PUMA and NOXA Expression in Tumor-Associated Benign Prostatic Epithelial Cells Are Predictive of Prostate Cancer Biochemical Recurrence

Background: Given that treatment decisions in prostate cancer (PC) are often based on risk, there remains a need to find clinically relevant prognostic biomarkers to stratify PC patients. We evaluated PUMA and NOXA expression in benign and tumor regions of the prostate using immunofluorescence techniques and determined their prognostic significance in PC. Methods: PUMA and NOXA expression levels were quantified on six tissue microarrays (TMAs) generated from radical prostatectomy samples (n = 285). TMAs were constructed using two cores of benign tissue and two cores of tumor tissue from each patient. Association between biomarker expression and biochemical recurrence (BCR) at 3 years was established using log-rank (LR) and multivariate Cox regression analyses. Results: Kaplan–Meier analysis showed a significant association between BCR and extreme levels (low or high) of PUMA expression in benign epithelial cells (LR = 8.831, p = 0.003). Further analysis revealed a significant association between high NOXA expression in benign epithelial cells and BCR (LR = 14.854, p < 0.001). The combination of extreme PUMA and high NOXA expression identified patients with the highest risk of BCR (LR = 16.778, p < 0.001) in Kaplan–Meier and in a multivariate Cox regression analyses (HR: 2.935 (1.645–5.236), p < 0.001). Conclusions: The combination of PUMA and NOXA protein expression in benign epithelial cells was predictive of recurrence following radical prostatectomy and was independent of PSA at diagnosis, Gleason score and pathologic stage.

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Evaluation of PUMA and NOXA expression as predictive biomarkers in prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.28 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 28-28

Author(s):

Sylvie Clairefond ◽

Benjamin Péant ◽

Veronique Ouellet ◽

Veronique Barres ◽

Anne-Marie Mes-Masson ◽

...

Keyword(s):

Prostate Cancer ◽

Epithelial Cells ◽

Tumor Tissue ◽

Prostate Cancer Cell ◽

Cox Regression ◽

Predictive Biomarkers ◽

Tissue Microarrays ◽

Kaplan Meier ◽

Puma Expression ◽

Risk Patients

28 Background: PUMA and NOXA are two pro-apoptotic members of the BH3-only subgroup of the BCL-2 family. These two proteins play a role in the initiation of apoptosis. The objective of this study is to analyse their expression by immunofluorescence, alone or in combination, in benign and tumor prostate tissues to determine if there is a correlation between their expression and patient biochemical recurrence (BCR). Methods: Biomarker antibodies were verified for specificity and optimized by western blot and with tissue microarrays (TMA) containing prostate cancer cell lines and cell line derived xenograft tissues. Subsequently, quantification of expression for both biomarkers was performed on six TMA generated from radical prostatectomy samples (285 patients). The TMA were constructed using two cores of benign adjacent to the tumor and two cores of tumor tissue from each patient. Analysis of biomarker expression was semi-automated using the VisiomorphDP software. To optimize the analysis, we developed 2 different immunofluorescence masks: a cocktail of anti-cytokeratin-8 and -18 antibodies to identify epithelial cells and a combination of anti-p63 and anti-cytokeratin high marker weight to discriminate benign glands within tumor cores. Correlation with patient clinical outcome was determined with SPSS V20 software. Results: There was no correlation of PUMA and NOXA expression and BCR in tumor cores and stroma. In contrast, in benign epithelial cells Kaplan-Meier analysis showed a significant association between an extreme (low or high) PUMA expression and BCR (Log rank = 11.349, p = 0.001). Further analysis revealed a significant association between high NOXA expression in benign epithelial cells and BCR (Log rank = 6.133, p = 0.013). The combination of extreme PUMA and high NOXA identified patients with a poor prognosis (Log rank = 16.041, p = 0.000). In a multivariate Cox regression model, PUMA and NOXA proteins were also identified as independent predictive biomarkers of BCR. Conclusions: By studying benign epithelial cells adjacent to the tumor we identified two potential biomarkers that discriminate high-risk patients, independent of Gleason score or pathologic stage.

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Identification and Validation of a Prognostic 5-Protein Signature for Biochemical Recurrence Following Radical Prostatectomy for Prostate Cancer

Frontiers in Surgery ◽

10.3389/fsurg.2021.665115 ◽

2021 ◽

Vol 8 ◽

Author(s):

Daojun Lv ◽

Zanfeng Cao ◽

Wenjie Li ◽

Haige Zheng ◽

Xiangkun Wu ◽

...

Keyword(s):

Prostate Cancer ◽

Survival Analysis ◽

Biochemical Recurrence ◽

Cox Regression ◽

Characteristic Curve ◽

The Cancer Genome Atlas ◽

Medical Decision ◽

Regression Analyses ◽

Cox Regression Analysis ◽

Protein Signature

Background: Biochemical recurrence (BCR) is an indicator of prostate cancer (PCa)-specific recurrence and mortality. However, there is a lack of an effective prediction model that can be used to predict prognosis and to determine the optimal method of treatment for patients with BCR. Hence, the aim of this study was to construct a protein-based nomogram that could predict BCR in PCa.Methods: Protein expression data of PCa patients was obtained from The Cancer Proteome Atlas (TCPA) database. Clinical data on the patients was downloaded from The Cancer Genome Atlas (TCGA) database. Lasso and Cox regression analyses were conducted to select the most significant prognostic proteins and formulate a protein signature that could predict BCR. Subsequently, Kaplan–Meier survival analysis and Cox regression analyses were conducted to evaluate the performance of the prognostic protein-based signature. Additionally, a nomogram was constructed using multivariate Cox regression analysis.Results: We constructed a 5-protein-based prognostic prediction signature that could be used to identify high-risk and low-risk groups of PCa patients. The survival analysis demonstrated that patients with a higher BCR showed significantly worse survival than those with a lower BCR (p < 0.0001). The time-dependent receiver operating characteristic curve showed that the signature had an excellent prognostic efficiency for 1, 3, and 5-year BCR (area under curve in training set: 0.691, 0.797, 0.808 and 0.74, 0.739, 0.82 in the test set). Univariate and multivariate analyses indicated that this 5-protein signature could be used as independent prognosis marker for PCa patients. Moreover, the concordance index (C-index) confirmed the predictive value of this 5-protein signature in 3, 5, and 10-year BCR overall survival (C-index: 0.764, 95% confidence interval: 0.701–0.827). Finally, we constructed a nomogram to predict BCR of PCa.Conclusions: Our study identified a 5-protein-based signature and constructed a nomogram that could reliably predict BCR. The findings might be of paramount importance for the prediction of PCa prognosis and medical decision-making.Subjects: Bioinformatics, oncology, urology.

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Tumor Infiltration by OX40+ Cells Enhances the Prognostic Significance of CD16+ Cell Infiltration in Colorectal Cancer

Cancer Control ◽

10.1177/1073274820903383 ◽

2020 ◽

Vol 27 (1) ◽

pp. 107327482090338

Author(s):

Fabian Haak ◽

Isabelle Obrecht ◽

Nadia Tosti ◽

Benjamin Weixler ◽

Robert Mechera ◽

...

Keyword(s):

Colorectal Cancer ◽

Immune Cell ◽

Cox Regression ◽

Prognostic Significance ◽

Tumor Necrosis Factor Receptor ◽

Tissue Microarrays ◽

Cell Infiltration ◽

Prognostic Impact ◽

Cox Regression Analysis ◽

Kaplan Meier

Objectives: Analysis of tumor immune infiltration has been suggested to outperform tumor, node, metastasis staging in predicting clinical course of colorectal cancer (CRC). Infiltration by cells expressing OX40, a member of the tumor necrosis factor receptor family, or CD16, expressed by natural killer cells, monocytes, and dendritic cells, has been associated with favorable prognosis in patients with CRC. We hypothesized that assessment of CRC infiltration by both OX40+ and CD16+ cells might result in enhanced prognostic significance. Methods: Colorectal cancer infiltration by OX40 and CD16 expressing cells was investigated in 441 primary CRCs using tissue microarrays and specific antibodies, by immunohistochemistry. Patients’ survival was evaluated by Kaplan-Meier and log-rank tests. Multivariate Cox regression analysis, hazard ratios, and 95% confidence intervals were also used to evaluate prognostic significance of OX40+ and CD16+ cell infiltration. Results: Colorectal cancer infiltration by OX40+ and CD16+ cells was subclassified into 4 groups with high or low infiltration levels in all possible combinations. High levels of infiltration by both OX40+ and CD16+ cells were associated with lower pT stage, absence of peritumoral lymphocytic (PTL) inflammation, and a positive prognostic impact. Patients bearing tumors with high infiltration by CD16+ and OX40+ cells were also characterized by significantly longer overall survival, as compared with the other groups. These results were confirmed by analyzing an independent validation cohort. Conclusions: Combined infiltration by OX40+ and CD16+ immune cells is an independent favorable prognostic marker in CRC. The prognostic value of CD16+ immune cell infiltration is significantly improved by the combined analysis with OX40+ cell infiltration.

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Does perineural invasion in a radical prostatectomy specimen predict biochemical recurrence in men with prostate cancer?

Canadian Urological Association Journal ◽

10.5489/cuaj.2619 ◽

2015 ◽

Vol 9 (5-6) ◽

pp. 252 ◽

Cited By ~ 12

Author(s):

Fairleigh Reeves ◽

Christopher M. Hovens ◽

Laurence Harewood ◽

Shayne Battye ◽

Justin S. Peters ◽

...

Keyword(s):

Prostate Cancer ◽

Regression Analysis ◽

Radical Prostatectomy ◽

Gleason Score ◽

Biochemical Recurrence ◽

Perineural Invasion ◽

Cox Regression ◽

Clinicopathological Parameters ◽

Positive Surgical Margin ◽

Cox Regression Analysis

Introduction: The ability of perineural invasion (PNI) in radical prostatectomy (RP) specimens to predict biochemical recurrence (BCR) is unclear. This study investigates this controversial question in a large cohort.Methods: A retrospective analysis was undertaken of prospectively collected data from 1497 men who underwent RP (no neoadjuvant therapy) for clinically localized prostate cancer. The association of PNI at RP with other clinicopathological parameters was evaluated. The correlation of clinicopathological factors and BCR (defined as prostate-specific antigen [PSA] >0.2 ng/mL) was investigated with univariable and multivariable Cox regression analysis in 1159 men.Results: PNI-positive patients were significantly more likely to have a higher RP Gleason score, pT3 disease, positive surgical margins, and greater cancer volume (p < 0.0005). The presence of PNI significantly correlated with BCR on univariable (hazard ratio 2.30, 95% confidence interval 1.50–3.55, p < 0.0005), but not multivariable analysis (p = 0.602). On multivariable Cox regression analysis the only independent prognostic factors were preoperative PSA, RP Gleason score, pT-stage, and positive surgical margin status. These findings are limited by a relatively short follow-up time and retrospective study design.Conclusions: PNI at RP is not an independent predictor of BCR. Therefore, routine reporting of PNI is not indicated. Future research should be targeted at the biology of PNI to increase the understanding of its role in prostate cancer progression.

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Outcomes and Prediction Models for Exclusive Prostate Bed Salvage Radiotherapy among Patients with Biochemical Recurrence after Radical Prostatectomy

Cancers ◽

10.3390/cancers13112672 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2672

Author(s):

Chi-Shin Tseng ◽

Yu-Jen Wang ◽

Chung-Hsin Chen ◽

Shuo-Meng Wang ◽

Kuo-How Huang ◽

...

Keyword(s):

Radical Prostatectomy ◽

Biochemical Recurrence ◽

Prediction Models ◽

Cox Regression ◽

Multivariable Analysis ◽

Salvage Radiotherapy ◽

Free Survival ◽

Prostate Bed ◽

Kaplan Meier ◽

Observational Cohort

Background: The addition of androgen-deprivation therapy (ADT) or pelvic radiation to prostate bed salvage radiotherapy (SRT) has been debated for prostate cancer patients with biochemical recurrence (BCR) after radical prostatectomy. This study aimed to assess the outcomes and propose prediction models for exclusive prostate bed SRT. Methods: This is a prospective observational cohort study with patients who underwent SRT with a pre-SRT PSA < 1.5 ng/mL after radical prostatectomy. Patients were treated with 70-Gy SRT to the prostate bed exclusively. Kaplan–Meier survival analyses and Cox regression analyses were applied for depicting and predicting BCR-free survival, ADT-free survival, and metastasis-free survival (MFS). Regression-based coefficients were used to develop nomograms. Results: A total of 105 patients were included and 91 patients were eligible. The median follow-up period was 39 months. The 5-year BCR-free survival, ADT-free survival, and MFS were 37%, 50%, and 66%, respectively. Multivariable analysis showed that a pre-SRT PSA < 0.45 ng/mL was the only independent factor associated with longer BCR-free survival (p = 0.034), while a PSA-DT > 8 months had better ADT-free survival (p = 0.008). Patients with a PSA-DT > 8 months showed a 100% MFS and a 43% 5-year absolute benefit in MFS than a PSA-DT ≤ 8 months. All patients with a pre-SRT PSA < 0.45 ng/mL and PSA-DT > 8 months were free from subsequent ADT and any metastasis. Conclusions: In patients with a PSA < 0.45 ng/mL and PSA-DT > 8 months for post-prostatectomy BCR, prostate bed SRT provided excellent outcomes without the need for concomitant ADT or pelvic radiotherapy.

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Predictors of biochemical recurrence of prostate cancer

Kazan medical journal ◽

10.17750/kmj2017-890 ◽

2017 ◽

Vol 98 (6) ◽

pp. 890-894 ◽

Cited By ~ 3

Author(s):

F A Guliev

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Prostate Specific Antigen ◽

Biochemical Recurrence ◽

Tumor Volume ◽

Prognostic Significance ◽

Specific Antigen ◽

Surgical Margin ◽

Surgical Margins ◽

Operative Risk

Aim. To study the role of postoperative parameters in predicting the probability of development of biochemical recurrence in patients with prostate cancer with low pre-operative risk of its progression. Methods. 95 patients who underwent radical prostatectomy, were included in the study, the average age being 59.5±0.7 (44-76) years. The average levels of total and free prostate-specific antigen were 5.8±0.2 (1.71-9.9) and 1.03±0.07 (0.2-3.6) ng/ml respectively. Biochemical recurrence was defined as the level of prostate-specific antigen higher than 0.2 ng/ml after radical prostatectomy. Results. 8 (8.4%) patients during the follow-up period were diagnosed with biochemical recurrence. The average period to biochemical recurrence development was 45.8±6.7 (24-84) months. Pathomorphological examination revealed presence of tumor cells at surgical margin in 18 (18.9%) cases. Biochemical recurrence was diagnosed in 5 out of 77 (6.5%) patients with negative surgical margins and in 3 out of 18 (1.7%) patients with positive surgical margins. In our study, no correlation between the state of surgical margin and biochemical recurrence development was revealed (χ2=1.958; р=0.162). In the study group postoperative Gleason score was not prognostically significant as well (р=0.294). The average tumor volume in resected material was 11.8±1.0% (1-55%) of prostate volume (мм3). Extraprostatic extension was diagnosed in 10 (10.5%) cases. Results of univariate dispersion analysis of postoperative parameters revealed prognostic significance of tumor volume in removed specimen (р=0.007) and extracapsular extension (р=0.027). Conclusion. In our study we determined that tumor volume and extracapsular extention are independent risk factors for biochemical recurrence in prostate cancer patients with low pre-operative risk of disease progression.

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The Long-Term Outcomes after Radical Prostatectomy of Patients with Pathologic Gleason 8–10 Disease

Advances in Urology ◽

10.1155/2012/428098 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Dan Lewinshtein ◽

Brandon Teng ◽

Ashley Valencia ◽

Robert Gibbons ◽

Christopher R. Porter

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Cox Regression ◽

Surgical Margin ◽

Cancer Control ◽

Positive Surgical Margin ◽

Cancer Specific Survival ◽

Free Survival ◽

Kaplan Meier

Background. We explored the long-term clinical outcomes including metastases-free survival and prostate cancer-specific survival (PCSS) in patients with pathologic Gleason 8–10 disease after radical prostatectomy (RP).Methods. We report on 91 patients with PCSS data with a median followup of 8.2 years after RP performed between 1988 and 1997. Cox regression and Kaplan-Meier analysis were used to evaluate year of surgery, pathologic stage, and surgical margin status as predictors of PCSM.Results. Median age was 65 years (IQR: 61–9), and median PSA was 9.7 ng/ml (IQR: 6.1–13.4). Of all patients, 62 (68.9%) had stage T3 disease or higher, and 48 (52.7%) had a positive surgical margin. On multivariate analysis, none of the predictors were statistically significant. Of all patients, the predicted 10-year BCR-free survival, mets-free survival, and PCSS were 59% (CI: 53%–65%), 88% (CI: 84%–92%), and 94% (CI: 91%–97%), respectively.Conclusions. We have demonstrated that cancer control is durable even 10 years after RP in those with pathologic Gleason 8–10 disease. Although 40% will succumb to BCR, only 6% of patients died of their disease. These results support the use of RP for patients with high-risk localized prostate cancer.

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Prognostic significance of the PSA nadir after salvage radiotherapy following radical prostatectomy in prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.207 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 207-207

Author(s):

Thomas Wiegel ◽

Detlef Bartkowiak ◽

Dirk Bottke ◽

Alessandra Siegmann ◽

Volker Budach ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Radical Prostatectomy ◽

Cox Regression ◽

Prognostic Significance ◽

Salvage Radiotherapy ◽

Long Term Results ◽

Logrank Test ◽

Clinical Recurrence ◽

Psa Nadir

207 Background: Salvage radiotherapy (SRT) is a curative approach in recurrent prostate cancer after radical prostatectomy. The outcome depends on various parameters. We report the long term results of SRT with special respect to the course of PSA after SRT. Methods: Between 1997 and 2007, 307 patients received SRT with 66.6 (N=240) or 70.2 Gy (N=67) using CT-based 3D planning. The median pre-SRT PSA was 0.297 ng/ml. Post-SRT progression was defined as either PSA rising >0.2 ng/ml above nadir, or hormone treatment, or clinical recurrence. Data were analyzed with the Kaplan-Meier method (Logrank-test) and with multivariate Cox regression. Results: Patients were followed up for median 7.2 (max. 14.4) years. Recurrence occurred in median 9.4 months post-RP. In 112 patients, SRT was administered before their PSA reached 0.2 ng/ml, 195 men were above that threshold. After SRT, 222 patients achieved a PSA nadir <0.1 ng/ml, 85 retained higher values. SRT given at a PSA <0.2 ng/ml correlated with achieving a post-SRT nadir <0.1 ng/ml (p<0.0001) and with improved freedom from progression (p=0.0133). Men with a post-SRT nadir <0.1 ng/ml (undetectable range) had significantly less recurrences (p<0.0001) and a better overall survival (p=0.0248). In multivariate analysis of pre-SRT parameters, pT≥3, Gleason Score ≥7, a post-RP PSA nadir ≥0.1 ng/ml and pre-SRT PSA ≥0.2 ng/ml increased the risk of progression. If failing the post-SRT nadir <0.1 ng/ml was included in the model, then this was the strongest risk factor (hazard ratio 7.93). Conclusions: Our data suggest early salvage RT at a PSA level below 0.2 ng/ml to be a favorable treatment option for post-RP PSA recurrence. It increases the chances of achieving a post-SRT PSA-nadir <0.1 ng/ml, which is associated with an improved outcome in terms of PSA progression and overall survival.

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The role of fatal family history and mode of inheritance in prostate cancer for long-term outcomes following radical prostatectomy

World Journal of Urology ◽

10.1007/s00345-020-03147-6 ◽

2020 ◽

Vol 38 (12) ◽

pp. 3091-3099 ◽

Cited By ~ 1

Author(s):

Valentin H. Meissner ◽

Jamila G. H. Strüh ◽

Martina Kron ◽

Lea A. Liesenfeld ◽

Stephanie Kranz ◽

...

Keyword(s):

Prostate Cancer ◽

Prognostic Factors ◽

Family History ◽

Radical Prostatectomy ◽

Cox Regression ◽

Long Term Outcomes ◽

Long Term Outcome ◽

Kaplan Meier ◽

Mode Of Inheritance

Abstract Purpose To determine whether fatal family history (FFH) or mode of inheritance in prostate cancer (PCa) has an impact on long-term outcomes following radical prostatectomy (RP). Methods 1076 PCa patients after RP with at least one deceased first-degree relative with PCa were included and stratified by FFH (four subgroups: fraternal, paternal, multiple, and none) and by mode of inheritance (two subgroups: male to male, non-male to male). We compared clinicopathological characteristics between subgroups with Fisher’s exact or Chi-square tests. Biochemical recurrence-free survival (BRFS) and cancer-specific survival (CSS) were analyzed using the method of Kaplan and Meier. Simple and multiple Cox regression with backward elimination were performed to select prognostic factors for BRFS and CSS. Results Median age at surgery was 63.3 (range 35.9–79.4) years. The overall Kaplan–Meier estimated BRFS rate at 10 and 15 years was 65.6% and 57.0%, respectively. The overall Kaplan–Meier estimated CSS rate at 10 and 15 years was 98.1% and 95.7%, respectively. Neither FFH nor mode of inheritance were factors associated with worse BRFS. However, in multiple Cox regression, paternal FFH was an important prognostic factor for a better CSS (HR 0.19, CI 0.05–0.71, p = 0.014) compared to non-FFH. Conclusion FFH and mode of inheritance do not seem to be prognostic factors of worse long-term outcomes following RP. Rather, a paternal FFH was associated with a better CSS; however, the reasons remain unclear. Nevertheless, patients after RP and FFH could be reassured that their own PCa diagnosis is not associated with a worse long-term outcome.

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Lymphatic micrometastases predict biochemical recurrence in patients undergoing radical prostatectomy and pelvic lymph node dissection for prostate cancer

Aktuelle Urologie ◽

10.1055/a-0856-6545 ◽

2019 ◽

Vol 50 (06) ◽

pp. 612-618

Author(s):

Andreas Maxeiner ◽

Andreas Grevendieck ◽

Therese Pross ◽

Marc Rudl ◽

Alexander Arnold ◽

...

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Biochemical Recurrence ◽

Diagnostic Value ◽

Nodal Metastasis ◽

Rank Test ◽

P Value ◽

Kaplan Meier ◽

Negative Findings

Abstract Background Nodal metastasis is a strong prognostic parameter in prostate cancer (PCa). We analysed the detection of micrometastases (miN + ) in initially nodal-negative (pN0) radical prostatectomy specimens from pT2a-c and pT3a PCa patients by immunohistochemistry (IHC). Material and Methods A total of 2352 lymph nodes of 193 PCa patients were centrally re-examined for miN + or miN- status using IHC. Results were correlated with clinical and follow-up data. Recurrence-free survival (RFS) was calculated with the log-rank test using the Kaplan-Meier method. In addition, a logistic regression analysis was performed. Results IHC detected miN + in a total of 17 patients (8.8 %). miN + seemed to be significantly associated with a higher Gleason score and was detected in more advanced pT stages. A total of 45 patients (23.1 %) had a biochemical recurrence (BCR). BCR was associated with miN +. Patients with miN + had a significantly shorter RFS (22.9 versus 58.7 months; p < 0.001). In the univariate (OR: 5.04; 95 % CI: 2.46 – 10.6; p-value: < 0.0001) and multivariate (OR: 3.29; 95 % CI: 1.54 – 7.08; p-value: 0.002) regression model, the miN + status was the strongest predictor of a BCR. Conclusions IHC seems to be of high diagnostic value for the detection of micrometastases in initially nodal-negative PCa patients. IHC should therefore be performed in PCa patients with nodal-negative findings.

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