Navigating Systemic Therapy in Advanced Thyroid Carcinoma: From Standard of Care to Personalized Therapy and Beyond

Abstract

Thyroid cancer, with the exception of anaplastic thyroid cancer, typically has very favorable outcomes with the standard therapy. However, those that persist, recur, or metastasize are associated with a worse prognosis. Targeted therapy with kinase inhibitors has shown promise in advanced cases of thyroid cancer, and currently five drug regimens are approved for use in clinical practice in the treatment of differentiated, medullary, and anaplastic thyroid cancer, with more options in the pipeline. However, one of the greatest dilemmas is when and how to initiate one of these drugs, and this is discussed herein.

Keywords: BRAF inhibitors; anaplastic thyroid cancer; differentiated thyroid cancer; immunotherapy; kinase inhibitors; medullary thyroid cancer.

Figure 1.

Schematic of the two commonly activated pathways and genetic aberrations involved in thyroid cancer, as well as the targeted therapies studied in thyroid cancer. The MAPK and the PI3K pathways are activated by the receptor tyrosine kinase (RTK). Increased activity of the receptor tyrosine kinases (purple bars) by growth factors, as well as mutations along the pathway, results in oncogenic activation of the MAPK pathway, leading to activation of MEK and ERK and, subsequently, tumor progression. The PI3K pathway is negatively regulated by PTEN and is activated by mutations in PIK3CA, PTEN, AKT, and mTOR. The PI3K pathway can also be activated by RAS and NF1 mutations, as there is a cross-talk mechanism with the MAPK pathway. TP53 is a tumor suppressor gene and plays a role in apoptosis. TERT activation via TERT promotor mutations promotes cell immortality. Patients with TERT promotor mutations that coexist with BRAF or RAS mutations have a worse prognosis. In green are drugs that can potentially target along these signaling pathways to shrink tumors or halt their growth. AKT, protein kinase B.

Figure 2.

Algorithm for management of patients with DTC. Patients with active disease should first be considered for surgery and/or RAI. If this is not feasible, or the patient is RAI refractory, observation for progression should be considered, as many patients have indolent disease. Patients who should not be observed are those who in the absence of treatment are at risk for organ (i.e., bronchial obstruction or respiratory failure) or limb dysfunction (i.e., pathologic fracture). These patients should be treated with focal therapies or systemic therapy. In those patients who do require systemic therapy due to clinically significant disease (lesion >1.5 cm) and who have progression within 6 months (12 months, case by case) or who are at risk for organ/limb dysfunction without systemic therapy, molecular testing can help guide treatment. In particular, knowing the BRAF status, as well as the presence of genetic fusions in NTRK, RET, ALK, or ROS, is important, as these are potentially actionable genetic aberrations with selective KIs. In patients who are non–BRAF V600E mutated or where the BRAF status is unknown, a determination regarding whether antiangiogenic drugs will increase the risk of a serious AE, and therefore relatively contraindicated, should be made. Relative contraindications to antiangiogenic drugs include poor cardiac function, recent myocardial infarction, uncontrollable hypertension, large and unhealed wounds, history of colitis, diverticulitis, intestinal perforation, or recent bowel surgery, tumor invading trachea/esophagus/great vessels, hemoptysis or use of anticoagulants, and very low body weight (may be exacerbated with antiangiogenic TKIs). If no contraindication to antiangiogenics exists, regardless of the BRAF status, either one of the FDA-approved drugs for DTC should be initiated. If there is a relative contraindication to antiangiogenics, the less potent of the two drugs, sorafenib, should be favored. Alternatively, a lower dose of lenvatinib can be started. In either scenario, these patients require close follow-up in this setting. If the patient has a relative contraindication to antiangiogenics and is BRAF mutated, a selective BRAF inhibitor should be favored. Particularly in patients with poor tolerance of BRAF inhibitors, radioactive iodine while on the BRAF inhibitor (“redifferentiation therapy”) may be considered. TKIs, tyrosine KI.