In recent years, prostate cancer has grown to become the most common carcinoma affecting men in terms of incidence and the second most common in terms of mortality. The American Cancer Society estimates that in 2020, there will be 191,930 new cases and 33,330 deaths from prostate cancer.

 It was well known for many years that approximately a quarter of men who develop metastatic castration-resistant prostate cancer (mCRPC) have a mutation in DNA repair genes, with the most common mutated genes being 

 It was previously thought that these patients harbored somatic mutations that could develop at any time in a patient’s life, with the frequency of these DNA repair aberrancies increasing with continued disease progression. However, recent discoveries in the last 5 years have indicated that up to 12% of all men with mCRPC have germline/inherited defects in DNA repair genes.

 This distinction is important because new data suggest that patients with prostate cancer with 

 mutations have earlier onset of disease, lower overall survival rates, and shorter progression-free survival rates.

The discovery of germline DNA repair gene mutations is significant in that it changes the entire paradigm of family history investigation algorithms that occur during the first clinical encounter with a patient with a new diagnosis of prostate cancer. The increased risk is specifically correlated to the 

 DNA repair genes, which have been well established as genes whose mutations confer an increased chance of breast and ovarian cancer development in women. Now clinical investigation on the part of physicians must include the consideration that just as having a father or brother with prostate cancer can double a man’s risk of developing prostate cancer, having a mother or sister with breast or ovarian cancer can increase this same man’s risk of developing prostate cancer. This rationale has been reflected in the most recent National Comprehensive Cancer Network (NCCN) guidelines for 2020, while only 2 years ago genetic testing was not widely promoted. Now, germline genetic testing is recommended for every patient with prostate cancer with high-risk disease, regional spread, and metastases. In addition to these disease statuses, patients with a family history of high-risk germline mutations (

, etc), a family history of cancer, and Ashkenazi Jewish ancestry are also candidates for genetic testing.

 Somatic tumor testing is recommended in prostate cancer with both regional and metastatic spread. Thus, it is strongly encouraged that almost every patient with prostate cancer, except for the very low-risk patients, undergo genetic testing according to the new NCCN guidelines.

The answer to the question of how one can account for germline mutations in DNA repair genes for the treatment of mCRPC lies in the mechanism of action of poly (ADP-ribose) polymerase (PARP) inhibitors (

). When a single strand break in DNA occurs, PARP1 proteins repair the break in a mechanism called base excision repair. With a double-strand DNA break, DNA repair genes (the most recognizable being 

) initiate repair through a mechanism known as homologous recombination.

 When there is a knockout mutation in DNA repair genes (somatic or inherited germline), aberrant DNA with breaks that cannot be repaired begin to accumulate. This is the catalyst for carcinogenesis. PARP inhibition works through a rationale called synthetic lethality, which essentially is a mechanism of cell death that occurs when both the single-strand and double-strand DNA repair pathways are inhibited.

 In the case of a germline mutation of DNA repair genes, the double-strand DNA repair pathway (homologous recombination) is already knocked out. Therefore, the last step for synthetic lethality of cancer cells to work would be to impair the single-strand repair pathway (base excision repair) through the inhibition of PARP1. This can be achieved through PARP inhibitors and lead to a cascade of cell death in tumor cells.

Before discussing the available PARP inhibitors that physicians can employ in targeting prostate cancer, it is important to distinguish that there are 2 main mechanisms of action by which PARP inhibitors work. One method of inhibition is through the direct blockade of the enzymatic activity of PARP1 and PARP2, and the second is through “PARP trapping” on the DNA and preventing its release.

 There are many PARP inhibitors available, but the most important for the field of prostate cancer treatment are olaparib (Lynparza), rucaparib (Rubraca), niraparib (Zejula), and talazoparib (Talzenna) (

The PROfound Study (NCT02987543) was a trial that studied 387 patients with mCRPC who had progressed on a hormonal agent such as enzalutamide (Xtandi) or abiraterone (Zytiga) and had 1 or more homologous gene repair mutations in a 15-gene panel that was utilized for this study. Cohort A consisted of 245 patients with 

 gene mutations, and cohort B consisted of 142 patients with 1 or more of the other 12-gene panel aberrations.

 Patients were randomized 2:1 to receive 300 mg of olaparib orally twice daily or physician’s choice of either 160 mg of enzalutamide orally once daily or 1000 mg of abiraterone acetate orally once daily with 5 mg of prednisone twice daily.8 Median progression-free survival (PFS) in cohort A in the patients who received olaparib was 7.39 months compared with a PFS of 3.55 months in the patients who received enzalutamide or abiraterone (HR, 0.34; 95% CI, 0.25-0.47; 

 Overall survival in cohort A with the patients receiving olaparib was 18.5 months versus 15.1 months in the patients receiving the physician's choice of treatment (HR, 0.64; (95% CI, 0.43-0.97;

 Common adverse events (AEs) of olaparib that physicians must be aware of are anemia, fatigue, nausea, anorexia, diarrhea, thrombocytopenia, creatinine elevation, cough, and dyspnea. Very rare but serious complications of olaparib are myelodysplastic syndrome development, acute myeloid leukemia development, pneumonitis, and deep vein thrombosis or pulmonary embolism.

 The groundbreaking PROfound Study led the FDA, on May 19, 2020, to approve olaparib for the treatment of patients with mCRPC who have pathogenic germline or somatic homologous DNA gene repair mutations, and who have progressed following prior treatment on enzalutamide or abiraterone.

The TRITON2 study (NCT02952534) was a phase 2 trial that examined the efficacy of rucaparib in patients with metastatic castration-resistant prostate cancer who had 1 or more somatic or germline mutations in homologous DNA repair genes and who had progressed on prior androgen receptor (AR)–directed therapy and 1 prior taxane-based chemotherapy. Patients were randomized to receive 600 mg of rucaparib twice daily in 28-day cycles every 8 weeks for 24 weeks then every 12 weeks.9 Primary end points that were measured were objective response rates (ORRs) and prostate-specific antigen (PSA) rates among each homologous DNA repair gene mutation. The most notable responses were among the 57 patients that had a 

 mutation; 44% of these patients had an ORR, and there was a PSA response rate in 52% of these same patients. Among the patients with 

 mutations, the median time to PSA progression was 6.5 months (95% CI, 5.7-7.5).

 The AE profile associated with rucaparib that physicians must be aware of includes anemia, fatigue, nausea, anorexia, diarrhea, constipation, thrombocytopenia, abnormal liver function tests, creatinine elevation, and rash. Extremely rare but very serious complications include myelodysplastic syndrome development, acute myeloid leukemia development, and teratogenic effects to the fetus if taken while pregnant.9 The ongoing TRITON3 study (NCT02975934) is studying efficacy of rucaparib in patients with mCRPC who had progressed on prior AR-directed therapy but are chemotherapy naïve. The TRITON2 study led to accelerated approval of rucaparib on May 15, 2020, for patients with mCRPC with 

 knockout mutations who have been previously treated with AR-antagonist therapy or taxane-based chemotherapy.

The time has now come to think about and treat mCRPC from a genetic basis, especially in the case of patients with earlier carcinogenesis and more aggressive disease. Though the vast majority of mCRPC cases will be acquired in a patient’s lifetime, thousands of patients with inherited germline mutations will benefit from a thorough family history screening and genetic testing. Clinicians can interpret the new prostate cancer NCCN guidelines regarding genetic panel testing as essentially applying to all patients with prostate cancer, as low-risk disease is rarely present at the time of presentation in an oncology new patient visit. PARP inhibitors truly offer the solution needed to combat germline mutation-driven mCRPC. When choosing between the 2 current FDA-approved PARP inhibitors it is important for clinicians to consider that olaparib has shown efficacy against a wide range of homologous DNA repair gene mutations and rucaparib is mainly indicated to combat 

 mutations at this time. There are several ongoing trials studying the efficacy of combinations of PARP inhibitors with other novel agents, and we believe the future is truly exciting in terms of the expansion of the number of patients that will benefit from treatment and the number of therapeutic options that will become available to physicians in the coming decade.

 is an internal medicine resident at Baylor Scott and White Medical Center-Temple, Temple, Texas; 

is a doctor of pharmacy student at Ohio Northern University Raabe College of Pharmacy, Ada, Ohio; 

 is Associate Professor at Texas A&M University College of Medicine, Dallas, Texas; 

 is a urologist with Urology Clinics of North Texas, Dallas; 

 is a nurse practitioner at Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, Texas; 

 is with Baylor Scott and White Medical Center-Round Rock, Round Rock, Texas; 

is with the University of Texas at Houston Medical Center, Houston, Texas; 

 is an internal medicine resident at Louisiana State University Health-Shreveport; and

 is with Texas Tech University Health Sciences Center School of Pharmacy, Amarillo.

1. American Cancer Society. Key statistics for prostate cancer: prostate cancer facts.Revised: January 8, 2020. Accessed October 16, 2020. www.cancer.org/cancer/prostate-cancer/about/key-statistics.html

2. 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

3. 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

4. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer.

. 2013;31(14):1748-1757. doi:10.1200/JCO.2012.43.1882

5. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2020. Accessed October 16, 2020. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

6. Banerjee S, Kaye SB, Ashworth A. Making the best of PARP inhibitors in ovarian cancer. 

. 2010;7(9):508-519. doi:10.1038/nrclinonc.2010.116

7. Carney B, Kossatz S, Lok BH, et al. Target engagement imaging of PARP inhibitors in small-cell lung cancer. 

. 2018;9(1):176. doi:10.1038/s41467-017-02096-w

8. De Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. 

. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440

9. Abida W, Bryce AH, Vogelzang NJ, et al. Preliminary results from TRITON2: a phase II study of rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. 

. 2018;29(suppl 8):viii271-viii302. doi:https://doi.org/10.1093/annonc/mdy284.002

Articles

Treatments provide a targeted therapeutic strategy for metastatic
castration-resistant prostate cancer. 

PARP inhibitors: Treating mCRPC from a genetic basis 

As we move into the last quarter of 2020, although much of the news has been dominated by the challenges of adapting to the ongoing coronavirus disease 2019 (COVID-19) pandemic and associated lockdown, as well as the most recent election, there have been some real breakthroughs as we continue our march toward precision medicine in cancer care. When I brought this term up the other day in conversation with a friend in the music industry, his comment was, “I hear this all the time from acquaintances and in the press, but what does this mean and what is its effect in benefiting patients?”

It is my hunch that most people, in and out of the health care world, have this basic question without true clarity as to its importance and profound impact on the treatment of patients with benign or malignant conditions. For urologists, there is no question that the global work in prostate cancer has led the way, primarily due to the sheer number of patients across the spectrum of disease that are available to study. All urologists understand the importance of the Gleason grading system and the association of aggressiveness and possible disease progression for those with higher Gleason scores. In fact, current National Comprehensive Cancer Network risk stratification is based, for the most part, on this parameter—basic histopathology, cellular architecture and appearance under the microscope, which our anatomic pathologists are skillfully trained to identify. For car aficionados, it is akin to the ability on inspection to differentiate between a Ferrari versus a Lamborghini versus a Ford Mustang.

But keeping with the car analogy, what makes these cars (prostate cancer) so vastly different in performance and value (currently measured by Gleason)? They all have engines, drive trains, tires, exhaust, etc (androgen receptors), but with rare exceptions, the price of 1 Italian supercar is equivalent to a minimum of 4 or 5 iconic American ponies. Thus, to really understand why certain individuals spend vast sums of money for, in its most simplistic definition, a transportation vehicle, it behooves one to have a complete working knowledge of what it takes to build and design the components that make these high-priced motorcars so unique and desired.

We are finally gaining on our understanding of the major molecular drivers that are responsible for the progression of the disease beyond Gleason. Poly (ADP-ribose) polymerase (PARP) inhibitors in the management of heavily treated metastatic castrate–resistant prostate cancer (mCRPC) received FDA approval in 2020. However, for our patients to receive these agents, it mandates that the physician order genomic testing for mutations in DNA damage repair genes involved in homologous recombination. In a similar fashion, testing for variants in mismatch repair genes might allow the use of specific immunotherapies/checkpoint inhibitors, just as an identified splice variant mutation of the androgen receptor, measured by circulating tumor cells, could point us down the therapeutic pathway of who might respond to taxane chemotherapy. In less than 10 years, we have progressed a long way from the days we initiated therapy solely based on the presence of a metastatic lesion and rising prostate-specific antigen.

A highly anticipated new line of precision medicine–based treatment for mCRPC, which we hope will be approved soon, is radioligand PSMA targeted therapy. The use of radiopharmaceuticals for both palliation and prolonged survival in the management of bone metastasis has been readily available for more than 2 decades. However, the development of a “theranostic” approach, based on the patient’s expression of PSMA detected on molecular imaging, represents yet another therapeutic option that is predicated not just on the presence of abnormalities based on traditional nonspecific bone scans but also on actual tumor activity that requires advanced imaging technique. It’s worth noting that on December 1, the FDA approved Gallium 68 PSMA-11 for PET imaging of PSMA-positive lesions in men with prostate cancer.

As previously mentioned, this quest to identify key genetic mutations, and ultimately targeted therapies, is not strictly confined to oncology and malignant transformation. Amyotrophic lateral sclerosis (Lou Gehrig disease) is a devastating progressive neurogenerative disorder, uniformly fatal. However, identification of subtypes, based in part on newly identified genetic mutations, hopefully will result in therapies that can delay progression.

As we slowly move toward the promise of precision medicine, it is important to understand fully this concept and the importance of testing and how it is to be used for diagnosis, management, and risk assessment for the family. We will have to get comfortable in the vast lexicon associated with genomic classification and begin to think in terms of mechanistic pathways, not just the disease. After all, who would not want the chance to drive and hear the roar of an Italian racing machine?

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

1. van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis.

. 2017;390(10107):2084-2098. doi:10.1016/S0140-6736(17)31287-4

"As we slowly move toward the promise of precision medicine, it is important to understand fully this concept and the importance of testing and how it is to be used for diagnosis, management, and risk assessment," writes Raoul S. Concepcion, MD, FACS.

The promise of precision medicine for urologic cancers

Cytoreductive nephrectomy (CN) is a debulking procedure intended to reduce the overall cancer burden in the setting of metastatic disease by extirpating the renal unit containing the primary tumor. This is done without intending to eradicate the disease and is performed with the goal of improving survival outcomes. CN prior to or following upfront systemic therapy has long been considered an important treatment paradigm for metastatic renal cell carcinoma (mRCC). The recent publication of 2 highly anticipated randomized controlled trials, however, has renewed controversy regarding the role of CN for mRCC.

The scientific rationale for performing CN has long been on the basis of level 1 evidence from 2 trials published in 2001. These demonstrated superior overall survival (OS) for mRCC patients undergoing CN plus interferon alfa compared with interferon alfa alone.

 However, since the introduction of targeted agents in 2005, the assumption that CN portends a survival benefit has always been extrapolated from this data, which was formed on that basis of inferior and now obsolete systemic therapy. Prior to 2018, multiple retrospective series demonstrated an OS benefit to CN, but no level 1 data existed to support it.

 All of this ignores the fact that we have again ushered in a revolution in systemic therapeutics for mRCC with immuno-oncology therapy, further clouding the picture of who should or should not receive CN.

Interpreting the CARMENA and SURTIME trials

The CARMENA randomized trial (NCT00930033), published by Méjean et al in 2018, compared OS in mRCC patients receiving the tyrosine kinase inhibitor sunitinib (Sutent) alone versus those receiving sunitinib and CN.

 They were able to demonstrate that OS for the sunitinib-alone arm was non-inferior to sunitinib plus CN (18.4 vs 13.9 months) in the intention-to-treat (ITT) analysis. Naturally, the publication of this trial raises important questions about the validity of CN as a therapeutic endeavor in the targeted therapy era.

However, this trial has significant limitations, and its findings must be interpreted with caution. Patient accrual was slow and the accrual goal was not reached. More significantly, only 0.7 procedures per center were performed. The trial cohort also contained a high proportion of high-risk patients (43%) by Memorial Sloan Kettering Cancer Center (MSKCC) criteria,

 and the remainder (57%) were intermediate risk. Taken together, this suggests that some exclusion bias likely exists, because more favorable patients were presumably being offered CN outside of the trial.

It is also probable that the inclusion of such a high proportion of MSKCC high-risk patients limited the overall survival (OS) of the study cohort. This is reflected by the truncated median OS experienced by the CN arm. Median OS of 13.9 months is very short and does not reflect most contemporary CN cohorts. Additionally, significant contamination of the study arms occurred, with 7% of the CN arm not undergoing surgery and 17% of the sunitinib-only arm receiving CN.

The SURTIME trial (NCT01099423) was intended to evaluate survival outcomes for patients receiving upfront CN followed by sunitinib versus those receiving sunitinib followed by deferred CN.

 Due to poor recruitment (n = 99), the authors were forced to revise the primary end point from OS to a 28-week progression-free survival (PFS) rate, which limits the generalizability of the results. No difference in PFS rates was found between cohorts. Only in an exploratory OS analysis could an OS benefit for the deferred CN arm be identified (15 vs 32 months, HR 0.57; 95% CI, 0.34-0.95; 

 = .03) in the ITT population. This difference was not maintained in the per-protocol analysis.

The SURTIME cohort was 88% MSKCC intermediate risk, which would seem to make it more generalizable to a typical candidate for CN, but very poor accrual limits the interpretation of the results. The study was not powered to detect an OS difference, so conclusions cannot be drawn from their exploratory analysis.

How should CARMENA and SURTIME alter my practice?

These important studies should be viewed as practice-confirming rather than practice-altering. Appropriate patient selection using objective criteria has always been paramount in managing mRCC with CN. The European Association of Urology updated its guidelines

 for managing mRCC to reflect the findings of these randomized trials by stating that MSKCC poor-risk patients should not undergo CN. However, I venture that most urologic oncologists would not have offered an MSKCC poor-risk patient CN prior to the publication of CARMENA. Importantly, these guidelines also state that MSKCC intermediate-risk patients should be considered for upfront systemic therapy. This key point highlights the need for objective scoring criteria to evaluate patients suitable for surgical cytoreduction. Any patient suspected to be high risk for disease progression or perioperative morbidity should be considered for upfront systemic therapy, and this likely includes many intermediate-risk patients. Initial systemic therapy can serve as a litmus test for the clinician—a favorable response may prompt a re-evaluation for CN. The goal of CN should be to prolong survival, and therefore clinicians must endeavor to minimize time spent off of systemic therapy.

Multiple studies and guideline panels utilize the MSKCC criteria to risk-stratify patients with mRCC. It should be noted that the MSKCC criteria were initially published to stratify predicted survival outcomes for mRCC patients receiving therapy with interferon.7 They were never intended to incorporate surgical risk and perioperative morbidity and mortality into their model. The International mRCC Database Consortium (IMDC) has published a risk model,

 which has been validated in cytoreductive nephrectomy patient cohorts and includes 6 easily measured preoperative variables. These include Karnofsky perfoxqrmance status less than 80%, hemoglobin less than 12 g/dL, corrected serum calcium higher than 10.2 mg/dL, neutrophils higher than 7 x109/L, and platelets higher than 400k cells/μL. This model was also published during the targeted therapy era, so it likely represents a more generalizable application to modern mRCC patients. However, because this model includes “less than 1 year from diagnosis to systemic therapy” as the sixth risk factor, it automatically excludes all patients presenting with de novo mRCC from the favorable risk category. For this reason, these criteria may not be ideally suited for clinical application in surgical candidates.

The University of Texas MD Anderson Cancer Center criteria (MD Anderson), recently published in Cancer (as an update from a prior study

), provides clinicians with 9 objective preoperative clinical variables by which patients with mRCC can be stratified into 3 tiers of risk for increased likelihood of death following CN 

 Patients are considered low, intermediate, and high risk for poor survival outcomes following CN if they have 0-1, 2-3, and 4 or more risk factors, respectively. The risk groups not only directly correlated with survival outcomes but also with adverse features on pathology and adverse perioperative outcomes. These findings suggest that the model can predict those patients in whom increased surgical risk may exist outside of their tumor biology. The cohort was derived from consecutive patients undergoing CN in the targeted therapy era and are therefore generalizable to a typical patient with mRCC presenting to a urologist’s office. Notably, median survival in the poor risk group in the MD Anderson cohort was 19 months as compared with 13.9 months in the combined arm (sunitinib + CN) of CARMENA. It seems that when appropriately selected, even poor risk patients receiving CN fare better than those enrolled in CARMENA.

On the basis of the MD Anderson study, patients who fall into a good risk category can be considered for CN and those who are poor risk should not be offered upfront CN. For intermediate-risk patients, careful patient selection based on these risk factors, individual performance status, and other patient comorbid conditions should be undertaken to individualize recommendations. Those patients who elect to receive upfront systemic therapy should be restaged and risk-stratified for CN once a favorable response is documented. Again, the goal should be to prolong survival and CN should only be undertaken when it can be reasonably expected that the patient can resume/begin systemic therapy in a timely fashion post operatively. As the therapeutic landscape continues to evolve and shift to rely more heavily on immuno-oncology therapy, we must be diligent in continuing to develop tools to appropriately risk-stratify patients with mRCC for CN.

 is assistant professor of urology, University of Oklahoma Stephenson Cancer Center, and acting section chief of urology, VA Medical Center, Oklahoma City.

1. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. 

. 2001;345(23):1655-1659. doi:10.1056/NEJMoa003013

2. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. 

 2001;358(9286):966-970. doi:10.1016/s0140-6736(01)06103-7

3. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. 

. 2011;185(1):60-66. doi:10.1016/j.juro.2010.09.012

4. Bhindi B, Abel EJ, Albiges L, et al. Systematic review of the role of cytoreductive nephrectomy in the targeted therapy era and beyond: an individualized approach to metastatic renal cell carcinoma. 

. 2019;75(1):111-128. doi:10.1016/j.eururo.2018.09.016

5. Hanna N, Sun M, Meyer CP, et al. Survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a national cancer data base study.

. 2016;34(27):3267-3275. doi:10.1200/JCO.2016.66.7931

6. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. 

. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675

7. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. 

. 2002;20(1):289-296. doi:10.1200/JCO.2002.20.1.289

8. Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial.

. 2019;5(2):164-170. doi:10.1001/jamaoncol.2018.5543

9. Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology guidelines for cytoreductive nephrectomy in patients with synchronous metastatic clear-cell renal cell carcinoma. 

. 2018;74(6):805-809. doi:10.1016/j.eururo.2018.08.008

10. Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. 

. 2014;66(4):704-710. doi:10.1016/j.eururo.2014.05.034

11. Culp SH, Tannir NM, Abel EJ, et al. Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy? 

. 2010;116(14):3378-3388. doi:10.1002/cncr.25046

12. McIntosh AG, Umbreit EC, Holland LC, et al. Optimizing patient selection for cytoreductive nephrectomy based on outcomes in the contemporary era of systemic therapy. 

 2020;126(17):3950-3960. doi:10.1002/cncr.32991

Recent research has revived the controversy regarding the role
of cytoreductive nephrectomy in this setting.

Radical nephrectomy before or after systemic therapy for mRCC

Lynch syndrome (LS) is one of the most common hereditary cancer disorders and includes multiple urologic cancers within its spectrum. This autosomal dominant syndrome was one of the first hereditary cancer disorders to be identified and affects approximately 1 in 279 people.

 LS is historically known as hereditary nonpolyposis colorectal cancer (HNPCC) but is also associated with urothelial, prostate, testicular, and adrenal malignancies (

The carcinogenic mechanism of LS is caused by a mutation within the mismatch repair (MMR) genes, with the most common mutations being in the mutL homolog 1 (

), and postmeiotic segregation increased 2 (

 Mutations in the epithelial cellular adhesion molecule (EpCAM) can also lead to silencing of 

 MMR genes work together to identify and excise DNA mismatches during DNA synthesis, and mutation of a single protein in this pathway can lead to dysfunction of the entire repair system. The inherited germline mutation alone is not enough to lead to disruption of the MMR system. The second normal allele must be inactivated as well, typically through epigenetic silencing, somatic mutation, or loss of heterozygosity.

 The most common urologic cancer associated with LS is upper tract urothelial cancer (UTUC). It is rare, with an incidence of 2 in 100,000 people per year.4 However, MMR deficiency is seen in 5% to 11% of all patients with UTUC. The MMR genes most commonly associated with UTUC are 

 Urologists evaluating patients with UTUC who display certain characteristics should suspect an underlying genetic syndrome. Young patients, bilateral tumors, abnormal pathologic analysis, or family history compatible with LS all warrant further evaluation for LS.   

The risk of developing UTUC in a patient with LS is about 22 times higher than that of the general population and is estimated at between 0.4% and 20%.

A review of 288 patients with LS in Denmark showed that 22% developed UTUC and 17% developed urothelial carcinoma of the bladder. The mean age at diagnosis was 61, and 

 mutations were seen in 73% of cases. In addition, men and women appear equally affected in those with LS.

 Tumor stage and development of subsequent bladder cancer do not appear to differ in patients with LS versus sporadic patients.3 Bilateral tumors are more common in LS, and previous studies have observed bilateral tumors in 46% of patients.

Due to increased risk of UTUC among patients with LS, screening for urothelial cancer is recommended though there is no consensus on screening approach. Many groups use annual urinalysis with subsequent microscopic hematuria evaluation, because this is relatively low cost and minimally invasive.

 Other groups suggest addition of urogram phase to surveillance scans in those patients who had previous colorectal cancer (CRC).

 Annual computed tomography urogram or renal ultrasound may be particularly beneficial in patients with known 

mutation, because this is the MMR gene most commonly associated with UTUC. The National Comprehensive Cancer Network (NCCN) specifically recommends starting yearly urinalysis in patients with

Genetic testing for MMR mutations should be performed in certain patients with UTUC. Metcalfe et al screened patients without prior history of LS and with UTUC for risk of LS using the Amsterdam II criteria (

) and immunohistochemical (IHC) testing. This identified 13.9% of patients who were considered at risk for LS. Subsequent genetic testing confirmed that 5.2% of patients had LS.

 Therefore, those with positive screen using Amsterdam II criteria as well as those with positive IHC testing for MMR mutation should undergo genetic testing.

Bladder cancer occurring in multiple members of a family is still more likely to be a result of shared environmental risk factors than of heredity. However, emerging data demonstrate increased risk of bladder cancer in patients with LS, especially in men and those with 

mutations. In the previously cited article from Denmark, 17% of patients with LS may develop urothelial cancer of the bladder.

 A second study, from Canada, showed a lower percentage (6.21%) of patients with LS and 

mutations with bladder cancer; however, this was still significantly higher than the general Canadian population.

 These observations are likely high enough to justify a yearly urinalysis staring at age 30 in patients with known LS and 

Inclusion of prostate cancer as an LS-associated cancer remains controversial despite being clearly defined by Ryan et al in 2014.11This meta-analysis and systematic review showed that there is a 3.67-fold relative risk for developing prostate cancer in patients with MMR mutations, especially 

(95% CI, 2.32-6.67). Other studies have shown comparable results confirming increased prostate cancer risk in patients with LS.

Men with prostate cancer meeting certain criteria should be tested for LS. Based on the 2017 Philadelphia Prostate Cancer Consensus Conference, the recommendation is to screen for MMR gene mutations in men with family history of LS or with 2 or more blood relatives with an LS-associated cancer.

 These recommendations are similar to those for UTUC, though they do not specifically recommend use of the Amsterdam II criteria.

There are no data to suggest earlier onset of prostate cancer or higher stage at diagnosis. Some have proposed PSA screening starting at age 40; however, studies have shown a median age at diagnosis ranging from age 59 to 69 years.

 Therefore, men with LS should be strongly encouraged to undergo yearly PSA and physical exam testing. However, screening starting earlier than age 55 years is not supported by the literature.

The relationship between LS and testicular cancer is not well established. Current literature is conflicting, with some data showing up to 33% of testicular germ cell tumors containing MSI compared to other studies showing no MSI and no MMR deficiency on histopathologic analysis.

Due to the rarity of adrenocortical carcinoma (ACC), association with LS is difficult to establish. ACC is associated with poor prognosis and affects only about 1 to 2 patients per million each year.12 Various case studies have reported incidence of ACC within patients with LS and 

 mutations and, in a combined prospective and retrospective study, MMR mutations were found in 1.5% to 3.2% of patients with ACC.

 These data are not adequate to encourage screening for ACC in patients with LS; however, they do suggest that ACC should be a consideration when evaluating patients with LS with adrenal masses.

Lynch syndrome is one of the most common hereditary malignancy syndromes and is associated with multiple urologic cancers. To apply this knowledge of LS to daily practice, we should keep in mind the following:

UTUC is the third most common LS-associated cancer.

 mutations should undergo yearly urinalysis and microhematuria workup as indicated; they may also benefit from yearly renal ultrasound or CT urogram.

Patients with UTUC or prostate cancer meeting the Amsterdam II criteria or having abnormal immunohistochemical testing on pathology should undergo genetic screening for LS.

In patients with LS presenting with adrenal mass, ACC should be considered.

Beyond treating patients for urologic cancers, it is our role as urologists to identify patients at risk for undiagnosed Lynch syndrome and provide appropriate screening in this population.

 is associate professor of medicine at Mayo Clinic, Phoenix, Arizona.

1. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. 

. 2017;26(3):404-412. doi:10.1158/1055-9965.EPI-16-0693

2. Huang D, Matin SF, Lawrentschuk N, Roupret M. Systematic review: an update on the spectrum of urological malignancies in Lynch syndrome. 

. 2018;4(3):261-268. doi:10.3233/BLC-180180

3. Mork M, Hubosky SG, Rouprêt M, et al. Lynch syndrome: a primer for urologists and panel recommendations. 

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4. Rouprêt M, Zigeuner R, Palou J, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. 

. 2011;59(4):584-594. doi:10.1016/j.eururo.2010.12.042

5. Van der Post RS, Kiemeney LA, Ligtenberg MJ, et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. 

. 2010;47(7):464-470. doi:10.1136/jmg.2010.076992

6. Hubosky SG, Boman BM, Charles S, et al. Ureteroscopic management of upper tract urothelial carcinoma (UTUC) in patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). 

. 2013;112(6):813-819. doi:10.1111/bju.12008

7. Gupta S, Provenzale D, Llor X, et al. NCCN guidelines insights: genetic/familial high-risk assessment: colorectal, version 2.2019. 

. 2019;17(9):1032-1041. doi:10.6004/jnccn.2019.0044

8. Metcalfe MJ, Petros FG, Rao P, et al. Universal point of care testing for Lynch syndrome in patients with upper tract urothelial carcinoma. 

. 2018;199(1):60-65. doi:10.1016/j.juro.2017.08.002

9. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. 

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10. Skeldon SC, Semotiuk K, Aronson M, et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. 

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Research indicates Lynch syndrome is associated with urothelial, prostate, and other urologic cancers.

Urologic implications of Lynch syndrome

Since it was first described in 1910, transurethral resection of bladder tumor (TURBT) has evolved into the cornerstone of bladder cancer diagnosis and staging, and is one of the most common surgeries urologists perform. Following the introduction of video endoscopy in the late 1970s, TURBT has been characterized as a relatively simple procedure, often performed by junior residents in the academic setting. More recent data emphasize the importance of high-quality TURBT by experienced surgeons in order to improve patient outcomes.

Significant variation in recurrence rates among urologists has been described, supporting the assumption that experienced technical skill matters. At our institution, junior residents slowly gain more responsibility as their technical skills develop under the close supervision of an experienced surgeon with a low threshold to take over the case when accurate staging may be difficult to obtain. Below, we discuss our standard technique for TURBT and describe new advancements that may help standardize outcomes in a procedure that has experienced little evolution during the past century.

 Before operative intervention, a thorough history and physical should be performed. When possible, slides from prior resections are reviewed by our genitourinary specialized pathologists to ensure accurate staging and identify any variant histology. Routine lab work to assess renal function and rule out infection are obtained at the initial consultation, and imaging studies evaluating the upper urinary tract are performed before or at the time of TURBT. For patients with a history of non–muscle-invasive bladder cancer (NMIBC), we will often utilize blue light cystoscopy given the observed increased cancer detection (especially for carcinoma in situ [CIS]), decreased recurrence, and possibly decreased progression associated with its use. In addition, for those patients with discordant positive cytology and negative office cystoscopy, we will routinely use blue light technology in accordance with the American Urological Association (AUA) NMIBC guidelines. Although not yet incorporated into our practice, clinic blue light capabilities may further enhance patient care by increasing detection rates and avoiding unnecessary use of operative resources in patients with negative surveillance cystoscopy.

 Before and following resection, a bimanual exam is performed under sedation to assess clinical staging (fixation of bladder or palpable masses). The largest rigid resectoscope (ideally a 26 F with inflow and outflow ports to allow continuous irrigation) that the urethra will accommodate, with a 30° lens, is then introduced into the bladder. When indicated, a urine cytology is obtained. This can be performed by collecting the first emptied urine from the bladder (essentially a voided urine cytology) or as a formal bladder washing using saline. A careful white light cystourethroscopy is performed. In rare cases, a 70° lens may be needed to completely visualize the bladder. If enhanced cystoscopy techniques are planned, a repeat evaluation of the bladder is then performed using this technology. Obtaining photos of tumors can be useful for patient counseling and providing more detailed information for health care providers who are not present during the resection. Assessment of the size, location, grade, and presumed depth of invasion will inform the operative plan.

 Smaller tumors in patients with thin bladder walls may be managed with cold cup biopsy, thereby mitigating the risk of bladder perforation. Alternatively, cautery loop resection can be performed, often en bloc, with one swipe. Larger tumors require a fragmented approach with successive loop resection until the base is exposed.

 When resecting tumors in difficult locations where bladder injury is more likely, we will often use a staccato energy approach, which provides greater control and helps limit thermal injury. Tumors at the bladder dome and anterior wall may require abdominal pressure with the non-resecting hand to bring the mass into view. Occasionally, a long resectoscope may be required to reach the area of interest. The obturator reflex may be invoked when resecting lateral wall tumors, resulting in adduction of the ipsilateral leg and possible bladder perforation. Avoiding overdistention, use of bipolar energy source, resecting with decreased energy settings, and anesthetic paralysis may help limit this occurrence. For posterior wall tumors, bending the resection loop out to assimilate the contour of the bladder wall can provide safer and cleaner resection. For tumors near or overlying the ureteral orifices, pure cutting current should be used to avoid obstruction. The decision to leave a ureteral stent in this setting is surgeon dependent; however, existing data suggest that postresection hydronephrosis is rare regardless of stent use.

Diverticular tumor resection carries a greater risk of bladder perforation given the lack of underlying detrusor muscle. When invasion is suspected, bladder perforation may be required in order to obtain adequate staging. In such cases, postoperative indwelling catheter placement should be utilized to allow adequate healing and avoid further complications.

Low-grade tumors are associated with a low risk of progression and are increasingly being safely observed.

 Smaller low-grade tumors can often be managed without anesthesia in an office setting using cautery or laser ablation following intravesical instillation of a lidocaine/bicarbonate solution. For high-grade tumors, obtaining detrusor muscle in the specimen is critical for staging purposes. Loop resection is performed to expose the tumor base. Further loop resection is then performed to obtain muscle. Alternatively, cold cup biopsy of the resection base is used in instances where bladder perforation is a concern.

 Bipolar energy, originally developed for transurethral resection of the prostate, is commonly used in TURBT as well, because of several potential advantages. Saline irrigation is used, diminishing the risk of TUR syndrome, which can occur after more extensive resections with water. Monopolar energy travels from the resection electrode through the body to the electrode attached to the patient’s skin, whereas bipolar energy travels between electrodes on the resection device. For lateral tumors where an obturator reflex is likely, bipolar may offer some advantage and limit bladder perforation. The difference in energy propagation may also limit cautery artifact in pathology samples. Finally, bipolar may offer more safety for patients with pacemakers and for pregnant women.

 Despite these theoretical advantages, comparative data are conflicting. In a recent systematic review of 13 randomized control trials comparing monopolar and bipolar TURBT, there was no observed difference in operative time, recurrence rate, bladder perforation, thermal damage, or overall complications.

 Perioperative intravesical chemotherapy has been shown to reduce recurrence, especially in low-grade solitary tumors. Although data are more robust for the use of mitomycin C (MMC), we will often instill gemcitabine through an indwelling catheter in the operating room following resection of presumed low-grade tumors given the favorable adverse effect profile and recent phase 3 randomized control trial showing a recurrence rate reduction similar to that of MMC.

 Intravesical chemotherapy should be avoided following extensive resections or if bladder perforation is suspected.

Improvement in imaging modalities may help in performance of transurethral resection of the bladder tumor.

UCC December 2020

PARP inhibitors: Treating mCRPC from a genetic basis

The promise of precision medicine for urologic cancers

Radical nephrectomy before or after systemic therapy for mRCC

Urologic implications of Lynch syndrome

Transurethral resection of the bladder tumor: Standard technique and new advancements

The current state of adjuvant radiotherapy post prostatectomy: 3 take-home messages