Progress in molecular targeted therapy for thyroid cancer: vandetanib in medullary thyroid cancer.

Thyroid cancer, the most common endocrine neoplasm, is increasing in incidence and will account for an estimated 48,020 new cases and 1,740 deaths in the United States in 2011. Most thyroid cancers arise from thyroid follicular cells. These include differentiated thyroid cancers (DTCs)—papillary thyroid cancer (which accounts for 80% of all thyroid tumors) and follicular thyroid cancer (approximately 15% of thyroid tumors)—as well as the less common anaplastic thyroid cancer. Medullary thyroid cancer (MTC) is a tumor of the calcitonin-producing parafollicular or C cells of the thyroid and comprises 2% to 3% of all thyroid cancers. MTC occurs in familial forms as part of the multiple endocrine neoplasia syndromes (MEN2A or MEN2B) and familial MTC in 20% to 30% of cases but more commonly is apparently sporadic. Although the majority of thyroid cancers, other than anaplastic thyroid cancer, are effectively treated with surgery (combined with radioiodine and thyroidstimulating hormone suppression in high-risk DTC), treatment options with cytotoxic chemotherapy or radiotherapy for patients who develop unresectable recurrent or metastatic MTC or noniodine-avid DTC have been minimally effective. Several recurrent mutations or gene rearrangements have been identified in both DTC and MTC and seem to be important in the pathogenesis of thyroid cancers. The first of these, recognized more than two decades ago, was a gene rearrangement involving the protooncogene RET (rearranged during transformation) in papillary thyroid cancer (so-called RET/PTC gene rearrangements). The novel gene fusion results in aberrant expression and activation of the RET kinase in thyroid follicular tissue, which leads to the development of papillary thyroid cancer. Since then, several RET/PTC variants have been identified in 10% to 20% of sporadic papillary tumors in adults, but in up to 50% to 80% of papillary tumors that arise in childhood or after exposure to ionizing radiation (for example, by fallout from the Chernobyl nuclear accident). Activating mutations in RET are present in the germline of virtually all patients with hereditary MTC. These mutations may present as part of the MEN2A, familial MTC, or MEN2B syndromes in which there is a genotypic/phenotypic correlation between the type of RET mutation and clinical features such as age of onset and clinical aggressiveness of thyroid tumors, the incidence of pheochromocytoma or hyperparathyroidism, and the presence of developmental abnormalities, mucosal neuromas, and intestinal ganglioneuromas. RET mutations are also found in at least 50% of sporadic MTCs. Activating mutations in BRAF (in particular the V600E mutation) have been identified in approximately 50% of papillary thyroid cancers and correlate with poor outcome. RAS mutations, particularly those that involve NRAS and HRAS, are found in 10% to 20% of papillary thyroid cancers (usually in the follicular variant) and 40% to 50% of follicular thyroid cancers. Translocations that result in a fusion between PAX8 and the peroxisome proliferator-activated receptor gene are found in 30% to 40% of follicular thyroid cancers. Although characterization of these genetic events in thyroid cancer may have diagnostic and prognostic implications, it also provides an opportunity to develop therapies that are targeted at these potential molecular drivers. In the article that accompanies this editorial, Wells et al report the results of a phase III randomized trial using vandetanib (Caprelsa, ZD6474; AstraZeneca, Wilmington, DE), an orally available smallmolecule inhibitor of RET as well as the vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor, in patients with locally advanced or metastatic MTC. After the observation of responses to vandetanib in patients with hereditary MTC, a double-blind, placebo-controlled, phase III study was initiated in which patients with locally advanced or metastatic MTC were randomly assigned in a 2:1 ratio to receive 300 mg of vandetanib daily or a placebo. Remarkably, Wells et al were able to accrue 331 patients with this uncommon neoplasm from 23 countries during a period of less than 1 year. Most patients (90%) had sporadic MTC and 95% had metastatic disease. Although 51 patients (23 who received vandetanib and 28 in the placebo group) received open-label vandetanib before progression was documented on a central reading of scans, the study achieved its primary end point with prolongation of progression-free survival (PFS) on the basis of independently reviewed imaging in patients who were treated with vandetanib compared with those who received the placebo (hazard ratio, 0.46; 95% CI, 0.31 to 0.69; P .001). The median PFS with the placebo was 19.3 months and was not reached in the vandetanib group (but was estimated at 30.5 months). Objective responses were seen in 45% of patients who were treated with vandetanib, with disease control rates of 87% with vandetanib compared with 71% in patients treated with the placebo. Biochemical responses with falling calcitonin and carcinoembryonic antigen levels were seen in 69% and 52% of patients who were treated with vandetanib, respectively. With a median follow-up of 24 months, no differences were seen in overall survival, and although the survival analysis is to be repeated once 50% of patients have died, this end point may be confounded by cross-over. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S