PSMA as a Theranostic Target in Hepatocellular Carcinoma: Immunohistochemistry and 68Ga‐PSMA‐11 PET Using Cyclotron‐Produced 68Ga

Abstract

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68 Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68 Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68 Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA ( P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor‐associated neovasculature. Higher tumor grade was associated with PSMA expression ( P = 0.012) but there was no association with tumor size ( P = 0.14), fibrosis ( P = 0.35), cirrhosis ( P = 0.74), hepatitis B virus ( P = 0.31), or hepatitis C virus ( P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10 ‐5 ) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = −0.753; P = 1.58 × 10 ‐6 ). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68 Ga‐PSMA‐11 standardized uptake value: SUV max (median [range] 9.2 [4.9‐28.4]), SUV mean 4.7 (2.4‐12.7), and tumor‐to‐liver background ratio 2 (1.1‐11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68 Ga‐PSMA‐11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

PSMA Radioligand Uptake as a Biomarker of Neoangiogenesis in Solid Tumours: Diagnostic or Theragnostic Factor?

“…Five full-text papers assessing the potential role of PSMA radioligands in the diagnostics of hepatocellular carcinoma (HCC) were reviewed [ 64 , 65 , 66 , 67 , 68 ]. Out of the five included studies, four had a prospective design [ 64 , 65 , 66 , 68 ]. The sample size varied from 7 to 40 and from 37 to 142 for patient and lesion analyses, respectively.…”

“…In all studies, PET/CT was performed using 68 Ga-PSMA-11 as the diagnostic radiopharmaceutical [ 64 , 65 , 66 , 67 , 68 ].…”

“…With regard to the clinical setting in which PSMA radioligand imaging was employed, in all studies PET/CT had the purpose both to stage untreated HCC patients and to restage after at least one line of treatment (transarterial chemoembolization, surgery, radiofrequency or transarterial radioembolization) [ 64 , 65 , 66 , 67 , 68 ].…”

“…All the examined papers used CT and/or MRI as comparator to evaluate PSMA radioligand PET/CT performance [ 64 , 65 , 66 , 67 , 68 ] and two added 18 F-FDG PET/CT in the analysis [ 64 , 66 ].…”

“…All studies evaluating PSMA radioligand PET/CT in HCC reported a good performance in assessing the presence of pathological findings in liver and lymph-nodes, representing a potential novel imaging modality for patients with HCC, especially for extrahepatic disease detection [ 64 , 65 , 66 , 67 , 68 ]. When compared to other examinations, PSMA radioligand PET/CT showed better performance than 18 F-FDG PET/CT in two studies, both in liver lesion detection and extrahepatic involvement assessment (lymph nodes, bone, peritoneum) [ 64 , 66 ]; moreover, PSMA radioligand PET/CT showed quite similar performance compared to MRI, especially in liver lesion assessment [ 64 , 65 , 66 , 67 , 68 ].…”