Of note, the most significant benefits of cabozantinib treatment were observed in patients with RET M918T positive tumors (Hadoux & Schlumberger 2017). Despite these findings, there is no specific recommendation for treatment based on RET status. Some patients without documented RET mutations have benefited from MKI therapy. In vitro studies have shown that RET codon 804 and 806 mutations confer resistance to vandetanib therapy (Carlomagno et al. 2004, 2009).
MTC is a highly vascularized tumor, and overexpression of VEGF and its coreceptors have already been shown in MTC samples (Capp et al. 2010). Angiogenesis is critical for tumor growth, and the MKI anti-angiogenic effect is likely to play a role in response to therapy. Of interest, angiogenesis appears to be more intense in RET positive tumors, a feature that might increase their susceptibility to antiangiogenic treatment (Verrienti et al. 2016).
The choice of the first-line drug
The chronic use and side-effect profiles of MKIs must be taken into account when selecting patients since it is not clear which patients will benefit the most from TKI therapy. The criteria for initiating therapy include a high tumor burden and a rapid rate of disease progression, tumor involvement that threatens vital structures that cannot be managed by localized therapy. Only a selected group of patients with metastatic MTC should be considered for systemic therapy (Fig. 3).
Schematic diagram of the main aspects of disease presentation to be considered before recommend or not MKI therapy in patients with metastatic medullary thyroid carcinoma. *Evaluate case-by-case basis considering patients concomitant medical conditions, medical history, as well as the patient quality of life and lifestyle.
Citation: Endocrine-Related Cancer 26, 9; 10.1530/ERC-18-0574
Schematic diagram of the main aspects of disease presentation to be considered before recommend or not MKI therapy in patients with metastatic medullary thyroid carcinoma. *Evaluate case-by-case basis considering patients concomitant medical conditions, medical history, as well as the patient quality of life and lifestyle.
Citation: Endocrine-Related Cancer 26, 9; 10.1530/ERC-18-0574
Schematic diagram of the main aspects of disease presentation to be considered before recommend or not MKI therapy in patients with metastatic medullary thyroid carcinoma. *Evaluate case-by-case basis considering patients concomitant medical conditions, medical history, as well as the patient quality of life and lifestyle.
Citation: Endocrine-Related Cancer 26, 9; 10.1530/ERC-18-0574
Despite the established benefits of MKI for PFS, it is essential to consider the several adverse effects often noticed during their use and how much they can impact the patients’ life quality. The majority of MKI-related adverse events are familiar among the different drugs. The most frequent adverse events are diarrhea, rash, fatigue, and nausea. The most common AEs are usually of mild intensity (grade 1 or 2) and can be easily prevented or managed with symptom-related treatment, but in a non-negligible percentage of cases, dose reduction (up to 79% for cabozantinib and 35% for vandetanib) was needed in clinical trials (Elisei et al. 2013b , Viola et al. 2016). MKI-induced hypothyroidism is also frequent and requires an increase in the levothyroxine dose. Adverse events might be severe or life-threatening (G3–G4) in 5–10% of cases. MKI-related grade 5 adverse events have also been reported (de Groot et al. 2007, Schlumberger et al. 2009, Lam et al. 2010, Wells et al. 2012, Elisei et al. 2013b , Scheffel et al. 2013, Haugen et al. 2016). Of interest, recent studies examining the use of vandetanib and sorafenib outside of a clinical trial have reported similar adverse event profiles (Chougnet et al. 2015, de Castroneves et al. 2016).
In addition to the different side-effect profiles of the MKIs, the attending physician must also take into account the patient’s risk factors, past medical history, and adverse effect tolerance (Maia et al. 2017). Particular caution should be taken when prescribing MKIs for patients with a medical history of hemoptysis and hemorrhages, tumor invading vital structures of the neck, radiation treatment of the neck or mediastinum since they may be at higher risk for hemorrhages and fistula formation, a rare but life-threatening antiangiogenic MKI adverse event (Blevins et al. 2014). Vandetanib carries a higher risk for prolongation of the QT interval and should be avoided in patients with heart conduction disorders (Massicotte et al. 2013, Cabanillas et al. 2014). The use of vandetanib would be a better choice for patients whose occupation requires the use of the hands (e.g., carpenters, musicians) since the hand-foot syndrome is a common side effect of cabozantinib (Bastholt et al. 2016, Maia et al. 2017). The management of side effects related to MKI is essential to maximize the clinical benefits and increase the patient's quality of life (Grande et al. 2013, Bastholt et al. 2016).
Selective TKIs
Despite the advances in the management of metastatic MTC in the last decade, the clinical experience with the MKIs has been somewhat disappointing. While MKIs have increased the PFS, there was no improvement in OS. Almost all studies have shown a relatively low rate of partial responses, absence of complete response, and eventual tumor progression due to acquired drug resistance, which most commonly is due to secondary mutations in the kinase domains that sterically block the binding of MKIs in the target genes (Liu et al. 2018). These drawbacks of MKI therapy may be partially explained by ‘off-target’ side effects that limit the drug doses and consequently the degree of RET-specific inhibition. The vast and common adverse effects of MKIs results from concurrent inhibition of other targets, such as VEGFR2/KDR and lead to dose reductions or discontinuation (Romei et al. 2016, Wells 2018). Recently, new next-generation small-molecule TKIs designed for highly potent and selective targeting of oncogenic RET alterations have been developed with the goal of promoting a potent RET pathway inhibition and improve the pharmacokinetic properties of the currently available MKIs (Subbiah et al. 2018b ).
LOXO-292 and BLU-667
LOXO-292 is an orally bioavailable compound, selective and highly active RET inhibitor in preclinical models of RET-altered cancers in vitro and in vivo. In contrast to MKIs, LOXO-292 retains nanomolar potency against various RET alterations, with potential antineoplastic activity. A phase 1 study was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of LOXO-292 in patients with advanced solid tumors. The study included 82 patients, including 29 RET-mutant MTC tumors. The ORR in MTC patients was 45% (CI 95%: 24–68%). Tumor reduction was achieved in (9/20) 49% of MTC tumors, including a patient with a RET V804M mutation, and MKI-pretreated patients. Ninety percent (19/24) of the MTCs had a ≥50% decrease in serum calcitonin. Overall, the compound appeared to be well tolerated among the patients. AEs (≥10%) were fatigue (20%), diarrhea (16%), constipation (15%), dry mouth (12%), nausea (12%) and dyspnea (11%). Only two treatment-related AEs ≥grade 3 were reported: tumor lysis syndrome (DLT) and increased ALT. Most MTC patients (93%; 27/29) remained on treatment (ClinicalTrials.gov Identifier: NCT03157128) (Subbiah et al. 2018b ).
BLU-667 is also a highly selective RET inhibitor. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited the growth of thyroid cancer xenografts driven by various RET mutations and fusions without VEGFR-2 inhibition. The closest BLU-667 kinase off-target identified was Janus kinase 1 (JAK1). To investigate the clinical impact of BLU-667, a phase I, first-in-human, the dose-escalation study was conducted (ClinicalTrials.gov Identifier: NCT03037385). Fifty-one patients were enrolled with unresectable advanced solid tumors. Of them, 29 patients were found to have RET-mutant MTC. Overall, BLU-667 appeared to be well tolerated among the patients. The most common AE was grade 1 constipation (23%). Grades 3 to 4 AEs were also found, including hypertension (8%) and neutropenia (4%). Additional AEs included fatigue, diarrhea and a decrease in white blood cells (2% each). There were no reports of grades 4/5 AEs (Subbiah et al. 2018a ). Of interest, the potential side effects of JAK inhibition (reduced reticulocytes, red blood cells, neutrophils/monocytes) has not been observed among the patients tested, suggesting the preferential activity of BLU-667 for RET versus JAK.
Immunotherapy
In the last few years, immunotherapy has transitioned from a promising to a well-established option as an oncological treatment for several types of malignancies, acting as an immune checkpoint inhibitor (Emens et al. 2017). Preclinical studies on MTC have revealed potential new treatments through the use of immunotherapy (Naoum et al. 2018). Several ongoing trials are investigating this type of therapy, including a phase II trial studying a therapy directed toward cells presenting CEA (GI-6207), a therapy focused on programmed death ligand 1 (PDL1) with the use of pembrolizumab (Arasanz et al. 2017). Despite the lack of published results regarding the efficacy of these compounds on advanced MTC, all of these drugs have the potential to serve as new treatments.
Conclusion and perspectives
MTC is a very rare cancer with a good prognosis when diagnosed at early stages. For patients with advanced or metastatic disease, there is no effective therapeutic, curative option. In recent years, MKI therapy led to increases in the PFS, but no changes in the OS have been demonstrated to date. These compounds commonly cause toxicity, and it is crucial to establish an appropriate stratification of the clinical risk of patients to whom these drugs will be administered. The relatively low rate of partial responses and eventual tumor progression indicate the need to synergistic combinations of therapeutic targets whereas significant off-target toxicities may occur, limiting the degree of TKI-specific inhibition. Recently, next-generation small-molecule TKIs designed for highly potent and selective targeting of oncogenic RET alterations have been developed, and with the emergence of immunotherapy as an effective cancer treatment, there is hope for new promising drugs for the treatment of advanced MTC.
Declaration of interest
A L M has served as an advisor/speaker for Sanofi-Genzyme within the past 2 years. A L M and C V F V have served as principal investigator and coordinator, respectively, in multicenter studies for Astra-Zeneca and Sanofi-Genzyme within the past 2 years. The other authors have nothing to disclose.
Funding
This work was supported by grants from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (PRONEX/FAPERGS).
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