Category: Article of the Week

Editorial: Fusion‐guided biopsy to guide active surveillance in African‐American men?

November 6, 2019/by Brandon Mahal

This timely and important article by Bloom et al. [1] highlights findings that warrant special attention in an effort to address and reduce racial disparities in low‐risk prostate cancer. At the population level, African‐American (AA) men are 76% more likely to be diagnosed with prostate cancer and 2.2‐times more likely to die from prostate cancer compared with other men in the USA. Emerging evidence suggests that racial disparities in patients diagnosed with advanced stage or higher‐risk disease may be predominantly accounted for by social factors and healthcare access [1,2]. In contrast, there is growing evidence that raises the question of whether disparities in low‐risk disease may be driven by underlying tumour and/or biopsy misclassification differences [2,3,4].

Bloom et al. [1] examined a USA study cohort from the National Cancer Institute (NCI) and found that amongst men referred to the NCI with a prior 12‐core systematic biopsy (SB), AA men with Gleason Grade (GG) 1 disease were nearly twice as likely to be upgraded by targeted multiparametric (mp)MRI fusion‐guided biopsy when compared with non‐AA men. These findings are consistent with contemporary data in the USA‐based Surveillance, Epidemiology and End Results Program, where amongst 20 125 men (including 2594 AA men) with clinical National Comprehensive Cancer Network (NCCN) low‐risk prostate cancer (GG 1 on biopsy) who underwent radical prostatectomy (RP) from 2010 to 2015, AA men were more likely to have pathological upgrading at the time of RP when compared with non‐AA men (47.3% vs 45.3%; adjusted hazard ratio 1.12, 95% CI 1.03–1.22, P = 0.007; unpublished analysis). Furthermore, the study findings are consistent with prior work that has shown that AA men with NCCN very‐low‐risk disease who underwent RP were more likely to have disease upgrading at RP (27.3% vs 14.4%; P < 0.001), positive surgical margins (9.8% vs 5.9%; P = 0.02), and higher Cancer of the Prostate Risk Assessment Post‐Surgical scoring system (CAPRA‐S) scores [5]; notably these AA men with very‐low‐risk disease also had a distinct zonal distribution of prostate cancer when compared with other men, with anterior tumours that are more difficult to sample by standard 12‐core SB alone [3].

Although low‐grade/risk disease is considered prognostically favourable and can be managed conservatively with active surveillance (AS), racial differences in outcome and zonal distribution of disease observed in favourable‐risk cohorts has led to controversy over the use of AS in AA men. Furthermore, conservative management trials have severely under‐represented patients of African descent. In this setting, most treatment guidelines advise caution when applying AS to AA patients. As such, although AS rates for low‐risk disease have nearly tripled in the USA from 14.5% to 42.1% from 2010 to 2015, there is lower relative uptake of AS for AA men compared with other men, even after adjusting for socioeconomic status, suggesting that providers and patients may be ‘risk‐stratifying’ AA patients with low‐risk disease into a higher‐risk category, and therefore less willing to proceed with AS [6].

Ultimately, the application of AS to AA patients with low‐risk disease will remain controversial and providers will make decisions based on observational data until a representative trial can help answer: (i) whether AA men diagnosed with low‐risk disease who are eligible for AS might be more likely to have distinct aggressive disease features compared with non‐AA men, and (ii) whether there might be strategies, such as guided‐fusion biopsy and/or incorporation of tumour genomics prior to AS, to help identify AA patients with underlying aggressive disease and appropriately select AA men with low‐risk disease for AS protocols.

The most interesting and important result found by Bloom et al. [1] is that amongst men who underwent mpMRI fusion‐guided biopsy after initial diagnosis of low‐risk disease on SB and who ultimately were continued on AS (those who were upgraded at the time of fusion‐guided biopsy became ineligible for AS), AA and non‐AA men had similar progression rates on AS. This result suggests that incorporation of techniques such as mpMRI and fusion biopsy may help better select AA men for AS when compared with standard 12‐core SB. Specifically, MRI guided‐biopsy may reduce disparate misclassification errors by increasing detection of higher grade and more anterior tumours that are more likely to be found in AA men who initially present with low‐risk disease after standard SB. As such, this strategy may represent one mechanism to better select AA men for AS and therefore may be able to reduce disparities in low‐risk disease.

The authors should be applauded for their important work, and this study builds on a growing body of evidence that clearly demonstrates the need for prospective trials examining different diagnostic/prognostic strategies that may reduce disparities in low‐risk disease by more appropriately selecting AA men for AS strategies.

by Brandon A. Mahal (@BrandonMahal)

References

Krimphove MJ, Cole AP, Fletcher SA et al. Evaluation of the contribution of demographics, access to health care, treatment, and tumor characteristics to racial differences in survival of advanced prostate cancer. Prostate Cancer Prostatic Dis 2019; 22: 125– 36
Mahal BA, Berman RA, Taplin ME, Huang FW Prostate cancer‐specific mortality across Gleason scores in black vs nonblack men. JAMA 2018; 320: 2479– 81
Sundi D, Kryvenko ON, Carter HB, Ross AE, Epstein JI, Schaeffer EM Pathological examination of radical prostatectomy specimens in men with very low risk disease at biopsy reveals distinct zonal distribution of cancer in black American men. J Urol 2014; 191: 60– 7
Mahal BA, Alshalalfa M, Spratt DE Prostate cancer genomic‐risk differences between African‐American and white men across Gleason scores. Eur Urol 2019; 75: 1038– 40
Sundi D, Ross AE, Humphreys EB et al. African American men with very low‐risk prostate cancer exhibit adverse oncologic outcomes after radical prostatectomy: should active surveillance still be an option for them? J Clin Oncol 2013; 31: 2991– 7
Butler S, Muralidhar V, Chavez J et al. Active surveillance for low‐risk prostate cancer in black patients. N Engl J Med 2019; 380: 2070– 2

Video: Use of mpMRI and fusion‐guided biopsies to properly select and follow African‐American men on active surveillance

November 6, 2019/by Jonathan B. Bloom

Use of multiparametric magnetic resonance imaging and fusion‐guided biopsies to properly select and follow African‐American men on active surveillance

Read the full article

Abstract

Objectives

To determine the rate of Gleason Grade Group (GGG) upgrading in African‐American (AA) men with a prior diagnosis of low‐grade prostate cancer (GGG 1 or GGG 2) on 12‐core systematic biopsy (SB) after multiparametric magnetic resonance imaging (mpMRI) and fusion biopsy (FB); and whether AA men who continued active surveillance (AS) after mpMRI and FB fared differently than a predominantly Caucasian (non‐AA) population.

Patients and methods

A database of men who had undergone mpMRI and FB was queried to determine rates of upgrading by FB amongst men deemed to be AS candidates based on SB prior to referral. After FB, Kaplan–Meier curves were generated for AA men and non‐AA men who then elected AS. The time to GGG upgrading and time continuing AS were compared using the log‐rank test.

Results

AA men referred with GGG 1 disease on previous SB were upgraded to GGG ≥3 by FB more often than non‐AA men, 22.2% vs 12.7% (P = 0.01). A total of 32 AA men and 258 non‐AA men then continued AS, with a median (interquartile range) follow‐up of 39.19 (24.24–56.41) months. The median time to progression was 59.7 and 60.5 months, respectively (P = 0.26). The median time continuing AS was 61.9 months and not reached, respectively (P = 0.80).

Conclusions

AA men were more likely to be upgraded from GGG 1 on SB to GGG ≥3 on initial FB; however, AA and non‐AA men on AS subsequently progressed at similar rates following mpMRI and FB. A greater tendency for SB to underestimate tumour grade in AA men may explain prior studies that have shown AA men to be at higher risk of progression during AS.

View more videos

Residents’ podcast: Artificial intelligence applications in urology

October 31, 2019/by Maria Uloko

Maria Uloko is a Urology Resident at the University of Minnesota Hospital. In this podcast she is joined by Dr Christopher Weight, an Associate Professor in the Department of Urology at the University of Minnesota. They are discussing a recent BJUI Article of the month:

Current status of artificial intelligence applications in urology and their potential to influence clinical practice

Read the full article

Abstract

Objective

To investigate the applications of artificial intelligence (AI) in diagnosis, treatment and outcome prediction in urologic diseases and evaluate its advantages over traditional models and methods.

Materials and methods

A literature search was performed after PROSPERO registration (CRD42018103701) and in compliance with Preferred Reported Items for Systematic Reviews and Meta‐Analyses (PRISMA) methods. Articles between 1994 and 2018 using the search terms “urology”, “artificial intelligence”, “machine learning” were included and categorized by the application of AI in urology. Review articles, editorial comments, articles with no full‐text access, and nonurologic studies were excluded.

Results

Initial search yielded 231 articles, but after excluding duplicates and following full‐text review and examination of article references, only 111 articles were included in the final analysis. AI applications in urology include: utilizing radiomic imaging or ultrasonic echo data to improve or automate cancer detection or outcome prediction, utilizing digitized tissue specimen images to automate detection of cancer on pathology slides, and combining patient clinical data, biomarkers, or gene expression to assist disease diagnosis or outcome prediction. Some studies employed AI to plan brachytherapy and radiation treatments while others used video-based or robotic automated performance metrics to objectively evaluate surgical skill. Compared to conventional statistical analysis, 71.8% of studies concluded that AI is superior in diagnosis and outcome prediction.

Conclusion

AI has been widely adopted in urology. Compared to conventional statistics AI approaches are more accurate in prediction and more explorative for analyzing large data cohorts. With an increasing library of patient data accessible to clinicians, AI may help facilitate evidence‐based and individualized patient care.

More podcasts

BJUI Podcasts now available on iTunes, subscribe here https://itunes.apple.com/gb/podcast/bju-international/id1309570262

Dr Weight specializes in the surgical treatment of urologic cancers including prostate, bladder, kidney, adrenal, testis and penile cancer. He performs open, endoscopic, laparoscopic, robotic (da Vinci) and retroperineoscopic surgery.

Dr Weight completed his residency training at Cleveland Clinic where he received several awards including the George and Grace Crile Traveling Fellowship Award, the Society of Laparoendoscopic Surgeons Resident Achievement Award and the ASCO Genitourinary Cancer Symposium Merit Award. Dr. Weight then completed a fellowship in Urologic Oncology at Mayo Clinic, where he also completed a Masters degree in Clinical and Translational Research from Mayo Graduate School and was awarded the Mayo Fellows Association Humanitarian Award.

Dr Weight believes that medical research is a key component to offering excellent patient care. His research is focused on improving patient outcomes and the use of artificial intelligence in different urologic applications. He is an author of more than 45 peer-reviewed publications and book chapters and has been invited to speak at regional, national and international conferences.

Article of the week: mpMRI and follow‐up to avoid prostate biopsy in 4259 men

October 30, 2019/by Wulphert Venderink

Every week, the Editor-in-Chief selects an 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 editorial written by a prominent member of the urological community and a video prepared by the authors. These are 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.

Multiparametric magnetic resonance imaging and follow‐up to avoid prostate biopsy in 4259 men

Wulphert Venderink*, Annemarijke van Luijtelaar*, Marloes van der Leest*, Jelle O. Barentsz*, Sjoerd F.M. Jenniskens*, Michiel J.P. Sedelaar^†,Christina Hulsbergen-van de Kaa^‡, Christiaan G. Overduin* and Jurgen J. Fütterer*

*Department of Radiology and Nuclear Medicine, ^†Department of Urology, and ^‡Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands

Read the full article

Abstract

Objective

To determine the proportion of men avoiding biopsy because of negative multiparametric magnetic resonance imaging (mpMRI) findings in a prostate MRI expert centre, and to assess the number of clinically significant prostate cancers (csPCa) detected during follow‐up.

Patients and method

Retrospective study of 4259 consecutive men having mpMRI of the prostate between January 2012 and December 2017, with either a history of previous negative transrectal ultrasonography‐guided biopsy or biopsy naïve. Patients underwent mpMRI in a referral centre. Lesions were classified according to Prostate Imaging Reporting And Data System (PI‐RADS) versions 1 and 2. Negative mpMRI was defined as an index lesion PI‐RADS ≤2. Follow‐up until 13 October 2018 was collected by searching the Dutch Pathology Registry (PALGA). Gleason score ≥3 + 4 was considered csPCa. Kaplan–Meier analysis and univariable logistic regression models were used in the cohort of patients with negative mpMRI and follow‐up.

Fig. 2. Distribution of PI‐RADS scored in the entire cohort.

Results

Overall, in 53.6% (2281/4259) of patients had a lesion classified as PI‐RADS ≤2. In 320 patients with PI‐RADS 1 or 2, follow‐up mpMRI was obtained after a median (interquartile range) of 57 (41–63) months. In those patients, csPCa diagnosis‐free survival (DFS) was 99.6% after 3 years. Univariable logistic regression analysis revealed age as a predictor for csPCa during follow‐up (P < 0.05). In biopsied patients, csPCa was detected in 15.8% (19/120), 43.2% (228/528) and 74.5% (483/648) with PI‐RADS 3, 4 and 5, respectively.

Conclusion

More than half of patients having mpMRI of the prostate avoided biopsy. In those patients, csPCa DFS was 99.6% after 3 years.

Editorial: Avoiding biopsy in men with PI‐RADS scores 1 and 2 on mpMRI of the prostate, ready for prime time?

October 30, 2019/by Mark Frydenberg

In 2019 is it safe to avoid prostate biopsy in men with Prostate Imaging Reporting and Data System (PI‐RADS) score 1 and 2 lesions reported on their multiparametric MRI (mpMRI)? In this journal, Venderink et al. [1] suggest that more than half the men being investigated for suspected prostate cancer could indeed safely avoid an initial biopsy. However, like other investigators in this field, the authors make an assumption in their study that there is such a paucity of clinically significant cancer in men with PI‐RADS 1 and 2 lesions, that biopsy is not deemed necessary, as in the PRECISION study [2]. In this study [1] from the Netherlands, of the 2281 men with an initial diagnosis of PI‐RADS 1 or 2 lesions, only 320 men had follow‐up mpMRI, and biopsies were only performed in a small number of men with PI‐RADS scores ≥ 3. Whilst one could conclude that 84% of men did not progress, based on serial imaging, one cannot prove what may have been missed.

Comparing mpMRI of the prostate to the reference standard of radical prostatectomy whole‐mount specimens, a study from the University of California, Los Angeles showed that mpMRI can potentially miss up to 35% of clinically significant cancers, and up to 20% of high grade cancers. It found that 74% of missed solitary tumours were clinically significant, including 23% with Gleason ≥4 + 3 = 7, and that 38.7% were >1 cm in diameter [3]. As such, these missed cancers were not all small, low grade and clinically insignificant. An Italian study confirmed these findings with a detection rate of clinically significant prostate cancer outside the index lesion seen on mpMRI in 30% of patients [4]. All urologists are aware that biopsy by any means can never detect all the cancers seen on formal whole‐mount histopathology, but we do have evidence using transperineal prostate mapping biopsies as the reference standard as to what may be missed. The PROMIS study [5] provides the best evidence using several definitions of clinically significant cancer. Using Gleason ≥4 + 3 or cancer core length >6 mm the negative predictive value (NPV) of a negative mpMRI was 89%. However, if the criteria were altered to any Gleason 7 cancer, the NPV falls to 76%. This is also supported by a multicentre study by Hansen et al. [6], which demonstrated that the NPV of a negative mpMRI for excluding Gleason 7–10 cancer was 80%, but improved to 91% with a PSA density of <0.1 ng/mL/mL, and to 89% with a PSA density of <0.15 ng/mL/mL. It is important to note that these studies used transperineal biopsies rather than 12‐core transrectal biopsies, suggesting the latter to be a more unreliable reference test with a greater probability of missing clinically significant cancer on systematic sampling.

Are all Gleason 3 + 4 = 7 cancers < 6 mm in core length, for example, 5 mm Gleason 3 + 4 (40%) = 7 cancer, truly clinically insignificant? If that were the case, favourable intermediate‐risk prostate cancer would have to be an accepted indication for active surveillance (AS) in men, and in most cases this is not the case. National Comprehensive Cancer Network guidelines recommend that men with favourable intermediate‐risk prostate cancer should only be offered AS if the PSA is <10 ng/mL, the lesion is cT1 and the percentage of positive cores is <50%. Prostate Cancer Research International Active Surveillance (PRIAS) criteria only accept men with favourable intermediate‐risk prostate cancer if there is a maximum of two cores involved, PSA density is <0.2 ng/mL/mL, and if it represents <10% of the core. Both European Association of Urology and AUA guidelines caution that if men are offered AS with favourable intermediate‐risk disease, they should be warned of the greater risk of developing metastatic spread. It is therefore clear that major international guidelines do not fully support AS for intermediate‐risk prostate cancers and therefore it may not be acceptable to be missing Gleason 3 + 4 cancers in up to 10–20% of men with normal prostate mpMRI results.

Multiparametric MRI of the prostate has been a huge advance in prostate cancer diagnostics and is now widely used internationally, but does have limitations. Based on the available data, men who choose not to be biopsied with a normal prostate mpMRI should be warned, as part of informed consent, that a clinically significant cancer could be missed in up to 10–20% of cases (depending on PSA density) and close follow‐up should be recommended. One could easily argue that men with normal prostate mpMRI but with PSA density >0.15 ng/mL/mL should still be offered a systematic biopsy. Perhaps the future lies in the genomics of mpMRI‐visible vs ‐invisible lesions, with a recent study showing that there is a confluence of aggressive molecular and pathological features in lesions visible on MRI. Future research may be able to determine if indeed it is safe to leave some Gleason 3 + 4 = 7 cancers undetected if invisible on mpMRI because of their lack of genomic and metabolic aggression rather than based on their Gleason pattern [7].

by Mark Frydenberg

References

Verderink W, Van Luijtelaar A, Van der Leest M et al. Multiparametric MRI and follow up to avoid prostate biopsy in 4259 men. BJU Int 2019; 124: 775– 84
Kasivisvanathan AS, Rannikko M, Borghi V et al. MRI targeted or standard biopsy for prostate cancer diagnosis. N Engl J Med 2018; 378: 1767– 77
Johnson DC, Raman SS, Mirak SA et al. Detection of individual prostate cancer foci via multiparametric magnetic resonance imaging. Eur Urol 2019; 75: 712– 20
Stabile A, dell’Oglio P, de Cobelli F et al. Association between prostate Imaging Reporting and data system (PIRADS) score for the index lesion and multifocal clinically significant prostate cancer. Eur Urol Oncol 2018; 1: 29– 3336
Ahmed HU, Basally A, Brown LC et al. Diagnostic accuracy of multiparametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017; 389: 815– 22
Hansen NL, Barrett T, Kesch C et al. Multicentre evaluation of magnetic resonance imaging supported transperineal prostate biopsy in biopsy naïve men with suspicion of prostate cancer. BJU Int 2018; 122: 40– 9
Houlahan KE, Salmasi A, Sadun TY et al. Molecular hallmarks of multiparametric magnetic resonance imaging visibility in prostate cancer. Eur Urol 2019; 76: 18– 23

Video: mpMRI and follow-up to avoid prostate biopsy in 4259 men

October 30, 2019/1 Comment/by Wulphert Venderink

Multiparametric magnetic resonance imaging and follow-up to avoid prostate biopsy in 4259 men

Read the full article

Abstract

Objective

Patients and methods

Results

Conclusion

More than half of patients having mpMRI of the prostate avoided biopsy. In those patients, csPCa DFS was 99.6% after 3 years.

View more videos

Article of the week: Androgen receptor (AR) splice variant 7 and full‐length AR expression is associated with clinical outcome: a translational study in patients with castrate‐resistant prostate cancer

October 23, 2019/by Romano Danesi

In addition to the article itself, there is an editorial written by a prominent member of the urological community. These are 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.

Androgen receptor (AR) splice variant 7 and full‐length AR expression is associated with clinical outcome: a translational study in patients with castrate‐resistant prostate cancer

Marzia Del Re*, Stefania Crucitta*, Andrea Sbrana^†, Eleonora Rofi*, Federico Paolieri^†, Giulia Gianfilippo*, Luca Galli^†, Alfredo Falcone^†, Riccardo Morganti^‡, Camillo Porta^§¶, Eleni Efstathiou**, Ron van Schaik^††, Guido Jenster^‡‡and Romano Danesi*

*Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, ^†Medical Oncology Unit, Department of Translational Research and New Technologies in Medicine, ^‡Section of Statistics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ^§Department of Internal Medicine, University of Pavia, ^¶Division of Translational Oncology, I.R.C.C.S. Istituti Clinici Scientifici Maugeri, Pavia, Italy, **Division of Cancer Medicine, Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Centre, Houston, TX, USA, ^††Department of Clinical Chemistry, and ^‡‡Department of Urology, Erasmus University Medical Centre, Rotterdam, The Netherlands

Read the full article

Abstract

Objectives

To investigate if full‐length androgen receptor (AR‐FL) is associated with resistance to androgen receptor (AR)‐directed therapy independently and/or combined with AR splice variant 7 (AR‐V7).

Patients and Methods

Plasma samples were prospectively collected from 73 patients with castrate‐resistant prostate cancer before first‐ or second‐line AR‐directed therapy. mRNA was isolated from exosomes and AR‐FL and AR‐V7 were analysed by droplet digital PCR.

Results

AR‐FL was detected in all patients and 22% of them were AR‐V7‐positive at baseline. AR‐FL expression was significantly higher in AR‐V7‐positive vs AR‐V7‐negative patients (P < 0.0001). After stratifying patients by tertile for AR‐FL expression, progression‐free survival (PFS) was 22 vs 18 vs 4 months for lower vs intermediate vs higher tertile, respectively (P = 0.0003). The median PFS and overall survival were significantly longer in AR‐V7‐negative vs AR‐V7‐positive patients (20 vs 4 months, P < 0.0001; not reached vs 9 months, P < 0.0001, respectively).

Conclusions

Resistance to AR‐directed therapy was associated with the presence of AR‐V7; however, AR‐FL expression may help better refine response and survival of patients to AR‐directed therapy. Both biomarkers, if validated in prospective trials, could be used to select the best treatment strategy.

Editorial: Androgen receptor splice variant 7 (AR‐V7) and AR full‐length (AR‐FL) as predictive biomarkers of therapeutic resistance: partners in crime?

October 23, 2019/by William D. Figg

The prostate cancer treatment armamentarium has expanded over the last decade to include taxane‐based chemotherapies (docetaxel, cabazitaxel), sipulecel‐T, radium‐233, and newer androgen receptor (AR) signalling (ARS) inhibitors (abiraterone, enzalutamide, apalutamide). Despite these improvements, persistent ARS remains a key driver of prostate cancer progression after androgen‐deprivation therapy (ADT), transition to castrate‐resistant prostate cancer (CRPC), and even after resistance to ARS inhibitors. Cross‐resistance between ARS inhibitors is common. Predictive biomarkers are therefore needed to optimise treatment selection. Mechanisms of resistance have been attributed to genomic heterogeneity; molecular alterations to the AR and/or upregulation of bypass mechanisms that drive AR activation, including expression of AR splice variants lacking the ligand‐binding domain. AR splice variant 7 (AR‐V7), the most abundant AR splice variant, has been implicated in abiraterone and enzalutamide resistance and poor patient outcomes. Whilst knowledge of AR‐V7 status may guide treatment decisions, AR‐V7 alone cannot sufficiently predict response; detection of other variants (AR^v567es) or partners, such as AR full‐length (AR‐FL), might improve prediction.

In this issue of BJUI, Del Re et al. [1] evaluated the expression of AR‐V7 and AR‐FL in exosomal RNA as combined predictive biomarkers of resistance to ARS therapy. AR‐FL was detected in all 73 patients (22% were AR‐V7 positive), and AR‐FL expression was significantly higher in AR‐V7‐positive vs AR‐V7‐negative patients (P < 0.001). These findings that AR‐V7 detection has the higher impact on response to therapy confirmed several previous studies; however, the authors took a novel approach to refine the predictive value by stratifying the patient pool into AR‐V7‐positive and ‐negative populations, and then into tertiles based on AR‐FL expression. Analysis of patient outcomes, both in terms of overall (OS) and progression‐free survival (PFS), in these six groups reveals a more nuanced potential treatment strategy. Although AR‐V7 expression better predicts OS and PFS to ARS therapy than does AR‐FL expression, patients with discordant AR‐FL expression relative to their AR‐V7 expression may also benefit from treatment different from that which their AR‐V7 status would suggest. For example, patients positive for AR‐V7 but in the bottom tertile of AR‐FL expression may be effectively treated with anti‐androgen therapies; a breakthrough for patients ineligible for chemotherapy. Additionally, patients negative for AR‐V7 but in the top tertile of AR‐FL expression may respond better to front‐line taxane chemotherapy. Thus, the addition of AR‐FL to AR‐V7 may aid in better treatment selection.

Recently, the Development of Circulating Molecular Predictors of Chemotherapy and Novel Hormonal Therapy Benefit in Men With Metastatic Castration‐Resistant Prostate Cancer (PROPHECY) trial (NCT02269982) prospectively validated the clinical utility of AR‐V7 by demonstrating that detection of AR‐V7 in circulating tumour cells (by two blood‐based assays) is predictive of whether patients with CRPC have become resistant to ARS inhibitors, thereby reducing future benefit from further ARS inhibitor therapy. Although the PROPHECY study found a strong association between positive AR‐V7 and anti‐androgen therapy resistance, some AR‐V7‐negative men did still exhibit resistance to anti‐androgen therapy, showing that a second predictive marker (like AR‐FL) would be helpful to further guide patient selection [2]. It would be interesting to see whether the approach described in Del Re et al. [1] could be replicated using the PROPHECY trial data. Moreover, a recent study established that AR‐V7 is very rarely expressed in primary tissue, with expression emerging in response to primary ADT (and in CRPC progression) and further enhanced in resistance to ARS inhibitors [3]. AR‐V7 was shown to associate with AR‐FL expression and copy number in CRPC, with many cases of high AR‐FL expression having undetectable/low AR‐V7 expression, indicating that mRNA splicing remains crucial for AR‐V7 generation. Although AR‐V7‐negative tumours responded to ARS therapy as expected, some AR‐V7‐positive tumours also responded, suggesting that AR‐V7 detection does not preclude response to ARS therapy and providing further evidence that a second marker could be useful as a predictive tool. Finally, AR‐V7 status in determining taxane response/resistance remains in conflict with studies either showing that taxanes retain activity in patients with positive AR‐V7 or that the absence of AR splice variants (AR‐V7 and AR^v567es) may be associated with superior response to taxane treatment, leading to the hypothesis that AR‐FL would be most sensitive to taxane treatment, followed by AR^v567es and AR‐V7 [4,5].

While several studies have shown that the AR‐V7/AR‐FL ratio tends to be elevated in CRPC tissues, the role of AR‐FL as a predictive biomarker for AR‐targeted therapy remains controversial. One study found that positive AR‐V7, but not higher AR‐FL, was associated with worse prognosis [6]. As detection methodologies in liquid biopsies and AR data analysis improve over time, the interplay between AR‐FL and AR‐V7, as well other AR variants, warrants further study, which should shed light on whether AR‐V7 and/or AR‐FL (either as homodimers or possibly heterodimers with AR‐V7) are driving resistance to ARS inhibitors. Are they equal partners or is one the dominant driver of the crime?

by Roberto H. Barbier, Cindy H. Chau and William D. Figg

References

Del Re M, Crucitta S, Sbrana A et al. AR‐V7 and AR‐FL expression is associated with clinical outcome: a translational study in patients with castrate-resistant prostate cancer. BJU Int 2019; 124: 693– 700
Armstrong AJ, Halabi S, Luo J et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high‐risk castration‐resistant prostate cancer: the PROPHECY study. J Clin Oncol 2019; 37: 1120– 9
Sharp A, Coleman I, Yuan W et al. Androgen receptor splice variant‐7 expression emerges with castration resistance in prostate cancer. J Clin Invest 2019; 129: 192– 208
Scher HI, Graf RP, Schreiber NA et al. Assessment of the validity of nuclear‐localized androgen receptor splice variant 7 in circulating tumor cells as a predictive biomarker for castration‐resistant prostate cancer. JAMA Oncol 2018; 4: 1179– 86
Tagawa ST, Antonarakis ES, Gjyrezi A et al. Expression of AR‐V7 and ARv(567es) in circulating tumor cells correlates with outcomes to taxane therapy in men with metastatic prostate cancer treated in TAXYNERGY. Clin Cancer Res 2019; 25: 1880– 8
Zhu Y, Sharp A, Anderson CM et al. Novel junction‐specific and quantifiable in situ detection of AR‐V7 and its clinical correlates in metastatic castration‐resistant prostate cancer. Eur Urol 2018; 73: 727– 35

Article of the week: The global prevalence of erectile dysfunction: a review

October 16, 2019/by Mieke Van Hemelrijck

In addition to the article itself, there is a video prepared by the authors. Please 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.

The global prevalence of erectile dysfunction: a review

Anna Kessler*, Sam Sollie*, Ben Challacombe^†, Karen Briggs^† and Mieke Van Hemelrijck*

*School of Cancer and Pharmaceutical Sciences, King’s College London, Translational Oncology and Urology Research (TOUR) and ^†Urology Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Read the full article

Abstract

Objective

To evaluate the global prevalence of erectile dysfunction (ED); as well as its association with physiological and pathological ageing by examining the relationship between ED and cardiovascular disease (CVD), benign prostatic hyperplasia (BPH), and dementia. We also aimed to explain the treatment for erectile dysfunction and characterize discrepancies caused by the use of different ED screening tools.

Methods

The Excerpta Medica dataBASE (EMBASE) and Medical Literature Analysis and Retrieval System Online (MEDLINE) were searched to find population‐based studies investigating the prevalence of ED and the association between ED and CVD, BPH and dementia in the general population.

Results

The global prevalence of ED was 3–76.5%. ED was associated with increasing age. Use of the International Index of Erectile Function (IIEF) and Massachusetts Male Aging Study (MMAS)‐derived questionnaire identified a high prevalence of ED in young men. ED was positively associated with CVD. Men with ED have an increased risk of all‐cause mortality odds ratio (OR) 1.26 (95% confidence interval [CI] 1.01–1.57), as well as CVD mortality OR 1.43 (95% CI 1.00–2.05). Men with ED are 1.33–6.24‐times more likely to have BPH then men without ED, and 1.68‐times more likely to develop dementia than men without ED.

Conclusion

ED screening tools in population‐based studies are a major source of discrepancy. Non‐validated questionnaires may be less sensitive than the IIEF and MMAS‐derived questionnaires. ED constitutes a large burden on society given its high prevalence and impact on quality of life, and is also a risk factor for CVD, dementia and all‐cause mortality.

Video: The global prevalence of erectile dysfunction

October 16, 2019/by Mieke Van Hemelrijck

The global prevalence of erectile dysfunction: a review

Read the full article

Abstract

Objective

To evaluate the global prevalence of erectile dysfunction (ED); as well as its association with physiological and pathological ageing by examining the relationship between ED and cardiovascular disease (CVD), benign prostatic hyperplasia (BPH), and dementia. We also aimed to characterise discrepancies caused by the use of different ED screening tools.

Methods

Results

Conclusion

ED screening tools in population‐based studies are a major source of discrepancy. Non‐validated questionnaires may be less sensitive than the IIEF and MMAS‐derived questionnaire. ED constitutes a large burden on society given its high prevalence and impact on quality of life, and is also a risk factor for CVD, dementia, and all‐cause mortality.

View more videos