Biopsy Cores Research Articles

Transperineal 3-Core Magnetic Resonance Imaging Ultrasound Fusion Targeted Plus Laterally 6-Core Systematic Biopsy in Prostate Cancer Diagnosis

IntroductionIt is important to explore strategies reducing the number of SB cores taken to minimize biopsy-related morbidity and patient's discomfort during biopsy. This study aims to optimize prostate biopsy procedures by reducing the number of systematic biopsy (SB) cores while preserving cancer detection rates in the era of combined biopsy. Patients and MethodsWe prospectively recruited patients with ≥1 magnetic resonance imaging (MRI) lesions and they underwent transperineal combined 12-core SB+3-core targeted prostate biopsy (TB, reference standard). New strategy was defined as a laterally 6-core SB+3-core TB. Patients were served as their own control. Detection rates for overall prostate cancer (PCa) and clinically significant PCa (csPCa) were compared among the standard SB, MRI-TB, 6-core SB +3-core TB, and reference standard. Pathology consistency was assessed using the Kappa test. ResultsA total of 204 men were included, of which 111 (54.41%) and 92 (45.10%) harbored overall PCa and csPCa. Referenced combined biopsy detected significantly 6.86% (P = .0005) or 4.90% (P = .0044) more csPCa than performing only SB or 3-core TB, but was comparable to the new biopsy strategy. (45.10% vs. 43.14%, P = .1336) Similar results persisted when limiting patients in biopsy-naïve men or stratified by Prostate Imaging Reporting and Data System scores, PSAD, and index lesion parameters. Additionally, performing 6-core SB+3-core TB demonstrated high consistency with reference standard in grade group distribution (Kappa coefficient: 0.952 for all, 0.961 for biopsy-naïve men) and achieved superior sensitivity of 95.7% (All: 95% CI: 89.2%-99.8%) and 96.9% (Biopsy-naïve: 95% CI: 91.1%-99.7%), respectively. ConclusionsThe 6-core SB+3-core TB approach maintains expected detection rates while reducing the total core count, offering a promising alternative to the reference standard, which may help to tailor transperineal combined biopsy procedures.

Differences in Rural Versus Urban Patients With Prostate Cancer in Diagnosis and Treatment: An Analysis of a Population-Based Cohort.

Patients living in rural communities have greater barriers to cancer care and poorer outcomes. We hypothesized that rural patients with prostate cancer have less access and receive different treatments compared with urban patients. We used a population-based prospective cohort, the North Carolina Prostate Cancer Comparative Effectiveness and Survivorship Study, to compare differences in prostate cancer diagnosis, access to care, and treatment in patients by geographic residence. The 2013 rural-urban continuum code (RUCC) was used to determine urban (RUCC 1-3) versus rural (RUCC 4-9) location of residence. Patients with rural residence comprised 25% of the cohort (364 of 1,444); they were less likely to be White race and had lower income and educational attainment. Rural patients were more likely to have <12 cores on biopsy (47.1% v 35.7%; P < .001) and less likely (40.8% v 47.6%; P = .04) to receive multidisciplinary consultation. We observed significant differences in treatment between urban and rural patients, including rural patients receiving less active surveillance or observation (22.6% v 28.7%), especially in low-risk cancer (33.2% v 40.7%). On multivariable analysis that adjusted for patient and diagnostic factors, rural residence was associated with less use of active surveillance or observation over radical treatment (ie, surgery or radiation therapy; odds ratio, 0.49 v urban; P < .001) in patients with low-risk cancer. Patients with prostate cancer who live in rural versus urban areas experience several differences in care that are likely clinically meaningful, including fewer cores in the diagnostic biopsy, less utilization of multidisciplinary consultation, less use of active surveillance, or observation for low-risk disease. Future studies are needed to assess the efficacy of interventions in mitigating these disparities.

Can 3D Multiparametric Ultrasound Imaging Predict Prostate Biopsy Outcome?

ObjectivesTo assess the value of 3D multiparametric ultrasound imaging, combining hemodynamic and tissue stiffness quantifications by machine learning, for the prediction of prostate biopsy outcomes. MethodsAfter signing informed consent, 54 biopsy-naïve patients underwent a 3D dynamic contrast-enhanced ultrasound (DCE-US) recording, a multi-plane 2D shear-wave elastography (SWE) scan with manual sweeping from base to apex of the prostate, and received 12-core systematic biopsies (SBx). 3D maps of 18 hemodynamic parameters were extracted from the 3D DCE-US quantification and a 3D SWE elasticity map was reconstructed based on the multi-plane 2D SWE acquisitions. Subsequently, all the 3D maps were segmented and subdivided into 12 regions corresponding to the SBx locations. Per region, the set of 19 computed parameters was further extended by derivation of eight radiomic features per parameter. Based on this feature set, a multiparametric ultrasound approach was implemented using five different classifiers together with a sequential floating forward selection method and hyperparameter tuning. The classification accuracy with respect to the biopsy reference was assessed by a group-k-fold cross-validation procedure, and the performance was evaluated by the Area Under the Receiver Operating Characteristics Curve (AUC). ResultsOf the 54 patients, 20 were found with clinically significant prostate cancer (csPCa) based on SBx. The 18 hemodynamic parameters showed mean AUC values varying from 0.63 to 0.75, and SWE elasticity showed an AUC of 0.66. The multiparametric approach using radiomic features derived from hemodynamic parameters only produced an AUC of 0.81, while the combination of hemodynamic and tissue-stiffness quantifications yielded a significantly improved AUC of 0.85 for csPCa detection (p-value < 0.05) using the Gradient Boosting classifier. ConclusionsOur results suggest 3D multiparametric ultrasound imaging combining hemodynamic and tissue-stiffness features to represent a promising diagnostic tool for biopsy outcome prediction, aiding in csPCa localization.

The clinical meaning of lymphovascular invasion: preoperative predictors and postoperative implications in prostate cancer - a retrospective study.

Lymphovascular invasion (LVI) is a pivotal histopathological parameter in prostate cancer (PCa), holding significant prognostic implications. Our study pursued a dual objective: firstly, to identify preoperative factors associated with LVI, aiming to unveil markers facilitating the recognition of patients prone to LVI during postoperative examination; and secondly, to assess postoperative outcomes correlated with LVI. We retrospectively analyzed 861 nonmetastatic PCa patients who underwent radical prostatectomy (RP), investigating preoperative factors and postoperative outcomes. Surgical specimens were processed following established guidelines. Statistical analyses utilized non-parametric tests to assess the association between LVI and both pre- and postoperative factors. Furthermore, logistic regression analyses were utilized to develop models aimed at identifying the most significant predictors of LVI and pN1 status, respectively. Numerous preoperative factors exhibited significant correlations with LVI, offering valuable clinical insights. Logistic regression identified magnetic resonance imaging (MRI)-based clinical tumor stage (cT) 3-4, biopsy Gleason Grading Group (GGG) 3-5, preoperative prostate specific antigen (PSA) ≥20 and percentage of positive biopsy cores (PPBC) ≥50% as the strongest preoperative predictors of LVI. Additionally, the study uncovered an association between LVI and postoperative outcomes, including postoperative PSA (p value <0.001), extracapsular extension (ECE) (<0.001), positive surgical margins (PSM) (<0.001), perineural invasion (PNI) (<0.001), pathological tumor stage (pT) (<0.001), pathological lymph node status (pN) (<0.001), postoperative GGG (<0.001), and operative time (0.023). Notably, the study revealed a novel and substantial association between LVI and an increased number of positive lymph nodes in pN+ patients in the univariate analysis (<0.001). Furthermore, we have found an association between LVI and pN1 status in the logistic regression analysis (odds ratio [OR] = 23.905; p <0.001). Our findings underscore the pivotal role of LVI in influencing the prognosis of prostate cancer (PCa). The study acknowledges the challenges associated with preoperative LVI assessment and emphasizes the need for future research to unravel the factors associated with this histopathological finding. Significantly, our research stands out as the first, to the best of our knowledge, toreveal the association between LVI and the number of positive lymph nodes in pN+ patients.

The Added Value of Prostate Magnetic Resonance Imaging to Patient Selection.

There has been a rapid increase in the utilization of magnetic resonance imaging (MRI) for prostate cancer detection. The objective of this study was to measure the increase in utilization of MRI before prostate biopsy and the effects on the distribution of Prostate Imaging Reporting and Data System (PI-RAD) scores and Gleason grades over a 5-year interval in an integrated health system. The authors conducted a retrospective analysis of prostate MRI studies prior to biopsy in the calendar years of 2017 and 2022. Peak PI-RADS score, peak Gleason grade of suspected prostatic lesions, and the number of biopsy cores were collected from radiology reports and pathology reports from patients' electronic health records, respectively. All statistical tests were 2-tailed with a significance level set at p < 0.05. Categorical data analyses were performed using Mann-Whitney tests. Continuous data analyses were performed using t-tests. The total number of prostate MRIs and the number of MRIs with subsequent biopsy respectively increased by 178% and 215% over a 5-year interval (2017-2022). There was a higher proportion of MRI studies with an associated biopsy given a PI-RADS score of ≥ 3 (91%) and a Gleason grade of ≥ 7 (61%) in 2022 than in 2017 (PI-RADS: 75%; Gleason: 28%). Increased utilization of prostate MRI has been associated with a higher proportion of biopsies with high PI-RADS and Gleason scores consistent with improved patient selection in this integrated health system.

The impact of mpMRI-targeted vs systematic biopsy on the risk of prostate cancer downgrading at final pathology.

Although targeted biopsies (TBx) are associated with improved disease assessment, concerns have been raised regarding the risk of prostate cancer (PCa) overgrading due to more accurate biopsy core deployment in the index lesion. We identified 1672 patients treated with radical prostatectomy (RP) with a positive mpMRI and ISUP ≥ 2 PCa detected via systematic biopsy (SBx) plus TBx. We compared downgrading rates at RP (ISUP 4-5, 3, and 2 at biopsy, to a lower ISUP) for PCa detected via SBx only (group 1), via TBx only (group 2), and eventually for PCa detected with the same ISUP 2-5 at both SBx and TBx (group 3), using multivariable logistic regression models (MVA). Overall, 12 vs 14 vs 6% (n = 176 vs 227 vs 96) downgrading rates were recorded in group 1 vs group 2 vs group 3, respectively (p < 0.001). At MVA, group 2 was more likely to be downgraded (OR 1.26, p = 0.04), as compared to group 1. Conversely, group 3 was less likely to be downgraded at RP (OR 0.42, p < 0.001). Downgrading rates are highest when PCa is present in TBx only and, especially when the highest grade PCa is diagnosed by TBx cores only. Conversely, downgrading rates are lowest when PCa is identified with the same ISUP through both SBx and TBx. The presence of clinically significant disease at SBx + TBx may indicate a more reliable assessment of the disease at the time of biopsy potentially reducing the risk of downgrading at final pathology.

Development of single-pin, un-barbed, pole-tagging of free-swimming dolphins and sharks with satellite-linked transmitters

BackgroundTo tag large marine vertebrates, without the need to catch them, avoiding using barbs for tag retention, and precisely controlling tag location, the remote Tag Attachment Device on a pole (TADpole) was developed. This allows single-pin tags (Finmount, Wildlife Computers) to be attached to the dorsal fins of free-swimming large marine vertebrates.ResultsTADpole comprises a pole-mounted holster that carries a tag. It uses compressed air, and a micro-controller, to rapidly insert a stainless-steel pin through a corrodible metal retaining ring in the first tag attachment wing, the animal’s dorsal fin, and then a press fit Delrin retaining ring in the tag wing on the other side of the fin. Tagging only occurs when the trailing edge of the dorsal fin touches a trigger bar in the holster, ensuring optimal pin placement. It was developed using fins from cadavers, then trialed on briefly restrained coastal dolphins that could be followed in successive days and weeks, and then on free-swimming animals in the field. The latter showed very short touch/response intervals and highlighted the need for several iterative revisions of the pneumatic system. This resulted in reducing the total time from triggering to tag application to ~ 20 ms. Subsequent efforts expanded the TADpole’s applicability to sharks. One free-swimming Atlantic spotted dolphin, two white sharks, and one whale shark were then tagged using the TADpole.ConclusionsBeing able to tag free-swimming dolphins and sharks remotely and precisely with satellite-linked telemetry devices may contribute to solving conservation challenges. Sharks were easier to tag than dolphins. Dolphin touch-to-response times were 28 ms or less. Delphinid skin has unique polymodal axon bundles that project into the epidermis, perhaps a factor in their uniquely fast response, which is 10 × faster than humans. Their primary reaction to tagging is to abduct the flippers and roll the fin out of the TADpole holster. This device has the potential to deliver high-quality tag data from large vertebrates with dorsal fins without the stress and logistics associated with catch-and-release, and without the trauma of tags that use barbs for retention. It also collects a dorsal fin biopsy core.

Is Fragmentation of Prostate Core Biopsies Inevitable? A Quality Improvement Initiative.

Core biopsies are standard of care for diagnosis and surveillance of prostate cancer. Fragmentation makes numeric assessment of cancer challenging and increases risk of inaccurate staging with direct implications on management. To determine factors responsible for fragmentation at our institution. Prostate core biopsies performed at 2 hospital sites during 1 week were prospectively identified. Biopsies were received in multipart formalin jars, either mounted on a nonadherent dressing pad (Telfa, Medtronic Inc) or freely suspended, and grossed by experienced pathologists' assistants. Fragmentation was defined as the difference between number of cores sent by the clinician and number of cores counted by the pathologist on microscopy. Forty-six cases (15 benign; 31 malignant) with 535 specimen jars were identified of which 309 of 535 (57.8%) had >1 biopsy core per jar; 230 of 535 (43%) were received mounted on Telfa and 185 of 535 (34.6%) had histologic evidence of adenocarcinoma. Overall fragmentation rate was 157 of 535 (29.3%). Lowest fragmentation rate was seen when 1 core was submitted per jar regardless of mounting method (31 of 226; 14% for single versus 126 of 309; 41% for >1 per jar; P < .001). For 1 Telfa-mounted core, rate of fragmentation was 5 of 18 (27.8%) versus 26 of 203 (12.8%) when unmounted (P = .24). Significant increase in fragmentation of Telfa-mounted cores was seen when there were 3 per jar (32 of 70; 46% mounted fragmented versus 9 of 47; 19% unmounted fragmented specimens; P = .01). Submission of >1 biopsy core per jar and use of Telfa for mounting are associated with increased fragmentation. We recommend limiting submission to 1 core per jar and avoid mounting on Telfa pads.

Discrepancies in Gleason score between needle core biopsy and radical prostatectomy specimens with correlation between clinical and pathological staging.

The studies have shown that GS given after assessment of the entire prostate gland on the radical prostatectomy specimen may differ from GS given after examination of a small sample from needle core biopsy. We conducted this study to assess discrepancies in the Gleason score between NCB and RP specimens and to find out the correlation between the clinical stage and pathological stage. The study included 174 patients with carcinoma prostate which underwent robotic-assisted radical prostatectomy (RARP). Pre-operative Gleason score was determined on 12-core biopsy samples under trans-rectal ultrasound (TRUS) guidance. The Gleason score obtained from the radical prostatectomy specimen was compared with that of the NCB Gleason score to find out differences. The preoperative Gleason score (GS) ranges from 6 to 9 with a mean GS of 6.97 ± 1.02. The post-operative GS ranges between 6 and 10 with mean and GS of 7.5 ± 1.10. On the pre-operative assessment of biopsy specimens, 70 (43.2%) patients had a GS of 6, while 44 patients had a GS of 7 (27.1%) and 48 (29.8%) patients had a GS of more than 7. On the postoperative assessment of specimens, 31 (19.1%) patients had post-operative GS of 6, while 66 (41%) patients had GS of 7 and 74 (41.1%) patients had GS of more than 7. When pre-operative GS and post-operative GS were compared, no changes were observed in the GS of 79 patients, whereas 83 patients showed the difference in GS, with 75 patients showing up-gradation and eight patients marked as down-graded. concordance between biopsy and the pathology results directly affects the prognosis of the patient. The results of our study demonstrated the rate of discordance between Gleason scores obtained from transrectal prostate biopsy and RP surgical specimens. This rate brings into question the accuracy of the chosen treatment.

Factors associated with pain sensation in patients with ultrasound-guided prostate biopsy.

TRUS-guided prostate biopsy is a current method used to obtain the histopathological material necessary to make a definitive diagnosis of prostate cancer. To investigate patient-related variables affecting the level of pain felt during prostate biopsy to determine what can be done to minimize pain. The study included 241 patients scheduled for prostate biopsy. Four patients who did not meet the criteria were excluded. Local anesthesia was administered intrarectally 10 minutes before the biopsy to 237 patients, and a conventional 12-core biopsy was performed. The level of pain felt by all patients during the biopsy was measured using the Visual Analog Scale (VAS) score. Pain scores were compared by forming groups according to the selected parameters. The mean age of the 237 included patients was 66.0±7.8 years, the mean serum PSA level was 33.7±197.5 ng/dL, and the mean prostate volume was 33.7±197.5 ml. The mean VAS score was 4.3±1.9. The pain score was higher in patients with positive digital rectal examination findings and lower in patients using 5-alpha reductase inhibitors(5-ARİ). At the same time, no significant difference was found in patients with positive tumor pathology, perineural invasion, alpha-blockers, or combination therapy. Some patient parameters may affect the level of pain felt during TRUS-guided prostate biopsy.

The Clinical Significance of Flat Epithelial Atypia on Core Biopsy: A Single Institution Experience

The clinical significance and management (surgical excision vs. follow-up) of the patients with the diagnosis of Flat Epithelial Atypia (FEA) on Core Needle Biopsy (CNB) varies between institutions, largely due to uncertainty of its biologic potential and its association with more advanced lesions. In this study, we attempted to determine the clinical significance of FEA on CNB based on the upgrade on subsequent excisions, using a single institution experience. Retrospective histopathologic review was performed on CNB with diagnosis of pure FEA for a period of 11 years (January 2010-December 2021) and subsequent excisions by using standardized criteria and precise terminology. Cases with co-existing Atypical Ductal Hyperplasia (ADH) or more advanced lesions (ductal carcinoma in-situ or invasive mammary carcinoma) within the same biopsy cores were excluded from the study. Cases with FEA on CNB without subsequent excisions were also excluded. Our results showed 26.7% upgraded cases of pure FEA to either ADH or in situ carcinoma on the subsequent excisions. Overall, therefore, our findings support surgical excision when FEA is diagnosed on CNB.

Open-Ended Coaxial Probe for Effective Reconstruction of Biopsy-Excised Tissues' Dielectric Properties.

Dielectric characterization is extremely promising in medical contexts because it offers insights into the electromagnetic properties of biological tissues for the diagnosis of tumor diseases. This study introduces a promising approach to improve accuracy in the dielectric characterization of millimeter-sized biopsies based on the use of a customized electromagnetic characterization system by adopting a coated open-ended coaxial probe. Our approach aims to accelerate biopsy analysis without sample manipulation. Through comprehensive numerical simulations and experiments, we evaluated the effectiveness of a metal-coating system in comparison to a dielectric coating with the aim for replicating a real scenario: the use of a needle biopsy core with the tissue inside. The numerical analyses highlighted a substantial improvement in the reconstruction of the dielectric properties, particularly in managing the electric field distribution and mitigating fringing field effects. Experimental validation using bovine liver samples revealed highly accurate measurements, particularly in the real part of the permittivity, showing errors lower than 1% compared to the existing literature data. These results represent a significant advancement for the dielectric characterization of biopsy specimens in a rapid, precise, and non-invasive manner. This study underscores the robustness and reliability of our innovative approach, demonstrating the convergence of numerical analyses and empirical validation.

Predictive model of positive surgical margins after radical prostatectomy based on Bayesian network analysis.

This study aimed to analyze the independent risk factors for marginal positivity after radical prostatectomy and to evaluate the clinical value of the predictive model based on Bayesian network analysis. We retrospectively analyzed the clinical data from 238 patients who had undergone radical prostatectomy, between June 2018 and May 2022. The general clinical data, prostate specific antigen (PSA)-derived indicators, puncture factors, and magnetic resonance imaging (MRI) characteristics were included as predictive variables, and univariate and multivariate analyses were conducted. We established a nomogram model based on the independent predictors and adopted BayesiaLab software to generate tree-augmented naive (TAN) and naive Bayesian models based on 15 predictor variables. Of the 238 patients included in the study, 103 exhibited positive surgical margins. Univariate analysis revealed that PSA density (PSAD) (P = 0.02), Gleason scores for biopsied tissue (P = 0.002) and the ratio of positive biopsy cores (P < 0.001), preoperative T staging (P < 0.001), and location of abnormal signals (P = 0.002) and the side of the abnormal signal (P = 0.009) were all statistically significant. The area under curve (AUC) of the established nomogram model based on independent predictors was 73.80%, the AUC of the naive Bayesian model based on 15 predictors was 82.71%, and the AUC of the TAN Bayesian model was 80.80%. The predictive model of positive resection margin after radical prostatectomy based on Bayesian network demonstrated high accuracy and usefulness.

High-resolution Diffusion-weighted Imaging to Detect Changes in Tumor Size and ADC, and Predict Adverse Biopsy Histology during Prostate Cancer Active Surveillance.

Majority of men with low-risk prostate cancer can be managed with active surveillance (AS). This study evaluates a high-resolution diffusion-weighted imaging (HR-DWI) technique to predict adverse biopsy histology (AH), defined as Gleason score ≥7 on any biopsy or ≥3 increase in number of positive biopsy cores on systematic biopsies. We test the hypothesis that high-grade disease and progressing disease undergo subtle changes during even short intervals that can be detected by HR-DWI. In a prospective clinical trial, serial multiparametric MRIs, incorporating HR-DWI and standard DWI (S-DWI) were performed approximately 12 months apart prior to prostate biopsy (n = 59). HR-DWI, which uses reduced field-of-view and motion compensation techniques, was compared with S-DWI. HR-DWI had a 3-fold improvement in spacial resolution compared with S-DWI as confirmed using imaging phantoms. For detecting AH, multiparametric MRI using HR-DWI had a sensitivity of 75% and specificity of 83.9%, and MRI using S-DWI had a sensitivity of 71.4% and specificity of 54.8%. The AUC for HR-DWI was significantly higher (0.794 vs. 0.631, P = 0.014). Secondary analyses of univariable predictors of AH showed tumor size increase [OR 16.8; 95% confidence interval (CI): 4.06-69.48; P < 0.001] and apparent diffusion coefficient (ADC) decrease (OR 5.06; 95% CI: 1.39-18.38; P = 0.014) on HR-DWI were significant predictors of AH. HR-DWI outperforms S-DWI in predicting AH. Patient with AH have tumors that change in size and ADC that could be detected using HR-DWI. Future studies with longer follow-up should assess HR-DWI for predicting disease progression during AS. We report on a prospective clinical trial using a MRI that has three times the resolution of standard MRI. During AS for prostate cancer, two high-resolution MRIs performed approximately a year apart can detect tumor changes that predict the presence of aggressive cancers that should be considered for curative therapy such as prostatectomy or radiation.

Abstract 935: Co-clinical endometrial cancer (EC) patient-derived organoids (PDO) to assess functional effects of replication stress (RS)-targeting agents

Abstract Background: EC is the most commonly diagnosed gynecologic cancer in the US and has both rising incidence and mortality. Uterine serous cancer (USC) and uterine carcinosarcoma (UCS) are high grade ECs characterized by TP53 mutation and molecular alterations suggesting high replication stress (RS) and cell cycle dysregulation. These molecular alterations could engender sensitivity to RS-targeting strategies such as WEE1 inhibition. In a single arm phase 2 of 35 patients, the WEE1 inhibitor adavosertib demonstrated clinical activity in recurrent USC, with an overall response rate of 29.4%. To support the development of predictive biomarkers of sensitivity to RS targeting agents, we report on the establishment of co-clinical EC PDOs from pre- and on-treatment biopsies from patients with USC or UCS enrolled to a translational trial of adavosertib. Methods: Patients with USC or UCS consented for trial participation underwent pre- and on-treatment biopsies while receiving adavosertib monotherapy. Biopsies were dissociated and passaged as 3D organoid cultures in Matrigel in an optimized media. Established PDOs were seeded in 3D microfluidic devices, treated with adavosertib in a dose-dependent manner and assessed for viability after 6 days of treatment by dual labeling live/dead imaging. IC50 values were calculated using log(inhibitor) vs response - variable slope (four parameters) model in GraphPad Prism. To assess the effect of adavosertib on replication fork speed, DNA fiber assays were conducted with PDOs treated with adavosertib for 72 hours. Finally, FFPE blocks were created from PDOs for assessment of DNA damage repair biomarkers by IHC. Results: 19 biopsies were obtained from 11 participating patients. 6 biopsies did not yield sufficient tumor cells for PDO generation. From the remaining 13 samples, 5 PDOs were successfully established (3 USC and 2 UCS), with a higher success rate when 3 biopsy cores were received (3 of 4; 75%) compared to when 2 biopsy cores were received (2 of 9; 22 %). Dual labeling live/dead imaging of PDOs treated with adavosertib resulted in IC50 values ranging from 113nM to 856nM. DNA fiber assays revealed consistent decrease in fork speed with adavosertib exposure, consistent with the hypothesized effect of adavosertib in increasing RS in these cells. A dose dependent effect on replication fork speed was observed, with greater decreases in fork speed with increasing concentrations of adavosertib. Due to the limited number of samples and the number of PDOs generated from on-treatment as opposed to pre-treatment biopsies, clinical correlation between PDO adavosertib sensitivity and clinical activity was not formally assessed. IHC analysis of potential DNA damage biomarkers is ongoing. Conclusions: We describe the successful establishment of co-clinical EC PDOs for functional evaluation of sensitivity to RS targeting agents. Citation Format: Elena Ivanova, Aisha L. Saldanha, Shrabasti Roychoudhury, Bose Kochupurakkal, Ari P. Zlota, Clare E. Padrick, Ha V. Vo, Eli K. Greenberg, Hannah Sawyer, Carina Feeney, Courtney H. Qi, Swati Narayan, Jennifer D. Curtis, Nabihah Tayob, Marisa R. Nucci, Panagiotis Konstantinopoulos, Dipanjan Chowdhury, Geoffrey Shapiro, Cloud P. Paweletz, Ursula A. Matulonis, Joyce F. Liu. Co-clinical endometrial cancer (EC) patient-derived organoids (PDO) to assess functional effects of replication stress (RS)-targeting agents [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 935.

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 &amp;gt;50% of prostate cancer (PCa) patients diagnosed with low-risk disease, where five-year survival rates are &amp;gt;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.

Prognostic utility of biopsy-based PTEN and ERG status on biochemical progression and overall survival after SBRT for localized prostate cancer.

Phosphatase and tensin homolog (PTEN) genomic deletions and transmembrane protease, serine 2/v-ets avian erthyroblastosis virus E26 oncogene homolog (ERG) rearrangements are two of the most common genetic abnormalities associated with prostate cancer. Prior studies have demonstrated these alterations portend worse clinical outcomes. Our objective is to evaluate the impact of biopsy-determined PTEN losses and TMPRSS2-ERG fusion on biochemical progression-free survival (bPFS) and overall survival (OS) in patients who receive SBRT for localized prostate cancer. Patients received SBRT for localized prostate cancer on a prospective quality-of-life (QoL) and cancer outcomes study. For each patient, the single biopsy core with the highest grade/volume of cancer was evaluated for PTEN and ERG abnormalities. Differences in baseline patient and disease characteristics between groups were analyzed using ANOVA for age and χ2 for categorical groupings. bPFS and OS were calculated using the Kaplan Meier (KM) method with Log-Rank test comparison between groups. Predictors of bPFS and OS were identified using the Cox proportional hazards method. For all analyses, p <0.05 was considered statistically significant. Ninety-nine consecutive patients were included in the analysis with a median follow-up of 72 months. A statistically significant improvement in bPFS (p = 0.018) was observed for wild type ERG patients with an estimated 5-year bPFS of 94.1% vs. 72.4%. Regarding PTEN mutational status, significant improvements in were observed in both bPFS (p = 0.006) and OS (p < 0.001), with estimated 5-year bPFS rates of 91.0% vs. 67.9% and 5-year OS rates of 96.4% vs. 79.4%. When including both ERG and PTEN mutational status in the analysis, there were statistically significant differences in both bPFS (p = 0.011) and OS (p < 0.001). The estimated 5-year bPFS rates were 100%, 76.6%, 72.9%, and 63.8% for patients with ERG+/PTEN+, ERG-/PTEN+, ERG+/PTEN-, and ERG-/PTEN- phenotypes respectively. The estimated 5-year OS rates were 93.9%, 100%, 80.0%, and 78.7% for patients with ERG+/PTEN+, ERG-/PTEN+, ERG+/PTEN-, and ERG-/PTEN- phenotypes respectively. ERG rearrangements and PTEN deletions detected on biopsy samples are associated with poorer oncologic outcomes in prostate cancer patients treated with SBRT and merit further study in a dedicated prospective trial.

Abstract 4200: A novel 3D culture platform, E-slice, retains intact tumor microenvironment and tumor infiltrating immune cells

Abstract Human cancer tissue is a complex ecosystem with heterogeneous cell types that communicate with each other dynamically to promote tumor progression and immune evasion. Hence, experimental systems that destroy or select for cancer cells in culture have often failed to accurately predict clinical responses of new drugs. Therefore, a technology that can retain the intact tumor microenvironment (TME) and accurately predict cancer patient’s response to anti-cancer treatments, including immunotherapies, will greatly benefit patients and dramatically reduce the cost of new drug development. E-slice is a proprietary 3D human tumor culture platform that maintains individual patient tumor’s unique ecosystem and the TME ex vivo for up to 30 days. It is generated by making thin sections of intact, fresh tumor tissues and culturing them in serum-free, defined media. As such, immune components and the TME in E-slices faithfully recapitulate human tumors ex vivo. We demonstrate that E-slices can be used to: 1) measure viability changes upon anti-cancer agent treatment longitudinally; 2) retain the native TME and tissue architecture since E-slices are never dissociated or artificially reconstituted; 3) culture any solid tumor types from patient needle biopsy cores or surgical samples, PDX, or mouse models; 4) perform high content drug screening on human tissues; 5) discover secreted biomarkers and to 6) discover or validate molecular mechanisms of action or therapy resistance; and 7) measure immunotherapy responses ex vivo from human tissues. Importantly, it has been shown to accurately predict individual patient treatment responses to chemotherapies and targeted therapies in 4-8 days, paving the way for evidence-based personalized treatment selections in a clinically actionable time frame. Furthermore, single cell RNA-sequencing analysis demonstrates that E-slices can retain the viability and molecular phenotypes of tumor infiltrating immune cells for up to 8 days ex vivo, providing a unique platform to study human tumor-immune interactions and evaluate efficacy of immune modulators on human tumor tissues ex vivo. Citation Format: Viridiana Leyva-Aranda, Thomas Gallup, Jose Maldonado, Corina Margain, Sang Yun, David Gallup, Min Kim, Kyuson Yun. A novel 3D culture platform, E-slice, retains intact tumor microenvironment and tumor infiltrating immune cells [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 4200.

O266: Transcriptomic signature from spatially inferred histologically benign ancestral clone predicts high risk prostate cancer

Abstract Introduction Prostate cancer (PCa) is a multifocal disease driven by heterogenous spatial and temporal branching evolution of tumour clones. Spatial transcriptomic analysis has revealed, clonally distributed copy number alterations even in histologically benign regions. We aim to evaluate if the genetic signature comprised within these genetically aberrant histologically benign regions, or “ancestral clones” may predict presence of high-risk disease. Methods Fresh-frozen, radical prostatectomy specimen was profiled using the 10x Genomics Visium Spatial Gene Expression platform. Via hierarchical clustering, spatial tumour clonal relations were inferred. Differentially expressed genes (DEGs) between high-grade tumour and histologically benign ancestral clones were identified. DEGs (|log2FC|&amp;gt;0.75) were input into a LASSO regression algorithm with normalised mRNA expression of normal adjacent tissue from the TCGA PCa database to train a genetic risk model to predict presence of high risk PCa (Gleason&amp;gt;8). Derived risk score was validated on an external cohort (GSE21032). Results A total of 683 DEGs were identified. These were enriched for organic acid metabolic pathways. Regression analysis on 57 normal adjacent tissue samples from TCGA PCa dataset was performed to develop a predictive model comprising of 3 genes (SLC22A3, CRIP2, LSAMP). External validation of the genetic risk score on matched histologically benign tissue from 131 patients, had good performance for prediction of high-risk PCa (AUC 0.807; 95% CI 0.693-0.921). Conclusion Our model has good performance for predicting high-risk PCa from matched normal tissue. Developed genetic risk score has translational potential to improve detection of unsampled clinically significant prostate cancer from histologically benign biopsy cores.

The impact of the relationship between lesion diameter and total core length on the detection rate of clinically significant prostate cancer for PI-RADS 3 lesions

BackgroundThe aim of our study was to determine the effect of total core length (TCL) for prostate imaging reporting and data system (PI-RADS) 3 lesions to facilitate clinically significant prostate cancer (csPCa) detection based on the lesion diameter.Materials and methodsA total of 149 patients with at least 1 lesion with a PI-RADS 3 were evaluated retrospectively. The lesions with diameters of < 1 cm were categorized as small lesions and lesions of ≥ 1 cm were categorized as large lesions. The lengths of biopsy cores from PI-RADS 3 lesions were summed for each lesion separately, and TCL was calculated. The relationship between TCL and csPCa was analyzed separately for the small and large groups with multiple logistic regression analyses.ResultsA total of 208 lesions were detected by multiparametric magnetic resonance imaging (MpMRI) in 149 males included in the study. The mean TCL was 44.68 mm (26–92) and the mean lesion diameter was 10.73 mm (4–27) in PIRADS 3 lesions. For small diameter lesions (< 1 cm), the odds of finding clinically insignificant prostate cancer (ciPCa) increase by 1.67 times if TCL increases by one unit. Hence, increasing TCL for small lesions only increases the odds of ciPCa detection. For large diameter lesions (≥ 1 cm), if TCL increases by one unit, the odds of finding ciPCa increase 1.13 times and the odds of finding csPCa increases1.16 times. Accordingly, large lesions are more likely to have both csPCa and ciPCa as TCL increases.ConclusionsOur study showed that for PI-RADS 3 lesions, both more csPCa and more ciPCa were detected as TCL increased. However, in lesions with a size of < 1 cm, only ciPCa was detected more frequently as TCL increased. In conclusion, taking more and longer biopsy cores in PI-RADS 3 lesions below 1 cm does not contribute to the detection of csPCa.