Dr. Mary Samplaski discusses online resources regarding male infertility.

Speaking of Urology Podcast 

Shaakir Hasan, DO, New York Proton Center, discusses socioeconomic characteristics associated with the diagnosis and management of bladder cancer. Hasan was the lead author on a research paper shared during the 2021 Genitourinary Cancers Symposium that focused on disparities in bladder cancer. Hasan and his coauthors wrote in their conclusion, "In the largest study of its kind, we report that several socioeconomic, racial, and gender factors are associated with the diagnosis of bladder cancer at a later stage, as well as the use of less cancer-directed treatments” (

 39, 2021 (suppl 6; abstr 403). doi: 10.1200/JCO.2021.39.6_suppl.403).

Videos

Shaakir Hasan, DO, discusses socioeconomic characteristics associated with the diagnosis and management of bladder cancer.

Dr. Shaakir Hasan discusses disparities in bladder cancer diagnosis and treatment

Lisette Hilton is president of Words Come Alive, based in Boca Raton, Florida.

The most common medications used in routine care to manage lower urinary tract symptoms due to benign prostate hyperplasia (BPH) are associated with an increased risk of cardiac failure, according to a recently published population-based study.

Investigators studied data on more than 175,200 men with BPH treated with 5-alpha reductase inhibitors, alpha blockers, or a combination. They found that men treated with either therapy or a combination had a statistically increased risk of cardiac failure compared with those who did not take the medications. The highest risk for cardiac failure was among BPH patients taking alpha blockers alone or in combination, according to the study published in 

There are 2 key points for urologists, said study author D. Robert Siemens, MD, professor and Chair of Urology at Queen’s University School of Medicine, Ontario, Canada.

“This adds to the evidence that there may be some degree of association between symptomatic BPH and cardiovascular health. When we looked at those men with a diagnosis of BPH, there was a stronger association with new cardiac failure for those who had filled a subsequent prescription for medical therapy compared to those who didn’t. Conceptually, those who are diagnosed with lower urinary tract symptoms bad enough to fill a script for medical therapy may share some risk factors for cardiovascular disease,” Siemens said. “Secondly, the alpha blockers (maybe specifically nonselective alpha blockers) have a higher association with new cardiac failure. The absolute increase is low but still independent after adjusting for other well-known heart disease risk factors.”

The issue of cardiac failure and alpha blockers arose almost 20 years ago in the ALLHAT trial (NCT00000542), among the first studies to highlight a possible link between alpha blockers and hypertension. The landmark trial created some splash in the urological community, according to Siemens, but was followed with relatively little investigation and mixed results from other nonrandomized studies, he said.

“Potential mechanisms for the associations between cardiac failure and [5-alpha reductase inhibitors] include the deleterious impact on metabolic disorders and cardiac function through their antiandrogen effect and blockage of serum testosterone conversion to dihydrotestosterone,” wrote the authors of the current study. “[Alpha blocker] association with cardiac failure, on the other hand, may be linked to their vasodilatory effects and blood pressure variability.”

The data set Siemens and colleagues studied included 8339 BPH patients exposed to 5-alpha reductase inhibitors, 55,383 exposed to alpha blockers, and 41,491 who had taken a combination. Cardiac failure risk was an average 22% higher among those exposed to alpha blockers alone; 16% higher on combination; and 9% higher among men exposed to 5-alpha reductase inhibitor therapy alone. Nonselective alpha blocker treatment had an 8% higher risk of cardiac failure than selective alpha blocker therapy, according to the paper.

“Although it hasn’t changed my practice that much—I still of course use alpha blockers—it has made me more diligent in assessing cardiovascular health,” Siemens said.

The evidence also makes Siemens discuss the choice of his primary care colleagues’ use of nonselective alpha blockers when they are being prescribed for lower urinary tract symptoms. Hopefully, he said, the study highlights for urologists and primary care physicians that having lower urinary tract symptoms due to BPH should indeed make them think about cardiovascular health and consider it when evaluating and managing symptoms.

“Perhaps it should add to the shared decision-making discussion around long-term medical management for BPH [adding to the list of already well described, albeit usually minor side effects]. And perhaps it should add to the discussion around earlier surgical management, especially increasing minimal invasive techniques. That said, the evidence level this provides does not allow one to advocate for any changes in routine, guideline-concurrent care,” he said.

Siemens said that he believes this is the largest observational, population-based study of all men diagnosed with BPH and managed in routine care.

 Omar Salim Akhtar of the Government Medical College in Kashmir, India, asked about the incidence of cardiac failure in patients younger than 65 who need to be treated for BPH, who were not part of this study. Conceptually, the mechanism of alpha blocker association with cardiac failure may been linked to vasodilatory effects and BP variability, as well as other risks in the aging male, according to Siemens. “So, one could only make conjecture that there would be less of a strong association with those younger men with lower urinary tract symptoms,” Siemens said.

1. Lusty A, Siemens DR, Tohidi M. Cardiac failure associated with medical therapy of benign prostatic hyperplasia: a population based study. 

Published online February 22, 2021. doi:10.1097/JU.0000000000001561

Published online February 24, 2021. doi:10.1097/JU.0000000000001561.01

Articles

The highest risk was observed in patients exposed to alpha blocker therapy alone.

Alpha blockers and 5-alpha reductase inhibitors raise cardiac failure risk

The results of 2 pivotal trials supporting an FDA application for the PSMA PET imaging agent 18F-DCFPyL (Pyl) in prostate cancer have now been published in peer-reviewed academic journals.

Findings for the 2 trials, the CONDOR study and the OSPREY study, have been published in 

, respectively. The FDA is currently reviewing the results of these trials and is scheduled to make an approval decision by May 28, 2021.

“The limitations of conventional imaging modalities for prostate cancer create a need for targeted imaging in the initial assessment of high-risk patients as well as in men with early biochemically relapsed disease,” Michael J. Morris, MD, Prostate Cancer Section Head, Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, and lead author of the CONDOR manuscript and senior author on the OSPREY manuscript, stated in a press release.

“The OSPREY trial data highlighted the high positive predictive value, negative predictive value and specificity of PyL in staging high-risk patients. The CONDOR trial demonstrates its high positive predictive value to accurately locate and identify recurrent cancer early and non-invasively. Assuming FDA approval, physicians will be able to use this clinically meaningful information to identify disease, guide treatment plans, and improve disease management,” added Morris.

The multicenter phase 3 CONDOR study enrolled men with rising PSA after definitive therapy and negative or equivocal standard-of-care imaging. Patients were required to have a PSA level ≥0.2 if they had undergone radical prostatectomy (RP) or a PSA level ≥2.0 if they were treated with radiation therapy or cryotherapy.

The primary end point was correct localization rate (CLR), defined as percentage of patients with a 1:1 correspondence between at least 1 lesion identified by PyL–PET/CT and the composite standard of truth (pathology, correlative imaging, or PSA response). PyL scans were read by 3 blinded independent central readers.

Overall, there were 208 evaluable patients, about 85% of whom underwent RP, either alone or with radiation. Median PSA level of the cohort was 0.8 ng/mL, and 68.8% had a PSA level <2.0 ng/mL. Some 27.9% had received at least 1 prior systemic therapy.

Detection of disease as manifested by a positive 18F-DCFPyL–PET/CT scan was 65.9%, 59.6%, and 59.1% by the 3 readers.

The prespecified criterion for CLR success was for the lower limit of the 95% CI to exceed 20% for at least 2 of the 3 readers. For every reader, the lower bound of the 95% CI for the CLR was well in excess of the 20% benchmark, meeting the primary end point of the study.

The CLRs were 85.6% (95% CI, 78.8%-92.3%), 87.0% (95% CI, 80.4%-93.6%), and 84.8% (95% CI, 77.8%-91.9%) by the 3 readers. Some 64% of the evaluable patients had a change in intended management due to the scan.

In the phase 2/3 OSPREY trial, PyL was assessed in 2 patients cohorts. Cohort A included men with high-risk, locally advanced prostate cancer, and the researchers assessed the capacity of PyL to detect prostate cancer in pelvic lymph nodes. Cohort B comprised patients with metastatic or recurrent disease and the researchers examined the performance of PyL in detecting distant metastases.

In cohort A, results for PyL in detecting disease in pelvic lymph nodes showed a specificity of 96%-99%, a sensitivity of 31%-42%, and positive predictive value (PPV) of 78%-91%. The sensitivity and PPV rates for detecting metastatic lesions in cohort B were 93%-99% and 81%-88%, respectively.

The OSPREY investigators observed that Pyl was well tolerated. Across all grades, the most common adverse events were dysgeusia (2.6%), headache (1.8%), and fatigue (1.3%).

1. Lantheus Announces Publication of PyL™ (18F-DCFPyL) Results from Pivotal Studies. Published online March 2, 2021. Accessed March 2, 2021. https://bwnews.pr/2Ol170g.

2. Morris MJ, Rowe SP, Gorin MA, et al. Diagnostic performance of 18F-DCFPyL-PET/CT in men with biochemically recurrent prostate cancer: results from the CONDOR phase 3, multicenter study [published online before print February 26, 2021.] doi: 10.1158/1078-0432.CCR-20-4573

3. Pienta KJ, Gorin MA, Rowe SP, et al. A Phase 2/3 Prospective Multicenter Study of the Diagnostic Accuracy of Prostate-Specific Membrane Antigen PET/CT with 18F-DCFPyL in Prostate Cancer Patients (OSPREY) [February 26, 2021]. 

The FDA is currently reviewing the results of these trials and is scheduled to make an approval decision by May 28, 2021.

Pivotal data published for PSMA PET imaging agent 18F-DCFPyL in prostate cancer

I am considering a new position. What should I look for in a benefits package?

A benefits package is an important piece of the puzzle when evaluating job opportunities. For physicians, the type of employer often affects what is provided. For example, many private medical practices provide very little in terms of traditional benefits. As a partner or shareholder, you operate more as an entrepreneur and must pay your own way when it comes to most benefits. Large hospitals and university hospitals often have a more robust benefits package, but you practice medicine as an employee. Private equity groups sometimes land more in the middle.

Regardless of whether you choose your own benefits or they are provided to you by your employer, these are the most common benefits physicians should look for.

Two to 3 weeks per year is common. An important question to ask is whether sick days and time off for continuing medical education (CME) are included in your PTO or if they fall into a separate category.

 Typically, reimbursement amounts range from $2500 to $3500 annually. Make sure to verify what items are reimbursable because many employer policies have caps on airfare and hotel expenses.

 Premiums, co-pays, and coinsurance are important, but be sure to give extra consideration to the deductible and out-of-pocket maximums. The deductible is the amount you must pay before the insurance starts paying. The out-of-pocket maximum is the most you will pay in a calendar year for your deductible, co-pays, and coinsurance. Once the out-of-pocket maximum is reached, the insurance plan will cover 100% of the costs above that amount.

 Most dental plans are standard in terms of deductibles, co-pays, and coinsurance. Pay attention to the annual maximum benefit. These typically range from $500 to $2000. This is the maximum amount the plan will pay for dental work within a calendar year.

Most plans have relatively low co-pays for eye exams ($10 to $20) and provide allowances ($130 to $150) for eyeglasses and contact lenses. Medically necessary contacts are often covered in full. Elective and specialty lenses will likely have a co-pay.

There are 2 types of FSAs: a health care FSA and a dependent care FSA. These accounts let you contribute pretax money and then spend it on qualified expenses. The maximum you can contribute to a health care FSA in 2021 is $2750, and the maximum you can contribute to a dependent care FSA is $5000. Use caution with these accounts because for most, money remaining at the end of the calendar year is forfeited back to the plan.

Employer-provided monthly benefit amounts vary. We recommend physicians have at least 60% of their predisability monthly income covered by an LTD policy. If the employer-provided plan is insufficient, then a physician should acquire a supplemental disability policy to make up the difference. When reviewing disability plans, pay close attention to how disability is defined. A “true own occupation” definition is a specialty-specific policy. If the employer-provided policy does not have this definition, consider getting as much coverage from a supplemental policy
as possible.

 Employers often provide coverage equal to 1 to 2 times a physician’s salary. Some limit coverage to $50,000, but that is done for your tax purposes. If an employer provides life insurance above $50,000, the premium paid for the insurance above $50,000 must be included in the employee’s income and they must pay income taxes on it.

 These retirement plans allow for tax-advantaged retirement saving and investing. In 2021, an employee can contribute $19,500 of their own money to the plan on a pretax or Roth basis. Employers often contribute by making a guaranteed 3% safe harbor contribution, matching a percentage of employee contributions or a mixture of both. Employers may also make discretionary contributions. Pay attention to the vesting schedule, which will tell you how much of the employer contribution you can take with you if you leave the company. You are always 100% vested in your own contributions.

Less commonly offered plans are a 401(a), a pension plan, and a 457.

Additional benefits you may have include a health savings account (HSA), short-term disability, accidental death and dismemberment insurance, adoption assistance, tuition reimbursement, wellness programs, and discounted services.

 is educational program director at MEDIQUS Asset Advisors, Inc in Chicago, Illinois. He welcomes readers’ questions and can be reached at 800-883-8555 or witz@mediqus.com.

The information in this column is designed to be authoritative. The publisher is not engaged in rendering legal, investment, or tax advice. If you would like assistance with your individual investment strategy, please email witz@mediqus.com.

CME reimbursement amount and 401(k)/401(b) are among elements to consider.

What to look for in an employment benefits package

Michael Philip O’Leary, MD, a professor of surgery at Harvard Medical School, discusses potential risks of surgical implantation Penuma, an FDA-cleared penile enhancement implant. O’Leary is 1 of 10 surgeons in the United States capable of performing this surgery, and he recently performed the first Penuma implant at Brigham and Women's Hospital, part of Harvard Medical School. Penuma is a permanent cosmetic penile implant customized to an individual patient’s anatomy.

O’Leary discusses safety related to instillation of the Penuma penile enhancement implant.

Dr. Michael Philip O'Leary on potential risks of penile implant surgery

Neal D. Shore, MD, medical director of the Carolina Urologic Research Center, highlights the next steps for darolutamide (Nubeqa) in prostate cancer. The FDA approved the androgen receptor pathway inhibitor in July 2019 for the treatment of patients with nonmetastatic castration-resistant prostate cancer, based on findings from the phase 3 ARAMIS trial.

Darolutamide is currently approved for the treatment of patients with nonmetastatic castration-resistant prostate cancer.

Dr. Neal Shore on the future of darolutamide in prostate cancer

Subgroup data from the pivotal phase 3 JAVELIN Bladder 100 trial showed that frontline maintenance with avelumab (Bavencio) plus best supportive care (BSC) improved median overall survival (OS) in Japanese patients with advanced urothelial cancer.

The trial enrolled patients who had not progressed on frontline chemotherapy and randomized them to avelumab plus BSC versus BCS alone. The subgroup findings showed a median OS of 24.7 months versus 18.7 months in patients who received the combination (n = 36) versus BSC alone (n = 37), respectively (HR, 0.81). In Japanese patients with PD-L1–positive tumors, the median OS was 18.6 months and 19.4 months, respectively (HR, 1.00; 95% CI, 0.41-2.41). However, the 95% confidence intervals were wide due to the small number of patients.

The findings were consistent with the overall study population of JAVELIN Bladder 100, lead study author Norihiko Tsuchiya, MD, of the Department of Urology at Yamagata University Faculty of Medicine, and co-investigators, stated in a poster presentation during the 2021 Genitourinary Cancers Symposium.

“The interpretation of findings in the Japanese subgroup is limited by the small number of patients compared with the overall trial population,” Tsuchiya noted. “Overall, these results support the consideration of avelumab [as first-line] maintenance as a potential new standard of care in Japanese patients with advanced urothelial cancer that has not progressed with [first-line] platinum-containing chemotherapy.”

In the phase 3 JAVELIN Bladder 100 study (NCT02603432), investigators sought to determine the efficacy and safety of avelumab plus BSC versus BSC alone as a frontline maintenance therapy in 700 patients with locally advanced or metastatic urothelial cancer that did not progress on frontline chemotherapy with cisplatin/gemcitabine or carboplatin/gemcitabine.

Following a treatment-free interval of 4 to 10 weeks, patients were randomized to receive avelumab at 10 mg/kg intravenously every 2 weeks plus BSC or BSC alone until disease progression, unacceptable toxicity, or withdrawal.

PD-L1 status was defined using the Ventana SP263 immunohistochemistry assay. Patients were stratified by best response to first-line chemotherapy (complete response [CR] or partial response [PR] vs stable disease [SD]).

The primary end point of the trial was OS in the primary analysis populations, which included all randomized patients and PD-L1–positive patients. Secondary end points were progression-free survival (PFS) and objective response rate (ORR) per RECIST v1.1 criteria by blinded independent central review, safety and tolerability, and patient-reported outcomes. 

Overall results, which were presented at the 2020 ASCO Virtual Scientific Program, showed that avelumab plus BSC demonstrated significantly prolonged OS versus BSC alone (HR, 0.69; 

 <.001). The benefit was also seen in PD-L1–positive patients (HR, 0.56; 

 Based on these data, the FDA approved the combination of avelumab and BSC in June 2020 as a frontline maintenance regimen in this setting.

In this analysis, investigators evaluated the outcomes of all patients enrolled in sites in Japan (n = 73) in the same trial. Baseline characteristics of Japanese patients compared with the overall population were similar; however, of note, Japanese patients weighed less (62.9 kg on avelumab and 61.9 kg on BSC) versus the overall group (72.4 kg and 73.0 kg, respectively) and were more likely to have upper tract disease as the site of their primary tumor (Japanese, 58.3% and 56.8%; overall, 30.3% and 23.1%). Japanese patients were also less likely to have received gemcitabine/carboplatin as their first-line chemotherapy regimen (Japanese, 25.0% and 21.6%; overall, 42.0% and 34.9%) and were less likely to experience a CR or PR to first-line chemotherapy (Japanese, 61.1% and 59.5%; overall, 72.3% and 72.0%).

Additional findings showed that the median PFS in Japanese patients was 5.6 months with avelumab/BSC compared with 1.9 months with BSC alone (HR, 0.63). In PD-L1–positive patients who were Japanese, the median PFS was 5.6 months and 1.9 months, respectively (HR, 0.62).

In all Japanese patients, the ORR in the avelumab/BSC arm was 5.6% versus 0% with BSC. The ORR on the avelumab arm was comprised of 1 CR and 1 PR; 3 patients had stable disease, 7 patients had non-CR/non-progressive disease (PD), 17 patients had PD, and 7 patients were not evaluable. The disease control rates were 33.3% and 27.0% with avelumab/BSC and BSC alone, respectively. The response rate data were comparable with the overall study population.

Twenty-two (61.1%) Japanese patients on avelumab/BSC discontinued treatment and received subsequent therapy compared with 30 (81.1%) on BSC alone. In the avelumab arm, subsequent therapy included a PD-1/PD-L1 inhibitor (38.9%), FGFR inhibitor (2.8%), and other (52.8%); these rates were 67.6%, 0%, and 54.1% in the BSC-alone arm. The investigators noted that more Japanese patients on BSC received a subsequent checkpoint inhibitor compared with the overall study population (43.7%).

Regarding safety, the tolerability in the avelumab arm was consistent with the overall study population, and no safety concerns in the Japanese subgroup was identified. All-grade treatment-emergent adverse effects (TEAEs) occurred in 100% of patients on avelumab and 56.8% on BSC; grade 3 or higher TEAEs occurred in 50.0% and 8.1% of patients, respectively. On avelumab, these included anemia (11.1%), pyelonephritis (5.6%), urinary tract infection (2.8%), increased amylase (5.6%), increase in blood triglycerides (5.6%), and fatigue (2.8%).

TEAEs led to treatment discontinuation in 4 patients on avelumab, and 1 patient died due to sepsis.

All-grade treatment-related AEs (TRAEs) occurred in 75% (n = 27) of patients on avelumab, and 5 patients were reported as having TRAEs grade 3 or higher. Immune-related AEs were reported in 36.1% of avelumab-treated patients, 8.3% of which were grade 3. Additionally, 27.8% of patients on this arm had grade 1/2 infusion-related reactions.

1. Tsuchiya N, Yamaoto Y, Uemura H, et al. Avelumab first-line maintenance plus best support care (BSC) vs BSC alone for advanced urothelial carcinoma: JAVELIN Bladder 100 Japanese subgroup analysis. 

. 2021;39(suppl 6):425. doi:10.1200/JCO.2021.39.6_suppl.425

2. Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. 

. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1

3. FDA approves Bavencio as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma. News release. Pfizer. June 30, 2020. Accessed March 1, 2021. https://bit.ly/2YO7gVk.

The subgroup analysis assessed data from the pivotal phase 3 JAVELIN Bladder 100 trial showed.

OS benefit with frontline avelumab maintenance in urothelial cancer sustained in Japanese subgroup 

 paper, “Tobacco screening and treatment during outpatient urologic office visits in the United States,” for which he served as a study author. Matulewicz is a clinical instructor in urology at NYU Grossman School of Medicine.   

“Very, very few patients actually had any counseling documented or any medications ordered that would help with smoking cessation,” says Richard S. Matulewicz, MD.

Are urologists counseling patients on smoking cessation?

Historically, the urology community has depended on eliciting a family history (FH) of prostate cancer and race as determinants when an individual may be at increased risk for harboring the disease. Often, these parameters were taken into consideration when a patient was referred for an elevated prostate-specific antigen (PSA) and may require a biopsy or was inquiring on when to start an early detection program. With the full understanding that certain low-risk prostate cancers do not lead to progressive disease and death and may be managed conservatively with active surveillance, the push over the past decade has been to tailor early detection/screening and biopsy protocols to try to identify those patients who truly would benefit from active treatment.

 in 2015 and 2016 highlighted the significance that men at risk of dying of prostate cancer, especially in the metastatic castration-resistant prostate cancer (mCRPC) space, harbored mutations in the DNA damage repair (DDR) gene pathway and that up to 12% of the time these may be inherited germline mutations. This is a much higher incidence than those historical data sets in men with localized disease. In these advanced cases, this was regardless of family history of prostate cancer or race.

 Consequently, there has been a deep push over the past 3 years to incorporate germline testing using next-generation sequencing (NGS) in patients with newly diagnosed prostate cancer or those with advanced disease and progression.

Taking all this into account, will the same testing strategy work in identifying patients at high risk who currently do not have a diagnosis? At the core and cellular level, all cancers are genetic. This predisposition to unregulated cell growth and carcinogenesis can at times be inherited, but often, depending on the gene, it requires that “second” environmental exposure, the “second hit,” that knocks out the other allele and will result in loss of function. Most of the heritable mutations are involved in the DDR pathway, which can then be subdivided into genes integral to homologous recombination repair (

A mutation in the transcription factor HOXB13 is probably the most common inherited mutation but is not actionable at this time and does not differentiate low- versus high-grade disease.

 For the most part, specific mutations in many of these genes are considered high penetrance (the lifetime risk of developing prostate cancer is 2- to 5-fold higher) but rare (< 2%) in the general population. Unless you met National Comprehensive Cancer Network criteria based on family history connected with other associated cancers for these genes (breast, ovary, colorectal, pancreatic, for example, diagnosed at a younger age), using NGS to detect pathogenic variants in these specific candidate genes, despite the availability of broad cancer-specific testing panels offered by many of the molecular labs, would probably be of low yield and not cost effective.

However, another genetic predictor that could be utilized for risk assessment would be the use of single nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS). By definition, SNPs are often used in ancestry testing and are present in at least 1% of the population. There are millions of SNPs that have been identified in the human genome, but approximately 160 have been associated with prostate cancer.

They can be found in both coding (exons) and noncoding (introns) of the genome and are inherited independently of one another. Taken individually, a single SNP may have limited usefulness in assessing the risk of developing prostate cancer. But studied cumulatively as a PRS, they may be a stronger predictor for prostate cancer risk assessment. Given their more common presence in the population and shorter sequence, the potential cost will be much less than whole exon or genome sequencing.

In a number of studies, you may see reference to a genetic risk score (GRS), which can be defined as a tool that takes into account a PRS and has been standardized for the population and can then be interpreted as a relative risk (RR) to the population. For example, it has been reported in many studies that a (+) FH of prostate cancer carries RR of 1.5.

 Or, interpreted differently and easier for many clinicians (and patients) to understand, a person with a FH of prostate cancer has a 50% increased risk of developing the disease sometime in his life relative to the general population.

With the understanding that FH is an independent predictor of prostate cancer risk (and does not require additional testing), a number of studies have examined how GRS compares to FH in predicting prostate cancer risk, as well as how the 2 perform when added cumulatively. Utilizing a 110 prostate cancer-associated SNP panel, a GRS was calculated in the 3225 men enrolled in the chemoprevention REDUCE trial (NCT00056407). When considering FH and GRS only, 14% and 19%, respectively, were stratified to high-risk disease. When both FH and/or GRS were used, this increased to 30%.

 Using a similar cohort but focusing on 410 men with diagnosed prostate cancer and a 33-SNP panel, multiple variables, including both binary (FH, digital rectal exam) and continuous (age, PSA, volume, calculated GRS), the highest area under the curve for the independent variables was 0.59 for the GRS, 0.52 for FH. When all the clinical parameters (age, FH, PSA, vol, # of + cores), the AUC was 0.62, but increased to 0.66 when the GRS was added.

Finally, a recent study looked at a large cohort of over 1900 patients with prostate cancer who had undergone radical prostatectomy and a matching number of unaffected controls.

 But unique to this design was that all patients had undergone NGS and germline testing, and patients were excluded for analysis if they had identified pathogenic mutations in the DDR genes commonly associated. They constructed a GRS based on 72 validated prostate cancer-associated SNPs. Their results demonstrated that the GRS was superior to FH, which can be somewhat difficult to accurately assess, in predicting the relative and lifetime risk of both low- and high-grade prostate cancer.

There are some data gaps in the literature when determining the potential of using GRS as a tool for prostate cancer risk assessment in the general population. The most significant is that the library of prostate cancer-associated SNPs, as well as most patients in many of these studies, have been primarily of European ancestry and/or Caucasian males. Extrapolation of this data to other races and ethnicities should be interpreted with caution and more studies, especially in the African American population, are needed and ongoing. Additionally, the cost of SNP/GRS testing needs to be evaluated. FH taking is free but can be quite variable and accuracy often questionable.

As we move into gaining a better understanding of the influence of the genome on prostate cancer, whether that be known pathogenic gene mutations or cancer associated SNPs, new computational models are required to incorporate these inputs beyond our traditional clinical values. At this point, we are making gains in adopting germline testing, when appropriate, in patients newly diagnosed with high risk as well as those with advanced disease. Part of this shift does require obtaining and documenting a detailed FH, preferably across 3 generations. Along with this, there is clearly an opportunity to develop superior risk assessment models that consider FH, GRS, and identified pathogenic variants, much like our colleagues who manage patients with breast cancer. Given that the actual testing platform (NGS) can provide the information on the latter 2 sources and that studies continue to show the improvement of adding genomic data for more accurate risk assessment, there is a growing need to build a superior algorithm that will identify the at-risk patient.

is director of the Comprehensive Prostate Center and clinical associate professor of urology at Vanderbilt University School of Medicine, Nashville, Tennessee. He is editor-in-chief of 

1. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. 

 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001

2. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. 

2016;375(5):443-453. doi:10.1056/NEJMoa1603144

3. Ewing CM, Ray AM, Lange EM, et al. Germline mutations in HOXB13 and prostate-cancer risk. 

 2012;366(2):141-149. doi:10.1056/NEJMoa1110000.

4. Schumacher FR, Al Olama AA, Berndt SI, et al. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. 

. 2018;50(7):928-936. doi:10.1038/s41588-018-0142-8

5. Johns LE, Houlston RS. A systematic review and meta-analysis of familial prostate cancer risk. 

 2003;91(9):789-794. doi:10.1046/j.1464-410x.2003.04232.x

6. Na R, Labbate C, Yu H, et al. Single-nucleotide polymorphism-based genetic risk score and patient age at prostate cancer diagnosis. 

 2019;2(12):e1918145. doi:10.1001/jamanetworkopen.2019.18145

7. Kader AK, Sun J, Reck BH, et al. Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative biopsy: findings from the REDUCE trial. 

 2012;62(6):953-961. 10.1016/j.eururo.2012.05.006

8. Black MH, Li S, LaDuca H, et al. Validation of a prostate cancer polygenic risk score. 

 2020;80(15):1314-1321. doi:10.1002/pros.24058

Opportunity exists to develop superior risk assessment models in prostate cancer.

Polygenic risk scores and potential use in risk assessment in prostate cancer

Thomas Powles, MBBS, MRCP, MD, director, Barts Cancer Institute, discusses standard treatment for patients with metastatic urothelial cancer in the frontline setting and beyond.

Treatment following progression on chemotherapy and an immune checkpoint inhibitor remains an unmet medical need.

Are urologists counseling patients on smoking cessation?

Polygenic risk scores and potential use in risk assessment in prostate cancer

Dr. Thomas Powles explains standard treatment for metastatic urothelial cancer