Prostate Cancer and Prostatic Diseases

Prostate Cancer and Prostatic Diseases

Role of Physical Activity and Its Link with Lower Rates of Progression in Men on Active Surveillance - Editorial

“Eat right and exercise”. As a prostate cancer provider, I can’t count how many times I have given this advice to my patients. I am always afraid when they ask back, “Will it actually help”? The truth is, we don’t know. While increasing data suggest that diet and exercise may modulate prostate cancer risk and even progression in some studies, the totality of the evidence remains weak. Into this void, steps an important paper exploring the role of physical activity (i.e. exercise) and its link with lower rates of progression in men on active surveillance.

In this study, the authors assessed 85 men with low-risk prostate cancer being managed by active surveillance. All men completed a physical activity questionnaire at baseline and were categorized as sedentary (n=24), moderately active (n=46), or active (n=15). The authors then assessed the risk of grade reclassification, commonly used criteria for “progression” among men on active surveillance. The authors found that those who progressed were less physically active (p=0.056). Importantly, over time, the level of physical activity was significantly predictive of who progressed (p=0.033). Indeed, on multivariable analysis, the level of physical activity was the only significant predictor of progression (p=0.016). The authors concluded that physical activity may influence prostate cancer evolution.

Physical Activity Decreases the Risk of Cancer Reclassification in Patients on Active Surveillance: A Multicenter Retrospective Study - Full-Text Article

Background: Physical activity (PA) is associated with favorable outcomes in prostate cancer (PCa) patients. We assessed its effect on the risk of PCa reclassification (PCaR) during active surveillance.

Methods: Anthropometric, demographic, and clinical data concerning men diagnosed with a low-risk PCa and initially managed with active surveillance at the two participating institutions were retrospectively collected. The Physical Activity Scale for the Elderly (PASE) was used for patients’ self-assessment of their daily exercise and their consequent stratification into three groups: sedentary (PASE ≤ 65), moderately active (65 < PASE < 125), active (PASE ≥ 125). Kaplan–Meier model was used to evaluate the predictive role of PA on PCaR, computed at 2, 5, 10 years after diagnosis; differences between lifestyle groups were assessed using the log-rank and uni-/multivariable Cox analyses applied to identify predictors of reclassification.

PSA Response to Antiandrogen Withdrawal To Identify the Response on Type of Antiandrogens - Editorial

In 2021-2022, many more men globally will receive a potent AR inhibitor in either the metastatic hormone sensitive prostate cancer (mHSPC), non-metastatic castration resistant prostate cancer (nmCRPC), or mCRPC settings, with improved long term outcomes based on multiple positive phase 3 trials of abiraterone, enzalutamide, apalutamide, and darolutamide. This new form of maximal or combined androgen blockade in addition to ADT has extended survival, delaying symptomatic and metastatic progression, improving durable remissions based on PSA and imaging response criteria, major successes for our patients.

With first generation AR inhibitors such as flutamide and bicalutamide, prolonged responses to these therapies often led to anti-androgen withdrawal responses which were observed at progression after the patient stopped these agents. These withdrawal responses were due to point mutations in the ligand binding domains of the AR (such as T877A), turning these older agents into agonists that stimulated AR activity and PSA production. Withdrawal responses typically would last 3-6 months, but occasionally patients would experience prolonged withdrawal responses lasting over a year. However, the prevalence of withdrawal responses to stopping these novel AR inhibitors has not been well described.

PSA Response to Antiandrogen Withdrawal: A Systematic Review and Meta-Analysis - Full-Text Article

Background: Antiandrogen withdrawal (AAW) response is the paradoxical decrease in prostate-specific antigen (PSA) following the withdrawal of antiandrogen in patients with advanced prostate cancer. Currently, the reported literature on the proportion of patients exhibiting AAW response and the differences in PSA response between the types of antiandrogens is unclear.

Methods: This review aimed to explore the PSA response to AAW and to identify if the response depends on the type of antiandrogens. A literature search was performed using databases PubMed, Cochrane and EMBASE with a cut-off date of 23rd of November 2020. Studies reporting on outcomes of AAW and prostate cancer were included. Studies were screened by two reviewers and relevant data extracted. Meta-analysis of outcomes was reported using random-effects and fixed-effects model. A subgroup analysis was performed for type of antiandrogen.

Real-World Clinical Utility of Decipher Biopsy Testing in Localized Prostate Cancer

In prostate pre- and post-biopsy decision making, more precision is urgently needed. Whereas expert imaging and biomarker-based risk scores already enable the clinician in this respect, the dilemma remains for those patients that are diagnosed with apparent indolent cancer. Additional diagnostic tools that (de)select patients for active surveillance (AS) would provide a great benefit for the patient.

A commercially available test is Decipher Biopsy. The potential of this test on post-radical prostatectomy decision-making is well documented. This is also shown for other molecular gene expression-based classifiers. This paper describes the outcome of a state-wide registry of patients in AS. The test is significantly associated with time to treatment and time to failure. The paper shows that the Decipher score correlates with Grade Group, NCCN- and CAPRA risk scores.

Impact of Decipher Biopsy Testing on Clinical Outcomes in Localized Prostate Cancer in a Prospective Statewide Collaborative - Full-Text Article

BACKGROUND: Decipher Biopsy is a commercially available gene expression classifier used in risk stratification of newly diagnosed prostate cancer (PCa). Currently, there are no prospective data evaluating its clinical utility. We seek to assess the clinical utility of Decipher Biopsy in localized PCa patients.

METHODS: A multi-institutional study of 855 men who underwent Decipher Biopsy testing between February 2015 and October 2019. All patients were tracked through the prospective Michigan Urological Surgery Improvement Collaborative and linked to the Decipher Genomics Resource Information Database (GRID® ; NCT02609269). Patient matching was performed by an independent third-party (ArborMetrix Inc.) using two or more unique identifiers.

Diagnostic Accuracy of Magnetic Resonance Imaging Targeted Biopsy Techniques Compared to Transrectal Ultrasound Guided Biopsy of the Prostate: A Systematic Review and Meta-Analysis - Full Text

BACKGROUND: Multiparametric MRI localizes cancer in the prostate, allowing for MRI guided biopsy (MRI-GB) 43 alongside transrectal ultrasound-guided systematic biopsy (TRUS-GB). Three MRI-GB approaches exist; visual estimation (COG-TB); fusion software-assisted (FUS-TB) and MRI ‘in-bore’ biopsy (IB-TB). It is unknown whether any of these are superior.We conducted a systematic review and meta-analysis to address three questions. First, whether MRI-GB is superior to TRUS-GB at detecting clinically significant PCa (csPCa). Second, whether MRI-GB is superior to TRUS-GB at avoiding detection of insignificant PCa. Third, whether any MRI-GB strategy is superior at detecting csPCa.

MRI Prior to Prostate Biopsy Is Best Evidence Practice and a Standard of Care

As a randomised controlled trial, the PRECISION study¹ showed a clear benefit of an MRI pathway in terms of improved detected of clinically significant prostate cancers and decreased detection of clinically insignificant prostate cancers. However, it seems that not all urologists are convinced by the data or sufficiently motivated to change clinical practice on the strength of this study. That said, it is accepted that access to prostate MRI due to reimbursement issues could play a role in some jurisdictions.

The 2021 EAU Guidelines² have clearly spelt out a recommendation that an MRI should be performed prior to prostate biopsy whether it be those men who are biopsy naïve or have previously had a negative prostate biopsy. The strength rating for both recommendations is “strong”. The 2021 NCCN Guidelines³ are a little more guarded in that the recommendation for an MRI prior to prostate biopsy is qualified by the words ‘if available’. Particularly in the US, 3T MRI is widely available but sadly, it is an issue of reimbursement despite the highest level of evidence to support its routine use prior to prostate biopsy.

What Is the Minimal Dose for Resistance Exercise Effectiveness in Prostate Cancer Patients? Systematic Review and Meta-Analysis on Patient-Reported Outcomes - Full-Text Article

Background: Active treatments for prostate cancer are well known to result in several adverse effects such as fatigue, depression and anxiety symptoms, impacting the overall quality of life (QoL) and wellbeing of a considerable proportion of patients. Resistance-based exercise interventions have shown positive effects to reduce or mitigate these treatment-related side effects. However, the minimal dosage required to derive these benefits is unknown. We systematically reviewed the resistance training effects in prostate cancer patients to determine the minimal dosage regarding the exercise components (mode, duration, volume and intensity) on fatigue, QoL, depression and anxiety.

The Resistance Training Effects in Prostate Cancer Patients, Determining the Minimal Dosage – Editorial

Doctor: “You have prostate cancer.”

Patient: “Doctor, that’s awful. What can I do to help it grow slower and feel better?”

Doctor: “Eat right and exercise.”

Patients: “How much exercise should I do?”

Doctor: “I don’t know.”

While the above is a fictitious discussion between doctor and patient, my guess is that similar discussions occur every day. When diagnosed with cancer, patients want to improve their lifestyle and clamor for any information their provider can give them. Unfortunately, most providers don’t know what advice to give. Even if the provider is knowledgeable and interested, discerning the literature and coming up with an answer to a straightforward question such as “how much exercise” is not an easy task. Into this void, steps the systematic review and meta-analysis by Lopez and colleagues.

Bone Targeted Therapy and Skeletal Related Events in the Era of Enzalutamide and Abiraterone Acetate for Castration Resistant Prostate Cancer With Bone Metastases – Full Text Article

Background In an era of multiple life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC), the optimal timing of initiation and duration of antiresorptive bone-targeted therapy (BTT) to prevent skeletal-related events (SREs) is unknown.

Methods To assess practice patterns of BTT use and its associations with clinical outcomes in a high-volume center in the modern era of metastatic CRPC management, a retrospective cohort of patients treated for mCRPC with BM between 2007 and 2017 was identified from a single institutions clinical research database.

The Importance of Bone Health Management in Men with mCRPC - Editorial

It is well appreciated that men with bone metastases are at risk for fracture and symptomatic skeletal-related events (SREs), and that men on long-term potent hormonal therapies are at risk for fragility fractures due to ongoing bone loss. However, the utilization of denosumab and zoledronic acid, despite the widespread guideline recommendations for their consideration, remains low internationally. This was recently highlighted at ASCO 2021 with the PEACE3 clinical trial, where the mandated use of bone antiresorptive therapy in this bone mCRPC protocol of enzalutamide +/- radium-223 led to an improvement in the use of these agents in this population from 55% to 97%, and reduced the observed fracture rate at 18 months with enzalutamide alone from 22% to 2.6%, a major reduction in risk.¹

Novel Prostate Cancer Susceptibility Gene SP6 Predisposes Patients to Aggressive Disease - Editorial

Genes predisposing to prostate cancer have been investigated now for more than three decades resulting in the identification of ~170 germline susceptibility loci, mostly in mixed European ancestry cohorts.

In this study based on a ‘’narrow/isolated’’ Finnish cohort, 21 low penetrance susceptibility loci were identified, of which 10 are novel. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. These are important as they are associated with significant prostate cancer. Such variants may be useful in the stratification of patients for population based screening.

Novel Prostate Cancer Susceptibility Gene SP6 Predisposes Patients to Aggressive Disease - Full Text Article

Abstract

Prostate cancer (PrCa) is one of the most common cancers in men, but little is known about factors affecting its clinical outcomes. Genome-wide association studies have identified more than 170 germline susceptibility loci, but most of them are not associated with aggressive disease. We performed a genome-wide analysis of 185,478 SNPs in Finnish samples (2738 cases, 2400 controls) from the international Collaborative Oncological Gene-Environment Study (iCOGS) to find underlying PrCa risk variants. We identified a total of 21 common, low-penetrance susceptibility loci, including 10 novel variants independently associated with PrCa risk. Novel risk loci were located in the 8q24 (CASC8 rs16902147, OR 1.86, padj = 3.53 × 10−8 and rs58809953, OR 1.71, padj = 4.00 × 10−6 ; intergenic rs79012498, OR 1.81, padj = 4.26 × 10−8 ), 17q21 (SP6 rs2074187, OR 1.66, padj = 3.75 × 10−5 ), 11q13 (rs12795301, OR 1.42, padj = 2.89 × 10−5 ) and 8p21 (rs995432, OR 1.38, padj = 3.00 × 10−11) regions. Here, we describe SP6, a transcription factor gene, as a new, potentially high-risk gene for PrCa.

Overall Survival of Black and White Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC): A 20-Year Retrospective Analysis in the Largest Healthcare Trust in England - Editorial

Every medical school textbook lists three risk factors for developing prostate cancer: age, family history, and race. Specifically, Black men (i.e. those of African ancestry) are at increased risk. On the population level, Black men are ~67% more likely to be diagnosed with prostate cancer than White men. When it comes to aggressive cancers, however, the picture is less clear. Yes, Black men are 2 to 2.5 times more likely to die from prostate cancer than White men. Does that mean the disease is more aggressive or does that reflect poorer access to care and less aggressive treatments? Increasing data suggest that though on the population level among men with prostate cancer, Black men are more likely to die when given equal access and equal treatments, outcomes among men with localized disease are similar between Black and White men. What about men with advanced disease – specifically those with metastatic castration resistant prostate cancer (mCRPC)? Several studies from the United States found that among men with mCRPC, survival was actually better for Black men vs. White men. The question is whether these findings (more cancers, equal aggressiveness, but better survival in mCRPC) are unique to the United States, or can the results be replicated in other countries too?

Overall Survival of Black and White Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC): A 20-Year Retrospective Analysis in the Largest Healthcare Trust in England - Full Text Article

Abstract

Background: Prostate cancer in black men is associated with poorer outcomes than their white counterparts. However, most studies reporting this disparity were conducted in localized prostate cancer and primarily in the United States.

Methods: Data regarding prostate cancer incidence and mortality for East London between 2008 and 2010 were obtained from the UK National Disease Registration Service. We further evaluated survival outcomes of 425 cases of mCRPC in St Bartholomew’s Hospital, East London, between 1997 and 2016, and analyzed whether ethnicity impacted on responses to different treatment types.

Differences in the Use of Fusion Biopsy Between Black and White Men Presenting with Suspicion of Prostate Cancer - Editorial

For decades, clinicians and researchers alike have been aware of major racial disparities in prostate cancer. Black men in the United States present more often, with higher PSA values, at younger ages, and are more likely to die from prostate cancer than their White counterparts. Within this framework of indisputable facts, there is a lot of discussion to what factors lead to these racial disparities. Is it genetics? Is it social determinants of health? Is it attitudes to the health system due to mistrust from many past horrible failed experiments (i.e. Tuskegee)?

Is it lifestyle differences? Is it all access to care? Recent data from the Veterans Affairs Health System have suggested that when given equal access, outcomes among Black and White men can be similar. While this certainly supports the importance of access to care, this does not mean Black and White men present with equal rates of prostate cancer indicating residual disparities that cannot be explained by access alone. However, as we move forward with newer technologies (MRI, genomics, next generation imaging), whether Black patients truly have equal access to these advances is unknown.

Racial Disparity in the Utilization of Multiparametric MRI–Ultrasound Fusion Biopsy for the Detection of Prostate Cancer - Full Text Article

Background
Black men have significantly higher incidence and are up to three times more likely to die of prostate cancer (PCa) than White men. Multiparametric magnetic resonance imaging-ultrasound fusion biopsy (FBx) has emerged as a promising modality for the detection of PCa. The goal of our study is to identify differences in utilization of FBx between Black and White men presenting with suspicion of PCa.

Methods
We performed a retrospective review of Black and White men who presented with suspicion of PCa and required biopsy from January 2014 to December 2018. Multivariate logistic regression analysis was done to study the influence of race on the utilization of FBx.

The Role of Androgen Receptor (AR) in Liquid Biopsy to Predict Clinical Outcome to AR Signaling Inhibitors in Metastatic Castration Resistance Prostate Cancer Patients - Editorial

The ability to predict clinical outcomes prior to starting therapy is the hallmark of precision oncology. The detection of the androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) has now been externally and prospectively validated in the multicenter PROPHECY study using both the Hopkins mRNA and the Epic Sciences nuclear protein assays, demonstrating strong and significant associations with worse progression free and overall survival (PFS and OS) and a lack of responses in men with mCRPC,¹ but such AR-V7 positive men can still have good outcomes with taxane chemotherapy.² However, a limitation of CTC AR-V7 detection is that CTCs are required to be present, and nearly half of men with mCRPC have low to absent CTCs despite disease progression. In addition, AR-V7 likely only explains about 20-30% of AR therapy cross-resistance, meaning that other resistance mechanisms such as AR indifference and neuroendocrine transformation/lineage plasticity are also important.

Androgen Receptor Gain in Circulating Free DNA and Splicing Variant 7 in Exosomes Predict Clinical Outcome in CRPC Patients Treated with Abiraterone and Enzalutamide - Full-Text Article

Background - Androgen receptor (AR) signaling inhibitors represent the standard treatment in metastatic castration resistance prostate cancer (mCRPC) patients. However, some patients display a primary resistance, and several studies investigated the role of the AR as a predictive biomarker of response to treatment. This study is aimed to evaluate the role of AR in liquid biopsy to predict clinical outcome to AR signaling inhibitors in mCRPC patients.

Methods - Six milliliters of plasma samples were collected before first-line treatment with abiraterone or enzalutamide. Circulating free DNA (cfDNA) and exosome-RNA were isolated for analysis of AR gain and AR splice variant 7 (AR-V7), respectively, by digital droplet PCR.

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