¹⁸F-prostate specific membrane antigen positron emission tomography/computed tomography for pancreatic ductal adenocarcinoma: not specific enough

Prostate specific membrane antigen (PSMA) is a membrane-bound glycoprotein that is primarily expressed in a relatively low degree in benign prostate epithelium but overexpressed in malignant prostate adenocarcinoma tissue. However, despite its name, PSMA is not specific to prostatic tissue alone, and is has been reported in multiple other organs including urothelial cancer, colonic adenocarcinoma, soft tissue sarcoma, and even pancreatic ductal adenocarcinoma (PDAC) (1). Given this, more focused research has been conducted to evaluate the degree of PSMA expression in PDAC to see if the protein target has a role in both diagnosis and treatment of this malignancy (i.e., theranostics).

At the histologic level, Ren et al. noted that compared to normal pancreatic tissue, studied samples of PDAC had a more frequent likelihood of PSMA overexpression, with 100/147 (68%) studied specimens to be positive for moderate to high PSMA expression (2). In the same study, the authors demonstrated that analyzing the outcomes of patients whose the samples of PDAC had strong PSMA expression have reduced overall survival (OS) of 8 months compared to weak expressing PDAC sample patients of 13 months. However, subsequent research suggests that PDAC PSMA expression is more complex than originally thought. In 2017, Stock et al. demonstrated in their evaluation of 61 samples of PDAC that while PSMA was significantly expressed in the neovascularity associated with PDAC tumor cells (detectable in 53.2% of the cases), only a small fraction of pancreatic tumor tissue itself had detectable PSMA expression (5.3% of cases) (3). Notably in contrast to previous suggestion that PSMA positivity was a negative factor for prognosis, they also found that for patients undergoing palliative chemotherapy who had PDAC samples with PSMA⁺ neovascularity, there was a statistically significant improved OS compared to those without [894 vs. 400 days; hazard ratio (HR) 0.42; 95% confidence interval (CI); 0.12 to 0.87; P<0.05]. By having this biomarker suggesting a clinical treatment target, there is more recent work to examine if this protein can be used for radioligand therapy: analogous to the use of (lutetium-177) lutetium-prostate-specific antigen-617 for the treatment of metastatic castrate resistant prostate cancer.

Synchronously, PSMA positron emission tomography/computed tomography (PET/CT) has expanded across the globe in the past decade and has become a cornerstone of imaging in prostate cancer. Multiple PSMA radioligands exist and include tracers tagged with both ¹⁸F and ⁶⁸Ga, all of which have been shown to demonstrate comparable sensitivity and specificity for prostate cancer (4). Having been integrated into the National Comprehensive Cancer Network clinical practice guidelines for prostate cancer (5), widespread use has led to the incidental discovery of multiple non-prostate malignancies demonstrating PSMA uptake on imaging thought to be due to neoangiogenesis rather than true PSMA glycoprotein expression (6,7). Specifically, PSMA is expressed in the endothelium of tumor-associated neovasculature, thought to potentially be due to the effect of tumor-assicated angiogenesis although this specific mechanism remains under investigation. Of the investigated malignancies, PDAC is one which has demonstrated PSMA tracer activity in multiple case reports (8,9) thought to be secondary to tracer binding to tumor-associated neovasculature.

As a result, PSMA PET/CT remains a focus of investigation for use in non-prostate malignancies to improve tumor detection and staging. One such study is a clinical trial (PANSCAN-2), recently published in Cancer Imaging, which evaluated the use of ¹⁸F-PSMA for detection of PDAC prior to surgical resection (10). The study, conducted by Puik et al. from the Netherlands, was a phase 1/2 study that evaluated a total of 17 patients with PDAC and planned surgical resection, with 13 of 17 patients demonstrating a positive PSMA PET/CT scan and acceptable tumor-to-background ratio. Following surgery, histopathological specimens were stained for both PSMA expression and ERG. An important finding was that in patients with histologically proven regional lymph node metastases and distant metastases (later discovered either intraoperatively or on subsequent follow-up), none of these lesions were detected on PSMA PET/CT. Thus, while the authors conclude that PSMA PET/CT was able to detect several hepatobiliary cancers (some of which pathologically returned as non-PDAC malignancies), the uptake was low, not specific to PDAC, and not detected in metastatic disease. Therefore, the authors concluded that the added value of PSMA PET/CT in staging of PDAC appears to be limited.

This study, albeit negative, is an important first step in assessing whether PSMA PET/CT will demonstrate improved performance for non-prostate malignancies when compared to conventional imaging with CT or magnetic resonance imaging (MRI). Although multiple case reports exist describing PSMA tracer activity in a variety of malignancies, there is no high-level evidence to support use of PSMA PET/CT for non-prostatic malignancies in the literature at this time. This study demonstrates that while the primary lesions can be detected, PSMA PET/CT appeared to be insufficiently sensitive to detect metastatic disease in this patient population. However, multiple clinical trials remain underway evaluating the use of PSMA PET/CT in other malignancies, including renal cell carcinoma, gliomas, hepatobiliary malignancies, gynecological malignancies, and salivary gland malignancies. Targeted imaging and therapy with multiple PET radiotracers have continued to expand in recent years, with theranostics establishing a critical role in the management of neuroendocrine tumors and prostate cancer (with other roles and indications emerging). Thus, it is of considerable interest in the era of targeted therapy and personalized medicine to expand approaches that utilize targeted PET radiotracer imaging which could be subsequently coupled with a therapeutic radionuclide (11).

To use PSMA as a target for radioligand therapy for PDAC, there must be clear evidence on diagnostic PET imaging that the tumoral target is detectable for both diagnosis, treatment planning, and treatment response. For ⁶⁸Ga-PSMA, Krishnaraju et al. demonstrated ⁶⁸Ga-PSMA PET has excellent sensitivity and specificity for distinguishing malignant PDAC and benign pancreatic disease (94.5% and 90%, respectively) (12). While important, their research does not encompass another very commonly used PSMA diagnostic agent ¹⁸F-PSMA. Compared to ⁶⁸Ga-PSMA, which is produced via a generator and has a short half-life of 68 minutes, ¹⁸F-PSMA is cyclotron derived and has an approximately 2 times longer half-life at 110 minutes. Both factors allow for larger scale production and distribution of ¹⁸F-PSMA, especially if centers do not already possess ⁶⁸Ga generator capabilities (13). Thus, if there is a similar sensitivity and specificity profile for ¹⁸F-PSMA compared to ⁶⁸Ga-PSMA, ¹⁸F-PSMA may be a critical theranostic agent going forward. Although in the early stages of investigation, this theranostic approach has been explored in instances of non-prostate malignancy PSMA uptake with limited efficacy, thought to be attributed to differences between true PSMA glycoprotein binding (and subsequent cellular internalization of the radionuclide) vs. transient binding of the surface neovasculature without internalization of the theranostic agent (and subsequent washout) (14). The authors therefore posit that a successful theranostic approach in these cases will require a radionuclide half-life that more closely matches the transient binding of the PSMA radiotracer to the surface neovasculature. Alternatively, a theranostic approach to PDAC may instead involve development of radiotracers that undergo internalization and prolonged retention within the tumor microenvironment.

Consequently, more research is needed to establish the role of PSMA PET/CT beyond prostate cancer. Important trials are underway to evaluate these potential uses and the publication of PANSCAN-2 is valuable despite its negative results, underscoring the importance of high-level research in validating the performance of novel PET agents for novel indications. As stated earlier, key differences in tracer binding of the PSMA glycoprotein and surface neovasculature receptors will likely necessitate different theranostic approaches if PSMA PET is found to have sufficient sensitivity and specificity in non-prostate malignancies. Additionally, further investigation and validation of other targeted approaches in PDAC that include fibroblast-associated protein inhibitors (FAPI) (15) and integrin (16) are underway which may offer additional diagnostic and therapeutic opportunities if studies can demonstrate value and/or therapeutic benefit.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article has undergone external peer review.

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-26-0026/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-26-0026/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Mhawech-Fauceglia P, Zhang S, Terracciano L, et al. Prostate-specific membrane antigen (PSMA) protein expression in normal and neoplastic tissues and its sensitivity and specificity in prostate adenocarcinoma: an immunohistochemical study using mutiple tumour tissue microarray technique. Histopathology 2007;50:472-83. [Crossref] [PubMed]
2. Ren H, Zhang H, Wang X, et al. Prostate-specific membrane antigen as a marker of pancreatic cancer cells. Med Oncol 2014;31:857. [Crossref] [PubMed]
3. Stock K, Steinestel K, Wiesch R, et al. Neovascular Prostate-Specific Membrane Antigen Expression Is Associated with Improved Overall Survival under Palliative Chemotherapy in Patients with Pancreatic Ductal Adenocarcinoma. Biomed Res Int 2017;2017:2847303. [Crossref] [PubMed]
4. Rais-Bahrami S, Davis P, Chau A, et al. Detection Rates of PSMA-PET Radiopharmaceuticals in Recurrent Prostate Cancer: A Systematic Review. Diagnostics (Basel) 2025;15:1224. [Crossref] [PubMed]
5. National Comprehensive Cancer Network. Prostate Cancer (Version 5.2026). Available online: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
6. Van de Wiele C, Sathekge M, de Spiegeleer B, et al. PSMA-Targeting Positron Emission Agents for Imaging Solid Tumors Other Than Non-Prostate Carcinoma: A Systematic Review. Int J Mol Sci 2019;20:4886. [Crossref] [PubMed]
7. Perry E, Talwar A, Sharma S, et al. Non-prostate cancer tumours: incidence on (18)F-DCFPyL PSMA PET/CT and uptake characteristics in 1445 patients. Eur J Nucl Med Mol Imaging 2022;49:3277-88. [Crossref] [PubMed]
8. Sahbai S, Rieping P, Pfannenberg C, et al. Pancreatic Ductal Adenocarcinoma With High Radiotracer Uptake in 68Ga-Prostate-Specific Membrane Antigen PET/CT. Clin Nucl Med 2017;42:717-8. [Crossref] [PubMed]
9. Sirtl S, Todica A, Ilhan H, et al. Incidental Finding of a PSMA-Positive Pancreatic Cancer in a Patient Suffering from a Metastasized PSMA-Positive Prostate Cancer. Diagnostics (Basel) 2021;11:129. [Crossref] [PubMed]
10. Puik JR, Poels TT, Hooijer GKJ, et al. (18)F-Prostate-Specific Membrane Antigen PET/CT imaging for potentially resectable pancreatic cancer (PANSCAN-2): a phase I/II study. Cancer Imaging 2025;25:2. [Crossref] [PubMed]
11. Sandhu K, Chen D, Hennes D, et al. PSMA Theranostics in Prostate Cancer and Beyond: Current and Future Perspectives. Cancers (Basel) 2025;17:3717. [Crossref] [PubMed]
12. Krishnaraju VS, Kumar R, Mittal BR, et al. Differentiating benign and malignant pancreatic masses: Ga-68 PSMA PET/CT as a new diagnostic avenue. Eur Radiol 2021;31:2199-208. [Crossref] [PubMed]
13. Evangelista L, Maurer T, van der Poel H, et al. (68)GaGa-PSMA Versus (18)FPSMA Positron Emission Tomography/Computed Tomography in the Staging of Primary and Recurrent Prostate Cancer. A Systematic Review of the Literature. Eur Urol Oncol 2022;5:273-82.
14. Bogsrud TV, Engelsen O, Lu TTT, et al. All that glitters is not gold: high uptake on PSMA PET in non-prostate cancers does not mean that treatment with (177)LuLu-PSMA-radioligand will be successful. EJNMMI Res 2024;14:95. [Crossref] [PubMed]
15. Pabst KM, Weber MM, Laschinsky C, et al. (68)GaGa-FAPI-46 PET accuracy for cancer imaging with histopathology validation: a single-centre, single-arm, interventional, phase 2 trial. Lancet Oncol 2025;26:1204-14. [Crossref] [PubMed]
16. Turaga RC, Sharma M, Mishra F, et al. Modulation of Cancer-Associated Fibrotic Stroma by An Integrin α(v)β(3) Targeting Protein for Pancreatic Cancer Treatment. Cell Mol Gastroenterol Hepatol 2021;11:161-79. [Crossref] [PubMed]