Evolution of anaplastic thyroid cancer management: perspectives in the era of precision oncology

Abstract

Anaplastic thyroid cancer is a rare aggressive malignancy resulting in poor outcomes, including significant morbidity and mortality. Historically, the overall survival of patients with anaplastic thyroid cancer has been less than 12 months. Multidisciplinary approaches combining surgery, radiation, and chemotherapy have been implemented to control this ominous disease. The evolution in science and technology has promoted deeper knowledge in the genetic pathways and mechanisms driving advance thyroid cancer. Furthermore, understanding molecular pathways resulted in the application of antineoplastic agents used in other tumors to thyroid cancer and the development of new highly selective drugs. A major landmark in anaplastic thyroid cancer management history was recently reached with the approval of BRAF and MEK inhibitor combination, specifically dabrafenib and trametinib for BRAF-mutated anaplastic thyroid cancer; this treatment has improved survival and outcomes in this population. Similarly, newer kinase inhibitors and immunotherapy are further shifting advanced thyroid cancer management to consider as first-line therapy inhibiting actionable oncogenic alterations. Therefore, newer treatment paradigms are incorporating molecular testing to provide personalized cancer care in anaplastic thyroid cancer. In this review, the principal aim is to provide an overview of the available international data on tyrosine kinase inhibitors and immunotherapy in the management of anaplastic thyroid cancer.

Combination of Novel Therapies and New Attempts in Anaplastic Thyroid Cancer

“…These findings suggest that there are high gene mutations and abnormal expression of a large number of molecules in ATC, resulting in the imbalance of multiple signaling pathways. 13 , 15 , 18 For drugs through different molecular pathways, see Figure 1 , mechanism and therapeutic efficacy of different drugs are shown in Table 1 . Further randomized clinical trials are also ongoing.…”

“…Therefore, in preclinical models, blocking their binding in vitro can enhance the immune response and antitumor activity. 13 , 16 One study revealed the effect of PD-L1 and anti-PD-L1 antibody immunotherapy alone or in combination with BRAF inhibitors on the intratumoral immune response; that is, the combination of PD-L1 antibody and PLX4720 can reduce the tumor volume and increase tumor infiltrating lymphocytes. 37 In addition, the study published by LIN Gui et al reported that a 67-year-old ATC patient had a rapid local recurrence after radical thyroidectomy.…”

“…Therefore, more active compounds need to be used in the treatment of ATCs. 9,[13][14][15] Although doxorubicin, docetaxel/paclitaxel and cisplatin have been recognized by ATA guidelines in the treatment of ATC, the survival rate of advanced ATC has not improved. 16 Many current clinical trials are trying to apply various combinations of targeted therapy and immunotherapy to the treatment of ATC.…”

Combination therapy of tyrosine kinase inhibitor sorafenib with the HSP90 inhibitor onalespib as a novel treatment regimen for thyroid cancer

“…The vast majority of PTC and FTC cases are well-differentiated and patients respond excellently to conventional treatments that include surgery, external beam radiotherapy (EBRT), radio-iodine ( 131 I) and cytotoxic chemotherapies such as paclitaxel 3 – 5 . However, the outcomes for ATC patients are less favorable as the disease is notoriously difficult to treat 6 . The median survival of ATC patients is less than six months post diagnosis and the 5-year overall survival rate falls below 10% 7 .…”

“…Worse still, the majority of ATC tumors are radio-iodine refractory and unresponsive to conventional chemotherapies. ATC is a highly mutated disease and several tyrosine-kinase inhibitors (TKIs) are approved for treatment of ATC, including sorafenib (nexavar) and lenvatinib (lenvima) 6 . The former is a multi-kinase inhibitor primarily targeting the vascular endothelial growth factor receptor VEGFR, platelet-derived growth factor receptor (PDGFR) and the Raf-kinases, including c-Raf and b-Raf 9 , 10 .…”