Raoul S. Concepcion, MD

 is chief clinical urologist officer, Integra Connect, West Palm Beach, FL, and clinical associate professor of urology, Vanderbilt University School of Medicine, Nashville, TN.

Prostate cancer is a clinically heterogenous disease with variability in progression once diagnosed, ranging from the very indolent cases that may require no therapy to patients who present with de novo metastasis. In 2019, there were approximately 174,650 newly diagnosed prostate cancer cases in the United States and a cancer-specific mortality of 31,620 directly attributable to the disease or 5.2% of all cancer deaths.

A number of newer therapies (all mechanistically different) and treatment regimens have been approved for the management of both patients with metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). A unique dynamic progressive model estimates the incidence of these two subsets may approach 42,970 patients in 2020.

Unfortunately, despite the availability of superior agents, optimal sequences or a combination of these oncolytics have yet to determined, as there are no predictive biomarkers to inform the provider what is the most ideal initial line of therapy (LOT) and as patients progress, what will be the most appropriate next LOT. What makes this situation even more challenging is that these newer therapies, as well as those that we anticipate will be approved in 2020 and beyond, are targeted for molecular drivers of prostate cancer. For the patient with mCSPC or mCRPC, how can we best determine the initial and subsequent LOTs, given the limitations of the monotherapy registration trials?

A number of key genomic mutations have been consistently identified in patients with prostate cancer (hormone naive and mCRPC). These mutations include gene fusion/chromosomal rearrangements 

 androgen receptor (AR) amplification, inactivation of tumor suppressor genes (

/PI3-K/AKT/mTOR, TP53, Rb1), and oncogene activation (

 More significantly, defects in DNA repair appear to be central in increasing one’s susceptibility to malignant transformation.

It is critical to patient management that we determine whether these mutations are inherited (germline) or acquired (somatic). Germline mutations are changes in DNA that are present in the patient’s reproductive cells (sperm or ovum) and are thus passed from generation to generation and will be identified in every cell of the body. Therefore, germline testing can be conducted with just a swab from the mouth, saliva, or blood from the patient. There are many companies in the United States that currently offer germline testing.

It is paramount that in order to obtain the most comprehensive analysis and report, genetic testing through next-generation sequencing in a diagnostic laboratory is mandatory. This type of testing should be compared with many of the direct-to-consumer tests that are currently marketed to patients. The testing platforms deployed by many of these companies are much less robust and often include a very limited number of known genetic mutations in their panels.

For example, thousands of identified BRCA mutations have been identified, but only a handful may be tested in some of these direct-to-consumer testing kits. This situation can lead to an unacceptable number of studies with false-negative results and should not be used for clinical decision-making.

Acquired or somatic mutations can be defined as any alteration in DNA that occurs after conception. These can occur in any cell of the body (except the reproductive cells) and usually arise as a result of exogenous or environmental exposures, such as tobacco smoking or UV radiation. Therefore, somatic testing requires next-generation sequencing of cells extracted from the tumor itself and cannot be performed by using a sample of saliva or blood.

Pritchard and colleagues were among the first to demonstrate the value of assessing inherited genetic changes in prostate cancer. Among 692 patients with metastatic prostate cancer, they examined the prevalence of mutations in 20 DNA repair genes.

 Mutations were identified in 82 men (11.8%) with significant geographic heterogeneity, even among these recognized cancer centers (prevalence of 8.8% in patients treated at the University of Washington and 18.5% in those treated at Memorial Sloan Kettering), potentially reflecting referral biases. Subsequently, Castro et al found a prevalence of germline DNA damage repair gene mutations of 16.2% in patients with mCRPC.

Unlike other disease states in which commonly identified germline mutations may be actionable, actionable germline mutations are relatively uncommon in patients with prostate cancer. Nicolosi and colleagues found that actionable mutations were identified in 1.74% of their study cohort with a diverse patient population.

 In previous analyses, Robinson et al reported clinically actionable pathogenic germline mutations in 8% of 150 patients with mCRPC, in contrast to clinically actionable aberrations in the AR in 63% and aberrations in other cancer-related genes in 65% of patients.

 It is likely not surprising that actionable underlying germline mutations would be more common in a cohort with more advanced prostate cancer.

In patients with regional or metastatic prostate cancer, somatic tumor testing may also be considered on the basis of the observation that nearly 90% of men have potentially actionable mutations at the tumor level, whereas only a relatively small proportion of men would have actionable germline mutations (approximately 9% of patients with mCRPC, according to the National Comprehensive Cancer Network). In these patients, testing may be undertaken for somatic homologous recombination repair (HRR) gene mutations (eg, 

) and for microsatellite instability (MSI) or mismatch repair (MMR).

In patients with advanced prostate cancer, identification of underlying germline mutations may guide treatment selection to determine the most appropriate next LOT, especially in those who have progressed through multiple lines of prior therapy, including AR signaling agents. Patients with identified MSI-high status, defects in DNA MMR genes, or 

 biallelic loss may respond to checkpoint inhibition therapy.

Pembrolizumab (KEYTRUDA), an FDA-approved PD-1 inhibitor, is the first immunotherapy to win approval in a tumor-agnostic manner and not based on organ type. Further, patients with mutations in HRR genes (including 

, and genes that cause Fanconi anemia) may be better suited for treatment with PARP inhibitors, many of which are in ongoing phase III trials with expected approval in 2020.

Finally, patients with DNA repair defects may have increased sensitivity to platinum-based chemotherapeutics.

 Given the uncertainty regarding optimal treatment selection and pending approval of current agents in trial, the National Comprehensive Cancer Network prostate cancer guideline panel recommends clinical trial enrollment for all men with prostate cancer and identified DNA repair gene mutations. In addition, somatic testing for specific gene variants may be undertaken.

For the most part, this approach is used in patients with advanced disease with the goal of identifying specific actionable targets. For example, mutations in HRR or MMR genes and identification of MSI-high versus MSI-low status may suggest certain treatments are more likely to be beneficial.

In addition to genetic testing of tumor tissue, assessing circulating tumor cells may offer important information. For example, testing of AR variant status can be performed using circulating tumor cells and may be predictive of disease.

Generally, genetic testing yields results that are unambiguous and will show that a gene mutation is present or absent. However, the reporting of the significance and association of that mutation relative to a disease state can be quite variable. Given that the coding sequence for a particular gene has been defined and the sequencing machines are fairly similar, what is considered “positive” or deleterious versus “negative” or favorable/no mutation relative to risk of disease is predicated on the number of patients tested.

As noted, a number of genes have been identified as associated with an increased susceptibility risk for prostate cancer. Multigene panels are becoming used more often, but the makeup of these panels is not uniform. A recent analysis looking at various commercially available multigene panels shows that the average number of genes tested is 12 (range, 4-16). 

 are included in all the panels, but 20% did not include 

The clinical experience and number of patients tested with 

 is more extensive compared with other genes. More and more mutations continue to be discovered, but the significance to the patient has yet to be determined until even further samples are processed. These discoveries, classified as variants of unknown significance (VUS), represent a gray area in which there is a change in the genetic sequence; however, it is still unknown whether this change is associated with a deleterious or favorable prognosis. Among women with breast cancer, detection of a VUS is more common than identification of known pathogenic variants.

 Although ongoing work seeks to better delineate the importance of these VUS, the involvement of a genetic counselor is key to helping patients navigate this uncertain situation.

Urologists will need to incorporate comprehensive genomic testing, just as we embraced PSA testing back in the 1990s. A recent survey conducted among 52 single-specialty independent urology community practices identified the following three issues related to incorporation and development of a comprehensive testing program

• medical/legal liability for unaddressed identified mutations

• reimbursement concerns and cost of testing

• complexity and time involved to enter a complete family history and pedigree into the electronic health record.

None of these considerations, however, is insurmountable if the practice has a commitment to enhance and deliver precision medicine for our patients with prostate cancer.

1. Siegel RL, Miller KD Jemal A. Cancer statistics, 2019. 

2. 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. 

3. Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer.

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

5. Castro E, Romero-Laorden N, Del Pozo A, et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. 

6. Nicolosi P, Ledet E, Yang S, et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines.

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

8. Wu YM, CieÅlik M, Lonigro RJ, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. 

9. Humeniuk MS, Gupta RT, Healy P, et al. Platinum sensitivity in metastatic prostate cancer: does histology matter? 

10. Aldubayan SH. Considerations of multigene test findings among men with prostate cancer–knowns and unknowns. 

11. van Marcke C, Collard A, Vikkula M, et al. Prevalence of pathogenic variants and variants of unknown significance in patients at high risk of breast cancer: a systematic review and meta-analysis of gene-panel data. 

12. Concepcion RS. Germline testing for prostate cancer: community urology perspective. 

Articles

Advances in genomic testing will help determine lines of therapy in men with mCSPC and mCRPC, according to Raoul S. Concepcion, MD.

Role and rationale for molecular testing in advanced prostate cancer

	The physician work force crisis is upon us. A 

 released by the Association of American Medical Colleges reports that by 2025, there will be a projected shortage in the United States of 12,000–31,000 primary care physicians and 28,000–63,000 non-primary care doctors, most notably in the surgical specialties (“The Complexities of Physician Shortage and Demand: Projections from 2013–2015, Final Report,” Association of American Medical Colleges, March 2015). This takes into account the aging population, current medical school and resident program trends, and the effect of the Affordable Care Act. 

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	For urology, the outlook is even more dire. With the current age of practicing urologists in the country and the number of new residents projected, it is estimated by 2030, the United States will face a 32% shortage in order to provide adequate care for our aging population 

	To try and combat this paucity of physicians in both the academic and community/independent practice environment, utilization of advanced practice providers (APPs) has burgeoned over the past decade, especially in the urology world. Chaired by my friend and colleague Chris Gonzalez, MD, MBA, current vice-chair of its Public Policy Council, the AUA in 2014 issued a 

 in support of APPs and their role in urologic practice 

 published online May 6, 2015). I would encourage all readers to be familiar with this comprehensive document.

	As you likely know, the definition of APPs can be broken down into two broad categories: advanced practice registered nurses (APRNs) and physician assistants (PAs). Their educational background and scope of practice is different and very much state regulated. The purpose of this article is not to provide an exhaustive review of the particular nuances between the two professions. Rather, it is meant to use our group’s experience to illustrate how other urology groups can successfully incorporate APPs into their practice model and provide state-of-the-art care, given the ever-increasing demands on our time (with less reimbursement) in the fluid health care environment.

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	Urology Associates, P.C. in Nashville, TN is a single-specialty group with 32 MDs and 12 APPs (seven APRNs and five PAs) working in an integrated fashion. We have utilized APPs for well over a decade. Working them into our business model has allowed us to keep up with the demand of the growing population and need for urologic care in middle Tennessee.

	Traditionally, the canonical thinking about how to utilize APPs has been to see patients in the outpatient setting under the supervisory role of a board-certified urologist. This allows a higher volume of patients to be seen and possibly allows the physician to be more productive in other areas where reimbursement may be higher. We have continued that model to some degree, but have also created new service lines within the practice that are a source for not only new patients but revenue as well.

 The WISH clinic (Women’s Institute for Sexual Health) was one of our first forays into a dedicated specialty service line. The FDA approval of sildenafil citrate (Viagra) for male erectile dysfunction in 1998 started a new era of drug development for sexual issues. It became readily apparent to us that female sexual dysfunction was being largely ignored, not only by urology but also by primary care and gynecology as well. As we are well aware, there are many factors that contribute to this, including female sexual dysfunction’s multifactorial etiology, vague definitions of dysfunction, and lack of therapies.

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	In recognition and response to this demand, we hired an APRN whose background and clinical expertise was in women’s health (table 1). She was charged with developing the clinic. After spending time with experts at practices that had similar interests, she was able to launch our endeavor, which included establishing relationships with other health care professionals, including OB/GYNs, behavioral medicine experts, and compounding pharmacies, among others.

	The WISH clinic, supervised by one of our urologists who works with a team of dedicated APPs, has been able to provide comprehensive management to women with both sexual and pelvic health issues. The APRNs see the majority of new patients referred, whether from within our practice, primary care physicians, or self referred. They perform all the urodynamic testing and make referrals when appropriate.

 Dovetailing with the success of WISH, we also created a Men’s Health Clinic (MHC) within the practice. Under this umbrella, we manage and diagnose a number of disease states. Our APPs are vital and are often the first provider to evaluate these patients and institute therapies (table 2).

	The early catalyst was our involvement in clinical trials of bone-targeting therapies in men with both metastatic and non-metastatic prostate cancer. As urologists, we induce bone mineral density loss (and metabolic issues) with the delivery of androgen deprivation therapy (ADT) in men with advancing prostate cancer. This percentage loss can be significant, and the urology world has been slow to recognize and manage this potentially devastating complication. In men with metastatic castration-resistant prostate cancer, bone loss can obviously be further amplified.

	The recognition and willingness to identify and treat these patients within the practice is paramount and constitutes appropriate, evidence-based patient care. A PA with a background in primary care leads this initiative and serves as the main provider at our bone health clinic. Generally, we mandate that when a patient with prostate cancer is ready to start ADT, he is automatically referred to the clinic. The PA does a complete evaluation of risk factors, conducts a baseline bone mineral density evaluation, and makes recommendations on starting supplemental calcium, vitamin D, lifestyle changes, and when indicated, institution of bone-targeting agents. Along with the primary urologist, he follows patients on a routine basis and is also instrumental in the early identification of metastasis should they progress to castration-resistant disease.

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	The MHC also incorporates therapy and evaluation for hypogonadism and sexual dysfunction. In response to outside entities that advertise for the same services, we felt the urology practice should be the primary driver in this area. Again, whether patients be self referred or from within the practice, the APPs are crucial in their initial assessment, identifying risk factors, ordering appropriate lab testing, offering therapeutic options, and instituting therapy. This would also include injection therapy for low testosterone, erectile dysfunction, or Peyronie’s disease.

	The biggest challenge in this part of the practice is getting the practice’s physician partners to refer to the MHC. They are often reluctant, feeling that they will lose control of the patient. We have stressed that the function of the clinic is to work with the primary urologist for optimal patient care and retention within the practice.

Another area that is also important to both practice and physician efficiency is the use of the APP in a hospital setting. Again, depending on the scope of practice unique to your state, the APP can assist in making rounds, seeing consults, taking call, and even performing certain procedures. This allows the supervisory physician to be more flexible in scheduling and seeing patients.

	In preparation for writing this article, I asked a number of APPs within our practice a simple question: In your opinion, what are the keys to success in incorporating APPs into a urology practice? Their answers, in order of importance, were all in line:

		The APP and supervising physician need to work together as a team to promote the best patient care. The APP should viewed as a colleague and not a “helper” or somewhere down on the pecking order.

		The APP and supervising urologist must communicate effectively.

		The scope of practice and unique abilities that each APP can bring to patient management must be clearly understood.

		Stay current and make attempts to practice evidence-based medicine.

		Interact constantly with and provide educational events for the APP.

	A number of years ago, just prior to the explosion of online music and sharing, a good friend in the music industry continued to push his friends to buy compact discs. A decade later, I asked him, knowing what he knows now with digital, online, and cloud-based music-sharing capabilities, what he would have done differently if he could go back in time. His answer was very quick and simple: He would have embraced the model and figured out how to incorporate it into his business. With our looming physician shortage in urology, we need to embrace APPs into our practices in order to optimize patient care.

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Raoul S. Concepcion, MD, uses his group's experience to illustrate how other urology groups can successfully incorporate APPs into their practice model and provide state-of-the-art care.

Author | Raoul S. Concepcion, MD

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