*4.2. Genetically Guided Therapy*

Many reports showed that ATC has a singular genomic and transcriptomic landscape (ATC-like) [131]. In this singular genomic landscape, BRAF-MEK pathway was proposed as a potential target.

After the exciting results of BRAF inhibition in BRAF-mutated melanoma [132], a multicenter prospective "basket" trial, encompassing tumors with BRAF mutation, enrolled 7 patients affected by ATC for treatment with vemurafenib: 2 of them experienced a durable partial response (more than 11 months) [133]. In order to produce a stronger inhibition of BRAF-MEK pathway, dual inhibition of BRAF and MEK with dabrafenib and trametinib was proposed. Accordingly, in in-vitro ATC model, combined therapy induced greater growth inhibition than single agents [134]. Likewise, dabrafenib-trametinib therapy produced about 80% of 12-months progression free survival and overall survival in phase II clinical trial enrolling 16 patients [135]. Moreover, 1 patient experienced a complete response, 10 partial response, 3 stable disease and only 1 disease progression. In this trial, fatigue (44%), pyrexia (31%), and nausea (31%), were the most common adverse events, although the 50% of enrolled patients reported an adverse event with grade ≥ III [135]. This trial permitted the approval of this combination by FDA for treatment of BRAFV600E mutated ATC.

As previously reported, PI3K/Akt/mTOR has a crucial role in ATC cells and also antimTOR inhibitors have been proposed with conflicting results. Everolimus was used to treat one patient with ATC harboring a mutation of Tuberous Sclerosis 2 protein (TSC2), member of PI3K/AKT/mTOR pathway, obtaining an extraordinary 18-month response [136]. However, these promising results were not confirmed in other studies [137,138].

New perspectives have recently been opened for patients with ATC or PDTC harboring RET fusion genes, since highly selective RET inhibitors, such as selpercatinib and pralsetinib, are currently under investigation [139,140]. In 2020, a phase 1–2 clinical trial enrolled patients with thyroid cancer harboring an activating RET alteration for treatment with selpercatinib (LIBRETTO-001). In this trial, one patient with ATC and 3 with PDTC were enrolled. Interestingly, the patient with ATC reached PR as best response as well as 2 out of 3 patients with PDTC, while the other one with PDTC obtained SD [139]. Furthermore, selpercatinib presents a more tolerable toxicity profile with a rate of adverse events ≥ III of only 30% compared to other targeted therapies and the most common reported adverse events were hypertension, increased alanine or aspartate aminotransferase level, hyponatremia and diarrhea. Likewise, Cabanillas et al. have recently presented data about the use of larotrectinib, a NTRK fusion gene inhibitor, in 7 patients with ATC. Intriguingly, 3 out of 7 reached PR and SD, while 3 patients experienced PD [141]. Grade ≥ III adverse events occurred in 46% of patients, although only 7% of patients presented ones that were considered related to larotrectinib [141]. Recently, an excellent response was documented with crizotinib in one patient with ATC, harboring ALK-RET fusion gene [142].

Other agents such as HDAC inhibitors have been used but with disappointing results (NCT03002623 trial).
