Introduction
Prostate cancer is the most common cancer in men and the third cause of cancer deaths [
1]. It is also a multifocal disease as cancerous cells may arise from different locations within the prostatic gland. Thus, prostate cancer is a combination of different cancerous cells with their own metastatic risks. Prostate cancer classification, prognosis, and management are today based on the two major cell populations (Gleason score). Beside primary staging which includes multi parametric pelvic magnetic resonance imaging (mpMRI), thoraco-abdomino-pelvic computed tomography (CT), and bone scintigraphy, only
18F-Choline positron emission tomography/computed tomography (PET/CT) may be proposed to some patients with high metastatic risk but it has a low accuracy for detection of primary prostate cancer [
2].
Attractive targets for a more specific and sensitive imaging of primary prostate cancer are the prostate-specific membrane antigen (PSMA) and the gastrin-releasing peptide receptor (GRP-R). They can be effectively targeted with radiolabeled inhibitors [
3] and antagonists [
4], respectively.
Prostate-specific membrane antigen (PSMA) is a type 2 glycoprotein expressed in secretory cells of prostatic epithelium. Several radiolabeled PSMA inhibitors have been developed for imaging (
68Ga-PSMA-11,
68Ga-PSMA-617,
68Ga-PSMA I&T, or
18F-PSMA1007 [
5]). Uptake of radiolabeled PSMA inhibitors correlates well with Gleason score (GS) and PSA level [
6] indicating a role for this imaging procedure in high-risk prostate cancer.
The gastrin-releasing peptide receptor (GRP-R) is a G-protein-coupled receptor of the bombesin receptor family [
7] which can be targeted with radiolabeled antagonists such as
68Ga-RM2 [
8],
68Ga-NeoBOMB1 [
9], or
68Ga-RM26 [
10] for PET imaging. Contrarily to PSMA, GRP-R is overexpressed in low-risk prostate cancers (low Gleason score, low PSA value, and low tumor size) [
11,
12]. A study of initial staging of prostate cancer on 14 patients observed a detection rate of 83%, a sensitivity of 89%, and a specificity of 81% [
8].
Although few pilot clinical studies targeting PSMA or GRP-R for initial staging of prostate cancer suggest a complementary role of these imaging procedures, there have never been compared in the same patients. Therefore, in this preclinical work, we aimed to compare PSMA and GRP-R expression on the same histological samples of prostate tumors using radiolabeled probes.
Discussion
Several radiopharmaceuticals have been developed for accurate staging of prostate cancer.
11C-Acetate, marking lipid metabolism, cannot reliably distinguish benign prostatic hyperplasia from prostate tumors [
20]. Moreover, the radiolabeled amino-acid
18F-FABC (
18F-Flucicovine) did not show good diagnostic performances for characterization of primary lesions [
21]. Finally,
11C/
18F-Choline, also marking lipid metabolism, showed lower sensitivity than mpMRI for primary detection of prostate cancer [
22]. Thus, improvements in current molecular imaging of prostate cancer appear necessary for accurate characterization of primary prostate tumors.
PSMA and GRP-R are differently overexpressed in prostate cancer, which raises hopes for molecular imaging of tumor lesions in the prostate gland. Few studies have investigated PSMA and GRP-R-based PET/CT imaging at initial staging, before radical prostatectomy. In a recent prospective study performed by Liu et al. on 50 newly diagnosed patients with prostate cancer candidates for radical prostatectomy,
68Ga-PSMA-617 PET/CT was able to detect 95% of primary tumors. The detection rate was similar to that of
68Ga-PSMA-11 PET/CT [
23]. Another excellent work was performed by Touijer et al., in which authors prospectively investigate
68Ga-RM2 PET/CT in 16 patients before radical prostatectomy. The performances of
68Ga-RM2 PET/CT imaging did not significantly differ compared to mpMRI in terms of sensitivity, specificity, and accuracy. Moreover,
68Ga-RM2 binding did not correlate with Gleason score [
24]. To date, no intra-patient comparison of PSMA and GRP-R targeting at initial staging was reported. Therefore, the objective of this work was to investigate and compare in vitro the potential role of
111In-PSMA-617 and
111In-RM2 at the initial staging of prostate cancer.
Qualitative comparison of
111In-PSMA-617 and
111In-RM2 on our primary prostate cancer samples showed good detectability of both radiopharmaceuticals which is an essential quality for contrasted images in vivo. Then, we quantitatively compared
111In-PSMA-617 and
111In-RM2. When considering all metastatic risk groups together,
111In-PSMA-617 binding was significantly higher than
111In-RM2 (
p < 0.001).
111In-PSMA-617 binding was high and no differences were seen according to Gleason score or pre-operative PSA values (Table
2). This high
111In-PSMA-617 binding, whatever the characteristics of the sample, clearly reflects the ability of PSMA imaging to detect most prostate cancers [
23] whatever their grade or risk [
25]. Moreover, this high signal level may also be explained by a lower binding of
111In-PSMA-617 to normal tissues (
p = 0.0161), resulting in a higher TNR for
111In-PSMA-617.
An interesting result of our work is that
111In-RM2 was able to discriminate low metastatic risk samples (
p = 0.0046) and therefore low Gleason score samples (
p = 0.0061) and samples with low PSA value (
p = 0.0012). These results agree with the known high GRP-R expression in low-grade prostate cancer [
11]. However, data from GRP-R immunohistochemistry and our results did not necessarily translate into parallel findings at patient imaging in pilot studies. For instance, the only two GRP-R imaging study, performed at the initial staging of prostate cancer, did not show any correlation (positive or negative) between SUV
max on PET/CT and Gleason scores [
10,
24]. However, only 1/16 prostate cancers in the study by Touijer et al. and 2/17 in the study by Zhang et al were Gleason 6 [
10,
24]. Larger clinical studies are needed to elucidate the potential offered by GRP-R targeting at the initial staging of prostate cancer. Comparison with PSMA would also be helpful.
In intermediate and high-risk samples,
111In-PSMA-617 binding was substantially higher than
111In-RM2 binding, in agreement with the known expression of GRP-R which decreases in higher Gleason scores [
11].
111In-PSMA-617 binding was also higher than
111In-RM2 binding in patients for whom pre-surgical PSA value was > 10 ng/mL. These results agree with the known efficacy of PSMA imaging of intra-prostatic tumors in newly diagnosed high-risk prostate cancer patients [
6].
Our results may have future clinical value. Prostate cancer patients with low metastatic risk are today not eligible for radical treatments anymore but rather to active surveillance or focal treatments [
26]. Moreover, upgrading in Gleason score between biopsies and radical prostatectomy occurs in about 30% of patients [
27]. Hence, an imaging procedure capable to discriminate “true” low metastatic risks would be required to schedule focal treatments in this group of patients and not under-treat patients that would in fact be at higher risk. Results of this work indicate that GRP-R targeting is the only imaging procedure amenable to discriminate low metastatic risk from higher risks. We suggest that GRP-R-based imaging may be first proposed in low metastatic risk patients for biopsy guidance and follow-up of active surveillance. Absence or low uptake at GRP-R imaging would suggest a disease of higher risk (or no disease).
In newly diagnosed prostate cancer patients with intermediate and/or high metastatic risk, PSMA-based imaging is obviously the imaging procedure of choice to characterize intra-prostatic tumors. PSMA-based guided biopsies, staging or radiation treatment planning is being explored in prospective studies [
28‐
30].
We have translated GRP-R and PSMA-based imaging in our center. Patient candidates for radical prostatectomy benefit from sequential 68Ga-PSMA-617 PET/CT and 68Ga-RM2 PET/CT. Preliminary results would support our in vitro data presented in this article.
Limitation of our study is obviously the limited number of samples studied. Moreover, the clinical outcome of patient for whom samples have been used in this study is not known, and we could not assess the prognostic value of GRP-R- and/or PSMA-based imaging and therefore their role in the follow-up of patients.