Research ArticleClinical Investigation

Antihormonal-Treatment Status Affects 68Ga-PSMA-HBED-CC PET Biodistribution in Patients with Prostate Cancer

Kilian Kluge, David Haberl, Holger Einspieler, Sazan Rasul, Sebastian Gutschmayer, Lukas Kenner, Gero Kramer, Bernhard Grubmüller, Shahrokh Shariat, Alexander Haug and Marcus Hacker
Journal of Nuclear Medicine September 2023, jnumed.123.265980; DOI: https://doi.org/10.2967/jnumed.123.265980

Abstract

Androgen deprivation therapy (ADT) is known to influence the prostate-specific membrane antigen (PSMA) expression of prostate cancer, potentially complicating the interpretation of PSMA ligand PET findings and affecting PSMA radioligand therapy. However, the impact of ADT on PSMA ligand biodistribution in nontumorous organs is not well understood. Methods: Men (n = 112) with histologically proven prostate cancer who underwent 68Ga-PSMA-HBED-CC (68Ga-PSMA-11) PET/CT between November 2015 and July 2021 at the Medical University Vienna with known ADT status were retrospectively recruited. Fifty-six patients were on gonadotropin-releasing hormone–interfering ADT at the time of imaging (ADT group), whereas 56 patients with no history of ADT served as a control group. Physiologically PSMA-expressing organs (salivary glands, kidneys, liver, and spleen) were delineated, and their uptake was compared according to their data distributions. Multivariate regression analysis assessed the relationship between renal, hepatic, splenic, and salivary gland uptake and the explanatory variables metabolic tumor volume, glomerular filtration rate, and ADT status. Results: ADT was associated with lower levels of PSMA uptake in the kidneys (SUVmean: Δ[ADT − control] = −7.89; 95% CI, −10.73 to −5.04; P < 0.001), liver (SUVpeak: Δ[ADT − control] = −2.3; 95% CI, −5.72 to −0.93; P = 0.003), spleen (SUVpeak: Δ[ADT − control] = −1.27; 95% CI, −3.61 to −0.16; P = 0.033), and salivary glands (SUVmean: Δ[ADT − control] = −1.04; 95% CI, −2.48 to −0.13; P = 0.027). In a multivariate analysis, ADT was found to be associated with lower renal (SUVmean: β = −7.95; 95% CI, −11.06 to −4.84; P < 0.0001), hepatic (SUVpeak: β = −7.85; 95% CI, −11.78 to −3.91; P < 0.0001), splenic (SUVpeak: β = −5.83; 95% CI, −9.95 to −1.7; P = 0.006), and salivary gland (SUVmean: β = −1.47; 95% CI, −2.76 to −0.17; P = 0.027) uptake. A higher glomerular filtration rate was associated with a higher renal SUVmean (β = 0.16; 95% CI, 0.05 to 0.26; P = 0.0034). Conclusion: These findings suggest that ADT systemically modulates PSMA expression, which may have implications for treatment-optimizing and side-effect–minimizing strategies for PSMA radioligand therapies, particularly those using more potent 225Ac-labeled PSMA conjugates.

Molecular imaging and targeted radioligand therapy (RLT) with prostate-specific membrane antigen (PSMA) ligands have been major diagnostic and therapeutic advances in the management of men with prostate cancer (PCA).

In various preclinical and clinical studies (1), the expression of PSMA, a type II membrane glycoprotein found on most PCA cells (2) and physiologically on various organs (3), has been shown to be modulated by androgen signaling.

Although the exact underlying mechanism remains to be fully elucidated, early work hypothesized that the PSMA enhancer (4–6), 1 of 2 crucial regulatory elements of the PSMA gene FOLH1 (7), is, inter alia, inversely and indirectly regulated through sequestration of PSMA enhancer regulating transcription factors (i.e., SOX, SOX7, SRY) by activated and nuclear-translocated androgen receptors (4).

Since then, various preclinical and clinical studies (1) have investigated the effects of androgen deprivation therapy (ADT), a long-established therapeutic cornerstone of PCA management, on PSMA expression of tumorous lesions in an effort to unfold androgen-induced clinical caveats of diagnostic and therapeutic PSMA radioligand use.

Although these studies yielded partly heterogeneous (8) and conflicting results (9), there is a growing body of evidence suggesting a time-dependent early upregulation (10,11) followed by a decrease in PSMA expression of PCA cells after long-term ADT exposure (12,13).

Although previous studies focused on ADT influences on tumoral tissue or short-term impact on physiologic PSMA-expressing organs (14), literature on physiologic organ uptake after sustained ADT exposure, a commonly encountered clinical scenario in advanced disease before RLT, is currently lacking.

Yet, understanding the influences of ADT on PSMA uptake in nontumorous organs such as the salivary glands and kidneys might have important implications for PSMA RLT, since common side effects such as xerostomia, as well as dose-limiting renal radiotoxicity (15), are functions of the PSMA ligand biodistribution.

The present study is meant to address this gap in knowledge.

We hypothesized that the PSMA expression of healthy organs would differ in men with PCA depending on their hormonal treatment status.

The objective of this study was to retrospectively compare the 68Ga-PSMA-HBED-CC (68Ga-PSMA-11) PET uptake of the salivary glands, kidneys, liver, and spleen between patients on ADT and patients without any history of ADT.

MATERIALS AND METHODS

Study Design and Cohort Selection

The data of men with histologically proven PCA who underwent 68Ga-PSMA-11 imaging between November 2015 and July 2021 were screened retrospectively.

Patients with conclusive ADT history data were considered for inclusion. Patients on gonadotropin-releasing hormone analogs or antagonists (16) during imaging for at least 1 mo or with no history of any ADT were included.

Men on androgen-receptor, 5α-reductase, or CYP17A1 inhibitors were excluded to minimize confounding by heterogeneous treatment regimens.

Scans with metabolic tumor volumes (MTVs) greater than 25 cm3 were excluded to avoid an influence on 68Ga-PSMA-11 biodistribution by the tumor sink effect (17).

All scans were performed after written informed consent was obtained for application of the nonapproved imaging compound 68Ga-PSMA-11, and the need for written informed consent for retrospective data collection and analysis was waived (ethics committee identification number 1745/2021).

The primary endpoint of this study was the SUVmean and SUVpeak of organs with physiologic PSMA expression, namely the submandibular glands, kidneys, liver, and spleen. The secondary endpoints were the SUVmean of organs according to midterm (1–6 mo) and long-term (>6 mo) ADT exposure when the primary endpoint was met.

Imaging Protocol

All scans were obtained on a Biograph TruePoint PET/CT scanner (Siemens Healthineers). The patients were intravenously injected with a mean of 182.6 MBq (±18.7 [SD]) of 68Ga-PSMA-11. Sixty minutes after injection, static, whole-body scans were obtained from the skull base to the upper femur. First, CT scans were acquired at 120 kV and 230 mAs with intravenous contrast medium (CT matrix size, 512 × 512) unless contraindications for contrast application existed. Afterward, PET scans were acquired at 3–4 bed positions, reconstructed iteratively using a point-spread-function–based algorithm, and subsequently corrected for scatter and attenuation on the basis of the CT scan (PET matrix size, 168 × 168).

Image Analysis

Physiologically PSMA-expressing organs were assessed, namely the submandibular glands, kidneys, liver, and spleen. The submandibular glands were chosen as a surrogate for overall salivary gland PSMA uptake since they were fully included in most fields of view (except in 2 scans). The organs were delineated in a 2-step process. First, the deep-learning–based Multi-Organ Objective Segmentation framework (18) was used to obtain CT-defined organ delineations of the liver, spleen, and kidneys. Next, the framework-derived segmentations were reviewed and, if necessary, adjusted manually to the PET component using Slicer3D software (version 4.11) (19) by a nuclear medicine physician. The submandibular glands were delineated on the PET component using the semiautomated Slicer3D extension PETTumorSegmentation (20). Two nuclear medicine physicians delineated tumor lesions manually on a dedicated workstation using Hybrid 3D software (version 4.17; Hermes Medical Solutions). SUVmean and SUVpeak not corrected for lean body mass and MTV were extracted from the regions of interest.

Statistical Analysis

Numeric variables were expressed as mean (±SD), and discrete outcomes were expressed as absolute (n) and relative (%) frequencies. The group comparability of the control and ADT groups was assessed by comparing baseline demographic data. The normality and heteroskedasticity of continuous data were assessed with the Shapiro–Wilk and Levene tests, respectively. Continuous outcomes were compared using the unpaired Student t test, Welch t test, and Mann–Whitney U test according to the data distribution. Discrete outcomes were compared using the χ2 or Fisher exact test accordingly. All tests were 2-tailed.

Statistical tests for differences in visceral organ metastasis PSMA uptake could not be computed because of the sample size (n = 1 in the ADT group).

Differences between renal, hepatic, splenic, and salivary gland uptake were assessed according to prior cytotoxic treatments with chemotherapy or 177Lu-PSMA RLTs.

Additionally, differences between renal, hepatic, splenic, and salivary gland PSMA uptake were assessed according to midterm (1–6 mo) and long-term (>6 mo) ADT runtimes with ANOVA and the Kruskal–Wallis test according to the data distribution. If the null hypothesis of the ANOVA and the Kruskal–Wallis test was rejected, post hoc pairwise analyses were performed with the Tukey honestly significant difference test and the Dunn–Bonferroni test, respectively.

Multivariate Regression Analysis

Multivariate regression analysis was performed to assess the relationship between renal and salivary gland SUVmean, as well as the relationship of hepatic and splenic SUVpeak with the following explanatory variables: MTV, glomerular filtration rate, and ADT status. Data were checked for multicollinearity with the Belsley–Kuh–Welsch technique. The heteroskedasticity and normality of residuals were assessed by, respectively, the Breusch–Pagan test and the Shapiro–Wilk test. The α-risk was set for all statistical analyses to 5% (α = 0.05). Statistical analysis was performed with EasyMedStat software (version 3.24; EasyMedStat).

RESULTS

Clinical Cohort

Of 665 screened men with PCA and available PSMA PET/CT, 112 (17%) with a conclusive ADT treatment history at the time of imaging were entered into this study according to the inclusion criteria (Fig. 1). The demographic and clinical characteristics are summarized in Table 1.

FIGURE 1.
FIGURE 1.

CONSORT (Consolidated Standards of Reporting Trials) diagram. AR = androgen receptor; 5α- = 5α-reductase.

View this table:
TABLE 1.

Demographic and Clinical Patient Data

Organ PSMA Uptake Measurements

Differences in organ uptake between the ADT and control groups are summarized in Table 2.

View this table:
TABLE 2.

PSMA Uptake Levels of Normal Organs According to Antihormonal Treatment Status

There was a significantly lower mean renal SUVmean (Δ[ADT − control] = −7.89; 95% CI, −10.73 to −5.04; P < 0.001) and SUVpeak (Δ[ADT − control] = −14.12; 95% CI, −19.85 to −8.39; P < 0.001) in the ADT group than in the control group. Similarly, median hepatic SUVpeak (Δ[ADT − control] = −2.3; 95% CI, −5.72 to −0.93; P = 0.003), median splenic SUVpeak (Δ[ADT − control] = −1.27; 95% CI, −3.61 to −0.16; P = 0.033), and median salivary gland SUVmean (Δ[ADT − control] = −1.04; 95% CI, −2.48 to −0.13; P = 0.027) and mean SUVpeak (Δ[ADT − control] = −3.31; 95% CI, −5.3 to −1.31; P = 0.001) were significantly lower in the ADT group (Fig. 2).

FIGURE 2.
FIGURE 2.

Violin plots of significantly different exemplary PSMA uptake levels of normal organs according to ADT treatment status. White dots indicate median value. No = control; Yes = ADT.

Secondary Endpoint Analysis According to ADT Runtime Length

The mean renal SUVmean was 29.5 (SD, 7.2), 21.6 (SD, 8.37), and 21.61 (SD, 7.61) for the control group, patients on 1–6 mo of ADT, and patients on more than 6 mo of ADT, respectively (P < 0.001). Post hoc pairwise analysis revealed significant differences between the control group and the 1- to 6-mo ADT group (mean difference: 95% CI, −13.2 to −2.56; P = 0.002) and between the control group and the group receiving more than 6 mo of ADT (95% CI, −11.65 to −4.13; P < 0.001). No significant difference between the 2 ADT groups was observed (95% CI, −5.51 to 5.53; P > 0.999).

The median hepatic SUVpeak was 9.9 (interquartile range [IQR], 19.43), 6.64 (IQR, 8.74), and 7.61 (IQR, 5.17) in the control group, the group receiving 1–6 mo of ADT, and the group receiving more than 6 mo of ADT, respectively (P = 0.012). After post hoc adjustment, only the difference between the control group and the group receiving more than 6 mo of ADT remained significant (95% CI, −13.46 to −1.07; P = 0.006).

The mean salivary gland SUVmean was 11.34 (SD, 2.69), 10.2 (SD, 3.8), and 9.83 (SD, 2.94) for the control group, the group receiving 1–6 mo of ADT, and the group receiving more than 6 mo of ADT, respectively (P = 0.043). Pairwise analysis showed significant differences between the control group and the group receiving more than 6 mo of ADT (95% CI, −2.97 to −0.053; P = 0.041) (Fig. 3).

FIGURE 3.
FIGURE 3.

Violin plots of PSMA uptake levels of normal organs in ADT group according to different ADT runtimes and control group. Only significant values after post hoc testing are displayed as bars on figures. Nonsignificant P values are displayed in figure heading. White dots indicate median values.

Subgroup Analysis of ADT Group According to Previous Systemic Treatments

There was no statistical difference in mean renal or salivary gland SUVmean or median hepatic or splenic SUVpeak between patients who underwent prior additional systemic therapies, namely taxane-based chemotherapies, 177Lu-PSMA-617, or I&T RLT (24.93 [SD, 6.82], 10.02 [SD, 2.01], 7.8 [IQR, 6.16], and 8.54 [IQR, 2.96], respectively) and patients who did not receive prior additional systemic therapies (25.69 [SD, 8.97], 10.79 [SD, 3.18], 8.82 [IQR, 17.47], and 9.72 [IQR, 6.36], respectively) (Fig. 4).

FIGURE 4.
FIGURE 4.

Violin plots of PSMA uptake levels according to prior cytotoxic treatments (177Lu-PSMA RLT or chemotherapy) in normal organs. White dots indicate median value. Yes = prior systemic therapies; No = no prior systemic therapy.

Multivariate Analysis of PSMA Organ Uptake

In the multivariate analysis, ADT was identified as an independent predictor of lower renal SUVmean (β = −7.95; 95% CI, −11.06 to −4.84; P < 0.0001), hepatic SUVpeak (β = −7.85; 95% CI, −11.78 to −3.91; P < 0.0001), splenic SUVpeak (β = −5.83; 95% CI, −9.95 to −1.7; P = 0.0062), and salivary glandular SUVmean (β = −1.47; 95% CI, −2.76 to −0.17; P = 0.0274). In addition, a high glomerular filtration rate was predictive only of a high renal SUVmean (β = 0.16; 95% CI, 0.05 to 0.26; P = 0.0034) (Table 3).

View this table:
TABLE 3.

Multivariate Regression Analysis of Relationship Between Renal, Hepatic, Splenic, and Salivary Gland PSMA Uptake and Explanatory Variables MTV, Glomerular Filtration Rate, and ADT Status

DISCUSSION

This study presents the first evidence that PCA patients on sustained ADT exhibit significantly lower 68Ga-PSMA-11 uptake in the salivary glands, liver, spleen, and kidneys than do hormonal therapy-naïve patients.

Although it is widely appreciated that ADT influences the PSMA expression of cancerous lesions, most likely in a time-dependent dichotomous manner (1), the effect of ADT on physiologically PSMA-expressing organs such as the salivary glands, kidneys, liver, and spleen has been assessed only in a short-term setting (14).

This report therefore advances our understanding of the physiologic PSMA biodistribution in patients on sustained ADT and corroborates earlier findings (14) that hormonal changes exert a systemic influence on PSMA expression also in nontumorous tissues, holding possible implications for optimization strategies for PSMA RLTs.

Ettala et al. (14) investigated the short-term (pretreatment till a maximum of 8 wk after initiation) time-course effect of gonadotropin-releasing hormone–modulating ADT on the 68Ga-PSMA-11 SUVmax of cancer lesions and physiologic PSMA-avid organs (salivary glands, kidneys, liver, and spleen) in newly diagnosed men with high-risk PCA (n = 9) and observed heterogeneous and time-dependent uptake changes in tumorous and nontumorous tissues alike. Although they observed an initial heterogeneous uptake increase in all physiologically PSMA-avid organs, which peaked at around week 4, most patients who continued imaging beyond 1 mo started exhibiting stabilizing or falling PSMA organ uptake trajectories, which were most pronounced in the salivary glands and kidneys.

Analogously, several authors (12,21) have reported decreasing PSMA expression in tumorous lesions after long-term exposure to different classes of ADT. Although Vallabhajosula et al. (21) observed an initial increase in PSMA-expressing PCA lesions after 2 wk of abiraterone or enzalutamide (n = 4), followed by a decrease in uptake after 3 mo, Afshar-Oromieh et al. (12) reported decreased PSMA uptake in roughly two thirds of PCA lesions after sustained gonadotropin-releasing hormone antagonist or analog exposure (median ADT runtime, ∼7 mo) in a retrospective, longitudinal cohort of 10 patients.

In summary with the abovementioned studies (12,14,21), the found association between midterm or, predominantly, long-term ADT and significantly lower PSMA uptake in the submandibular glands, liver, spleen, and kidneys (Fig. 3) suggests that not just tumorous but also nontumorous tissues might be subject to androgen-induced, time-dependent, dichotomous PSMA expression changes in early upregulation and late downregulation (1).

Surprisingly, we did not observe any PSMA uptake level differences of cancerous lesions between patients on ADT and those without a history of ADT, as repeatedly reported in the literature (10–12). We hypothesize that this might be due to the cross-sectional study design incorporating patients at different stages. Although patients on ADT have more advanced disease (22), as signified by a higher number of osseous bone lesions on imaging, the reported effects of hormonal therapy on cancer lesions could be blurred by ADT-induced PSMA downregulation of yet more advanced lesions in our cohort.

Since PSMA biodistribution in itself is a complex function of uptake, retention, and excretion (17,23) in tumorous and nontumorous tissues, a multivariate regression analysis was performed to exclude the confounding effects of renal function and tumor tissue.

The MTV was not associated with salivary gland, hepatic, splenic, or renal uptake in the ADT group, most likely since the potential influence of the tumor sink effect (17), a sequestration phenomenon that occurs when extensive tumor masses reduce tracer accumulation in healthy tissues, was excluded by design (Fig. 1).

Interestingly, renal function was positively associated with renal PSMA uptake levels. We hypothesize that although there is a physiologic renal baseline PSMA expression, primarily in the proximal tubular cells (3), increased PSMA excretion in the case of higher glomerular filtration led to higher overall renal radioligand signal caused by count summation during static image acquisition.

Since sustained ADT is a commonly encountered clinical scenario in patients with advanced disease, a deeper understanding of the hormonal influences on PSMA biodistribution might have important implications for PSMA RLTs because common side effects, such as xerostomia and dose-limiting renal radiotoxicity (15), are functions of PSMA ligand biodistribution.

Even though dosimetric estimates of absorbed organ doses are the gold standard, 68Ga-PSMA-11 PET has been shown to provide robust estimates of therapeutic PSMA ligand biodistributions (24,25) in that regard.

Our study had several limitations, and the findings should therefore be interpreted with caution.

First, as a retrospective, cross-sectional, and monocentric study, it was prone to selection bias, recall bias, inaccuracies in record keeping, and incomplete data, which could negatively affect the generalizability of the findings. We tried to minimize this potential bias by focusing on a narrow definition of ADT treatment and including only patients with complete hormonal treatment data, as well as by ensuring balanced groups according to possible confounders such as renal function, MTV (17), and previous systemic treatments (Fig. 4). Furthermore, multivariate regression analysis was performed to discover potential confounders, which, however, cannot fully be excluded.

Second, as a cross-sectional study, no causal relationships can be inferred. However, a cross-sectional study is a suitable design to assess nontemporal relationships between variables and to generate hypotheses. Therefore, we envision that groups with longitudinal or dosimetric datasets are able to establish a cause–effect relationship between gonadotropin-releasing hormone–modulating ADT and more potent antiandrogens such as androgen receptor inhibitors, 5α-reductase, and CYP17a inhibitors on the PSMA biodistribution, as an understanding of hormonal influences might have important implications for efficacy-maximizing and side-effect–minimizing strategies for RLT.

CONCLUSION

These findings suggest that long-term ADT modulates PSMA expression in a systemic fashion, which may have implications for treatment-optimizing and side-effect–minimizing strategies for PSMA RLTs. Further, longitudinal studies also incorporating second-generation ADT are warranted to establish a cause–effect relationship and effect magnitude.

DISCLOSURE

This study was partially funded by the Austrian Federal Ministry for Digital and Economic Affairs; the National Foundation for Research, Technology, and Development; the Christian Doppler Research Association; and Siemens Healthineers. No other potential conflict of interest relevant to this article was reported.

KEY POINTS

QUESTION: Is ADT associated with the biodistribution of 68Ga-PSMA-11?

PERTINENT FINDINGS: In this monocentric, retrospective study, the 68Ga-PSMA-11 uptake of physiologically PSMA-avid organs was compared between patients on midterm and long-term ADT (n = 56) and a control group (n = 56). The ADT cohort had significantly lower PSMA uptake in the salivary glands, liver, spleen, and kidneys.

IMPLICATIONS FOR PATIENT CARE: These findings suggest that long-term ADT modulates PSMA expression in a systemic fashion, which may have implications for treatment-optimizing and side-effect–minimizing strategies for PSMA RLTs, particularly those using more potent 225Ac-labeled PSMA conjugates.

Footnotes

  • Published online Sep. 21, 2023.

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  • Received for publication May 3, 2023.
  • Revision received May 31, 2023.
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