Tag Archive for: biochemical recurrence

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Video: Gleason Grading in the Spotlight

The impact of the 2005 International Society of Urological Pathology consensus guidelines on Gleason grading – a matched pair analysis

Kasper D. Berg*, Frederik B. Thomsen*, Camilla Nerstrøm*, Martin A. Røder*, Peter Iversen*, Birgitte G. Toft, Ben Vainer† and Klaus Brasso*

 

*Department of Urology, Copenhagen Prostate Cancer Center and Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

 

Objectives

To investigate whether the International Society of Urological Pathology (ISUP) 2005 revision of the Gleason grading system has influenced the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), as the new guideline implies that some prostate cancers previously graded as Gleason score 6 (3 + 3) are now considered as 7 (3 + 4).

Patients and methods

A matched-pair analysis was conducted. In all, 215 patients with Gleason score 6 or 7 (3 + 4) prostate cancer on biopsy who underwent RP before 31 December 2005 (pre-ISUP group), were matched 1:1 by biopsy Gleason score, clinical tumour category, PSA level, and margin status to patients undergoing RP between 1 January 2008 and 31 December 2011 (post-ISUP group). Patients were followed until BCR defined as a PSA level of ≥0.2 ng/mL. Risk of BCR was analysed in a competing-risk model.

JunAOTMResults

Results

The median follow-up was 9.5 years in the pre-ISUP group and 4.8 years in the post-ISUP group. The 5-year cumulative incidences of BCR were 34.0% and 13.9% in the pre-ISUP and post-ISUP groups, respectively (P < 0.001). The difference in cumulative incidence applied to both patients with Gleason score 6 (P < 0.001) and 7 (3 + 4) (P = 0.004). There was no difference in the 5-year cumulative incidence of BCR between patients with pre-ISUP Gleason score 6 and post-ISUP Gleason score 7 (3 + 4) (P = 0.34). In a multiple Cox-proportional hazard regression model, ISUP 2005 grading was a strong prognostic factor for BCR within 5 years of RP (hazard ratio 0.34; 95% confidence interval 0.22–0.54; P < 0.001).

Conclusion

The revision of the Gleason grading system has reduced the risk of BCR after RP in patients with biopsy Gleason score 6 and 7 (3 + 4). This may have consequences when comparing outcomes across studies and historical periods and may affect future treatment recommendations.

Article of the Week: Radical prostatectomy – postoperative statin use and risk of biochemical recurrence

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Emma Allott discussing her paper. 

If you only have time to read one article this week, it should be this one.

Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Emma H. Allott, PhD 1, 2, 3, Lauren E. Howard, BA 3, 4, Matthew R. Cooperberg, MD 5, Christopher J. Kane, MD 6, William J. Aronson, MD 7, 8, Martha K. Terris, MD 9, 10, Christopher L. Amling, MD 11 and Stephen J. Freedland, MD 1, 3, 12

1 Division of Urology, Department of Surgery, 4 Department of Biostatistics and Bioinformatics, 12 Department of Pathology, Duke University School of Medicine, 2 Cancer Prevention, Detection and Control Program, Duke Cancer Institute, 3 Division of Urology, Veterans Affairs Medical Center Durham, NC, 5 Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, 6 Urology Department, University of California San Diego Health System, San Diego, 7 Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, 8 Department of Urology, UCLA School of Medicine, Los Angeles, CA, 9 Section of Urology, Veterans Affairs Medical Center, Augusta, 10 Department of Urology, Georgia Regents University, Augusta, GA, 11 Department of Urology, Oregon Health Sciences University, Portland, OR, USA

Read the full article
OBJECTIVE

To investigate the effect of statin use after radical prostatectomy (RP) on biochemical recurrence (BCR) in patients with prostate cancer who never received statins before RP.

PATIENTS AND METHODS

We conducted a retrospective analysis of 1146 RP patients within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Multivariable Cox proportional hazards analyses were used to examine differences in risk of BCR between post-RP statin users vs nonusers. To account for varying start dates and duration of statin use during follow-up, post-RP statin use was treated as a time-dependent variable. In a secondary analysis, models were stratified by race to examine the association of post-RP statin use with BCR among black and non-black men.

RESULTS

After adjusting for clinical and pathological characteristics, post-RP statin use was significantly associated with 36% reduced risk of BCR (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47–0.87; P = 0.004). Post-RP statin use remained associated with reduced risk of BCR after adjusting for preoperative serum cholesterol levels. In secondary analysis, after stratification by race, this protective association was significant in non-black (HR 0.49, 95% CI 0.32–0.75; P = 0.001) but not black men (HR 0.82, 95% CI 0.53–1.28; P = 0.384).

CONCLUSION

In this retrospective cohort of men undergoing RP, post-RP statin use was significantly associated with reduced risk of BCR. Whether the association between post-RP statin use and BCR differs by race requires further study. Given these findings, coupled with other studies suggesting that statins may reduce risk of advanced prostate cancer, randomised controlled trials are warranted to formally test the hypothesis that statins slow prostate cancer progression.

Editorial: Statins and biochemical recurrence after radical prostatectomy – who benefits?

In the present issue of the BJUI Allott et al. [1] report results from a study where they used the Shared Equal Access Regional Cancer Hospital (SEARCH) database to explore the risk of biochemical recurrence (BCR) after radical prostatectomy (RP) among men who used statins after RP. They report improved BCR-free survival among statin users, especially among men with high-risk disease at baseline. The results provide some new insights into the current discussion on statins and prostate cancer outcomes.

Statins have recently shown promise as chemotherapeutic agents against prostate cancer. There is conflicting evidence on the effect on overall prostate cancer risk, but most studies able to evaluate the risk by tumour stage have reported lowered risk of advanced prostate cancer among statin users compared with the non-users [2], and lowered prostate cancer-specific mortality [3].

Taken together, these epidemiological findings suggest that statins may not strongly lower the risk of initiation of prostate cancer, but may be able to slow down the progression of the most dangerous form of the disease. In vitro studies support this by reporting growth inhibition and lower metastatic activity of prostate cancer cells after statin treatment [4].

Despite this, there has been recent controversy on statins’ effect on BCR of prostate cancer after radical treatment. A recent meta-analysis concluded that statin users may have a lower risk of BCR after external beam radiation therapy, but not after RP [5]. This could be due to statins acting as radiation sensitizers. Reports of improved BCR-free survival in statin users after brachytherapy would support this [6].

However, there are also differences in the characteristics of patients managed with RP or radiation therapy. Men undergoing RP have localised disease, which usually means low- to medium-grade tumours (Gleason ≤7), as high-grade disease (Gleason 8–10) progresses early and is more often locally advanced or already metastatic at diagnosis, leading to the choice of radiation therapy with neoadjuvant androgen deprivation instead of RP if curative treatment is still deemed possible.

This leads to the question whether the differing association between statins and BCR by treatment method is explained by patient selection, and whether statins are most effective against progression of high-grade disease. The study reported by Allott et al. [1] in this issue of the BJUI certainly suggests so. They report lowered risk of BCR among men who used statins after RP. They were able to study the effect of statin usage occurring after RP, not just usage at the time of RP. When the analysis was stratified by tumour characteristics, the improvement in relapse-free survival was strongest among men with high-risk disease (Gleason score ≥4 + 3; positive surgical margins).

The present study [1] supports the notion that statins could target a mechanism that is essential for progression of high-risk prostate cancer. This would be in concordance with the previously reported lowered risk of advanced prostate cancer and decreased prostate cancer mortality among statin users, as high-grade/high-risk cancer is the type progressing into advanced and fatal stages. On the other hand, if statins do not affect low-grade prostate cancer, this could explain why many RP series have not observed differences in biochemical relapses by statin use, as patients in these studies often have low-grade disease.

As always, statins’ benefits against prostate cancer are not really proven until verified in randomised clinical trials properly designed and powered to detect a difference in cancer endpoints. Designers of such trials should consider targeting the statin intervention to men with high-grade and/or high-risk prostate cancer for efficient study design.

Read the full article

Teemu J. Murtola*†

*School of Medicine, University of Tampere, and † Department of Urology, Tampere University Hospital, Tampere, Finland

References

1 Allott EH, Howard LE, Cooperberg MR et al. Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BJU Int 2014; 114: 661–6

2 Bansal D, Undela K, D’Cruz S, Schifano F. Statin use and risk of prostate cancer: a meta-analysis of observational studies. PLoS ONE 2012; 7:e46691

3 Yu O, Eberg M, Benayoun S et al. Use of statins and the risk of death in patients with prostate cancer. J Clin Oncol 2014; 32: 5–11

4 Brown M, Hart C, Tawadros T et al. The differential effects of statins on the metastatic behaviour of prostate cancer. Br J Cancer 2012; 106: 1689–96

5 Park HS, Schoenfeld JD, Mailhot RB et al. Statins and prostate cancer recurrence following radical prostatectomy or radiotherapy: a systematic review and meta-analysis. Ann Oncol 2013; 24: 1427–34

6 Moyad MA, Merrick GS, Butler WM et al. Statins, especially atorvastatin, may improve survival following brachytherapy for clinically localized prostate cancer. Urol Nurs 2006; 26: 298–303

 

Video: Postoperative statin use and risk of biochemical recurrence following radical prostatectomy. Results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

Emma H. Allott, PhD 1, 2, 3, Lauren E. Howard, BA 3, 4, Matthew R. Cooperberg, MD 5, Christopher J. Kane, MD 6, William J. Aronson, MD 7, 8, Martha K. Terris, MD 9, 10, Christopher L. Amling, MD 11 and Stephen J. Freedland, MD 1, 3, 12

1 Division of Urology, Department of Surgery, 4 Department of Biostatistics and Bioinformatics, 12 Department of Pathology, Duke University School of Medicine, 2 Cancer Prevention, Detection and Control Program, Duke Cancer Institute, 3 Division of Urology, Veterans Affairs Medical Center Durham, NC, 5 Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, 6 Urology Department, University of California San Diego Health System, San Diego, 7 Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, 8 Department of Urology, UCLA School of Medicine, Los Angeles, CA, 9 Section of Urology, Veterans Affairs Medical Center, Augusta, 10 Department of Urology, Georgia Regents University, Augusta, GA, 11 Department of Urology, Oregon Health Sciences University, Portland, OR, USA

Read the full article
OBJECTIVE

To investigate the effect of statin use after radical prostatectomy (RP) on biochemical recurrence (BCR) in patients with prostate cancer who never received statins before RP.

PATIENTS AND METHODS

We conducted a retrospective analysis of 1146 RP patients within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Multivariable Cox proportional hazards analyses were used to examine differences in risk of BCR between post-RP statin users vs nonusers. To account for varying start dates and duration of statin use during follow-up, post-RP statin use was treated as a time-dependent variable. In a secondary analysis, models were stratified by race to examine the association of post-RP statin use with BCR among black and non-black men.

RESULTS

After adjusting for clinical and pathological characteristics, post-RP statin use was significantly associated with 36% reduced risk of BCR (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47–0.87; P = 0.004). Post-RP statin use remained associated with reduced risk of BCR after adjusting for preoperative serum cholesterol levels. In secondary analysis, after stratification by race, this protective association was significant in non-black (HR 0.49, 95% CI 0.32–0.75; P = 0.001) but not black men (HR 0.82, 95% CI 0.53–1.28; P = 0.384).

CONCLUSION

In this retrospective cohort of men undergoing RP, post-RP statin use was significantly associated with reduced risk of BCR. Whether the association between post-RP statin use and BCR differs by race requires further study. Given these findings, coupled with other studies suggesting that statins may reduce risk of advanced prostate cancer, randomised controlled trials are warranted to formally test the hypothesis that statins slow prostate cancer progression.

Article of the week: “Twist” of fate: epithelial–mesenchymal transition (EMT) markers predict recurrence in prostate cancer

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Expression patterns of epithelial–mesenchymal transition markers in localized prostate cancer: significance in clinicopathological outcomes following radical prostatectomy

Hosny M. Behnsawy, Hideaki Miyake, Ken-Ichi Harada and Masato Fujisawa

Read the full article
OBJECTIVE

• To analyse the expression patterns of multiple molecular markers implicated in epithelial–mesenchymal transition (EMT) in localized prostate cancer (PC), in order to clarify the significance of these markers in patients undergoing radical prostatectomy (RP).

PATIENTS AND METHODS

• Expression levels of 13 EMT markers, namely E-cadherin, N-cadherin, b-catenin, g-catenin, fibronectin, matrix metalloproteinase (MMP) 2, MMP-9, Slug, Snail, Twist, vimentin, ZEB1 and ZEB2, in RP specimens from 197 consecutive patients with localized PC were evaluated by immunohistochemical staining.

RESULTS

• Of the 13 markers, expression levels of E-cadherin, Snail, Twist and vimentin were closely associated with several conventional prognostic factors.

• Univariate analysis identified these four EMT markers as significant predictors for biochemical recurrence (BR), while serum prostate-specific antigen, Gleason score, seminal vesicle invasion (SVI), surgical margin status (SMS) and tumour volume were also significant.

• Of these significant factors, expression levels of Twist and vimentin, SVI and SMS appeared to be independently related to BR on multivariate analysis

• There were significant differences in BR-free survival according to positive numbers of these four independent factors. That is, BR occurred in four of 90 patients who were negative for risk factors (4.4%), 21 of 83 positive for one or two risk factors (25.3%) and 19 of 24 positive for three or four risk factors (79.2%).

CONCLUSION

• Measurement of expression levels of potential EMT markers, particularly Twist and vimentin, in RP specimens, in addition to conventional prognostic parameters, would contribute to the accurate prediction of the biochemical outcome in patients with localized PC following RP.

 

Read Previous Articles of the Week

Editorial: The promise of EMT-associated biomarkers in a clinical setting

Emily A. Matuszak  and Natasha Kyprianou
Departments of Toxicology, Urology and Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA

Radical prostatectomy is among the most successful treatment modalities for patients exhibiting clinically localized prostate cancer. Despite this, roughly one-third of all radical prostatectomy patients will experience biochemical recurrence following prostatectomy. Curing prostate cancer requires a greater understanding of distinct biological events that differentiate prostate cancer from advanced life-threatening disease. Thus, a current challenge facing the clinical management of prostate cancer is the need for novel prognostic biomarkers capable of predicting biochemical recurrence to direct therapeutic interventions at earlier disease stages.

The oncogenic epithelial–mesenchymal transition (EMT) plays a critical role in metastatic prostate cancer progression [1]. EMTs engender coordinated molecular and genetic events which provoke phenotypic transformations that are indicative of the acquisition of mesenchymal characteristics which yield altered cellular behaviours [2]. Such altered behaviours may include but are not limited to enhanced migratory capability, increased invasive capacity, heightened resistance to apoptosis and conferred stem-like properties [3,4]. Conversion of an epithelial-derived prostate cancer cell to a more mesenchymal-like state has recently been implicated in prostate tumourigenesis as a mechanism facilitating the progression to metastatic castration-resistant disease [5].While alterations in the expression profiles of numerous EMT-associated transcriptional regulators and their molecular targets have served as biomarkers for studying EMT programmes, less is known about the contributions of EMTs in the emergence of treatment failure and tumour recurrence. Recently, EMT has been suggested to be a programme involved in metastatic disease progression that may also profoundly influence therapeutic outcomes amongst patients. Thus, it may be advantageous to develop predictors for risk assessment among prostate cancer patients that include specific EMT-associated markers in clinical evaluations.

Despite our current lack of knowledge regarding the clinicopathological significance of EMT, the potential value of an EMT marker signature as a prognostic indicator of biochemical recurrence among prostate cancer patients has emerged with some promise. Behnsawy et al. establish an initial path towards estimating the clinical value of assessing EMT marker levels in tandem with conventional clinicopathological prognostic factors in radical prostatectomy specimens from patients with organ confined prostate cancer, without any neoadjuvant therapy. Their evaluation follows a robust profile and results intriguingly reflect a pattern that may facilitate prediction of biochemical recurrence among patients. Using an exhaustive immunohistochemical analysis, the expression patterns of 13 EMT markers were evaluated in 197 radical prostatectomy specimens of which the expression levels of two EMT-associated markers, Twist and vimentin, were the most promising factors for such predictions.

The novel aspect and translational significance of this study are both reflected in the homogeneity of the patient population, in terms of localized organ confined disease. It represents an initial step towards recognizing an expression signature for specific EMT-associated factors in the therapeutic outcome of localized prostate cancer, but not disease progression. While the clinical impact of the reported findings may not be fully apparent, one may begin to speculate the promise of incorporating EMT-associated biomarkers in a clinical setting to facilitate diagnosis, prognosis and/or directing treatment strategies among patients. Primary endpoints of acquisition of an EMT phenotype following androgen axis targeting treatment must be clearly defined in the design of future clinical trials for the treatment of prostate cancer patients, with caution being given to selection of biopsy specimens vs radical prostatectomy specimens at an ‘optimal’ EMT window and in order to mitigate bias in tissue sampling resulting from long duration of therapeutic intervention. Control groups will provide valuable biological material to identify alternative mechanisms of treatment resistance (MAPK signalling). The statistical power in the relatively large cohort analysed enhances our confidence in considering the EMT landscape as an attractive platform for prediction of therapeutic response in future clinical trials. The concern, however, of whether improved prediction of biochemical recurrence by EMT profiling in pretreatment biopsies justifies its integration in the clinicopathological parameters (Gleason score, PSA) remains. Thus high expectations and much promise surround the pathological exploitation of EMT biomarkers (as signatures) in identifying profiles of tumour aggressiveness and providing a significant contribution in our quest towards the development of personalized therapies in prostate cancer patients with advanced disease.

References
1 Matuszak E, Kyprianou N. Androgen regulation of epithelial–mesenchymal transition in prostate tumorigenesis. Expert Rev Endo Metab 2011; 6: 469–82
2 Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial–mesenchymal transition in development and disease. Cell 2009; 139: 871–90
3 Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9: 265–73
4 Kalluri R, Weinberg R. The basics of epithelial–mesenchymal transition. J Clin Invest 2009; 119: 1420–8
5 Tanaka H, Kono E, Tran CP et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat Med 2010; 16: 1414–20

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