Over the past decade, we have used the terms

 interchangeably. For the most part, patient care has always been personalized. Yes, some want to make it more standardized. Still, to adequately manage and treat our patients, we have to consider many comorbidities when providing a treatment benefit that minimizes the impact on quality of life. For example, what should be the oral agent of choice as first or second line of therapy in the management of metastatic castration-resistant prostate cancer (mCRPC)? Or, if a patient has localized prostate cancer, will surgery or radiation therapy provide the best chance of cure? It all depends.

In the first scenario, we would base our choice of oral therapies on the patient’s medical history, which, if significant, might give rise to a deleterious adverse event associated with the drug. In the latter, it is doubtful that we would think that radical prostatectomy would be the best choice for a patient with significant local disease who has had multiple abdominal/pelvic surgeries. We would all agree that fully understanding our patients’ medical histories helps to guide our final recommendations, regardless of whether we are writing a prescription or recommending surgery. This is personalized care.

We have now entered the era of precision medicine. In 1971, President Nixon declared a “war on cancer” by signing the National Cancer Act. Those of us who are old enough to remember Operation Desert Shield and Operation Desert Storm in 1990 and 1991 witnessed for the first time, as a result of live media coverage of frontline fighting, the use of radio- or laser-guided smart bombs that minimized collateral damage and required less explosive to damage a target. Essentially, that is what we are trying to achieve as we explore the biology of cancer. What are the molecular drivers that result in recurrence and resistance to therapy? More important, after we have identified the mechanisms, is it possible in some cases to target these pathways and minimize toxicity to healthy cells? Success in this regard amounts to a lessening of collateral damage.

This is the promise of precision medicine, which is mandated when we have multiple options for the same patient type. In localized prostate cancer, we now have genetic tissue assays that can potentially assist us in our shared decision making. This is particularly true if a patient has a lower risk for progression and is a candidate for active surveillance, thus potentially limiting qualityof- life issues that may result from active treatment. For our patients with muscle invasive bladder cancer, in which neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care, use of molecular subtyping may help identify which patients are unlikely to respond to NAC, making it possible for them to move directly to surgery and avoid the toxicity of methotrexate, vinblastine, doxorubicin, cisplatin, or gemcitabine and cisplatin. In the future, with this molecular subtype information, we might be able to identify patients in that 30% category who are complete responders to NAC and could avoid life-altering surgery entirely.

Case in point: Among patients with mCRPC who have been heavily pretreated with multiple lines of current therapy, immunotherapy seems to benefit those who test positive for microsatellite instability (MSI) or have biallelic loss of CDK12 with inactivation. We are also well aware of androgen receptor (AR) splice variant mutations that seem to directly correlate with treatment pressure selection, limiting the subsequent use of AR modulating agents. Testing for this in select patients will be essential, as we have more and more approved agents. Finally, because we have now established that lethal prostate cancer has a definite hereditary pattern, it will be imperative to incorporate genetic testing panels for potential treatment selection as well as to provide adequate family counseling.

Nothing has been stated in this missive that we have not heard before. For the most part, all of us entered urology, especially urologic oncology, for the challenge and satisfaction of extirpative surgery and reconstruction. However, to remain leaders in the management of our oncologic patients, we need to have total knowledge of the disease and not limit ourselves to the adoption of and adaptation to newer surgical techniques. It may take a restructuring of our current practice models, but we need to embrace, understand, and incorporate all these new technologies, both surgical and nonsurgical, to be at the forefront of precision medicine for our patients.

For our patients with mCRPC, the concept of precision medicine and testing becomes even more critical. After the early tsunami of novel agents that received FDA approval in the first half of this decade, we have seen movement of these therapies to more proximal stages but nothing new mechanistically. As we know, this will undoubtedly change by year’s end. Regardless of whether these new agents are PARP inhibitors, theranostic agents, or others, they will only add to the complexity of how to best layer or sequence therapies when treating patients with mCRPC. Furthermore, we are now in the infancy of predictive and prognostic molecular testing that will provide key information regarding resistance pathways but more than likely will be mandated for use with particular agents.

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It may take a restructuring of our current practice models, but we need to embrace, understand, and incorporate new technologies, both surgical and nonsurgical, to be at the forefront of precision medicine for our patients.

The Challenge of Precision Medicine in mCRPC

Prostate cancer is the most prevalent solid tumor in men over 50 years of age and the second-leading cause of cancer-specific mortality in the United States today. It was estimated that in 2018 alone, 165,000 men would be given a diagnosis of prostate cancer and more than 29,000 men would die from the disease.

 Most cases are localized at the time of diagnosis, but de novo metastatic disease is on the rise and may represent 4% of initial presentations. The median ages at diagnosis and death are 66 and 80 years, respectively. The statistics are worse for African American men, who are nearly twice as likely as Caucasian men to develop prostate cancer and more than twice as likely to die of the disease.

In addition, African American men with prostate cancer are more likely than Caucasian men (7.3% vs 2.2%) to have mutations in the DNA repair genes BRCA1 and BRCA2 and thus experience more aggressive prostate cancer with a shorter time to metastasis.

 Estimates vary, but 20% to 30% of all men treated for localized disease develop biochemical recurrence and eventually progress to terminal metastatic castration-resistant prostate cancer (mCRPC).

Historically, urologists have been the primary caretakers for men with localized prostate cancer. The first decade of the 21st century heralded a renaissance of drug development for the management of patients with mCRPC. Seven new therapies gained FDA approval for both metastatic and nonmetastatic CRPC. Many of these agents are oral and have a very manageable adverse event profile. As a result, urologists have become more active in the delivery of oncologic care across the spectrum of prostate cancer, even for patients with advanced prostate cancer.

In March 2007, the US Department of Health & Human Services launched the Personalized Health Care Initiative with the goal of integrating gene-based technologies into healthcare delivery so that therapies would be better tailored to individual patients.5 A year later, with the goal of barring the use of genetic information in health insurance or employment, Congress enacted the Genetic Information Nondiscrimination Act (GINA). Although far from perfect, it prevents employers from using genetic information as the basis for denial of health insurance and decisions about hiring, firing, and promotions.

The drive toward precision medicine has resulted in a deeper understanding of the molecular biology of cancer development. There are still gaps in the understanding of the respective roles of genetics and gene mutations, diet, and the environment. These factors, particularly the genetic component, are key to malignant cell development and, ultimately, cancer. As a result, there is a growing need to incorporate genetic counseling and testing into comprehensive cancer care.

Along these lines, urologists are becoming more and more aware that lethal prostate cancer has a distinct hereditary component. Just as hereditary testing has been incorporated into comprehensive care models for many specialties, this evolving platform must now be incorporated into advanced prostate cancer care. The tools for doing this are becoming increasingly available. The FDA recently approved a next-generation sequencing (NGS) testing panel for several hundred genes in solid tumors, thus advancing the current era of personalized molecular oncology. This test may justify the use of specific therapies across tumor types, regardless of initial labeling.

 has traditionally comprised individual genes and their inheritance patterns (some diseases, such as sickle cell anemia and cystic fibrosis, result from alterations in an isolated gene), the modern definition includes multiple gene inheritance patterns. Thus, modern genetic testing relies on genomics, encompassing an organism’s entire genetic makeup (genome) and an extensive number of genes interacting with one another and the environment.

Germline mutations are almost always inherited. They are present in every cell of the body but only half of all eggs and sperm. A child of a germline mutation carrier has a 50% chance of inheriting that gene. Multigene panels evaluate blood or saliva cells for the presence of these germline mutations. Somatic mutations develop when a cell becomes malignant. These changes can be found only in the tumor. When a germline mutation is present in a tumor suppressor gene, such as 

, it may accelerate the accumulation of somatic mutations, thus increasing the chance that cancer will develop.

NGS is performed mainly with tumor tissue, but liquid biopsies (blood based) are under development, using different assay types including circulating tumor cells (CTCs) and cell-free DNA. These new technologies may give us real-time information about tumors as they progress and mutate further. Urologists are familiar with somatic genomic tissue-based tests that inform treatment decision making by identifying patients with localized prostate cancer who may benefit from active surveillance versus treatment. However, when it comes to germline genetic testing, we have not caught up with our oncology brethren. Perhaps this is partly due to the prior lack of data on the hereditary component of prostate cancer.

Whereas all cancer is genetic but not all cancer is hereditary, the risk for cancer can be categorized as sporadic, familial, and hereditary.

Sporadic cancers are the most common and occur by chance. Typically, the patient does not have relatives with the same type of cancer.

Familial cancer is likely to be caused by a combination of inherited genetic and environmental factors. Patients with familial cancer may have 1 or more relatives with the same type of cancer, but there does not appear to be a specific pattern of inheritance. Familial patterns are seen in certain cancers (eg, breast, colon, and prostate).

Hereditary cancer involves an altered gene passed down from parent to child (germline). A single mutation is not likely to cause cancer; however, it will increase an individual’s chances. With 1 damaged gene already present, it would take fewer mutation-causing events over a patient’s lifetime for cancer to result. In hereditary cancer, patients are more likely to have relatives with the same or related types of cancer. The hallmark of hereditary cancer is the potential development of multiple cancers, rare cancers, and, often, cancers that are more aggressive biologically than sporadic cancers. Hereditary cancers may occur at earlier ages (<50 years) than other cancers but not always. In addition, some races and ethnicities may have a greater risk for hereditary cancer (eg, Ashkenazi Jewish individuals).

Hereditary-linked cancers represent 5% to 10% of patients with prostate cancer. 

mutations are linked to prostate cancer, and germline 

 mutations are associated with worse prostate cancer outcomes, as reported by Castro et al in a study evaluating response of 

 carriers versus others to conventional treatments.

 Another study found that 11.8% of 692 unselected men (regardless of family history) with metastatic prostate cancer demonstrated an inherited pathogenic mutation and concluded that routine testing for all men with metastatic prostate cancer may be justified. Among 16 identified genes, 

 was the most common (45% of total). Other genes included 

, among others. The same study found that 4.6% of 498 unselected men (regardless of family history) with localized prostate cancer (any Gleason score) had a pathogenic mutation.

Hereditary cancers of interest to urologists include hereditary breast and ovarian cancer (HBOC)syndrome as well as Lynch syndrome. HBOC links 

 genes to prostate cancer and can cause melanoma and breast, ovarian, pancreatic, and male breast cancers. Lynch syndrome is associated with DNA mismatch repair genes (MMRs) and is linked to colorectal, uterine, ovarian, stomach, prostate, and brain cancers, as well as leukemia and urothelial carcinomas of the renal pelvis and ureter. Keeping these associations top of mind could affect medical decision making and help prevent future cancers in patients and their family members. For example, active surveillance for localized prostate cancer would not be advised in men with 

 mutations. Radiation therapy may not be advisable for patients with prostate cancer with Lynch syndrome because of the increased risk of colorectal cancer.

The caveat when using multigene panels to identify risk for prostate cancer is that we do not know the clinical relevance of very many genes, and most are not actionable. This leads to questions: What is a positive result? Can the lab find all the variants, and does the lab classify variants correctly? Does the variant increase the risk of cancer? Often the answers are not black-and-white, and there are many shades of gray. New prostate cancer genetic panels are becoming available commercially but need validation. Because of these issues, it is important to involve the services of a genetic counselor before and after testing. Trained, professional genetic counselors can compile detailed personal and family cancer histories. They can explain all aspects of genomics and genetic testing, such as hereditary cancer issues; genetic test options, including individual and cascade testing (testing of multiple family members); and costs. They can also address the implications of genetic test results so that patients and their families can make informed decisions about therapeutic options. As therapies evolve, genetic information will be a powerful tool in healthcare. However, because of the limitations of GINA, it is important that trained professionals be available to inform patients about the benefits and risks of genetic testing. Although gene panels are commercially available, urologists should inform patients about the potential for adverse consequences.

Table 1. Gene Mutations Associated With PCa and Common Testing Panels

In March 2017, the Philadelphia Prostate Cancer Consensus Conference (PPCCC) convened an expert panel to develop a multidisciplinary perspective on the role of genetic testing for inherited prostate cancer in the era of multigene testing. Specifically, the panel addressed referral criteria, genetic counseling, genetic testing, and management.

 Prior to the PPCCC, there was a major unmet need for comprehensive guidelines on prostate cancer genetic testing from urology and oncology associations. In its own guidelines, the National Comprehensive Cancer Network (NCCN) previously focused on just 

testing. There were no specific guidelines regarding genetic counseling and testing for prostate cancer or interpretation of genomic profiles of tumors provided by commercial gene panels. The PPCCC group of international experts reviewed recent studies and cited high-level evidence in support of testing for not only 

 mutations associated with Lynch syndrome (

 Most of these specific mutations have been included in NCCN guidelines version 4.2018 for prostate cancer, which contain recommendations for germline testing. This latest version has expanded genetic testing guidelines for all risk categories (

 The PPCCC panel also recommended genetic counseling.

Identifying patients at risk for hereditary cancer is now a standard of care.Obtaining a good family history is recommended as part of the initial prostate cancer diagnosis guideline. This version recommends hereditary cancer testing for patients with prostate cancer who have meta- static prostate cancer or Gleason 7 or higher disease or any one of the following close blood relatives: 1 or more family members (<50 years) with breast cancer; 1 or more family members (any age) with ovarian cancer; or 2 or more family members (any age) with breast, pancreatic, or prostate cancer (Gleason 7 or higher or metastatic). Close blood relatives include parents, children, siblings, grandparents, great-grandparents, aunts and uncles, nieces and nephews, and first cousins. Genetic counseling is recommended for anyone with 3 or more of the following cancers: prostate, pancreatic, melanoma, uterine, kidney, sarcoma, adrenal, brain tumors, colon, and leukemia.

Table 2. NCCN Guidelines on Germline Testing for Prostate Cancer (Version 4.2018)

In December 2018, the Society of Urologic Oncology (SUO) issued a statement on genetic counseling and genetic testing in the management of prostate cancer that incorporates NCCN genetic evaluation criteria merged from Breast and Ovarian Version 2.2019 as well as Prostate Version 4.2018: “The SUO supports genetic testing of men with prostate cancer meeting the NCCN criteria as noted... and endorses the need for appropriate genetic counseling for men with prostate cancer before or after genetic testing as a central concept. This should also include considering the needs of the patient’s family as well.”

The era of precision medicine emphasizes the need for genetic testing to inform cancer treatment, especially in the advanced-stage setting.Studies reported by Mateo

 demonstrated prolonged tumor responses for PARP inhibitors across a spectrum of solid tumor malignancies. This suggests that PARP inhibitors may have overall survival benefits in patients with metastatic castration-resistant prostate cancer. Consequently, breakthrough designations have been issued for olaparib (Lynparza) and more recently rucaparib (Rubraca) in patients with 

 mutation—positive mCRPC who have progressed after next-generation oral oncolytics or chemotherapy (these patients may respond to platinum-based chemotherapy as well). Further, these agents offer value across solid-tissue tumor types with 

 gene mutations, making them agnostic by indication, nonspecific to organ of origin, and specific based on genetic mutations. The accelerated approval of the immune checkpoint inhibitor pembrolizumab (Keytruda) for microsatellite instability-high or MMR-deficient cancers across all solid tumor types, including prostate cancer, gives this agent an agnostic indication as well. Thus, multigene testing for inherited prostate cancer is now critical for prostate cancer risk determination, screening, and treatment implications.

So how should urologists incorporate genetic testing into clinical practice? The most important thing to do is capture detailed family histories to identify appropriate patients and their families for multigene testing. Consider referral to a genetics counselor to navigate patients and their families before and after hereditary testing. If patients with mCRPC progress after next-generation oral oncolytics or chemotherapy, genetic testing in and outside the context of clinical trials will inform available treatment options such as PARP and immune checkpoint inhibitors as well as platinum chemotherapy. There are still many unanswered questions: Where exactly are we regarding hereditary genetics in prostate cancer? Do we know who should undergo genetic testing and counseling? What genes and gene panels should be tested? Should genetic testing inform screening or guide treatment of different stages of prostate cancer? The field is evolving and so are the answers to these questions.

Prostate cancer: statistics. Cancer.net website. cancer.net/cancer-types/prostate-cancer/statistics. Published January 2018. Accessed January 11, 2019.

Cancer stat facts: prostate cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results Program website. seer.cancer.gov/statfacts/html/prost.html. Accessed December 2018.

Petrovics G, Ravindranath L, Chen Y, Ying K, Ali A, Young D. MP39-18 higher frequency of germline BRCA1 and BRCA2 mutations in African American prostate cancer. 

. 2016;195(4):e548. doi: 10.1016/j.juro.2016.02.143.

Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. 

. 2015;10(10):e01394404. doi: 10.1371/journal.pone.0139440.

Personalized Health Care Initiative workshop: “understanding the needs of consumers in the use of genome-based health information services” — executive summary. US Department of Health & Human Services: Office of the Assistant Secretary for Planning and Evaluation website. aspe.hhs.gov/execsum/personalized-health-care-initiative-workshop-understanding-needs-consumers-use-genome-based-health-information-services-execu-tive-summary. Accessed January 11, 2019.

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/NEJMoal603144.

Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutation on metastatic relapse and cause-specific survival after radical treatment for localized prostate cancer. 

. 2015;68(2):186-193. doi: 10.1016/j.eururo.2014.10.022.

Giri V, Knudsen K, Kelly WK, et al. Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017. 

. 2018;36(4):414-424. doi: 10.1200/JCO.2017.74.1173.

Giri VN, Knudsen KE, Kelly WK, et al. Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017. 

National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines): prostate cancer version 4.2018. NCCN.org. nccn.org/professionals/physician_gls/pdf/prostate.pdf. Published August 15, 2018. Accessed January 16, 2019.

Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. 

. 2015;373(18):1697-1708. doi: 10.1056/ NEJMoa1506859.

Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. 

. 2015;33(3):244-250. doi: 10.1200/JCO.2014.56.2728.

 Lauren R. Karsh, MD, assisted with the medical writing of this article.

Historically, urologists have been the primary caretakers for men with localized prostate cancer, which is the most prevalent solid tumor in men over 50 years of age and the second-leading cause of cancer-specific mortality in the United States today.

February 2019 | Oncology Live Urologists in Cancer Care®

The Challenge of Precision Medicine in mCRPC

Hereditary Prostate Cancer—What Urologists Should Know

February 2019 | Oncology Live Urologists in Cancer Care®

The Challenge of Precision Medicine in mCRPC

Hereditary Prostate Cancer&mdash;What Urologists Should Know

Hereditary Prostate Cancer—What Urologists Should Know