1. PSMA PET is routinely performed on many patients who have received or are receiving ADT at the time of the investigation; thus, the potential interaction of ADT on PSMA expression should be fully investigated, with implications for image interpretation and PSMA radioligand therapy timing. In vitro studies evaluating the effect of ADT on PSMA expression were first published by Wright et al. (57). Two elements regulate PSMA expression: PSMA promoter and PSMA enhancer, located within the third intron of FOLH1. FOLH1 gene expression is downregulated by androgens that reduce transcription of PSMA messenger RNA. On the other hand, antiandrogen administration upregulates the FOLH1 gene, causing an increased PSMA expression. In vivo studies showed that the PSMA expression is increased after ADT whereas the tumor size is decreased after administration of enzalutamide (58). Therefore, theoretically, the effect of ADT on images may be an increased PSMA expression before reduction in tumor size. Summarizing, we can say that ADT administration may lead to an increased PSMA uptake due to androgen receptor inhibition but that androgen receptor inhibitors may also lead to a reduction in tumor mass with consequent PCa cell death. Hope et al. showed that PSMA uptake significantly increased in 1 hormonal therapy–naïve patient imaged with PSMA PET before and after 4 wk of ADT (single administration of 7.5 mg of leuprolide and 50 mg of bicalutamide/die), in contrast to a significant reduction in PSA level, which dropped from 66 to 9 ng/mL (59). Moreover, some authors have postulated that modulation of PSMA expression after ADT differs depending on the status of the patient: CRPC or castration-sensitive PCa (CSPC). In this regard, Emmett et al. studied with sequential PSMA PET 8 CSPC patients at baseline and after 9, 18, and 28 d from ADT administration (luteinizing hormone–releasing hormone plus bicalutamide) (60). They also enrolled 7 CRPC patients studied with PSMA PET at the same time points after administration of abiraterone or enzalutamide. After 9 d, luteinizing hormone–releasing hormone plus bicalutamide stimulation caused a median 30% reduction in PSMA uptake in CSPC patients, whereas in CRPC patients, abiraterone/enzalutamide administration caused a median 45% increased PSMA expression. According to these data, it could be postulated that PSMA expression after ADT stimulation differs depending on the patient status. The authors concluded that there is a rapid dichotomous response to ADT depending on the presence of a CSPC or CRPC phenotype. If this hypothesis is correct, PSMA PET could be used in the future for early classification of patients after a few days of hormonal treatment. In a prospective clinical trial aimed to understand if ADT administration may improve the performance of PSMA PET in PCa patients at presentation, 9 treatment-naïve patients were enrolled (61). PSMA PET/MRI has been performed at baseline and 3 times after administration of ADT in a course ranging from 1 to 8 wk. The authors observed a heterogeneous increase in PSMA uptake after 3–4 wk of ADT administration, whereas none of the lesions showing deceased PSMA uptake after ADT disappeared. It is interesting that this finding was more evident in bone metastases. According to these data, the optimal imaging time point to perform a second PSMA PET exam might be 3–4 wk after ADT administration. Finally, Afshar-Oromieh et al. studied the effect of long-term ADT (mean, 7 mo) in 10 CSPC patients (62). PSMA uptake decreased in about 75% of the lesions, whereas in a small proportion of lesions (13%) PSMA uptake increased despite a complete or partial PSA response. The authors postulated that the lesions that showed an increased uptake despite a clinical and PSA response might correlate with those cell clones that become castration-resistant first. Summing up briefly, considering the paucity of literature about this topic, we can probably assume that in CSPC patients, a short duration of ADT administration may increase PSMA expression whereas long-term ADT might have the opposite effect, even if ▪▪▪ is possibly able to allow early detection of those lesions at risk of becoming castration-resistant. We can conclude by saying that there are still many unanswered questions and that foremost among these is the question of the optimal time point between ADT administration and PSMA imaging to reduce or increase (depending on the clinical needs) the effect of ADT on PSMA expression (63). In addition, further prospective studies are needed to clarify the influence of ADT administration on PSMA expression and the impact on PET imaging.
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