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To develop and validate a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer by quantifying the host response to tumor. We use digital image analysis and machine learning to develop a biomarker of the prostate stroma called quantitative reactive stroma (qRS). qRS is a measure of percentage tumor area with a distinct, reactive stromal architecture. Kaplan Meier analysis was used to determine survival in a large retrospective cohort of radical prostatectomy samples. qRS was validated in two additional, distinct cohorts that include international cases and tissue from both radical prostatectomy and biopsy specimens. In the developmental cohort (Baylor College of Medicine, n = 482), patients whose tumor had qRS > 34% had increased risk of prostate cancer-specific death (HR 2.94; p = 0.039). This result was replicated in two validation cohorts, where patients with qRS > 34% had increased risk of prostate cancer-specific death (MEDVAMC; n = 332; HR 2.64; p = 0.02) and also biochemical recurrence (Canary; n = 988; HR 1.51; p = 0.001). By multivariate analysis, these associations were shown to hold independent predictive value when compared to currently used clinicopathologic factors including Gleason score and PSA. qRS is a new, validated biomarker that predicts prostate cancer death and biochemical recurrence across three distinct cohorts. It measures host-response rather than tumor-based characteristics, and provides information not represented by standard prognostic measurements., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Loss of the phosphatase and tensin homolog (PTEN) tumor suppressor gene is a promising marker of aggressive prostate cancer. Active surveillance and watchful waiting are increasingly recommended to patients with small tumors felt to be low risk, highlighting the difficulties of Gleason scoring in this setting. There is an urgent need for predictive biomarkers that can be rapidly deployed to aid in clinical decision-making. Our objectives were to assess the incidence and ability of PTEN alterations to predict aggressive disease in a multicenter study., Methods: We used recently developed probes optimized for sensitivity and specificity in a four-color FISH deletion assay to study the Canary Retrospective multicenter Prostate Cancer Tissue Microarray (TMA). This TMA was constructed specifically for biomarker validation from radical prostatectomy specimens, and is accompanied by detailed clinical information with long-term follow-up., Results: In 612 prostate cancers, the overall rate of PTEN deletion was 112 (18.3%). Hemizygous PTEN losses were present in 55/612 (9.0%) of cancers, whereas homozygous PTEN deletion was observed in 57/612 (9.3%) of tumors. Significant associations were found between PTEN status and pathologic stage (P < 0.0001), seminal vesicle invasion (P = 0.0008), extracapsular extension (P < 0.0001), and Gleason score (P = 0.0002). In logistic regression analysis of clinical and pathological variables, PTEN deletion was significantly associated with extracapsular extension, seminal vesicle involvement, and higher Gleason score. In the 406 patients in which clinical information was available, PTEN homozygous (P = 0.009) deletion was associated with worse post-operative recurrence-free survival (number of events = 189), pre-operative prostate specific antigen (PSA) (P < 0.001), and pathologic stage (P = 0.03)., Conclusion: PTEN status assessed by FISH is an independent predictor for recurrence-free survival in multivariate models, as were seminal vesicle invasion, extracapsular extension, and Gleason score, and preoperative PSA. Furthermore, these data demonstrate that the assay can be readily introduced at first diagnosis in a cost effective manner analogous to the use of FISH for analysis of HER2/neu status in breast cancer. Combined with published research beginning 17 years ago, both the data and tools now exist to implement a PTEN assay in the clinic., (© 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.)

Purpose: Prostate cancer is detected with increasing frequency but has a highly variable natural history and prognosis and active surveillance of men with low-risk prostate cancer would benefit greatly from minimally invasive methods to identify progression. We describe here two novel in vivo metrics of cell proliferation in men with prostate neoplasia., Experimental Design: Three groups of men drank heavy water, a nonradioactive, stable isotopic tracer for 14 to 28 days: (i) healthy men, (ii) men scheduled for transrectal core needle biopsy, and (iii) men scheduled for radical prostatectomy. Prostate epithelial cells (PEC) were isolated from ejaculated seminal fluid in all subjects. Histologically graded lesions were microdissected from tissue slides obtained from subjects undergoing surgery and proliferation rates were measured from isolated cells via mass spectrometry., Results: Proliferation rates of seminal PEC in healthy men (0.10%-0.27%/d) were stable on repeat sampling. Rates above 0.34%/d were seen only in patients with cancer where rates increased progressively from normal tissue through benign prostate hyperplasia, prostate intraepithelial neoplasia, and tumor grades III and IV in all subjects. Seminal PEC kinetics correlated highly with the most proliferative microdissected region in each subject (r(2) = 0.94)., Conclusions: Prostate cell proliferation can be measured in vivo from microdissected histopathology sections or noninvasively from seminal fluid where the latter reflects the most proliferative region of the gland. This approach may allow monitoring of progression in men with low-risk prostate cancer., (©2012 AACR.)

Epidemiological and prospective studies indicate that comprehensive lifestyle changes may modify the progression of prostate cancer. However, the molecular mechanisms by which improvements in diet and lifestyle might affect the prostate microenvironment are poorly understood. We conducted a pilot study to examine changes in prostate gene expression in a unique population of men with low-risk prostate cancer who declined immediate surgery, hormonal therapy, or radiation and participated in an intensive nutrition and lifestyle intervention while undergoing careful surveillance for tumor progression. Consistent with previous studies, significant improvements in weight, abdominal obesity, blood pressure, and lipid profile were observed (all P < 0.05), and surveillance of low-risk patients was safe. Gene expression profiles were obtained from 30 participants, pairing RNA samples from control prostate needle biopsy taken before intervention to RNA from the same patient's 3-month postintervention biopsy. Quantitative real-time PCR was used to validate array observations for selected transcripts. Two-class paired analysis of global gene expression using significance analysis of microarrays detected 48 up-regulated and 453 down-regulated transcripts after the intervention. Pathway analysis identified significant modulation of biological processes that have critical roles in tumorigenesis, including protein metabolism and modification, intracellular protein traffic, and protein phosphorylation (all P < 0.05). Intensive nutrition and lifestyle changes may modulate gene expression in the prostate. Understanding the prostate molecular response to comprehensive lifestyle changes may strengthen efforts to develop effective prevention and treatment. Larger clinical trials are warranted to confirm the results of this pilot study.

To develop and validate a new tissue-based biomarker that improves prediction of outcomes in localized prostate cancer by quantifying the host response to tumor. We use digital image analysis and machine learning to develop a biomarker of the prostate stroma called quantitative reactive stroma (qRS). qRS is a measure of percentage tumor area with a distinct, reactive stromal architecture. Kaplan Meier analysis was used to determine survival in a large retrospective cohort of radical prostatectomy samples. qRS was validated in two additional, distinct cohorts that include international cases and tissue from both radical prostatectomy and biopsy specimens. In the developmental cohort (Baylor College of Medicine, n = 482), patients whose tumor had qRS > 34% had increased risk of prostate cancer-specific death (HR 2.94; p = 0.039). This result was replicated in two validation cohorts, where patients with qRS > 34% had increased risk of prostate cancer-specific death (MEDVAMC; n = 332; HR 2.64; p = 0.02) and also biochemical recurrence (Canary; n = 988; HR 1.51; p = 0.001). By multivariate analysis, these associations were shown to hold independent predictive value when compared to currently used clinicopathologic factors including Gleason score and PSA. qRS is a new, validated biomarker that predicts prostate cancer death and biochemical recurrence across three distinct cohorts. It measures host-response rather than tumor-based characteristics, and provides information not represented by standard prognostic measurements.

Aims: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. Methods and results: Two separate non‐overlapping cohorts were identified: a 419‐patient post‐radical prostatectomy cohort with long term clinical follow‐up and a 209‐patient post‐radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re‐reviewed for high‐risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord‐like growth. For the outcome cohort, Kaplan–Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post‐prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post‐prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. Conclusions: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post‐prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation. [ABSTRACT FROM AUTHOR]

In human prostate cancer, the microRNA biogenesis machinery increases with prostate cancer progression. Here, we show that deletion of the Dgcr8 gene, a critical component of this complex, inhibits tumor progression in a Pten-knockout mouse model of prostate cancer. Early stages of tumor development were unaffected, but progression to advanced prostatic intraepithelial neoplasia was severely inhibited. Dgcr8 loss blocked Pten null-induced expansion of the basal-like, but not luminal, cellular compartment. Furthermore, while late-stage Pten knockout tumors exhibit decreased senescence-associated beta-galactosidase activity and increased proliferation, the simultaneous deletion of Dgcr8 blocked these changes resulting in levels similar to wild type. Sequencing of small RNAs in isolated epithelial cells uncovered numerous miRNA changes associated with PTEN loss. Consistent with a Pten-Dgcr8 association, analysis of a large cohort of human prostate tumors shows a strong correlation between Akt activation and increased Dgcr8 mRNA levels. Together, these findings uncover a critical role for microRNAs in enhancing proliferation and enabling the expansion of the basal cell compartment associated with tumor progression following Pten loss.

PurposeWe assessed whether an association exists between a change in prostate specific antigen and biopsy progression in men on active surveillance.Materials and methodsA cohort of patients undergoing active surveillance for prostate cancer was identified from the urological oncology database at our institution. Multivariate logistic regression was performed to determine whether prostate specific antigen velocity, defined as the change in ln(prostate specific antigen) per year, is associated with biopsy progression, defined as a Gleason upgrade or volume progression on repeat biopsy within 24 months of diagnosis.ResultsA total of 241 men with a mean ± SD age of 61 ± 7 years and mean prostate specific antigen 4.9 ± 2.2 ng/ml met study inclusion criteria. Median time to repeat biopsy was 10 months (IQR 6-13). Biopsy progression developed in 55 men (23%), including a Gleason score upgrade in 46 (19%), greater than 33% positive cores in 11 (5%) and greater than 50% maximum single core positive in 12 (5%). The median prostate specific antigen ratio per year was 1.0 (IQR 0.95-1.03), although 1 man had a ratio of greater than 1.26 (doubled over 3 years) and 7 had a ratio of less than 1/1.26 (halved over 3 years). On multivariate analysis prostate specific antigen doubling within 3 years was associated with a 1.4-fold increase in the odds of biopsy progression (OR 1.4, 95% CI 0.6-3.4, p = 0.46).ConclusionsThere is little change in prostate specific antigen during the first 24 months of surveillance in men with well staged, low risk prostate cancer. We believe that these findings highlight the importance of repeat biopsy during surveillance.

Purpose: We evaluated the reproducibility of Gleason grading as relevant to the clinical treatment of men on active surveillance. Materials and Methods: Three sets of digital images of prostatic adenocarcinoma in biopsies were reviewed and assigned Gleason scores by a total of 11 pathologists from 7 institutions. Interobserver and intra-observer reproducibility were assessed for assignment of the highest Gleason pattern (3 vs 4 or higher). We also identified 97 consecutive patients on active surveillance. Prostate biopsy glass slides from 82 of the patients were available for re-review and the frequency of carcinoma requiring the distinction of tangentially sectioned Gleason pattern 3 from 4 was determined. Results: Interobserver reproducibility for classic Gleason patterns was substantial (Light''s κ 0.76). Interobserver reproducibility for the histological distinction of tangentially sectioned Gleason pattern 3 from Gleason pattern 4 was only fair (Light''s κ 0.27). Intra-observer reproducibility ranged from 65% to 100% (mean 81.5%). Of the 82 patients on active surveillance 61 had carcinoma and 15 (24.5%) had a set of biopsies with at least 1 focus in which the distinction between tangentially sectioned Gleason pattern 3 and poorly formed pattern 4 glands had to be considered. Conclusions: The reproducibility of grading classic Gleason patterns is high. However, variability in grading occurred when distinguishing between tangentially sectioned pattern 3 glands and the poorly formed gland subset of pattern 4. Developing universally accepted histological and/or molecular criteria to distinguish these patterns and subsequently characterizing their natural history would be useful when treating patients on active surveillance. [Copyright &y& Elsevier]