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Matrone et al. J Cancer Metastasis Treat 2021;7:23 https://dx.doi.org/10.20517/2394-4722.2021.47 Page 13 of 19

Recent evidence shows that MTC harbored a greater mutational load, with a potentially relevant
immunogenicity [125,127,128] . In addition, the presence of RET-mutated cells could induce changes in the tumor
microenvironment, influencing the surrounding stroma, activating cancer-associated fibroblasts, promoting
[129]
cancer-associated inflammation, and suppressing anti-cancer immune response . These findings, showing
the expression of single or multiple immune checkpoints in MTC tumor and immune cells, could be
hypothesized as a potential target for ICI.

Thus far, a phase II clinical trial (ClinicalTrials.gov, number NCT03072160) to evaluate the efficacy of
pembrolizumab in advanced MTC has been planned. Two arms were designed, one with a previous
immune stimulatory vaccine and the other without. The enrollment was completed, but to date no results
are available.

Clinical point of view
To date, no clinical results on the effects of pembrolizumab on MTC patients are available. However,
immunotherapy is at the beginning of its clinical application in several tumors and the promising results
should be a stimulus to continue the research also for thyroid cancers. However, at the moment, no clinical
application, either in clinical trials or as a compassionate or off-label use, is possible.

PEPTIDE RECEPTOR RADIONUCLIDE THERAPY
Rationale of treatment
MTC cells, similar to other neuroendocrine tumors, can express somatostatin receptors (SSTRs) [130-132] . For
[133]
this reason, diagnostic tools based on radionuclides with high affinity for SSTRs, such as octreoscan and
[134]
68Ga-DOTATATE or DOTATOC PET/CT , could be performed. The presence of SSTRs is the rationale
for peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs (SSAs). Several
radiolabeled SSAs have been explored as potential therapeutic agents. Most of the studies about PRRT in
MTC investigated the use of SSAs labeled with the radionuclide(s) 90 yttrium (90Y) and/or 177 lutetium
(177Lu) [135-143] . In addition, the use of 111 indium (111In) has been evaluated [144-146] .

Several of these studies showed a decrease ≥ 50% in post treatment CT values, compared to baseline, in 24%-
30% of patients treated with 90Y and 177Lu . Another study showed a prolongation of CT doubling
[135]
[137]
[147]
time (≥ 100%) in 18/31 (58%) patients , indicating a relevant reduction of the tumor growth rate.
However, most of these studies, although with a limited number of patients, showed that a stabilization of
the disease (43%-100%) was the main clinical response obtained after PRRT treatments with Y90 or
177Lu [136,140,142,148] . These results were confirmed in studies with greater numbers of patients in which stable
disease accounted for 57%-58% of cases [135,137] . Few and scattered data are available on the outcome of these
MTC patients, and Parghane et al. reported a median OS of 26 months in 43 patients treated with 177Lu‐
[137]
DOTATATE PRRT.

Since, in MTC cells, cholecystokinin 2 receptor (CCK2R) could be expressed, this receptor may represent a
[149]
potential target for PRRT , but this possibility has to be better explored. The possibility to use PRRT in
MTC seems to be another possible therapeutic way, however current experiences are very limited. More
reliable data could derive from several ongoing clinical trials (ClinicalTrials.gov, numbers NCT00002947,
NCT03647657, NCT02088645, and NCT04106843).

Clinical point of view
The knowledge about the efficacy and safety of the PRRT on MTC is still under construction. However,
reported data are in favor of using PRRT in specific cases such as those patients with metastatic advanced