Biochemical Recurrence Post Radical Prostatectomy Research Articles

Abstract 3516: AI-derived features of 3D glandular networks are associated with likelihood of biochemical recurrence post radical prostatectomy

Abstract Introduction: Prostate cancer is the most common cancer in American men and is mainly diagnosed from two-dimensional histology sections. Recently, three-dimensional (3D) prostate histopathology has emerged as a valuable strategy to enhance the understanding of the disease by increasing microscopic sampling of specimens. This strategy enhances the microscopic examination of specimens by facilitating the analysis of the volumetric shape of cells and glands, as well as the pathway structures through entire biopsies and other morphological features. These aspects hold the potential to be linked with biochemical recurrence (BCR) outcomes. This study highlights the potential of features derived from the 3D structure of glands in samples of patients with prostate cancer for identifying patients who are at higher risk of BCR. Methods: Radical prostatectomy specimens were collected from 50 patients along with 5-year postoperative BCR follow-up from the University of Washington. A total of 118 ex vivo whole-biopsy 3D pathology images were obtained from RP by an open-top light-sheet microscopy platform. Images were converted into a synthetic CK8 immunofluorescence dataset using an image-sequence translation model. From these 3D images, a glandular structure mask was generated by a computer-vision algorithm. The 3D structure of prostate glands was modeled through a Tree-structure Extraction Algorithm for Accurate and Robust Skeletons (TEASER), which provides a simplification of the length of the gland, its shape, and its pathway. 91 features were then extracted from the glandular skeleton architecture. A 3-fold cross-validation approach was used in which patients were divided into training (D1) and test (D2) sets of 33 and 17 patients, respectively. Fisher’s score, used to select features based on their correlation to the outcome, was applied to D1 to identify the top 5 features most correlated with BCR. We then utilized these features to train a K-Nearest Neighbors classifier on D1, aimed at predicting whether a patient would experience BCR. The model’s performance was evaluated on D2 and averaged across all folds. Results: The classifier was able to accurately differentiate between BCR+ and BCR- patients, achieving an average ROCAUC of 0.73 (±0.04) in D2. Significant differences in 3D skeletal features were observed between BCR+ and BCR- groups (p<0.05). Among the five selected features, three were related to the length and diameter of the gland, with the longest glands observed in BCR- patients. The remaining two features pertained to gland curvature and tortuosity, revealing more twisted glands in BCR+ patients. Conclusion: Features derived from a skeleton model of the 3D glandular structure of biopsies showed promise in identifying patients with prostate cancer who are at a higher risk of BCR. Additional, multi-site independent validation of these findings is warranted. Citation Format: Jennifer Salguero, Hisham Abdeltawab, Kamal Hammouda, German Corredor, Sarah Hawley, Pushkar Mutha, Rohan Dhamdhere, Sebastian Medina, Tilak Pathak, Kevin Bishop, Rob Serafin, Tuomas Mirtti, Priti Lal, Lawrence True, Jonathan Liu, Anant Madabhushi. AI-derived features of 3D glandular networks are associated with likelihood of biochemical recurrence post radical prostatectomy [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 3516.

Redefining 18F DCFPyl PSMA-PET detected local recurrence from radical prostatectomy histopathology.

18F-DCFPyL PET localises tumour recurrence in patients with biochemical recurrence post-radical prostatectomy. Correlations exist between disease recurrence and poor histopathological parameters such as the presence of extra prostatic extension (EPE) and positive surgical margins. We aim to assess topographic concordance between these histopathological features and the location of the PSMA PET local recurrences, qualitatively and quantitatively. Our cohort was selected from the 100 men who received a 18F-DCFPyL PET scan through IMPPORT trial, a prospective non-randomised study completed by GenesisCare Victoria. Eligibility included patients with a rising PSA (>0.2 ng/mL) post radical prostatectomy and PSMA PET detected local recurrence. Histopathological parameters collated included the location of tumour, EPE and positive margins. Criteria for the location and 'concordance' between histopathological features and local recurrences were predefined. 24 patients were eligible, median age was 71 years old, median PSA 0.37ng/ml and time between prostatectomy and PSMA PET was 2.6 years. 15 patients had recurrences within the vesicourethral anastomotic region and 9 within the lateral surgical margins. 100% concordance in the left to right plane between tumour location and local recurrence was found, with 79% of these lesions concordant three-dimensionally; across cranio-caudal, left-right and anterior-posterior planes. 10/16 (63%) patients' with EPE and 5/9 (55.5%) of patients' with positive margins had three-dimensional concordance between their pathology and their local recurrence. In quantitative assessment, 17 of the 24 patients, had local recurrences that correlated with the location of their original tumour in the cranio-caudal plane. Local recurrence is highly concordant with the position of the tumour within the prostate. Predicting the location of local recurrence using the location of the EPE and positive margins is less helpful. Further investigation into this field, could impact surgical technique and salvage radiotherapy clinical target volume.

Prostate Surface Distension and Tumor Texture Descriptors From Pre-Treatment MRI Are Associated With Biochemical Recurrence Following Radical Prostatectomy: Preliminary Findings.

ObjectiveTo derive and evaluate the association of prostate shape distension descriptors from T2-weighted MRI (T2WI) with prostate cancer (PCa) biochemical recurrence (BCR) post-radical prostatectomy (RP) independently and in conjunction with texture radiomics of PCa.MethodsThis retrospective study comprised 133 PCa patients from two institutions who underwent 3T-MRI prior to RP and were followed up with PSA measurements for ≥3 years. A 3D shape atlas-based approach was adopted to derive prostate shape distension descriptors from T2WI, and these descriptors were used to train a random forest classifier (CS ) to predict BCR. Texture radiomics was derived within PCa regions of interest from T2WI and ADC maps, and another machine learning classifier (CR ) was trained for BCR. An integrated classifier CS +R was then trained using predictions from CS and CR . These models were trained on D1 (N = 71, 27 BCR+) and evaluated on independent hold-out set D2 (N = 62, 12 BCR+). CS +R was compared against pre-RP, post-RP clinical variables, and extant nomograms for BCR-free survival (bFS) at 3 years.ResultsCS +R resulted in a higher AUC (0.75) compared to CR (0.70, p = 0.04) and CS (0.69, p = 0.01) on D2 in predicting BCR. On univariable analysis, CS +R achieved a higher hazard ratio (2.89, 95% CI 0.35–12.81, p < 0.01) compared to other pre-RP clinical variables for bFS. CS +R , pathologic Gleason grade, extraprostatic extension, and positive surgical margins were associated with bFS (p < 0.05). CS +R resulted in a higher C-index (0.76 ± 0.06) compared to CAPRA (0.69 ± 0.09, p < 0.01) and Decipher risk (0.59 ± 0.06, p < 0.01); however, it was comparable to post-RP CAPRA-S (0.75 ± 0.02, p = 0.07).ConclusionsRadiomic shape descriptors quantifying prostate surface distension complement texture radiomics of prostate cancer on MRI and result in an improved association with biochemical recurrence post-radical prostatectomy.

Outcomes of Salvage Lymph Node Dissection in Oligorecurrent Prostate Cancer Post Radical Prostatectomy: Experience of an Oncologic Center in Spain

Introduction and ObjectivesWe report our experience with salvage lymph node dissection (sLND) in oligorecurrent prostate cancer (PCa) post radical prostatectomy (RP).Material and MethodsWe retrospectively analyzed data of 24 patients who underwent sLND for biochemical recurrence (BCR) post RP, from July 2012 to February 2018. sLND was performed following an extended bilateral template. Clinical and pathological characteristics of primary RP and sLND were reported. Biochemical response and initiation of additional therapy post sLND were analyzed. Survival analysis was performed using KaplanMeier curves.Results24 sLND were performed. RP specimens showed 58.3% of Gleason score 7 and 50% of locally advanced disease. Median time to BCR post RP was 24 months with a median PSA value of 1.4 ng/ml pre sLND. 75% of patients underwent imaging prior to sLND. sLND showed oligometastasis on the final pathology report in 54.2% of patients. Metastatic lymph nodes were mainly identified in the iliac artery territory (61.5%). Complete biochemical response (PSA &amp;lt; 0.2 ng/ml) was maintained throughout the first 12 months of follow-up in 20.83% of patients and 8.33% of patients at the end of the study (median follow-up 70 months). Survival rates free of additional therapy (ADT/RT) were 45.83% at one year and 25% at 5 years.ConclusionsWe observed a biochemical response post sLND in 20.83% of our patients, lasting throughout the first year of follow up, with survival rates free of ADT and/or RT of 45.83% at one year and 25% at 5 years.

New Histopathological & Genetic Features to Improve Active Surveillance Selection for Low-Risk Prostate Cancer.

A recent surge in biomarkers to aid management of men with prostate cancer has occurred. Their applications are varied and not all tests are applicable to the active surveillance setting. To review primary evidence on genetic and immunohistochemical biomarkers, and their role on patient selection and risk stratification for men on active surveillance for prostate cancer. A PubMed electronic search using the terms (biomarker or genetic or histopathological) AND ("prostate cancer" AND "active surveillance") was performed from inception to April 2015. Of the biomarkers reviewed, Prostate Health Index (PHI) and Oncotype DX Genomic Prostate Score (GPS), were identified to currently hold greatest potential benefit to aid risk stratification of men for AS. Higher PHI, at baseline and during follow-up, was shown to predict pathological upgrading at rebiopsy at two single institutions, but with small cohorts (n<200). The Oncotype DX GPS test has been validated on men suitable for AS but having upfront radical prostatectomy. Increase in GPS was shown to predict upgrading and upstaging at radical prostatectomy and biochemical recurrence post radical prostatectomy. Prospective validation in AS cohorts is yet to be performed. PHI and Oncotype DX GPS show promise in aiding risk stratification for men on AS. However, larger prospective studies in AS cohorts are needed. Integration of biomarkers with existing clinical and imaging models remains a challenge.

SPINK1 Overexpression in Localized Prostate Cancer: a Rare Event Inversely Associated with ERG Expression and Exclusive of Homozygous PTEN Deletion.

SPINK1 is proposed as potential prognostic marker in prostate cancer (PCA). However, its relation to PTEN and ERG in localized PCA remains unclear. The study population consisted of two independent cohorts of men treated by radical prostatectomy for localized PCA (discovery n=218 and validation n=129). Patterns of association between SPINK1 and each of ERG and PTEN were evaluated by immunohistochemistry and fluorescence in situ hybridization. Associations between SPINK1 expression and various pathologic parameters and clinical outcome were also investigated. SPINK1 was expressed in 15.3% and 10.9% of cases in the discovery and validation cohort, respectively. SPINK expression was observed in 5.56% of high-grade prostatic intraepithelial neoplasia and 1.1% of adjacent morphologically benign prostatic glands. SPINK1 and ERG expression were almost exclusive, with only 1.0% of the cases co-expressing both in the same core sample. SPINK1 interfocal and within-core heterogeneity was noted in 29.2% and 64.6% of cases, respectively. SPINK1 expression was not significantly associated with PTEN deletion in the two cohorts (p=0.871 for discovery cohort and p=0.293 for validation cohort). While SPINK1 expression did occur with hemizygous PTEN deletion, there was a complete absence of SPINK1 expression in PCA showing homozygous PTEN deletion, which was confirmed in the validation cohort (p=0.02). Despite SPINK1's association with higher Gleason score (>7) (p=0.02), it was not associated with other pathological parameters or biochemical recurrence post-radical prostatectomy. We documented absolute exclusivity between SPINK1 overexpression and homozygous PTEN deletion in localized PCA. SPINK1 and ERG expressions are exclusive events in PCA. SPINK1 is not of added prognostic value in localized PCA.

Biochemical recurrence rates are similar for pT2-positive surgical margins and pT3a.

Histological details of positive surgical margins in radical prostatectomy specimens have been related to outcome after surgery in rare studies recently published. Our objective is to assess whether the status of surgical margins, the extent and the Gleason score of positive margins, and the extent of the extraprostatic extension are predictive of biochemical recurrence post-radical prostatectomy. Three hundred sixty-five radical prostatectomy specimens were analyzed. The length of the positive surgical margin and extraprostatic extension and the Gleason score of the margin were recorded. Statistical analyses examined the predictive value of these variables for biochemical recurrence. 236 patients were stage pT2R0, 58 pT2R1, 25 pT3R0 and 46 pT3R1. Biochemical recurrence occurred in 11%, 31%, 20% and 45.7% of pT2R0, pT2R1, pT3R0 and pT3R1, respectively. The extent of the positive surgical margins and the Gleason score of the positive surgical margins were not associated with biochemical recurrence in univariate analysis in a mean follow up period of 35.9 months. In multivariate analyses, only the status of the surgical margins and the global Gleason score were associated with biochemical recurrence, with a risk of recurrence of 3.1 for positive surgical margins and of 3.8 for a Gleason score > 7. Positive surgical margin and the global Gleason score are significant risk factors for biochemical recurrence post-radical prostatectomy, regardless of the extent of the surgical margin, the extent of the extraprostatic extension, or the local Gleason score of the positive surgical margin or extraprostatic tissue. pT2R1 disease behaves as pT3R0 and should be treated similarly.

Validation of a Genomic Classifier That Predicts Metastatic Disease Progression in Men With Biochemical Recurrence Post-Radical Prostatectomy

Validation of a Genomic Classifier That Predicts Metastatic Disease Progression in Men With Biochemical Recurrence Post-Radical Prostatectomy

Validation of a genomic classifier that predicts metastatic disease progression in men with biochemical recurrence post radical prostatectomy.

5033 Background: Almost 50,000 men per year will present with biochemical recurrence (BCR) following local treatment for prostate cancer. These men with rising PSAs as the lone indicator of recurrence present a management dilemma due to their varied outcomes with only a proportion developing subsequent metastatic disease. Thus, there is a clear need to improve patient risk stratification in this context. Here, we evaluate Decipher, a genomic classifier (GC) in men with BCR following radical prostatectomy (RP) for its ability to predict metastasis. Methods: The 22-marker GC was validated in a prospectively designed case-cohort study of 1,010 clinically high-risk RP patients. 219 patients, including 85 who developed BCR at least 6 months post-RP were subjected to microarray analysis and GC scores were generated. Survival ROC curves, weighted Cox proportional hazards, and decision curves were used to compare the performance of the GC to Gleason score (GS), PSA doubling time (PSAdT) and time to BCR (ttBCR). Results: GC scores significantly stratified these men into those who would or would not develop metastasis after BCR (8% versus 40% of patients developed metastasis at 3 years following BCR depending on GC score category, p&lt;0.001). The AUC for GC was 0.82 (95% CI, 0.76-0.86), compared to that of GS 0.64 (0.58-0.70), PSAdT 0.69 (0.61-0.77) and ttBCR 0.52 (0.46-0.59). In decision curve analysis, the GC had the highest overall ‘net benefit’ and in multivariable modeling with clinicopathologic variables, only GC (p=0.006) and GS (p=0.046) scores were significant predictors of metastasis. Conclusions: When compared to clinicopathologic variables, the GC better predicted metastatic progression among men with BCR following RP. While confirmatory studies in additional patient populations are required, these results suggest that use of the GC can allow for better selection of men requiring additional treatment at the time of BCR.

Validation of a genomic classifier that predicts metastatic disease progression in men with biochemical recurrence post radical prostatectomy.

52 Background: The majority of the 29,000 men who die annually from prostate cancer present initially with localized disease and develop biochemical recurrence (BCR) following radical prostatectomy (RP). While the post-RP recurrence group of patients is highly enriched for those who will develop lethal disease, many of these patients will experience BCR without subsequent metastases. Thus, there is a clear need to improve patient risk stratification in this context. Here, we evaluate Decipher, a genomic classifier (GC) in men with BCR for its ability to predict metastasis. Methods: The 22-feature GC model was validated in a prospectively designed case-cohort study of a clinically high-risk population of 1,010 RP patients treated at Mayo Clinic between 2000-06. A random sample of 20% of this population was subjected to microarray analysis and GC scores were generated for 219 patients, including 110 who developed BCR post RP. The c-index for predicting metastatic disease progression (i.e., positive bone or CT scans), Cox modeling, decision curves and multivariable analyses were used to compare the performance of GC to Gleason score (GS), PSA doubling time (PSAdT) and time to BCR (ttBCR). Results: The c-index for predicting metastatic disease progression 3 years after BCR was 0.82 (95% CI, 0.80-0.90) for GC, which compared favorably to GS 0.65 (0.54-0.69), PSAdT 0.60 (0.62-0.78) and ttBCR 0.54 (0.64-0.81). Decision curve analysis showed that GC had a higher overall ‘net benefit’ compared to GS, PSAdT and ttBCR for risk of metastasis. Cumulative incidence of metastasis 3 years after BCR was 9% versus 43% (p&lt;0.001) for patients with low and high GC scores, respectively. In multivariable modeling with clinicopathologic variables, GC (p&lt;0.001) and GS (p=0.02) scores remained the only significant predictors of metastasis. Conclusions: When compared to clinicopathologic variables, GC better predicted metastatic progression among our cohort of men with BCR following RP. While confirmatory studies in additional patient populations are required, these results suggest that use of GC can allow for better selection of men requiring additional treatment at the time of BCR.

Upgrade in Gleason score between prostate biopsies and pathology following radical prostatectomy significantly impacts upon the risk of biochemical recurrence

•To determine the effect of an upgrade in Gleason score between initial prostate biopsy and final prostatectomy specimen on the risk of postoperative biochemical recurrence. •A total of 1629 patients with paired biopsy and radical prostatectomy histology were identified from two prospectively recorded prostate cancer databases. •Information on key clinical and pathological characteristics as well as prostate-specific antigen follow-up was recorded. •Patients who experienced an upgrade in their Gleason score were compared with corresponding patients with concordant tumours of the lower and higher grade. •Kaplan-Meier curves and multivariate models were generated to examine the impact of Gleason score upgrade on the risk of postoperative biochemical recurrence. •Overall, 466 patients (28.6%) experienced an upgrade in their Gleason score post radical prostatectomy, in 88.4% of cases involving a change in a single Gleason score point. •Patients upgraded from Gleason 6 (3 + 3) to Gleason 7 (3 + 4) had pathological characteristics that were very similar to Gleason 7 (3 + 4) concordant tumours, with an identical risk of biochemical recurrence. In contrast, patients upgraded from Gleason score 6 (3 + 3) to Gleason 7 (4 + 3) had tumours with pathological characteristics intermediate between the two concordant groups, which was mirrored by their risk of biochemical recurrence. •Patients with Gleason 7 tumours who experienced a change in the predominant pattern from 3 + 4 to 4 + 3 had tumours that resembled Gleason 7 (4 + 3) concordant tumours, with a similar risk of biochemical recurrence. In contrast, patients upgraded from Gleason 7 to Gleason >7 had tumours with intermediate pathological characteristics, and a risk of biochemical recurrence that was significantly different to concordant tumours of the lower and higher grade. •In multivariate models, a change in Gleason score was an independent predictor of biochemical recurrence in the preoperative setting only. •Although a difference in Gleason score was an independent predictor of recurrence in concordant tumours in models based on postoperative variables, an upgrade in Gleason score in discordant tumours was not, with differences in co-segregated adverse pathological characteristics being more predictive. •Patients experiencing an upgrade in their Gleason score between biopsy and final specimen exhibit significantly more aggressive pathological features than corresponding concordant tumours, and a higher risk of biochemical recurrence post radical prostatectomy. •As Gleason score can be more accurately assessed preoperatively than other prognostic tumour features, continued effort is required to identify those most at risk of upgrading, and to refine biopsy strategies to reduce sampling error.