805: High-Level Cyclin D1 is Associated with High Gleason Grade and Predicts Worse Biochemical-Free Survival in Prostate Cancer

Introduction: We determined (1) the 10-year survival outcomes after radical treatment of prostate cancer and (2) the 10-year eventfree survival following radical prostatectomy (RP) at a populationlevel in British Columbia (BC), Canada.Methods: We identified all men with a new diagnosis of prostate cancer in BC between 1999 and 2000. Those treated with RP, external beam radiotherapy (EBRT) or brachytherapy (BT) were identified. Overall survival, and prostate cancer specific survival (PCSS) were calculated from diagnosis using the Kaplan-Meier method. For those men treated with RP, we calculated the 10-year event-free survival (freedom from salvage EBRT or androgen ablation, or death from prostate cancer). Reasons for initiating androgen therapy were unknown and may include symptomatic metastatic disease or asymptomatic biochemical recurrence. An important limitation was the absence of prostate-specific antigen data for staging or follow-up.Results: Among 6028 incident cases, RP was the curative-intent treatment within 1 year in 1360 (22.6%) patients, EBRT in 1367 (22.7%), and BT in 357 (5.9%). The 10-year PCSS was 98% for RP, 95% for EBRT and 98% for BT (log rank p < 0.0001). The 10-year overall survival was 87%. The 10-year event-free survival for those treated with RP was 79% and varied with Gleason grade: 87%, 74%, and 52% for Gleason 2–6, 7, and 8-10, respectively (p < 0.0001).Conclusions: This population-based study provides outcomes which can inform patient decision-making and provide a benchmark to which other therapies can be compared. Event-free rates for patients treated with RP vary with Gleason score. There is room for improvement in the outcomes of patients with high Gleason score treated with RP.

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Copy number profiles of primary tumors for risk stratification of advanced prostate cancer: A biomarker study embedded in the multicenter STAMPEDE trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5021 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5021-5021

Author(s):

Emily Grist ◽

Marina Parry ◽

Stefanie Friedrich ◽

Christopher D. Brawley ◽

Larissa Mendes ◽

...

Keyword(s):

Prostate Cancer ◽

Copy Number ◽

Clinical Utility ◽

Disease Burden ◽

Progression Free Survival ◽

Continuous Measure ◽

Gleason Grade ◽

Treatment Intensification ◽

Primary Tumors ◽

Free Survival

5021 Background: Men with advanced hormone-sensitive prostate cancer (HSPC) starting long term androgen deprivation therapy (ADT) follow a highly variable clinical course. Treatment intensification with docetaxel or AR targeted therapies improves outcomes but there is a risk of overtreatment, especially in non-metastatic (M0) or metastatic (M1) low volume disease. We established a framework for biomarker evaluation in the STAMPEDE trial. We aimed to evaluate the feasibility and clinical utility of assessing the burden of copy number (CN) aberrations in newly diagnosed advanced HSPC. We hypothesised that increased percentage genome altered (PGA) would associate with higher disease burden and worse prognosis. Methods: We implemented a scalable strategy using low coverage whole genome sequencing (lpWGS) of formalin fixed paraffin embedded (FFPE) diagnostic core biopsies from STAMPEDE participants randomised to the standard of care ADT arm, between 2005 and 2016. Tissue was retrieved from 136 trial sites. 315 cases were randomly selected, aiming for a biomarker population of 300, anticipating an assay failure rate ̃5%. We defined 40% as the minimum histopathologically determined tumor cellularity (TC) for inclusion. We performed a survival analysis investigating PGA at diagnosis as a continuous measure with fractional polynomial specification in Cox models adjusting for disease burden, Gleason grade, pre-ADT PSA (log-transformed), age at randomisation and TC. We pre-specified that all hypothesis tests required evidence at the 5% significance level to consider rejecting the null hypothesis. Results: We successfully CN profiled 300/315 cases. There were no significantly different baseline clinico-pathological features between the full trial comparison n = 3106 and final biomarker population n = 300, 290/300 cases were de novo presentations. PGA in the core with highest Gleason grade and TC was median 18% (range 0%-75%; n = 300). PGA was significantly higher in M1 (n = 169) compared to M0 (n = 131) cases (median: 21% vs 14%; p = 0.00006). 284/300 were subclassified by disease burden into M0 node negative and node positive, and M1 low and high volume. PGA was significantly associated with increased disease burden (p = 0.00002). Increased PGA was significantly and non-linearly associated with an increased hazard of failure-free survival (p = 0.004), progression-free survival (p = 0.002), metastatic progression-free survival (p = 0.003), overall survival (p = 0.045) and prostate cancer-specific survival (p = 0.011). Conclusions: Evaluation of the burden of CN aberrations in archival, poor quality FFPE diagnostic tissue from men randomised in the STAMPEDE trial is feasible using lpWGS and has potential clinical utility to identify better prognosis advanced HSPC patients, who may not require treatment intensification.

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ErbB3, Cyclin D1 and Ki67 nuclear staining predicts biochemical recurrence in prostate cancer treated by radical prostatectomy

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10096 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10096-10096

Author(s):

I. H. Koumakpayi ◽

P. O. Gannon ◽

C. Le Page ◽

M. Alam-Fahmy ◽

J. Madore ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Radical Prostatectomy ◽

Cyclin D1 ◽

Nuclear Localization ◽

Biochemical Recurrence ◽

Nuclear Accumulation ◽

Gleason Grade ◽

Nuclear Staining ◽

Proliferation Markers

10096 Background: The nuclear accumulation of growth factor receptor was reported to be associated to increased cell proliferation. Cyclin D1 and Ki67 are nuclear markers of cell proliferation. Deregulation of Cyclin D1 and Ki67 expression play a role in tumorigenesis and metastasis. Recently, we observed that nuclear localization of ErbB3 was associated with prostate cancer progression. The objective of this study was to determine if the association of cell proliferation markers and nuclear localization of ErbB3 could predict biochemical recurrence (BCR) in patients with prostate cancer following radical prostatectomy. Methods: Using immunohistochemistry we analyzed a tissue microarray containing 386 cores from 64 formalin-fixed paraffin embedded specimens from prostate cancer patients who had undergone radical prostatectomy. No patient had received hormone therapy prior to surgery and prior to BCR. Antibodies against Cyclin D1, ErbB3 and Ki67 proteins were used. Results: Nuclear staining was 60%, 67% and 86% for Cyclin D1, ErbB3 and Ki67 respectively. In our cohort, 29 of 64 PCa patients (45%) had a BCR after a median 3 years of follow-up. Thirty seven (37) percent of patients had positive nuclear staining for all three markers. BCR free survival probability at 3 years was not significant for each marker individually, except for ErbB3 in positive surgical margin patients. When all three markers were combined for nuclear staining Kaplan-Meier analysis BCR free was 0.4 and 0.1 for positive and negative nuclear staining respectively (p=0.0068). Univariate COX regression analysis shows a 2.98 fold (95% CI: 1.29 - 6.86, p=0.01) higher rate of BCR in patients positive for these three markers. In addition, in a multivariate model, including pre-operative PSA (p=0.19), pathologic stage (p=0.29), Gleason grade (p=0.40) and specimens that had positive nuclear staining for the 3 markers were associated with a 3.97 fold higher rate of BCR (95% CI: 1.54 - 10.25, p=0.0068). Conclusion: These results suggest that the association of cell proliferation markers and nuclear localization of ErbB3 could be useful in predicting recurrence following radical prostatectomy and guide therapeutic decisions. Large scale trials are needed to confirm these results. No significant financial relationships to disclose.

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High-level cytoplasmic cyclin D1 expression in lymph node metastases from prostate cancer independently predicts early biochemical failure and death in surgically treated patients

Histopathology ◽

10.1111/j.1365-2559.2011.03800.x ◽

2011 ◽

Vol 58 (5) ◽

pp. 781-789 ◽

Cited By ~ 14

Author(s):

Achim Fleischmann ◽

Carla Rocha ◽

Nikolina Saxer-Sekulic ◽

Inti Zlobec ◽

Guido Sauter ◽

...

Keyword(s):

Prostate Cancer ◽

Lymph Node ◽

Cyclin D1 ◽

Lymph Node Metastases ◽

Biochemical Failure ◽

Node Metastases ◽

High Level

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Role of miR-182/PDCD4 axis in aggressive behavior of prostate cancer in the African Americans

BMC Cancer ◽

10.1186/s12885-021-08723-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Marisa Shiina ◽

Yutaka Hashimoto ◽

Priyanka Kulkarni ◽

Pritha Dasgupta ◽

Varahram Shahryari ◽

...

Keyword(s):

Prostate Cancer ◽

African Americans ◽

Cell Line ◽

Cell Lines ◽

Critical Role ◽

Gleason Grade ◽

Tissue Samples ◽

Free Survival ◽

Increased Risk

Abstract Background Prostate cancer is one of the most commonly diagnosed cancers among men. African Americans (AA) are at an increased risk of developing prostate cancer compared to European Americans (EA). miRNAs play a critical role in these tumors, leading to tumor progression. In this study, we investigated the role of miR-182 in racial disparity in prostate cancer. Results We found significantly increased levels of miR-182 in prostate cancer tissues compared to BPH. Also, miR-182 shows increased expression in AA prostate cancer cell line and tissue samples compared to EA. We performed biochemical recurrence (BCR) - free survival time in AA and EA patients and found that high miR-182 expression had significantly shorter BCR-free survival than patients with low miR-182 expression (P = 0.031). To elucidate the role of miR-182, we knocked down miR-182 in EA (DU-145 and LNCaP) and AA (MDA-PCa-2b) cell lines and found an increase in apoptosis, arrest of the cell cycle, and inhibition of colony formation in the AA cell line to a greater extent than EA cell lines. Conclusions Our results showed that PDCD4 is a direct miR-182 target and its inhibition is associated with aggressiveness and high Gleason grade in prostate cancer among AA. These findings show that miR-182 is highly expressed in AA patients and miR-182 may be a target for effective therapy in AA patients.

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