Andrews, Jack R.

Prostate cancer lung metastasis represents a clinical conundrum due to its implications for advanced disease progression and the complexities it introduces in treatment planning. As the disease progresses to distant sites such as the lung, the clinical management becomes increasingly intricate, requiring tailored therapeutic strategies to address the unique characteristics of metastatic lesions. This review seeks to synthesize the current state of knowledge surrounding prostate cancer metastasis to the lung, shedding light on the diverse array of clinical presentations encountered, ranging from subtle radiological findings to overt symptomatic manifestations. By examining the diagnostic modalities utilized in identifying this metastasis, including advanced imaging techniques and histopathological analyses, this review aims to provide insights into the diagnostic landscape and the challenges associated with accurately characterizing lung metastatic lesions in prostate cancer patients. Moreover, this review delves into the nuances of therapeutic interventions employed in managing prostate cancer lung metastasis, encompassing systemic treatments such as hormonal therapies and chemotherapy, as well as metastasis-directed therapies including surgery and radiotherapy.

Purpose of review Low-volume prostate cancer is an established prognostic category of metastatic hormone-sensitive prostate cancer. However, the term is often loosely used to reflect the low burden of disease across different prostate cancer states. This review explores the definitions of low-volume prostate cancer, biology, and current evidence for treatment. We also explore future directions, including the impact of advanced imaging modalities, particularly prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scans, on refining patient subgroups and treatment strategies for patients with low-volume prostate cancer. Recent findings Recent investigations have attempted to redefine low-volume disease, incorporating factors beyond metastatic burden. Advanced imaging, especially PSMA PET, offers enhanced accuracy in detecting metastases, potentially challenging the conventional definition of low volume. The prognosis and treatment of low-volume prostate cancer may vary by the timing of metastatic presentation. Biomarker-directed consolidative therapy, metastases-directed therapy, and de-escalation of systemic therapies will be increasingly important, especially in patients with metachronous low-volume disease. Summary In the absence of validated biomarkers, the management of low-volume prostate cancer as defined by CHAARTED criteria may be guided by the timing of metastatic presentation. For metachronous low-volume disease, we recommend novel hormonal therapy (NHT) doublets with or without consolidative metastasis-directed therapy (MDT), and for synchronous low-volume disease, NHT doublets with or without consolidative MDT and prostate-directed radiation. Docetaxel triplets may be a reasonable alternative in some patients with synchronous presentation. There is no clear role of docetaxel doublets in patients with low-volume disease. In the future, a small subset of low-volume diseases with oligometastases selected by genomics and advanced imaging like PSMA PET may achieve long-term remission with MDT with no systemic therapy.

642 Background: Perioperative blood transfusion has been reported in up to 60% of patients undergoing RC. Unfortunately, perioperative blood transfusion in patient undergoing RC has been associated with poor oncological outcomes. Tranexamic acid (TXA) use has been proposed to decrease the need for perioperative blood transfusion. Here we seek to investigate the impact of intraoperative TXA on survival outcomes in patients undergoing radical cystectomy (RC) for bladder cancer. Methods: We queried the prospectively maintained Mayo Clinic Radical Cystectomy registry and identified all RC performed for bladder cancer between 1990-2021. Primary outcomes were patient’s overall survival and cancer specific survival among patients who received TXA versus patients who did not receive TXA. Results: Among 2929 patients who underwent RC in our institution between 1990-2021, 468 received TXA (IV) intraoperatively (Group A) and were propensity score matched 1:1 for age, neoadjuvant chemotherapy, adjuvant chemotherapy, pT stage, pN stage, and preoperative hemoglobin with a group who did not receive TXA (Group B, n= 468). At 8 years followup, 61% of patients who received TXA were alive versus 46% of patients who did not receive TXA. In univariable and multivariable analyses of factors associated with CSS (Table1), node positive disease, pT2-T4, peri-operative blood transfusion were associated with poor survival outcomes. While use of TXA was associated with improved CSS outcomes. Conclusions: In our study, TXA use in patients undergoing radical cystectomy was associated with decreased risk or peri-operative transfusion, improved patient’s overall survival, and cancer specific survival. We can’t explain the biological rational for improved survival however these findings warrant further prospective investigation. [Table: see text]

641 Background: Perioperative blood transfusion is associated with an increased risk of adverse events and tranexamic acid (TXA) use has been proposed to decrease the need for perioperative blood transfusion. Herein, we seek to investigate the impact of intraoperative TXA on perioperative risk of VTE in a subset of patients who underwent robotic-assisted radical cystectomy (RARC) for bladder cancer. Methods: We queried the prospectively maintained Mayo Clinic Radical Cystectomy registry and identified patients who underwent RARC between 2004-2021 and received TXA intraoperatively. In univariable and multivariable analyses, we investigated factors associated with bleeding and VTE within 30 days post-operatively. Results: Of 2862 patients, we identified 94 patients who received TXA (IV) intraoperatively (Group A) and were propensity score matched 1:1 for age, neoadjuvant chemotherapy, pT stage, pN stage, and preoperative hemoglobin with a group who did not receive TXA; 38 patients (Group B). In univariable and multivariable models, use of TXA has no statistically significant impact on patient’s risk of bleeding or VTE. In a univariable model, number of positive lymph nodes and extent of lymph node dissection were associated with increased risk of VTE (Table 1). Conclusions: In our study, use of TXA in patient’s undergoing RARC was safe and was not associated with increased risk of VTE. [Table: see text]

49 Background: Ductal carcinoma (DC) is the second most commonly encountered histologic variant of prostate cancer. Previous studies have described its molecular features and aggressive behavior, but few have explored the performance of PSMA PET/CT in the initial staging and follow-up of DC. Methods: To address this gap, we performed a single-institution retrospective analysis using the Mayo Clinic PSMA PET database. All patients receiving a PSMA PET/CT scan in the interval of January 1, 2021, to December 31, 2022, were eligible for inclusion. Cases were filtered and categorized by histology at the time of diagnosis to select for pure DAC and mixed ductal variants. Trained research personnel annotated disease- and treatment-related variables. A board-certified radiologist performed tumor burden segmentation with calculations of SUV max, total lesion SUV mean and volume, and total lesion uptake, and ascribed a miPSMA expression score. Results: We queried 1792 patients from our PSMA PET/CT registry and identified 32 (1.8%) patients with a pathologically confirmed DC, including 8 (25%) patients with pure ductal and 25 (75%) patients with mixed histology. The indication for PSMA PET/CT was biochemical progression or restaging for 29 (91%) patients and initial staging for 3 (9%) patients. The median (IQR) time from prostate cancer diagnosis to PSMA PET scan was 41.6 (11.5-64.7) months, during this time 50% (n= 16) of patients developed CRPC. At the time of the PSMA PET/CT scan, the median age was 70 years, the median (IQR) PSA was 0.5 ng/mL (0.2-2.6). The distribution of metastatic spread and quantitative imaging parameters from PSMA PET are shown in the Table. Conclusions: Despite low PSA at the time of imaging, PSMA PET/CT frequently detected high volume osseous and/or visceral metastases in patients with DC. However, it is noteworthy that more than 50% of patients with DC had a low miPSMA score (0-1). Additional studies are needed to better understand the performance of novel imaging modalities when evaluating variant prostate cancers. [Table: see text]

376 Background: Germline genetic testing (GGT) is becoming increasingly important in the management of genitourinary (GU) malignancies as novel targeted drug therapies emerge. Selection for genetic studies and testing has historically been highly selective and based on pathologic characteristics, family history, and age of diagnosis. The aim of our study was to investigate the prevalence of pathogenic variants (PGVs) in inherited cancer susceptibility genes utilizing a universal testing approach and to characterize the rate of PGVs that would have been missed based on current NCCN guidelines. Methods: A multisite single-institutional prospective study (INTERCEPT) offered GGT to all patients with new or active diagnoses of GU malignancies (bladder, prostate, and renal cancers) from April 1, 2018 to March 31, 2020 at Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester. Participants were offered GGT with a panel of >80 genes through Invitae Corp. Demographic, tumor characteristics and genetic results were evaluated. PGVs were classified as high-, intermediate-, or low- penetrance variants based on published literature. Respective NCCN GU GGT guidelines were used to determine if the PGVs discovered using our universal testing approach would have been missed with guideline-directed GGT. Results: A total of 3095 pan-cancer patients were enrolled in the study; 601 of which had a GU malignancy including: prostate cancer (358 patients), renal cancer (137), and bladder cancer (106). The mean age of enrollment was 66.8 years (SD 9.1), 89% were male, and 85.9% of patients were Non-Hispanic white. PGVs were identified in 82 of all GU patients (13.6%) and variants of undetermined significance (VUS) in 289 (48.1%) patients. PGV prevalence breakdown by cancer type was: 13.7% of prostate, 13.1% renal, and 14.2% bladder cancer patients. The proportion of high penetrance PGVs varied by malignancy type. Of all patients, 326 (54.2%) had advanced (stage III/IV) disease and 377 (64.4%) of these were metastatic upon initial evaluation. The majority of all PGVs identified were incremental, defined as PGVs that would not have been identified based on guideline-concordant GGT: 100% (15/15 patients) with bladder, 77.8% (14/18) with renal, and 57.1% (28/49) with prostate cancer. Conclusions: Universal GGT for prostate, renal and bladder cancer revealed that over 1 in 10 patients harbored potentially actionable PGVs, most of which would not have been identified with guidelines-based GGT. Utilization of GGT can impact our understanding of GU cancer pathogenesis, aid in familial cascade testing, and influence treatment decisions.

337 Background: Prostate cancer remains the most common solid organ malignancy among males in the United States. Commercial biomarkers and multiparametric MRI have been utilized to better triage men with elevated PSA and determine patients most likely to have clinically significant prostate cancer (csPCa) upon prostate biopsy. We studied the combination of MRI with PSA-based and novel extracellular vesicle (EV)-based biomarkers to determine the optimal pre-biopsy testing to reduce the number of unnecessary biopsies. Methods: Men presenting to our clinic with elevated PSA (≥ 2 ng/ml) were prospectively enrolled from October 2019 to March 2022. All men underwent multiparametric MRI and blood draws to determine prostate health index (PHI) scoring, EV density, and PSA density. MRI-fusion biopsy was performed with both systematic and targeted prostate sampling, with clinicians blinded to prior blood testing results. Blood concentrations of prostate EV (ProsEVs) were measured by nanoscale flow cytometry using antibodies against PSMA and STEAP1. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and receiver operator characteristic (ROC) curves were constructed separately for all patients, those without prior diagnosis of PCa, and biopsy-naïve patients. Bootstrapping analysis was performed to provide more accurate assessment of the predictive ability of all combinations. Results: Ultimately, 175 men enrolled and underwent MRI, blood testing, and prostate biopsy. Among the 175 patients included, 101 (58%) had never undergone biopsy, 38 (22%) had a previous negative biopsy, and 36 (21%) were on active surveillance (AS) for GS6 disease. AUC of mpMRI (PI-RADS≥3) to predict clinically significant PCa was 0.66 with a sensitivity, specificity, NPV and PPV of 95.2%, 37.6%, 76.0% and 79.26%. MRI combined with STEAP1-EV density had an AUC of 0.77 with a sensitivity, specificity, NPV and PPV of 90.1%, 46.7%, 64.4% and 80.9%. A multivariable model including MRI, STEAP1-EV density, PSA density and PHI density outperformed other combinations with an AUC, sensitivity, specificity, NPV and PPV of 0.90, 89.2%, 68.7%, 72.8% and 88.1%. Conclusions: Combination of mpMRI with ProsEV and PSA derivatives demonstrated better predictive ability for csPCa on biopsy compared to imaging or serum testing alone. Inclusion of prostate volume with biomarkers further increased predictive ability which could lead to a decrease in number of unnecessary biopsies for men with benign conditions and indolent cancer.

334 Background: Prostate cancer (PCa) screening has relied on prostate-specific antigen (PSA) levels to screen patients for biopsy. However, the limited specificity of serum PSA leads to high rates of negative biopsies and detection of clinically insignificant cancers. Tumor-derived extracellular vesicles, microscopic particles released by tumor cells and ubiquitously found in all bodily fluids, have emerged as novel biomarkers for a diverse set of malignancies. This study explored the utility of urine prostate-specific extracellular vesicles (ProsEVs) identified by unique surface protein markers with novel flow cytometry-based techniques as biomarkers for PCa screening. Methods: This prospective study recruited at a tertiary care center between Oct 2019 and Mar 2022. Patients with PSA≥2 ng/ml underwent prebiopsy mpMRI followed by transperineal prostate biopsy (PI-RADS 1-2) or combined MRI-guided biopsy (PI-RADS ≥ 3). Patients with metastatic PCa or prior systemic therapy were excluded. Urine samples were collected at MRI using Colli-Pee. ProsEVs were labeled using monoclonal antibodies for PSMA and STEAP1 and ProsEV concentrations were determined using nanoscale flow cytometry. EV densities were calculated by normalizing EV counts to prostate volume. Multivariable logistic regression models were constructed and model performance was compared used ROC curve analysis. Results: This study had a total of 179 patients prospectively recruited, 95 were diagnosed with Gleason score (GS) ≥ 7 prostate cancer (csPCa), while the remaining had GS <7 or benign disease. Analysis of urinary ProsEV densities revealed a significant dose-response relationship between benign, GS <7 PCa and GS ≥ 7 PCa groups and ProsEV densities (p=0.01 for PSMA, and <0.001 for STEAP1). The log sum of the PSMA and STEAP1 EV densities exhibited the strongest correlation with other ProsEV variables and was selected for model development. ROC curve analysis showed that the final model including Log Sum ProsEVs, PSA, and PI-RADS outperformed one including PSA and PI-RADS (0.733 vs 0.651, p=0.02). Specificity for detecting csPCa at a sensitivity of 90% was 39.5% in the final model compared to 37% for PSA and PI-RADS (Table). Conclusions: This study highlights the potential of urine ProsEVs as novel biomarkers for improving screening specificity for csPCa detection. Future works should explore analysis of intra-ProsEV content to further improve specificity and advance liquid biopsy techniques. [Table: see text]

220 Background: There is a critical need to identify biomarkers of response and resistance to 177Lu-PSMA-617. Post-hoc analyses of VISION have explored the prognostic and predictive value of select clinical parameters. However, we are still in the early stages of deciphering which molecular changes are associated with favorable or adverse treatment outcomes. Methods: We conducted a retrospective analysis of patients with metastatic castration-resistant prostate cancer (mCRPC), who received 177Lu-PSMA-617 at Mayo Clinic in Rochester, Minnesota, in the interval of March 2022 to March 2023. We included patients who provided research authorization, had a baseline PSA of at least 2 ng/mL, received at least 2 cycles of treatment, and had circulating tumor DNA (ctDNA) genomic profiling performed by Guardant (83 gene panel) within 60 days of treatment initiation. Clinical, laboratory, genomic, and radiomic parameters were abstracted by trained research personnel. Two independent analyses of “response” and “resistance” were performed. Response to treatment was defined as 50% or greater decrease in PSA from baseline (PSA50 response: dichotomized yes versus no), and resistance was defined as non-decreasing or rising PSA during treatment (PSA non-response: dichotomized yes versus no). Associations between gene alterations and response and resistance were evaluated via Fisher’s exact tests. Results: Between March 2022 and March 2023, 273 patients received cycle 1 of 177Lu-PSMA-617. A total of 108 patients met the inclusion criteria. The median number of cycles at data cutoff was 6 (IQR: 4,6) with 57 (53%) patients receiving all 6 planned cycles. The median PSA at baseline was 16.65 ng/ml (IQR: 5.20, 66.12). A total of 65 patients (60%) experienced a PSA50 response. No molecular alterations were associated with a higher rate of PSA50 response; however, alterations in ARID1A, AR, and CHEK2 were associated with lack of PSA50 response (Fisher’s exact p < 0.05). Of the 108 evaluable patients, 20 (19%) met criteria for PSA non-response. Alterations in AR, ARID1A, MYC, TP53, CHEK2, ATM, EGFR, and NOTCH1 were significantly associated with PSA non-response (Fisher’s exact p < 0.05); in each case, the presence of the alteration was positively associated with resistance (i.e., more instance of PSA non-response). No biomarkers were found to be inversely associated with PSA non-response. Conclusions: ctDNA assessed by commercially available, targeted sequencing panels prior to treatment may be useful in identifying the patients least likely to benefit from 177Lu-PSMA-617. Further work is ongoing to integrate ctDNA findings with clinical parameters in the hopes of understanding the factors mediating response and resistance to therapy.

191 Background: Two randomized clinical trials have demonstrated that SABR can prolong time to progression in oligometastatic castration-sensitive prostate cancer (omCSPC) patients. However, there is a need for predictive tools to identify patients who will benefit from SABR alone or with systemic therapy. We investigated the prognostic value of PSMA-positive extracellular vesicles (PSMA+EVs) in a blinded observational study using blood samples from three independent patient cohorts. Methods: We obtained plasma samples from 157 omCSPC patients treated with SABR from the ORIOLE cohort (N=30, JHU) and STOMP-like cohorts (N=80, UGhent; N=47, Iridium Net). Baseline PSMA+EV levels (EV/ml) were measured by nanoscale flow cytometry. Primary clinical endpoints were biochemical progression (bPFS) and radiographic progression (rPFS). Optimal cutoffs for PSA (ng/ml) and PSMA+EV (EVs/ml) were defined as the point with the most significant log-rank test split. Kaplan-Meier curves and univariate Cox regression models were used to determine the association of PSMA+EV levels with clinical outcomes. Results: Twenty percent of patients (N=157 total) were diagnosed with bone scan, 79% with PET imaging, and 1% with other modalities. Ninety-four percent of patients presented with ≤3 metastases on imaging. In the pooled STOMP-like cohorts, median bPFS was 27.9 and 18.0 months for PSMA+EV low and high groups, respectively (p=0.039). Median rPFS was 36.0 versus 27.0 months (p=0.029). In the ORIOLE cohort, median bPFS was 24.3 and 5.9 months in PSMA+EV low and high, respectively (p=0.021). Median rPFS was 36.0 versus 11.1 months (p=0.019). High baseline PSMA+EV levels were associated with higher risk of both biochemical and radiographic progression (Table). Combination of baseline PSA low and PSMA+EV low outperformed either biomarker alone and better predicted risk of disease progression after SABR. Conclusions: While prospective biomarker-guided trials are warranted, a PSMA+EV blood test can aid patient selection by identifying omCSPC patients who may have durable responses to SABR without ADT. [Table: see text]