Cohort Of Prostate Cancer Patients Research Articles

Neurologic Symptoms After 177Lu-Prostate-Specific-Membrane Antigen-617 Therapy: A Single-Center Experience.

Treatment with 177Lu-prostate-specific membrane antigen (PSMA)-617 (177Lu-vipivotide tetraxetan [Pluvicto]) prolongs both progression-free and overall survival in advanced PSMA-positive metastatic castration-resistant prostate cancer. Data examining specifically neurologic symptoms after 177Lu-PSMA-617 treatment are scarce. In this study, we aimed to review the neurologic findings in a large cohort of metastatic castration-resistant prostate cancer patients undergoing 177Lu-PSMA-617 therapy. Methods: The clinical records and imaging data of patients who received their initial dose of 177Lu-PSMA-617 between March 2022 and November 2022 were retrospectively reviewed. All patients presenting for medical evaluation, regardless of specific specialty appointments, with new or worsening neurologic symptoms were included in the study. Results: A total of 185 patients underwent 177Lu-PSMA-617 therapy. The median age was 70 y (range, 58-90 y). The mean follow-up time was 12.04 ± 2.87 mo. Fifty-five new or worsening neurologic symptoms were observed in 50 patients (27%, 50/185). Of these, 27 (11.9%, 27/185) reported altered taste. Eleven patients (6%, 11/185) experienced dizziness with no other clear etiology; 2 of these patients were admitted to the emergency department (ED). Paresthesia symptoms were reported in 6 patients (3.2%, 6/185). Five patients (2.7%, 5/185) reported headaches, 3 of these patients were admitted to the ED because of the severity of the symptoms. Two patients (1.08%, 2/185) presented with extremity weakness. Two patients (1.08%, 2/185) had an ischemic stroke and were admitted to the ED. One patient (0.05%, 1/185) exhibited gait disturbances. In total, 7 patients (3.78%, 7/185) were admitted to the ED because of neurologic symptoms. None of the patients discontinued or failed to complete the 177Lu-PSMA-617 therapy because of neurologic symptoms. Conclusion: After 177Lu-PSMA-617 treatment, the most common neurologic symptoms were dysgeusia and dizziness. In this study, our follow-up period and population size might not have been sufficient to detect delayed or uncommon neurologic symptoms. In patients without neurologic symptoms or central nervous system metastases before treatment, we found the development of severe neurologic problems to be rare and unlikely to require discontinuation of treatment.

Pan-cancer subclonal mutation analysis of 7,827 tumors predicts clinical outcome.

Intra-tumor heterogeneity is an important driver of tumor evolution and therapy response. Advances in precision cancer treatment will require understanding of mutation clonality and subclonal architecture. Currently the slow computational speed of subclonal reconstruction hinders large cohort studies. To overcome this bottleneck, we developed Clonal structure identification through Pairwise Penalization, or CliPP, which clusters subclonal mutations using a regularized likelihood model. CliPP reliably processed whole-genome and whole-exome sequencing data from over 12,000 tumor samples within 24 hours, thus enabling large-scale downstream association analyses between subclonal structures and clinical outcomes. Through a pan-cancer investigation of 7,827 tumors from 32 cancer types, we found that high subclonal mutational load (sML), a measure of latency time in tumor evolution, was significantly associated with better patient outcomes in 16 cancer types with low to moderate tumor mutation burden (TMB). In a cohort of prostate cancer patients participating in an immunotherapy clinical trial, high sML was indicative of favorable response to immune checkpoint blockade. This comprehensive study using CliPP underscores sML as a key feature of cancer. sML may be essential for linking mutation dynamics with immunotherapy response in the large population of non-high TMB cancers.

Clinical Application of ISO and CEN/TS Standards for Liquid Biopsies-Information Everybody Wants but Nobody Wants to Pay For.

Liquid biopsies are emerging as valuable clinical biomarkers for cancer monitoring. Although International Organization for Standards (ISO) and Technical Specifications from the European Committee for Standardization (CEN/TS) standardized workflows exist, their implementation in clinical practice is underdeveloped. We aimed to assess the applicability of ISO and CEN/TS standards in a real-world clinical setting, with a particular focus on evaluating the impact of preanalytical parameters and hemolysis on liquid biopsy analysis. We evaluated 659 peripheral blood samples from advanced prostate cancer patients against ISO and CEN/TS standards and documented all essential criteria, including tube draw order, filling level, temperature, and time tracking from blood draw to storage. We assessed hemolysis and its effect on circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) analysis. Our results demonstrated a high compliance rate, with 96.2% (634/659) of samples meeting essential ISO and CEN/TS criteria. We did not observe a significant impact on ctDNA or CTC detection rates between hemolytic and nonhemolytic samples. Hemolysis was identified in 12.9% (40/311) of plasma samples from our advanced prostate cancer cohort, and within the draw order of 5 blood collection tubes, hemolysis did not significantly increase from tube 1 to 5. In total, 83.8% (552/659) of blood collection tubes had high fill levels above 80% of nominal filling level. Our study demonstrates the feasibility and benefits of adhering to ISO and CEN/TS standards in a clinical liquid biopsy study. The standards revealed that hemolysis occurred frequently but did not impair downstream ctDNA and CTC analysis in our cohort of advanced prostate cancer patients.

Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2

While the elucidation of regulatory mechanisms of folded proteins is facilitated due to their amenability to high-resolution structural characterization, investigation of these mechanisms in disordered proteins is more challenging due to their structural heterogeneity, which can be captured by a variety of biophysical approaches. Here, we used the transcriptional master corepressor CtBP, which binds the putative metastasis suppressor RAI2 through repetitive SLiMs, as a model system. Using cryo-electron microscopy embedded in an integrative structural biology approach, we show that RAI2 unexpectedly induces CtBP polymerization through filaments of stacked tetrameric CtBP layers. These filaments lead to RAI2-mediated CtBP nuclear foci and relieve its corepressor function in RAI2-expressing cancer cells. The impact of RAI2-mediated CtBP loss-of-function is illustrated by the analysis of a diverse cohort of prostate cancer patients, which reveals a substantial decrease in RAI2 in advanced treatment-resistant cancer subtypes. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions.

External validation of the Memorial Sloan Kettering Cancer Center preoperative nomogram predicting lymph node invasion in a cohort of high-grade prostate cancer patients.

Commonly used preoperative nomograms predicting clinical and pathological outcomes in prostate cancer (PCa) patients have not been yet validated in high-grade only PCapatients. Our objective is to perform an external validation of the Memorial Sloan Kettering Cancer Center (MSKCC) preoperative nomogram as a predictor of lymph node invasion (LNI) in a cohort of high-grade PCa patients. We included patients with high-grade PCa (Gleason ≥8) treated at our institution between 2011 and 2020 with radical prostatectomy and pelvic lymph node dissection without receiving neoadjuvant or adjuvant therapy. The area under the curve (AUC) of the receiver operator characteristic (ROC) was used to quantify the accuracy of the model to predict LNI. A calibration plot was used to evaluate the model's precision, and a decision curve analysiswas computed to evaluate the net benefit associated with its use. This study was approved by our institution's ethics board. A total of 242 patients with a median age of 66 (60-71) years were included. LNI was observed in 70 (29%) patients with a mean of 16 (median = 15; range = 2-42) resected nodes. The MSKCC nomogram discriminative accuracy, as evaluated by the AUC-ROC was 79.0% (CI: [0.727-0.853]). The MSKCC preoperative nomogram is a good predictor of LNI and a useful tool associated with net clinical benefit in this patient population.

Comprehensive Prostate Fluid-Based Spectral Libraries for Enhanced Protein Detection in Urine.

Biofluids contain molecules in circulation and from nearby organs that can be indicative of disease states. Characterizing the proteome of biofluids with DIA-MS is an emerging area of interest for biomarker discovery; yet, there is limited consensus on DIA-MS data analysis approaches for analyzing large numbers of biofluids. To evaluate various DIA-MS workflows, we collected urine from a clinically heterogeneous cohort of prostate cancer patients and acquired data in DDA and DIA scan modes. We then searched the DIA data against urine spectral libraries generated using common library generation approaches or a library-free method. We show that DIA-MS doubles the sample throughput compared to standard DDA-MS with minimal losses to peptide detection. We further demonstrate that using a sample-specific spectral library generated from individual urines maximizes peptide detection compared to a library-free approach, a pan-human library, or libraries generated from pooled, fractionated urines. Adding urine subproteomes, such as the urinary extracellular vesicular proteome, to the urine spectral library further improves the detection of prostate proteins in unfractionated urine. Altogether, we present an optimized DIA-MS workflow and provide several high-quality, comprehensive prostate cancer urine spectral libraries that can streamline future biomarker discovery studies of prostate cancer using DIA-MS.

Abstract 6616: Polygenic risk score associated with risk of upgrading and tumor features in a prospective cohort of prostate cancer patients on active surveillance

Abstract BACKGROUND: Active surveillance (AS) is now the preferred treatment strategy for the >50% of prostate cancer (PCa) patients diagnosed with low-risk disease, where five-year survival rates are >99%. However, AS requires frequent and costly healthcare visits. In a case-only study of AS patients, we investigated whether polygenic risk scores (PRS) could identify patients who may benefit from intensive vs passive surveillance to reduce these burdens. METHODS: This study included 1,220 PCa patients on AS in the Canary Prostate Active Surveillance Study (PASS). A previously developed multi-ancestry PRS of 451 PCa risk variants (PRS451) was constructed in PASS, along with a PRS of 400 variants, excluding 51 PSA-associated variants (PRS400). Outcomes included upgrading and extreme upgrading at follow up and prostate volume, PSA, percent of biopsy cores with cancer, and Gleason grade at diagnosis. We investigated PRS associations with risk of upgrading with Cox proportional hazards regression adjusting for age at diagnosis and 10 principal components (PCs) of ancestry. Associations with risk of extreme upgrading were performed similarly but with a competing risk analysis, where the competing event was treatment. Discriminative ability was evaluated with Harrell’s C-index. To better account for population structure, we also fit mixed models with fixed effects for PRS, age at diagnosis, and 10 PCs, with a random effect for a genetic relationship matrix. RESULTS: Of the 1,220 AS patients, 38.5% (n=470) upgraded during the median 4.2 years of follow up and 85% (n=1041) self-reported as non-Hispanic White. In time-to-event analyses, each SD unit increase in PRS451 was associated with a 23% increased risk of upgrading (P=4.2 × 10−5), while PRS400 was associated with a 27% increased risk (P=1.6 × 10−6). PRS were similarly associated with 21% (95% CI=1.02-1.44, P=0.03) and 27% (95% CI=1.06-1.52, P=0.01) increased risk of extreme upgrading, respectively. Compared to a model with age at diagnosis, PCs, and clinical risk factors (C-index=0.617, 95% CI=0.590-0.644), including PRS400 slightly improved the ability to detect risk of upgrading (C-index=0.632, 95% CI=0.604-0.659). Mixed model results were highly consistent. Each SD unit increase in PRS400 was associated with 1.38 higher percentage points of biopsy cores with cancer (95% CI=0.76-2.00, P=1.1 × 10−5), 1.48 cc smaller prostate volume (95% CI=-2.82, -0.14, P=0.03), and 0.18 ng/mL higher PSA (95% CI=0.01-0.35, P=0.05) at diagnosis. Except for PSA, associations were similar or weaker for PRS451. CONCLUSION: In patients on AS, high PRS was associated with increased risk of upgrading, extreme upgrading, smaller prostate volume, and possibly tumor multifocality. As such, PRS could inform the intensity of surveillance for low-risk PCa patients, reducing the burden of AS for patients with low risk of disease progression. Citation Format: Louisa B. Goss, Menghan Liu, Yingye Zheng, Boya Guo, David V. Conti, Christopher A. Haiman, William J. Catalona, John S. Witte, Daniel W. Lin, Lisa F. Newcomb, Burcu F. Darst. Polygenic risk score associated with risk of upgrading and tumor features in a prospective cohort of prostate cancer patients on active surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6616.

Abstract 6188: Pathomics of prostate cancer incorporating histology and mass spectrometry imaging

Abstract Background: Recent evidence shows that interactions between tumor cells, immune cells, and extracellular matrix (ECM) proteins in the stroma play an important role in prostate cancer (PCa) progression. However, to date these factors are not accounted for in clinical evaluation of PCa patients. Our team has developed methods based on matrix-assisted laser desorption/ionization (MALDI) imaging to identify sets of ECM glycan and collagen molecules associated with PCa. In this study, we leverage computational imaging methods and pathomic textural features to assess the potential of MALDI imaging to guide the identification of regions in PCa hematoxylin and eosin stain (H&E) images as tumor or non-tumor. Methods: We used a cohort of PCa patients (n=10), who have undergone radical prostatectomy, with grade groups GG3−GG5, and with available H&E and N-glycan MALDI images. We used five MALDI images per patient representing the distribution of N-glycan species at 1419, 2539, 2686, 1663, and 1809 m/z. For each MALDI image, an N-glycan mask was generated and co-registered with the corresponding H&E image via computational imaging methods (i.e., Otsu thresholding, largest connected components labeling, sequential affine and B-spline registration using mutual information). To quantify the overlap of each mask with tumor regions, we calculated Dice scores between the masks and the pathology annotation in H&E. To assess differences in imaging patterns of regions indicated by the different masks, we extracted a set of pathomic textural features (n=70) from the H&E image within each mask using PyRadiomics, and we performed Wilcoxon signed rank tests across all pathomic textural features for all paired combinations of the five masks. Results: The mean Dice scores between the pathology tumor annotation and the N-glycan masks from 1419 (0.56 [0.44‒0.65]) and 2539 m/z (0.64 [0.59‒0.82]) was significantly higher (p<0.008) than the Dice score of 1663 (0.24 [0.17‒0.36]), 1809 (0.31 [0.13‒0.45]), and 2686 m/z (0.32 [0.19‒0.37]). This suggests a large overlap between 1419 and 2539 m/z and tumor, and large overlap between 1663 and 1809 m/z and non-tumor regions. Consistent with these results, our pathomic textural analysis showed that 50 out of 70 features were significantly different (p<0.05) between the masks derived from 1419 and 1663 m/z, 52 between 1419 and 1809 m/z, 62 between 2539 and 1663 m/z, and 57 between 2539 and 1809 m/z (p<0.05). Moreover, there were only 23 significantly different features between 1419 and 2539 m/z (p<0.05), and 0 features between 1663 and 1809 m/z. Further evaluation is needed for 2686 m/z for which a mean of 54 [45‒64] significantly different features (p<0.05) from all other masks were found. Conclusions: We provide preliminary evidence that MALDI imaging can elucidate tissue properties and guide pathomic textural analysis in H&E images, with potential applications in treatment guidance and prognostication of PCa. Citation Format: José Marcio Luna, Hani Nakhoul, Cody Weimholt, Eric H. Kim, Sheng-Kwei Song, Peggi M. Angel, Richard R. Drake, Joseph E. Ippolito. Pathomics of prostate cancer incorporating histology and mass spectrometry imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6188.

Abstract 6467: Causal personalized treatment estimation framework using real-world electronic health record (EHR) data to inform cancer care decisions

Abstract Background: The average treatment effects (ATEs) from randomized controlled trials often do not generalize across populations, or they are not sufficiently personalized to capture the benefits and risks to individual patients. Real-world data aids in validating and extending trial results, but can introduce biases that invalidate the causal interpretation. Here, we propose a robust statistical framework, which uses real-world EHR data to evaluate the efficacy of cancer treatments at both population and individual levels. We demonstrate the ability of our framework to deliver personalized insights in metastatic prostate cancer treatments. Methods: We assembled a retrospective cohort of metastatic prostate cancer patients from a large academic medical center. We gathered demographic, comorbidity, cancer treatment, and outcome data from the EHR or natural language processing of clinician narratives, and social determinants of health from Census data. We used doubly robust machine learning with bootstrap standard errors to compute the ATE and personalized treatment estimates (PTEs), comparing the impact of ADT (androgen depravation therapy) + chemotherapy (ACT) and ADT + combination anti-androgen therapy (ACAT) on percentage reduction in PSA levels in metastatic prostate cancer. Results: The baseline characteristics of our cohort are summarized in Table 1a. Our approach found that ACAT reduces PSA levels significantly more than ACT, and captured the heterogeneity in treatment effects across individuals (Table 1b). Through simulation studies, we demonstrated that any reasonable bias from unobserved confounding or missing information was small compared to the estimated treatment effects and their standard errors. Conclusion: We presented a doubly robust framework and demonstrated its utility in analyzing real-world data, enabling us to uncover the diversity in treatment responses among individuals with metastatic prostate cancer. Results summary a. Baseline demographic characteristics. ADT + chemotherapy N = 302 ADT + combination therapy N = 114 Treatments Any ADT + Docetaxel or Cabazitaxel Any ADT + Abiraterone or apalutamide or Enzalutamide Age Mean (SD) 69.3 (8.76) 66.7 (8.17) Median [Min, Max] 69.0 [47.0, 94.0] 66.5 [46.0, 86.0] Race Asian 8 (2.6%) 2 (1.8%) Black or African American 48 (15.9%) 7 (6.1%) White or Caucasian 224 (74.2%) 99 (86.8%) Other 22 (7.3%) 6 (5.3%) Max PSA treatment start (ng/mL) Mean (SD) 34.9 (98.5) 83.3 (448) b. Treatment effects estimation ATE (95% CI) 32.0% [24.6%, 40.8%] PTEs: 25th and 75th percentiles 29.0%, 34.3% Citation Format: Sumana Srivatsa, David Walsh, Mayada Aljehani, Jason Weinreb, Nathan Becker, Benjamin H. Ellis, Renee George, Xingyao Chen, Naim Matasci, Reva Basho, Mitchell E. Gross, Christine L. Swisher. Causal personalized treatment estimation framework using real-world electronic health record (EHR) data to inform cancer care decisions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6467.

Abstract 2769: Long non coding RNA H19/cell adhesion molecules circuitry as novel target and diagnostic tool for metastatic prostate cancer

Abstract In the complex tumor biology of prostate cancer (PCa), we previously contributed by demonstrating that estrogen receptor and hypoxia signaling promoted transcription of progression-associated genes. Notably, combined treatment, estrogens plus hypoxia, caused a significant down regulation of the long noncoding RNA H19, one of the most sensitive to these pro-tumoral stimuli. Mechanistically, H19 acts as transcriptional repressor: H19 over-expression decreases E-cadherin (CDH1) level causing epithelial-to-mesenchymal transition whereas H19 reduction promotes the expression of E-cadherin and β4 integrin (ITGB4) switching the tumor dissemination program toward an alternative mechanism, specifically the cohesive metastatic phenotype. We focused on this H19/cell adhesion molecules circuitry by investigating its role as: 1.Novel prognostic biomarker at the time of biopsies. eNOS, HIF2a and β4 integrin expression was evaluated by immunohistochemistry, H19 and CDH1 transcripts by Droplet Digital PCR on FFPE-biopsies in a retrospective cohort of PCa patients [n = 30; Gleason score GS≤ 7(3+4) n= 17, GS ≥7(4+3) n= 13; biochemical, local, or metastatic recurrence defining disease progression (n=8/30; time of recurrence: range 2-6 years)]. Importantly, multivariate analysis of combined biomarkers, named “Bioscore”, defined by the presence of at least 3 among HIF-2α, eNOS, CDH1, β4 integrin ≥cut off or H19≤cut off revealed its prognostic value for progression and Progression-Free Survival determined using the ROC analysis (p=0.003) and Kaplan Meier curve (p= 0.005), respectively. 2.Master regulator of metastatic program in vivo and ex vivo PCa experimental models. Upon H19 silencing, mimicking combined estrogens plus hypoxia treatment, luciferase-positive PC-3 and 22Rv1 cells led to increased E-cadherin and β4 integrin expression, enhanced tumor growth and metastasis formation at bone, lung, and liver in PCa mouse models. Further, treatment with H3K27 demethylase inhibitor, GSK-J4, rescued cell adhesion molecules expression by modulating H3K27me3 level at gene promoters, reduced metastasis number and size, and induced cell death in PCa-derived Organotypic Slice Cultures. Additionally, treatment with JQ1 and dBET6 BET protein family inhibitors) markedly reduced both E-cadherin and β4 integrin levels, cell proliferation and in vivo tumor growth. Intriguingly, H19 silencing increased BRD3 and BRD4 levels, implicating H19 in BRD transcription. Overall, this research enhances our understanding of the molecular mechanisms driving aggressive prostate cancer phenotypes, providing a foundation for new diagnostic and therapeutic strategies in prostate cancer management. Citation Format: Valeria Pecci, Aurora Aiello, Sara De Martino, Cristian Ripoli, Dante Rotili, Francesco Pierconti, Francesco Pinto, Claudio Grassi, Carlo Gaetano, Alfredo Pontecorvi, Lidia Strigari, Antonella Farsetti, Simona Nanni. Long non coding RNA H19/cell adhesion molecules circuitry as novel target and diagnostic tool for metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2769.

Abstract 3023: Master corepressor inactivation through oncogene suppressor RAI2 mediated polymerization

Abstract Imbalanced transcription of a large number of genes can be caused at various levels, ranging from alterations in individual transcription factors to dysfunctional corepressor and coactivator complexes [1]. C-terminal binding proteins (CtBPs) are ubiquitous master transcriptional coregulators associated with the Polycomb Repressive Complex 2 (PRC2), with essential functions in the development and oncogenesis of various tumor entities, including breast cancer and prostate cancer (PC) [2,3]. As CtBPs bind to short linear PxDLS-like sequence motifs (SLiMs), the presence of such motifs in tandem on the putative metastasis suppressor RAI2 [4] suggested a previously undiscovered dual interaction with CtBPs. Here, we show that RAI2 induces CtBP polymerization through well-ordered filaments of stacked tetrameric CtBP layers, as illustrated by a high-resolution single particle cryo electron microscopy structure. These filaments are mirrored by RAI2-mediated CtBP nuclear foci and relief of CtBP corepressor function in RAI2-expressing cancer cells. Analyses of a diverse PC patient cohort revealed a substantial decrease in RAI2 in the aggressive subtypes, suggesting a pivotal role of RAI2 in the transition to androgen receptor signaling-independent progression. Taken together, our data demonstrate a previously unknown mechanism of multivalent short linear sequence motif-induced polymerization. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions. The specific properties of these repeated interactions open up new therapeutic opportunities.

Abstract 3420: Androgen receptor (CAG)n polymorphism: A genomic marker for prostate cancer prognosis independent of histopathological parameters

Abstract The androgen receptor (AR) serves as a pivotal transcription factor in prostate cancer (PCa) development. Its transcriptional activity is linked to the number of glutamines in the N-terminal domain. While current screening for PCa and prognostic biomarkers include serum prostate-specific antigen (PSA) levels and histopathological characteristics (specifically, ISUP grade and margin involvement), the heterogeneity of these tumors underscores the need for additional markers to enhance clinical management. Thus, this study aimed at characterizing an Argentinian PCa patient cohort based on the CAG polymorphism (CAG)n in AR and establish associations between genotypes and clinical-pathological characteristics to refine disease prognosis. We designed a hospital-based case-case study for PCa patients to determine the association between AR polymorphisms and PCa biochemical relapse after radical prostatectomy (RP). We retrospectively recruited 112 patients histologically diagnosed with PCa at the Hospital de Clínicas José de San Martín, Buenos Aires, Argentina. All patients underwent RP as their primary therapeutic strategy. All patients were, by definition, Hispanics, predominantly of Caucasian ancestry and, at a lesser extent, Amerindian or African. Written informed consent and institutional review board approval were acquired. Blood samples were collected post-RP for genomic DNA extraction using the CTAB method. (CAG)n in AR was genotyped by fluorescent PCR followed by capillary electrophoresis, and correlations between genotypes and clinical-pathological variables were analyzed using R. Results categorized patients into three subgroups based on the length of the CAG tandem repeat in AR: long (>23 repeats, n=29), medium (20-23 repeats, n=44), and short (<20 repeats, n=38). No associations were found between the length of the polymorphism and age of diagnosis, pre-RP PSA serum values, ISUP grade, and margin involvement. However, patients with family cancer history had a higher frequency of the intermediate-length allele (p=0.02). Moreover, among patients with pre-RP PSA <10 ng/ml and intermediate-length allele had 2.72-fold risk of biochemical recurrence (BCR) (HR=2.72, 95%CI=1.05-7.03, p=0.039). Furthermore, multivariable BCR analysis including the ISUP grade and margin involvement as co-variates showed that the (CAG)n in AR was independent of these histopathological parameters (HRadj=3.37, 95%IC=1.24-9.10, padj=0.017). Altogether, the AR polymorphism is associated with family history of cancer. Consequently, determining the number of CAG repetitions in AR through a blood sample could serve as an independent prognostic marker in patients with PSA <10 ng/ml prior to PR, independent of the histopathological features. Citation Format: Gastón Mario Pascual, Agustina Sabater, Juan Bizzotto, Rocio Seniuk, Pablo Sanchis, Carlos M. Roggero, Carlos Scorticati, Osvaldo Mazza, Elba Vazquez, Ayelen Toro, Geraldine Gueron, Javier Cotignola. Androgen receptor (CAG)n polymorphism: A genomic marker for prostate cancer prognosis independent of histopathological parameters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3420.

Androgen deprivation therapy-related fracture risk in prostate cancer: an insurance claims database study in Japan

IntroductionAndrogen deprivation therapy (ADT) is widely used for the treatment of prostate cancer. ADT is associated with reduced bone density leading to an increased risk of osteoporotic fracture. The objective of this retrospective cohort study was to quantify fracture risk in men treated with ADT for prostate cancer in real-world practice in Japan.Materials and methodsData were extracted from the Japanese Medical Data Vision (MDV) database. Men initiating ADT for treatment of prostate cancer between April 2010 and March 2021 were identified and matched to a cohort of prostate cancer patients not taking ADT using a propensity score. Fracture rates were estimated by a cumulative incidence function and compared between cohorts using a Cox cause-specific hazard model. Information was extracted on demographics, comorbidities and bone densitometry.Results30,561 men with PC starting ADT were matched to 30,561 men with prostate cancer not treated with ADT. Following ADT initiation, <5% of men underwent bone densitometry. Prescription of ADT was associated with an increased fracture risk compared to not taking ADT (adjusted hazard ratio: 1.63 [95% CI 1.52–1.75]).ConclusionADT is associated with a 1.6-fold increase in the risk of osteoporotic fracture in men with prostate cancer. Densitometry in this population is infrequent and monitoring urgently needs to be improved in order to implement effective fracture prevention.

Variation in Access to Palliative Radiotherapy in Prostate Cancer: A Population-Based Study in Canada.

As a result of improvements in cancer therapies, patients with metastatic malignancies are living longer, and the role of palliative radiotherapy has become increasingly recognized. However, access to adequate palliative radiotherapy may continue to be a challenge, as is evident from the high proportion of patients dying of prostate cancer who never receive palliative radiotherapy. The main objective of this investigation is to identify and describe the factors associated with the receipt of palliative radiation treatment in a decedent cohort of prostate cancer patients in Ontario. Population-based administrative databases from Ontario, Canada, were used to identify prostate cancer decedents, 65 years or older who received androgen deprivation therapy between January 1, 2013, and December 31, 2018. Baseline and treatment characteristics were analyzed using univariate and multivariate logistic regression models for association with receipt of radiotherapy in a two-year observation period before death. We identified 3,788 prostate cancer decedents between 2013 and 2018; among these, 49.9% received radiotherapy in the two years preceding death. There were statistically significant positive associations between receipt of radiotherapy and younger age at diagnosis (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1-2.3); higher stage at diagnosis (OR 1.3, 95% CI 1.1-1.7); receipt of care at a regional cancer center (OR 1.8, 95% CI 1.3-2.4); and involvement of radiation oncologists (OR 155.1, 95% CI 83.3-288.7)or medical oncologists (OR 1.4, 95% CI 1.1-1.8). However, there were no associations between receipt of radiotherapy and income, distance to the nearest cancer center, involvement of urologists in cancer care, healthcare administrative region, home-care involvement, or number of hospitalizations in the observation period. We found the utilization of palliative radiotherapy for prostate cancer patients in Ontario varies depending on age, stage at diagnosis, number of comorbidities, registration at regional cancer centers, and involvement of oncologists. There were no differences detected based on incomeor distance from a cancer center. The findings of this study represent an important opportunity to facilitate better access to palliative radiotherapy and referrals to multidisciplinary regional cancer centers, to improve the quality of life of this patient population.

(012) Incidence of Peyronie’s Disease After Radical Prostatectomy Among Patients Undergoing Penile Rehabilitation Regimen

Abstract Introduction Radical prostatectomy remains one of the gold standard treatments for localized prostate cancer, the most prevalent solid organ cancer in men. Surgical management of prostate cancer has been theorized to increase the risk of developing Peyronie’s Disease (PD). In 2010, Drs. Tal and Mulhall’s team characterized the incidence of PD in a cohort of 1011 men after radical prostatectomy to be 13.7% at 2 years and 15.9% at 3 years of follow-up. These numbers, significantly higher than estimates in the general population, which range from 0.5 to 7.1% (Sharma et al., Sex Med Rev 2020;8:314–23), suggest radical prostatectomy is a risk factor for developing PD. Objective Our aim was to evaluate the incidence of PD among post-prostatectomy patients who undergo a formal multi-modal penile rehabilitation program that includes mechanical and pharmacologic interventions to promote penile smooth muscle activation after surgery. Methods In this retrospective, descriptive study we reviewed the charts of 581 patients who were diagnosed with prostate cancer, treated with robot-assisted laparoscopic radical prostatectomy (RALP), and were engaged in a penile rehabilitation program from January 2016 through January 2019. At our institution, patients scheduled for prostatectomy are referred preoperatively to an academic Men’s Health clinic to start a multi-modal program and follow up regularly for evaluation of sexual health. The program includes daily tadalafil, L-citrulline, and VED use (Table 1). Patients refractory to these therapies had the option to increase tadalafil dosing or undergo further treatment with intracavernosal injections at ~3 months post-op. We excluded patients who had PD pre-operatively or who did not have post-operative follow-up with the providers at this institution. The primary outcome of interest was the incidence of PD among this cohort. Secondary outcome included time to development or diagnosis of PD. Results 581 patients with prostate cancer treated with RALP engaged in penile rehabilitation and were included in this analysis. The median age of men was 62.6 y with additional demographics listed in Table 2. The incidence of PD in this cohort was 2.9% (17 patients) with a median follow-up of 21.4 mo (IQR 2.8 – 55.8 mo). The diagnosis of PD was made at a median of 28.7 mo (IQR 20 – 36 mo) after prostatectomy. The 17 patients with PD had a median follow-up of 38.9 mo (IQR 23.2 – 55.8 mo). Conclusions In this cohort of prostate cancer patients treated with RALP and undergoing a consistent, multi-modal penile rehabilitation program, the incidence of PD was 2.9%, and median time to diagnosis was 28.7 months. This is the first study to assess PD incidence in men who engage in mechanical and pharmacologic penile rehabilitation at time of RALP. Furthermore, diagnosis of PD was made more than two years after surgery; this warrants further evaluation on whether penile rehabilitation prevents PD. This retrospective analysis is a hypothesis-generating study that should inspire further research on the role of regular mechanical stimulation or daily PDE-5 inhibitors in delaying or preventing PD after pelvic surgery. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Endo Scientific.

Association of aggressive prostate cancer features on whole-mount histopathology and quantitative measures on PSMA PET.

289 Background: The intraductal carcinoma (IDC) and the large cribriform growth pattern (LCP) are two architectural patterns of prostate cancer (PC) associated to more aggressive disease, high Gleason scores, advanced tumor stage, biochemical relapse, and distant metastasis. Predicting the presence of these pathology features could be of significant help in case whole-mount pathology (WMHP) is not available. The goal of this analysis was to assess the distribution of quantitative parameters from 68Ga-PSMA-11 PET/CT (PSMA PET) in lesions with and without LCP/IDC patterns on WMHP. We assessed the ability of pre-surgical PSMA PET imaging to predict the presence of aggressive pathology features. Methods: With IRB approval and HIPAA compliance, we derived a study cohort of PC patients who underwent PSMA PET prior to robotic radical prostatectomy (RALP). WMHP analysis described presence/absence of LCP and IDC patterns in each identified PC lesion. Board-certified physicians contoured all PC lesions on PSMA PET. Only lesions matching with WMHP were included in the analysis. PSMA PET metrics (SUVmax, SUVmean and PSMA-volume) were extracted. All lesions were categorized in sub-cohorts as LCP+/IDC+, LCP+/IDC-, LCP-/IDC-, and LCP-/IDC+. One way-ANOVA assessed significant differences among the imaging parameters in the sub-cohorts. The area under the curve (AUC) from ROC analysis was used to assess the ability of imaging metrics to predict the presence of aggressive PC features on WMHP. Results: The final cohort comprised 155 patients and 177 lesions. The median (IQR) PSA at time of RALP was 9.2 (5.55-15.05). 73/177 lesions (41.2%) were categorized as LCP+/IDC+, 63/177 (35.6%) as LCP-/IDC-, 37/177 (20.9%) as LCP+/IDC-, and 4 (2.3%) as LCP-/IDC-. SUVmax (p=0.007), SUVmean (p=0.048) and lesion size on PSMA PET (p=0.003) were significantly higher in lesions showing LCP, whereas only lesion size was significantly higher in lesions showing IDC (p=0.003). Lesions showing LCP+/IDC- had significantly higher SUVmax (p=0.002) and SUVmean (p=0.001) than lesions showing LCP-/IDC-. SUVmean was significantly higher in LCP+/IDC- than in LCP+/IDC+ (0.043). SUVmax and SUVmean were not significantly different among other sub-cohorts. Lesion size on PSMA PET was significantly higher in LCP+/IDC+ than in LCP-/IDC- (0.009). A logistic regression model analysis showed that PSMA PET quantitative measures predict the presence of LCP and/or IDC with moderate accuracy (AUC= 0.69; p=0.001). Conclusions: Higher SUVmax and SUVmean are found in lesions showing LCP, but not in those showing IDC. A linear regression model including SUVmax, SUVmean and PSMA PET lesion volume was able to predict with moderate accuracy the presence of pathology features of aggressive prostate cancer (AUC: 0.69).

Deep learning-based automated pipeline for blood vessel detection and distribution analysis in multiplexed prostate cancer images.

Introduction: Prostate cancer is a highly heterogeneous disease, presenting varying levels of aggressiveness and response to treatment. Angiogenesis is one of the hallmarks of cancer, providing oxygen and nutrient supply to tumors. Micro vessel density has previously been correlated with higher Gleason score and poor prognosis. Manual segmentation of blood vessels (BVs) In microscopy images is challenging, time consuming and may be prone to inter-rater variabilities. In this study, an automated pipeline is presented for BV detection and distribution analysis in multiplexed prostate cancer images. Methods: A deep learning model was trained to segment BVs by combining CD31, CD34 and collagen IV images. In addition, the trained model was used to analyze the size and distribution patterns of BVs in relation to disease progression in a cohort of prostate cancer patients (N = 215). Results: The model was capable of accurately detecting and segmenting BVs, as compared to ground truth annotations provided by two reviewers. The precision (P), recall (R) and dice similarity coefficient (DSC) were equal to 0.93 (SD 0.04), 0.97 (SD 0.02) and 0.71 (SD 0.07) with respect to reviewer 1, and 0.95 (SD 0.05), 0.94 (SD 0.07) and 0.70 (SD 0.08) with respect to reviewer 2, respectively. BV count was significantly associated with 5-year recurrence (adjusted p = 0.0042), while both count and area of blood vessel were significantly associated with Gleason grade (adjusted p = 0.032 and 0.003 respectively). Discussion: The proposed methodology is anticipated to streamline and standardize BV analysis, offering additional insights into the biology of prostate cancer, with broad applicability to other cancers.

First-in-human study of PSMA-targeting agent, [18F]AlF-P16-093: dosimetry and initial evaluation in prostate cancer patients.

This is a first-in-human study to evaluate the radiation dosimetry of a new prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, [18F]AlF-P16-093, and also initial investigation of its ability to detect PSMA-positive tumors using PET scans in a cohort of prostate cancer (PCa) patients. The [18F]AlF-P16-093 was automatically synthesized with a GE TRACERlab. A total of 23 patients with histopathologically proven PCa were prospectively enrolled. Dosimetry and biodistribution study investigations were carried out on a subset of six (6) PCa patients, involving multiple time-point scanning. The mean absorbed doses were estimated with PMOD and OLINDA software. [18F]AlF-P16-093 was successfully synthesized, and radiochemical purity was > 95%, and average labeling yield was 36.5 ± 8.3% (decay correction, n = 12). The highest tracer uptake was observed in the kidneys, spleen, and liver, contributing to an effective dose of 16.8 ± 1.3 μSv/MBq, which was ~ 30% lower than that of [68Ga]Ga-P16-093. All subjects tolerated the PET examination well, and no reportable side-effects were observed. The PSMA-positive tumors displayed rapid uptake, and they were all detectable within 10 min, and no additional lesions were observed in the following multi-time points scanning. Each patient had at least one detectable tumor lesion, and a total of 356 tumor lesions were observed, including intraprostatic, lymph node metastases, bone metastases, and other soft tissue metastases. We report herein a streamlined method for high yield synthesis of [18F]AlF-P16-093. Preliminary study in PCa patients has demonstrated its safety and acceptable radiation dosimetry. The initial diagnostic study indicated that [18F]AlF-P16-093 PET/CT is efficacious and potentially useful for a widespread application in the diagnosis of PCa patients.

P042 - External Validation of the 2019 Briganti’s and 2019 Draulans’ nomograms for the identification of patients who should be considered for an extended pelvic lymph node dissection in a cohort of portuguese prostate cancer patients

P042 - External Validation of the 2019 Briganti’s and 2019 Draulans’ nomograms for the identification of patients who should be considered for an extended pelvic lymph node dissection in a cohort of portuguese prostate cancer patients

Ratiometric Inclusion of Fibroblasts Promotes Both Castration-Resistant and Androgen-Dependent Tumorigenic Progression in Engineered Prostate Cancer Tissues.

To investigate the ratiometric role of fibroblasts in prostate cancer (PCa) progression, this work establishes a matrix-inclusive, 3D engineered prostate cancer tissue (EPCaT) model that enables direct coculture of neuroendocrine-variant castration-resistant (CPRC-ne) or androgen-dependent (ADPC) PCa cells with tumor-supporting stromal cell types. Results show that the inclusion of fibroblasts within CRPC-ne and ADPC EPCaTs drives PCa aggression through significant matrix remodeling and increased proliferative cell populations. Interestingly, this is observed to a much greater degree in EPCaTs formed with a small number of fibroblasts relative to the number of PCa cells. Fibroblast coculture also results in ADPC behavior more similar to the aggressive CRPC-ne condition, suggesting fibroblasts play a role in elevating PCa disease state and may contribute to the ADPC to CRPC-ne switch. Bulk transcriptomic analyses additionally elucidate fibroblast-driven enrichment of hallmark gene sets associated with tumorigenic progression. Finally, the EPCaT model clinical relevancy is probed through a comparison to the Cancer Genome Atlas (TCGA) PCa patient cohort; notably, similar gene set enrichment is observed between EPCaT models and the patient primary tumor transcriptome. Taken together, study results demonstrate the potential of the EPCaT model to serve as a PCa-mimetic tool in future therapeutic development efforts.