Molecular diagnosis and targeted treatment of advanced follicular cell-derived thyroid cancer in the precision medicine era

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.

NTRK gene fusions involving either NTRK1 , NTRK2 , or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB, and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be mediated by the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005 that are being explored in clinical trials. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.

Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).