Despite that thyroid cancer accounts for over 90% of tumors that arise from the endocrine system, these tumors barely represent 2% of solid tumors in adults. Many entities are grouped under the general term of thyroid cancer, and they differ in histological features as well as molecular and clinical behavior. Thus, the prognosis for patients with thyroid cancer ranges from a survival rate of >97% at 5 years, in the case of differentiated thyroid tumors sensitive to radioactive iodine, to a 4-month median survival for anaplastic tumors. The high vascularity in these tumors and the important role that oncogenic mutations may have in the RAS/RAF/MEK pathway and oncogenicity (as suggested by activating mutations and rearrangements of the
Three different types of thyroid cancer have been defined according to their histological features: differentiated thyroid cancer (DTC) deriving from epithelial cells from the thyroid follicles; medullary thyroid cancer (MTC); anaplastic thyroid cancer (ATC). Approximately 90% of diagnosed thyroid cancers correspond to DTC, with papillary (PTC) histology being the most frequent (75%), followed by follicular (FTC) (10%), Hürthle cells (5%), and poorly differentiated carcinomas (1–6%) [
Thyroid cancer is considered a nonfrequent entity because it represents only 1% of all solid tumors in adults. Women are three-times more likely to suffer this disease, and the incidence of DTC has increased 2.4-fold over the past 30 years [
The last decade has seen advances in the molecular biology that may underlie the development and progression of these tumors. For example, DTC is mainly associated with mutations in the RAS/RAF/MAPK intracellular signaling pathway or with gene rearrangements such as
Classically, thyroid tumors are associated with high vascularization and high levels of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor (VEGF, FGF, and PDGF, resp.) [
Tyrosine kinases are enzymes that transfer phosphate groups from adenosine triphosphate (ATP) to tyrosine residues of another protein. Many tyrosine kinases are documented in humans as being involved in key processes of cellular control such as survival, proliferation, differentiation, function, and cell motility. In recent years, a large group of low molecular weight agents capable of inhibiting the function of tyrosine kinases have changed the natural history and management of various solid tumors such as kidney cancer, liver cancer, gastrointestinal stromal tumor (GIST), and, more recently, pancreatic neuroendocrine tumor. These drugs are called multitarget tyrosine kinase inhibitors and, due to their biochemical structure being similar to that of ATP, they are able to block the intracellular activation of several membrane receptors or proteins in the intracellular signaling cascade with tyrosine kinase activity. The degree of affinity and selectivity of this inhibitory activity is very variable (Table
Inhibitory concentration 50
Pharmaceutical compound | VEGFR1 | VEGFR2 | VEGFR3 | RET | RET/PTC | PDGFR |
BRAF | KIT | Others (IC50) |
---|---|---|---|---|---|---|---|---|---|
Sorafenib | 26 | 90 | 20 | 47 | 50 | 57 | 25 | 68 | — |
Motesanib | 2 | 3 | 6 | 59 | — | 84 | — | 8 | — |
Axitinib | 0.1 | 0.2 | 0.29 | 1.2 | — | 2 | — | 1.7 | — |
Sunitinib | 10 | 10 | 10 | 100 | 224 | 39 | — | 1–10 | — |
Vandetanib | — | 40 | 110 | 130 | 100 | — | — | — | EGFR (500) |
Pazopanib | 10 | 30 | 47 | — | — | 84 | — | 74 | — |
Lenvatinib (E7080) | 22 | 4 | 5.2 | 35 | — | 39 | — | — | FGFR1 (46) |
Cabozantinib (XL-184) | — | 0.035 | — | 4 | — | — | — | — | C-MET (1.8) |
Advances in understanding the molecular pathogenesis of different subtypes of thyroid cancer have, currently, made this field of research one of the busiest in the world of endocrine oncology. The application of discoveries in the laboratory to the patient (the “bench-to-bed” transfer) is one of the biggest challenges in translational research area, since these tumors can become a paradigm of therapy based on molecular features that govern the development and growth of tumors in each individual patient. This paper aims to summarize the key molecular determinants of each histological subtype of thyroid cancer and the data derived in recent years from clinical studies conducted with multitarget agents.
DTC represents the vast majority of thyroid tumors. Treatment is based on thyroidectomy with or without lymphadenectomy regarding papillary or follicular histology, followed by radioiodine ablation in those patients at high risk of lymph node metastases and levothyroxine in doses that suppress TSH levels. The semiannual or annual monitoring using cervical ultrasound, measurement of thyroglobulin levels as a tumor marker, and whole-body iodine scan is appropriate for these patients.
It is estimated that between 10 and 15% of patients undergoing DTC will have disease relapse. In 3 out of 4 cases, recurrence occurs at the cervical level in the thyroid bed or lymph node level. In these patients salvage surgery, radioiodine therapy and external radiotherapy is recommended in highly selected patients.
Distant metastases occur in <10% of DTC patients, and only half of them are apparent at the time of diagnosis. The lungs are the main receptor organs of these tumor metastases (50%), followed by bone (25%). Initial treatment of patients with disseminated disease includes TSH-suppressive doses of levothyroxine plus radioiodine administered in conditions of high serum TSH levels in those patients with positive total body scan uptake, albeit complete remission is achieved in only 30% of subjects [
A patient is considered resistant to the use of radioactive iodine when at least one tumor lesion is observed that does not show uptake of radioiodine, or when the lesion radiologically progresses in the first 12 months post-radioiodine administration, or when the patient has persistent disease following the administration of an accumulated dose of radioactive iodine of >600 mCi [
Molecular alterations present in different histological types of thyroid cancer.
In recent years, several different genetic events have been identified as being related to the genesis of the DTC. Further, a correlation has been reported between the manifestation of histological alterations of the disease and the presence of changes in the regulation of intracellular molecular pathways that confer a distinct clinical behavior. Two major molecular determinants that involve the same molecular pathway are responsible for the appearance of a PTC: the alteration of gene regulation of the
The abnormal chromosome rearrangement of proto-oncogene
Molecular aberrations observed in FTC are significantly different from those described in PTC, including RAS mutations in up to 45% of patients and rearrangements involving the transcription factor gene of the paired-box 8
Genetic alterations in the signaling pathway of RAS/RAF/MAPK constitute the most frequent genetic/molecular anomaly in patients with DTC. BRAF is a serine-threonine kinase that is key in the intracellular regulation of this cellular pathway. Activating mutations have been observed in the V600E codon of the
Point mutations in the gene encoding the
Mutations in
Activation and dysregulation of the intracellular signaling cascade PI3K/Akt/mTOR through loss of expression of tumor suppressor phosphatase PTEN has been implicated in the development of DTC and undifferentiated tumors of the thyroid. Likewise, mutations in the gene
Schematic representation of the follicular tumor cell.
Another molecular alteration frequently found in DTC is amplification of the gene encoding for the hepatocyte growth factor (
Angiogenesis is another potential area for the design of new molecular targets. Known receptors for VEGF (VEGFR-1, -2, and -3) and the FGF (FGFR) and PDGF (PDGFR-
Clinical data from studies with the main agents in clinical development in differentiated thyroid cancer.
Author (ref) | Pharmaceutical compound |
|
Response rate (%) | Stabilizations (%) | Progression-free survival (months) |
---|---|---|---|---|---|
Gupta-Abramson et al. [ |
Sorafenib | 30 | 23 | 53 | 20 |
Kloss et al. [ |
Sorafenib | 41 | 15 | 56 | 15 |
Ahmed et al. [ |
Sorafenib | 34 | 20 (DTC) | 48 | 12 |
Hoftijzer et al. [ |
Sorafenib | 31 | 24 | 34 | 14 |
Capdevila et al. [ |
Sorafenib | 34 (16 DTC) | 19 (DTC) | 50 (DTC) | 13.5 |
Leboulleux et al. [ |
Vandetanib | 145 | 8.3 versus 5.5 | 48 versus 37 | 11 versus 5.8 |
Cohen et al. [ |
Axitinib | 60 | 30 | 38 | 18 |
Carr et al. [ |
Sunitinib | 33 | 13 (DTC) | 68 (DTC) | 12.8 |
Cohen et al. [ |
Sunitinib | 31 | 13 | 63 | Not reported |
Sherman et al. [ |
Lenvatinib | 56 | 47 (DTC) | 36 (DTC) | Not reported |
Sherman et al. [ |
Motesanib | 93 | 24 | 67 | 10 |
Bible et al. [ |
Pazopanib | 37 | 49 | 46 | 11.8 |
Sorafenib is a multitarget agent for several major molecular pathways involved in the development and progression of PTC, including the serine-threonine kinase BRAF and the tyrosine kinases from the membrane receptors VEGFR-2 and PDGFR-
Vandetanib (ZD6474) is a low molecular weight inhibitor of tyrosine kinases, which acts mainly against VEGFR-2, VEGFR-3, and RET and, in higher concentrations, on the epidermal growth factor receptor (EGFR) (Table
Axitinib is one of the most selective and potent tyrosine kinase inhibitors currently under clinical development. The main targets blocked by axitinib are VEGFR-2, PDGFR-
Sunitinib is a multitarget inhibitor of 3 known receptors of VEGF, as well as of RET and PDGFR-
Lenvatinib (E7080) is a potent inhibitor in the nanomolar range of VEGFR-1 and -2 as well as PDGFR-
Motesanib (AMG706) is an oral inhibitor of multiple kinases, including VEGFR-1, -2, and -3 as well as the wild and mutant forms of the membrane receptor RET. In one of the initial phase I studies, focusing on recommended doses and major toxicities, motesanib was shown to achieve objective radiographic partial response in 3 of the 5 patients with thyroid cancer. This activity was not expected in these patients and led on to a prospective phase II study in 93 patients with DTC being carried out. One in every 3 patients remained on treatment for 48 weeks after commencement. The most common adverse events found at any grade were diarrhea (59%), hypertension (56%), fatigue (46%), and weight loss (40%). The radiological response rate assessed by independent reviewers was 14%, and up to 35% of patients benefited from a stabilization of their disease beyond 6 months. The median PFS was 9.3 months and, although the drug does not inhibit BRAF, the investigators observed that patients carrying a mutation in this pathway were less likely to progress if they received motesanib than patients without the mutation This finding suggested a greater involvement of angiogenesis in patients with the BRAF mutation [
Pazopanib shares the main targets with the other agents discussed above. However, it appears to have a marginal activity on
Currently, there were no officially approved therapy for the treatment of metastatic MTC until the recent approval of vandetanib by the American Food and Drugs Administration (FDA) and the European Medicine Agency (EMA). Following the failure of initial treatment by thyroidectomy and cervical lymphadenectomy, patients have received only symptomatic care measures. Therefore, this tumor has represented, and currently represents, a niche for the development of new active drugs, especially considering that between 35 and 50% of patients diagnosed with metastatic disease are likely to be diagnosed as having lympho-ganglionar metastases, and up to 15% of patients will develop distant metastases after diagnosis. Half of the patients diagnosed with MTC will ultimately present distant metastases during the clinical evolution of the disease.
MTC is considered a neuroendocrine tumor caused by the uncontrolled proliferation of para-follicular C cells producing calcitonin derived from the neural crest. It accounts for between 4 and 10% of thyroid cancers. In up to 30% of cases, the CMT is associated with an inherited syndrome and multiple endocrine neoplasia type 2 (MEN 2A or 2B) or with familial MTC (FMTC). Most hereditary MTC occur within MEN 2A that is often associated with pheochromocytoma or hyperparathyroidism [
Sporadic MTC is diagnosed in the 5th or 6th decade of life, while the hereditary versions of the disease can be diagnosed in 5-year-old children. Conventional therapy with chemotherapy has not proven to be particularly useful in patients with metastatic MTC. The most commonly used chemotherapy regimen has traditionally been that of doxorubicin monotherapy. This treatment achieves a clinical benefit, including the partial responses plus stable disease of 6 months, in about 21% of patients, with 79% of patients progressing within 5 months of treatment [
Approximately 50% of patients with sporadic MTC have a somatic mutation at codon 918 of the
The abnormal activation of
Clinical data from studies with the main multi-target agents in clinical development for the treatment of medullary thyroid cancer.
Author (ref) | Pharmaceutical compound |
|
Response rate (%) | Stabilizations (%) | Progression-free survival (months) |
---|---|---|---|---|---|
Wells Jr. et al. [ |
Vandetanib | 231 | 45 | — | Not achieved at 24 months. HR versus placebo = 0.46 |
Kurzrock et al. [ |
Cabozantinib | 37 | 49 | 41 | Not reported |
Lam et al. [ |
Sorafenib | 16 | 6 | 62 | 17.9 |
Capdevila et al. [ |
Sorafenib | 34 (15 MTC) | 47 | 40 | 10.5 |
Schlumberger et al. [ |
Motesanib | 91 | 2 | 48 | 11.2 |
Carr et al. [ |
Sunitinib | 7 | 37.5 | — | Not reported |
De Souza et al. [ |
Sunitinib | 25 | 35 | 57 | Not reported |
Vandetanib is the first drug approved in the US by the FDA and in Europe by the EMA for treatment of MTC in the last 30 years. The approval was as a consequence of the data reported in the ZETA study which was a phase III, double-blind trial with 2 : 1 randomization of patients to receive vandetanib at doses of 300 mg/day versus placebo. Between December 2006 and November 2007, a total of 331 patients with sporadic or inherited MTC were enrolled. The median PFS in the placebo arm was 19.3 months while the vandetanib treatment arm has not yet been concluded (HR: 0.46; 95% CI: 0.31–0.69;
Cabozantinib is an oral inhibitor that, in addition to acting against VEGFR-1 and -2, and c-KIT as are most of the drugs discussed above, is able to inhibit c-MET which, as also discussed above, is amplified in a large proportion of patients with DTC and MTC. It also acts against RET and against
The observed
In a multicentered, international, open-label phase II trial, motesanib demonstrated that it was able to induce a clinical benefit in 50% of 91 patients with locally advanced or metastatic MTC. The PFS was 12 months. Most study patients (84%) corresponded to sporadic MTC in 72% of whom the
In the study by Carr et al. [
ATC contributes less than 2% of all thyroid-derived tumors but is responsible for 14 to 39% of deaths from thyroid cancer. With a frequency 5-fold higher in men than in women, the median survival range depends on status between 3 and 9 months after diagnosis. Approximately 50% of patients diagnosed with ATC already have metastases at the time of diagnosis, and another 25% will eventually develop metastases. Treatment options are surgery, palliative radiotherapy, and chemotherapy. ATC tumors are considered chemo resistant. Doxorubicin in monotherapy achieves positive radiological response rates in <20% of patients, and this response is rarely protracted. Other platinum-based combinations such as taxanes, gemcitabine or vinorelbine can achieve up to 53% radiological response but does not have much impact on the overall survival of patients [
Most frequent mutations observed in ATC affect
In a phase II study conducted with single-agent axitinib in patients with thyroid cancer of all histology subtypes, there was an objective radiological response in approximately 50% patients with ATC who entered the study [
In the only study performed specifically in patients with ATC, 16 patients were treated with sorafenib alone. The rate of control of the disease was 40%, although time-to-progression barely reached 1.5 months. Of the 15 evaluable patients, 2 (13%) showed an objective radiological response that was maintained for a median of 5.3 months. The most frequently observed grade 3 and 4 adverse events were lymphopenia (31%), skin rash (12%), weight loss (12%), and chest pain (12%) [
CA4P is a vascular-disrupting agent, also called fosbretabulin tromethamine or combretastatin A4 phosphate. Unlike other antiangiogenesis agents that block tumor blood vessel formation, CA4P prevents blood flow in existing vessels. This drug has shown some activity as a single agent in patients with metastatic ATC who have not responded to at least one prior systemic therapy but in whom, on rare occasions, positive responses were observed and objective radiological PFS of 3 months was achieved. The final results in overall survival of the largest randomized trial conducted in patients with metastatic ATC were presented at American Society of Clinical Oncology (ASCO) annual meeting in 2011. A total of 80 of the planned 180 patients with ATC were recruited and randomized to receive carboplatin + paclitaxel with or without associated CA4P in a 2 : 1 randomization. The median overall survival was higher in the CA4P arm but did not reach statistical significance (5.2 versus 4.0 months; HR 0.65; 95% CI: 0.38–1.10); 27% of patients were alive at 1 year in the arm that received the experimental therapy compared to 9% in the standard treatment arm. The planned total patient sample could not be reached due to low recruitment [
Thyroid cancers are one of the greatest challenges for those treating advanced tumors. Thyroid cancer offers extensive opportunities to work in interdisciplinary teams that include not only oncologists and endocrinologists but also specialists in pathology, nuclear medicine, surgery, otolaryngology, radiology, clinical laboratory, and radiotherapy. Coordinated administration (whether concomitant or sequential) of the different therapeutic options for these patients make collaborative and efficient functioning of surgical and medical professionals more important than ever. The opportunity that presents itself is to apply the various treatments becoming available based on the genotypic characteristics of patients. Moreover, we have to consider the possibility of administering tyrosine kinase inhibitors for a long time with caution. We assume that these drugs are quite specific cytostatic and not cytotoxic agents, therefore, there is a need to give these agents until progression of the disease or toxicity. The concept of long-term treatment management of these new agents to patients in a childbearing age, with known cardiovascular toxicity, and perhaps many different side effects that could arise in the long-time followup, makes the monitoring of patients receiving inhibitors tyrosine kinase a must to be done very closely.
Maximizing clinical outcomes of tyrosine kinase therapy requires clear, effective communication, anticipation of side effects, and early intervention to avoid treatment delays and dose-limiting toxicities. There is a direct correlation between the plasmatic levels of the tyrosine kinase inhibitors with the activity of the drug, therefore, we would need to maintain as far as we can the highest dose of the targeted agent we consider is the most appropriate to our patients. In this sense, the experience in the management of tyrosine kinase inhibitors is crucial and probably the development of therapy management guidelines would be necessary in the next years.
To summarize, there is a need for a greater understanding of the molecular basis of the disease by the various health professionals charged with the care of these patient that could lead to a better optimization of treatment options in the advanced setting.
The authors declare that have no relevant conflict of interests in this paper. Pfizer funded the submission of the manuscript.