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

Scott M Thompson, Garima Suman, Michael S Torbenson, Zong-Ming E Chen, Danielle E Jondal, Anurima Patra, Eric C Ehman, James C Andrews, Chad J Fleming, Brian T Welch, Anil N Kurup, Lewis R Roberts, Kymberly D Watt, Mark J Truty, Sean P Cleary, Rory L Smoot, Julie K Heimbach, Nguyen H Tran, Amit Mahipal, Jun Yin, Tyler Zemla, Chen Wang, Zachary Fogarty, Mark Jacobson, Bradley J Kemp, Sudhakar K Venkatesh, Geoffrey B Johnson, David A Woodrum, Ajit H Goenka, Scott M Thompson, Garima Suman, Michael S Torbenson, Zong-Ming E Chen, Danielle E Jondal, Anurima Patra, Eric C Ehman, James C Andrews, Chad J Fleming, Brian T Welch, Anil N Kurup, Lewis R Roberts, Kymberly D Watt, Mark J Truty, Sean P Cleary, Rory L Smoot, Julie K Heimbach, Nguyen H Tran, Amit Mahipal, Jun Yin, Tyler Zemla, Chen Wang, Zachary Fogarty, Mark Jacobson, Bradley J Kemp, Sudhakar K Venkatesh, Geoffrey B Johnson, David A Woodrum, Ajit H Goenka

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: SUVmax (median [range] 9.2 [4.9-28.4]), SUVmean 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.

© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Figures

FIG. 1
FIG. 1
Study overview.
FIG. 2
FIG. 2
PSMA expression in HCC. (A‐E) Tumor associated endothelial cell staining as a percentage of area: 0% (A)

FIG. 3

A 68‐year‐old male with alcohol‐associated…

FIG. 3

A 68‐year‐old male with alcohol‐associated liver disease–related cirrhosis and a LI‐RADS 5 observation.…

FIG. 3
A 68‐year‐old male with alcohol‐associated liver disease–related cirrhosis and a LI‐RADS 5 observation. Axial dynamic contrast‐enhanced MRI images show a large, infiltrative lesion in right lobe of liver, showing nonrim arterial hyperenhancement (A) and washout in equilibrium phase (B) with tumor thrombus extending into right portal vein (arrows). Axial attenuation corrected gray‐scale PET image (C), fused PET/CT image (D), and maximum‐intensity projection image (E) from 68Ga‐PSMA PET showing intense PSMA uptake (grade 4) in the lesion as well as in the tumor thrombus.

FIG. 4

A 60‐year‐old female with biopsy…

FIG. 4

A 60‐year‐old female with biopsy proven well‐differentiated HCC. Axial MRI images show a…

FIG. 4
A 60‐year‐old female with biopsy proven well‐differentiated HCC. Axial MRI images show a large exophytic lesion arising from left hepatic lobe with arterial hyperenhancement (A) and pseudocapsule (B) (arrows). Axial attenuation corrected gray‐scale PET image (C) and fused PET/MR image (D) from 68Ga‐PSMA PET show no uptake of PSMA in the lesion (grade 1).
FIG. 3
FIG. 3
A 68‐year‐old male with alcohol‐associated liver disease–related cirrhosis and a LI‐RADS 5 observation. Axial dynamic contrast‐enhanced MRI images show a large, infiltrative lesion in right lobe of liver, showing nonrim arterial hyperenhancement (A) and washout in equilibrium phase (B) with tumor thrombus extending into right portal vein (arrows). Axial attenuation corrected gray‐scale PET image (C), fused PET/CT image (D), and maximum‐intensity projection image (E) from 68Ga‐PSMA PET showing intense PSMA uptake (grade 4) in the lesion as well as in the tumor thrombus.
FIG. 4
FIG. 4
A 60‐year‐old female with biopsy proven well‐differentiated HCC. Axial MRI images show a large exophytic lesion arising from left hepatic lobe with arterial hyperenhancement (A) and pseudocapsule (B) (arrows). Axial attenuation corrected gray‐scale PET image (C) and fused PET/MR image (D) from 68Ga‐PSMA PET show no uptake of PSMA in the lesion (grade 1).

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