Prospective Study of the Radiolabeled GRPR Antagonist BAY86-7548 for Positron Emission Tomography/Computed Tomography Imaging of Newly Diagnosed Prostate Cancer

Abstract

Background: Current imaging techniques may not detect all prostate cancer (PCa) lesions.

Objective: To evaluate positron emission tomography (PET)/computed tomography (CT) using the radiolabeled GRPR antagonist probe BAY86-7548 (68Ga-RM2) for localization of newly diagnosed PCa in comparison with multiparametric magnetic resonance imaging (mpMRI), histopathology, and immunohistochemistry (IHC).

Design, setting, and participants: This was a prospective study of 16 men with biopsy-proven PCa (2 low, 8 intermediate, and 6 high risk). 68Ga-RM2 PET/CT was performed within 4 wk after mpMRI and within 2 wk before radical prostatectomy and extended bilateral pelvic lymph node dissection.

Outcome measurements and statistical analysis: The presence of cancer was evaluated by blinded specialists using a 5-point Likert scale, with lesions scoring 4 or 5 considered positive, on 68Ga-RM2 PET/CT, mpMRI, and 68Ga-RM2 PET/CT-mpMRI fused images for each of 12 anatomic areas of the prostate. Whole-mount, step-section pathology served as the reference standard. Expression of GRPR and prostate-specific membrane antigen (PSMA) was analyzed via IHC of tumor paraffin sections.

Results and limitations: Of 192 areas analyzed, 128 contained cancer. The sensitivity, specificity, and accuracy of 68Ga-RM2 PET/CT imaging and mpMRI did not differ significantly; fusing the images maximized the sensitivity and accuracy (85.2% and 83.9%, respectively) and averaged the specificity (81.3%). The area under the receiver operating characteristic curve was 0.76 for PET visual analysis, 0.72 for PET quantitative analysis, 0.76 for mpMRI, and 0.85 for combined PET/CT and mpMRI analysis. 68Ga-RM2 uptake did not correlate with Gleason score. IHC analysis revealed weaker staining for GRPR than for PSMA, and the expression of these markers was not correlated (r=0.3882). The major limitation is the small sample size.

Conclusions: 68Ga-RM2 PET/CT is promising for detection and localization of primary PCa, and complements mpMRI. GRPR expression appears to be independent from PSMA expression, suggesting that GRPR- and PSMA-targeted PET imaging may be complementary.

Patient summary: This pilot prospective study shows that a positron emission tomography probe that binds to a marker of prostate cancer, GRPR, improves the ability of magnetic resonance imaging to detect prostate cancer.

Keywords: Gastrin-releasing peptide receptor; Imaging; Multiparametric magnetic resonance imaging; Positron emission tomography/computed tomography; Prostate-specific membrane antigen.

Copyright © 2018. Published by Elsevier B.V.

Figures

Fig. 1–

Maximum standardized uptake (SUVmax) of the dominant lesion according to Gleason score.

Fig. 2–

Receiver operating characteristic curves for each imaging modality and maximum standardized uptake (SUV) of 68Ga-RM2 on PET. PET = positron emission tomography; MRI = magnetic resonance imaging.

Fig. 3–

Maximum standardized uptake (SUVmax) of normal prostate tissue (PT), benign prostatic hyperplasia (BPH) and dominant tumor.

Fig. 4–

Lymph node metastasis on pathology correctly diagnosed by 68Ga-RM2 PET and missed by mpMRI. The patient was 61 yr of age and had prostate-specific antigen of 9.1 ng/ml. (A) 68Ga-RM2 PET/CT maximum intensity projection image showing the physiologic distribution of 68Ga RM2. (B) Transverse 68Ga-RM2 PET/CT-MRI fusion image reveals a lesion (maximum standardized uptake 21.9) involving all of the prostate, predominant on the left side, with potential extracapsular extension. (C) Transverse T2-weighted MRI and (D) apparent diffusion coefficient map revealing the same lesion with a low signal. (E) Histopathology section shows the lesion has a Gleason score of 9 (4 + 5). (F) Transverse 68Ga-RM2 PET/CT-MRI fusion image shows high focal uptake in a left internal iliac lymph node highly suspicious of metastasis (confirmed on histology). (G) On transverse T1-weighted MRI, the left internal iliac lymph node does not appear enlarged and is considered nonsuspicious (false-negative lymph node). PET = positron emission tomography; mpMRI = multiparametric magnetic resonance imaging; CT = computed tomography.

Fig. 5–

Lymph node metastasis on pathology correctly diagnosed by mpMRI and missed by 68Ga-RM2 PET. The patient was 56 yr of age and had prostate-specific antigen of 1.4 ng/ml. (A) 68Ga-RM2 PET/CT maximum intensity projection image showing the physiologic distribution of 68Ga RM2. (B) Transverse 68Ga-RM2 PET/CT fusion image reveals very low uptake (maximum standardized uptake 1.5) in the left mid-gland posterior, considered equivocal evidence of cancer. Of note, the avid area near the pubic bone is due to urine at the bladder neck. (C) Transverse T2-weighted and (D) apparent diffusion coefficient MRI show a low-signal lesion in the left posterior peripheral zone, consistent with prostate cancer. (E) Histopathology section shows the lesion has a Gleason score of 7 (4 + 3). (F) Transverse 68Ga-RM2 PET/CT-MRI fusion image reveals no uptake in an enlarged right internal iliac lymph node, considered negative for metastasis by 68Ga-RM2 PET. (G) Transverse T1-weighted MRI shows that the lymph node is enlarged and thus suspicious for metastasis (confirmed on histology). PET = positron emission tomography; mpMRI = multiparametric magnetic resonance imaging; CT = computed tomography.

Fig. 6–

Relationship between immunohistochemistry (IHC) staining scores for prostatespecific membrane antigen (PSMA) and GRPR.

Fig. 7–

Tumor negative for prostate-specific membrane antigen (PSMA). The patient had prostate-specific antigen of 4.3 ng/ml and a Gleason score of 7 (3 + 4). (A) Hematoxylin and eosin section revealing tumor on the left. (B) IHC for PSMA at (B1) low magnification and (B2) 20× magnification; score = 0.3. (C) Transverse 68Ga-RM2 PET/CT-MRI fusion image shows high tumoral uptake (maximum standardized uptake 11.3) in posterior lesions involving both sides of the prostate, predominant in the left, evocative of prostate cancer. (D) IHC for GRPr; (D1) low magnification, (D2) 20x magnification; score = 2.6. IHC = immunohistochemistry; PET = positron emission tomography; mpMRI = multiparametric magnetic resonance imaging; CT = computed tomography.

Fig. 8–

Tumor negative for GRPR. The patient had prostate-specific antigen of 9.7 ng/ml and a Gleason score of 7 (3+4). (A) Hematoxylin and eosin section shows tumor on the right. (B) IHC for PSMA at (B1) low magnification and (B2) 20× magnification; score = 2.5. (C) Transverse 68Ga-RM2 PET/CT-MRI fusion image shows moderate tumoral uptake (maximum standardized uptake 4.5) in the center of the prostate evocative of prostate cancer. (D) IHC for GRPR at (D1) low magnification and (D2) 20× magnification; score = 1.4. IHC = immunohistochemistry; PET = positron emission tomography; mpMRI = multiparametric magnetic resonance imaging; CT = computed tomography.