Dr. Brittany M. Szymaniak: Genetic Counselor at the Feinberg School of Medicine at Northwestern University, Chicago, IL, USA.

Dr. Alicia K. Morgans: Medical Oncologist at the Dana-Farber Cancer Institute, Boston, MA, USA.

Dr. Neal D. Shore: Urologist and Medical Director at the Carolina Urologic Research Center, Myrtle Beach, SC, USA.

Dr. Szymaniak: Hello and welcome to our podcast hosted in the journal of Targeted Oncology! My name is Dr. Brittany Szymaniak, and I am a genetic counselor at the Northwestern Medical Group in Chicago, Illinois. I am delighted to be joined today by Dr. Alicia Morgans, a medical oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts, and Dr Neal Shore, a urologist and medical director at the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

Dr. Morgans: Hi everyone!

Dr. Shore: Yeah, hi everyone.

Dr. Szymaniak: Today, we will be discussing the importance of genetic testing for homologous recombination repair, or HRR, gene alterations in patients with prostate cancer. We will also provide strategies to help overcome some of the obstacles to testing that healthcare professionals encounter in everyday clinical practice. Considering this is a multidisciplinary discussion, we will be sharing our different clinical perspectives on how to better integrate genetic testing into clinical practice.

Dr. Morgans: Thank you, Brittany, it’s great to be here and I’m looking forward to delving deeper into the topic of testing for HRR gene alterations from my perspective as a medical oncologist.

Dr. Shore: Yeah, likewise. Thank you very much Brittany and Alicia. As we know, genetic testing is increasingly important for our patients with prostate cancer, so I’m very happy to be a part of this discussion!

Dr. Szymaniak: Fantastic! Let’s start with some background to this topic. HRR is a cellular process that repairs double-strand DNA breaks [1, 2]. Any disruption of this process, such as genetic alterations within the HRR pathway, can impact a cell’s ability to repair DNA damage, leading to genomic instability [3]. Between 23 and 28% of patients with advanced prostate cancer have HRR gene alterations [4]; these genes include ATM, BARD1, BRCA1 and 2, BRIP1, CDK12, CHEK1 and 2, PALB2, RAD51B/C/D, and RAD54L [4]. Such alterations are associated with aggressive disease and a poorer prognosis [4,5,6,7,8,9,10,11]. For the patient, identifying an HRR gene alteration can open the door to treatment options and help inform clinical trial eligibility [12]. For the patient’s family, this could lead to earlier diagnosis and intervention for prostate or other cancers, such as breast, colorectal, ovarian, upper tract urothelial carcinoma, and pancreatic cancers [13, 14].

Several guidelines recommend testing for the presence of germline and somatic HRR gene alterations as standard of care [12, 15, 16]. If we consider the National Comprehensive Cancer Network, or NCCN®, guidelines specifically, they include germline testing recommendations for affected patients with a positive family history and/or for those with a personal history of high-risk, very high-risk, or metastatic prostate cancer [12, 17]. Germline testing is also recommended for patients with Ashkenazi Jewish ancestry and those with a personal or family history of specific types of cancer, including breast cancer [17]. On another note, somatic testing is recommended in patients with metastatic prostate cancer [12]. In the setting of metastatic castrate-resistant prostate cancer, or mCRPC, germline and somatic tumor testing for HRR gene alterations is recommended by the NCCN® guidelines for all patients [12]. Despite these guidelines, real-world data from the US show that many patients in the advanced prostate cancer disease state, mCRPC, do not undergo HRR gene alteration testing [18, 19]. A cross-sectional retrospective study, which obtained data from the Flatiron Health Enhanced Datamart to analyze HRR testing rates in over 9000 patients with metastatic CRPC in the US, showed that only 37.7% of those patients were tested for HRR gene alterations between 2014 to 2022 [18].

So, thinking about your individual disciplines and based on your clinical experience, why is it important to test for HRR gene alterations in patients with prostate cancer?

Dr. Shore: Well, from a urologist’s perspective, or anyone’s perspective for that matter, a 38% HRR genetic testing rate for the most advanced stage of prostate cancer [18] is far too low. We need to be doing better! We must use all of the tools at our disposal to accurately inform our clinical decision-making. It’s our responsibility as clinicians to identify patients with a high risk of disease progression and personalize their care plan accordingly. For me, finding an HRR gene alteration means that this patient is likely to progress faster than others who don’t have that alteration [4, 20,21,22,23,24]. And by the time they become castration-resistant, I want to already know their HRR status because they may be eligible for poly(ADP-ribose) polymerase, or PARP, inhibitors [25].

Dr. Szymaniak: You mentioned about finding an HRR gene alteration might inform your care plan, but it can be a little complicated looking at the guidelines and seeing somewhat different recommendations for when and how to conduct germline versus somatic testing. Can you highlight for us the important differences between these types of alterations?

Dr. Shore: Certainly. Somatic, or acquired, HRR gene alterations are traditionally assessed using tumor tissue but now can also be identified by circulating tumor DNA, or ctDNA, in blood samples [25, 26]. In contrast, germline testing will find inherited gene alterations in blood and/or saliva samples [26], making it even easier to obtain. Testing for both germline and somatic alterations can identify problematic HRR alterations associated with aggressive prostate cancer [5, 20, 24, 27]. But with germline alterations, you can work to identify other affected family members through the process we call cascade testing [14]. This gives us the rare advantage over certain aggressive cancers, potentially catching those patients early, allowing for optimization of their care plan and to cure them.

Dr. Szymaniak: Thank you, Neal. And for any of our listeners who are unfamiliar with this term, cascade testing is an approach used to identify additional carriers of a previously identified germline alteration in the family; it typically starts from first-degree relatives of the patient and moves out to more distant relatives as further carriers of that alteration are identified [14]. Cascade testing is important since it may identify healthy, unaffected family members who carry germline alterations who may not have received genetic testing, or received it much later in life, had it not been for this initial person that was tested [14]. Cascade testing can lead to cancer prevention, reduced cancer mortality, and decreased health care costs due to preventing cancer rather than having to treat it [14].

Alicia, what about HRR testing from your perspective as a medical oncologist?

Dr. Morgans: Thank you Brittany, I certainly agree with Neal that knowing a patient’s HRR alteration status allows more time to develop a treatment algorithm in the event of prostate cancer progression. In keeping with this, it’s important to understand that germline HRR gene alterations are not only more prevalent in those patients with early-onset prostate cancer, but also patients with alterations in certain HRR genes, such as BRCA1/2 or ATM, have shorter overall survival [4, 20,21,22,23,24]. Furthermore, re-evaluation of HRR gene alterations along the patient’s disease course with somatic next-generation sequencing may also be informative. Repeat testing might identify those somatic newly acquired, but still-actionable alterations that were not present during initial testing [28].

Dr. Szymaniak: This is a great point Alicia, but there may be instances when HRR gene alterations are not considered actionable, correct?

Dr. Morgans: Yes, for example, HRR gene alterations stemming from clonal hematopoiesis of indeterminate potential, or CHiP, or those secondary to high tumor mutational burden. In such patients, additional testing may be warranted [29], since knowledge of their HRR gene alteration status may have potential implications for enrollment in future clinical trials as well as future treatment options [12].

Dr. Szymaniak: I agree Alicia, and I think all these points emphasize the importance of genetic testing for HRR gene alterations. Unfortunately though, as we highlighted earlier, we know that less than 40% of patients with prostate cancer are being tested for the presence of HRR gene alterations [18]. Furthermore, a real-world study found that out of the 674 patients who underwent testing for HRR gene alterations between July 2013 and March 2019, 82% were only tested once [19]. Again, considering your particular discipline, what potential obstacles could help explain this underutilization of testing for HRR gene alterations and how do you think those can be overcome? Neal, let’s start with your perspective.

Dr. Shore: Thank you very much Brittany. You briefly touched upon the guidelines. I think that the differences between the various guidelines, particularly in relation to the stage of prostate cancer at which patients should undergo testing for HRR gene alterations, results in confusion among many healthcare professionals. For example, the NCCN® guidelines recommend germline testing for patients with prostate cancer who either have a positive family history and/or a personal history of high-risk, very high-risk, or metastatic prostate cancer [12, 17]. Thinking next about the AUA/SUO guidelines, these recommend that clinicians offer germline testing for patients with metastatic prostate cancer and somatic testing for patients with metastatic castration-resistant disease specifically, although somatic testing can also be considered in the castration-sensitive setting [15]. Then, there are the AUA/ASTRO guidelines, which recommend germline testing for patients with clinically localized prostate cancer and any one of the following: a strong family history of prostate cancer, strong personal or family history of related cancers, known family history of familial cancer risk alteration, Ashkenazi Jewish ancestry, and adverse tumor characteristics [13]. And finally, I draw attention to the ASCO guidelines, which recommend germline testing in all patients with metastatic prostate cancer. Somatic testing is also recommended by the ASCO guidelines in patients with castration-sensitive and castration-resistant metastatic prostate cancer and who are being considered for biomarker-directed systemic treatment [30]. The bottom line here, there is a consensus across the various guidelines that all patients with metastatic prostate cancer, especially those with resistant disease, mCRPC, should absolutely be tested, but sadly, and based on the real-world data that you shared with us earlier, there are still incredibly low rates of genetic testing in patients with prostate cancer.

Dr. Szymaniak: I couldn’t agree more. There is definitely a need for education about the guidelines to help healthcare professionals understand which patients should be tested and when.

Dr. Shore: So absolutely! Both healthcare professionals and patients should be educated on these guidelines and provided with relevant sources of information to support their understanding of why to test, and when to test and what to do with the information. Furthermore, I think to really overcome these obstacles, we need to ensure that patient care involves a coordinated, multidisciplinary approach involving urologists, medical oncologists, genetic counselors, advanced practice providers, and nurse navigators. This will ultimately allow healthcare professionals to offer our patients routine genetic testing as a matter of course and optimize their care. Alicia, what are your thoughts on this?

Dr. Morgans: I wholeheartedly agree - a multidisciplinary approach to patient care is so important, especially regarding the nuances of genetic testing. But another factor influencing the underutilization of testing for HRR gene alterations that I wanted to highlight is the time it takes to get the results from the testing laboratory, especially if there is no facility to perform the genetic testing in-house, since there may be concerns about delaying treatment initiation. In some cases, it can take around 1 month to receive results from tumor tissue samples [25]. Furthermore, the success of testing for gene alterations with tumor tissue is influenced by purity of the sample [25]. As an alternative, and as Neal mentioned at the start of this podcast, ctDNA samples can be used to analyze both somatic and germline gene alterations. This type of testing is non-invasive, and the results are typically available in about 2 weeks [25].

Dr. Szymaniak: So, Alicia, do you think such logistical issues deter some physicians from testing for HRR gene alterations?

Dr. Morgans: In my experience, I would say so, and this is another reason why it is important to test as early as possible in anticipation of any delays in obtaining results. Another obstacle is that results can be complex to interpret, and there can be uncertainty among healthcare professionals about how this information can be used to guide treatment decisions, especially when the impact of a genetic alteration may be unclear. To overcome this, physicians, especially those who are new to testing, may actively seek out educational opportunities, such as continuing medical education materials on genetic testing. Also, and to go back to Neal’s point about the importance of a multidisciplinary approach to care, in cases where the potential impact of a genetic alteration identified during somatic testing is unclear, healthcare professionals should discuss the need for additional germline testing with their patients, and they should be referred to genetic counselors who can provide them with a deeper understanding of the possible implications of the results. A final point here is that we know far less about the specific impact of HRR gene alterations for our Asian, Black, and Hispanic patients due to them often being underrepresented in prostate cancer clinical trials [31]. Hence, it’s important for healthcare professionals to test everyone eligible based on the guidelines and to help ensure patients from all racial and ethnic groups are being considered for clinical trials when appropriate.

Dr. Szymaniak: Great point Alicia. We should also be mindful that cost and accessibility of testing for HRR gene alterations through insurance can be a concern for patients; however, I would like to point out that patients can file an appeal if denied insurance coverage, and there are laboratories that can be recommended to patients who will offer financial assistance or access to low-cost genetic testing [32]. In addition, most health plans cover the cost of genetic testing when recommended by a healthcare professional [33]. However, do be aware that even tests covered by insurance may still have associated out-of-pocket costs. Coming back again to the importance of multidisciplinary care, it’s worth highlighting that there are several programs that can help patients locate genetic counselors either in their local area or who provide counseling options via telehealth [32, 34]. We need to work with our nurse navigators and providers to inform patients about these programs, thereby improving accessibility to genetic counselors.

Dr. Shore: Brittany, from your perspective as a genetic counselor, do you find that some patients may refuse to undergo genetic testing due to anxiety about the results?

Dr. Szymaniak: Absolutely Neal, and in some cases, patients are fearful about the implications a positive result will have for their family members. However, a systematic review published in 2018 also found that there were positive consequences following genetic testing for susceptibility to breast and ovarian cancer specifically, and this correlated with more frequent screenings and follow-ups, with patients reporting a sense of self-efficacy [35]. Furthermore, levels of test-related distress decreased in the first 4–6 months, and remained low in the years following the test [35].

Bringing this back to you Neal, to help overcome uncertainty in terms of what to do next when a patient tests positive for HRR gene alterations, what advice would you offer healthcare professionals?

Dr. Shore: I appreciate that question. As urologists, many patients we treat are in the localized or early hormone-sensitive metastatic setting. For our discipline, identifying a germline or somatic HRR gene alteration can really inform prognosis and open up very important clinical trial opportunities for these patients [5, 12]. And let’s face it, a clinical trial is, by ASCO, a standard of care [36, 37]. And, going back to what we talked about earlier in relation to cascade testing, germline testing can help identify healthy, unaffected family members who may be at risk for developing an aggressive cancer [5]. Wouldn’t it be better to identify them when it’s early and can be cured as opposed to metastatic? So, if a patient with localized disease comes into my clinic and I already know they have a BRCA2, or ATM, gene alteration from earlier cascade testing, that’s a huge head start! It allows me to be better prepared as a physician for what the data show may be a faster and more aggressive tumor biology.

Dr. Szymaniak: Thank you, Neal. Alicia, same question to you and what advice would you offer healthcare professionals who don’t have as much experience with genetic testing?

Dr. Morgans: As an oncologist, my advice would be that the presence of an HRR gene alteration should always be considered and integrated into care plans for patients with metastatic disease. For example, multiple Phase 3 studies have shown that therapy with PARP inhibitors, either alone or in combination with other therapies, is effective in patients with certain HRR gene alterations [38,39,40]. In the US, some PARP inhibitors have been approved by the FDA for the treatment of patients with mCRPC and specific HRR gene alterations [41,42,43,44,45]. Healthcare professionals should note, however, that the course of action may be slightly different if a non-BRCA HRR gene alteration is found or if the patient is at an earlier stage of disease where PARP inhibitors alone or in combination may not be indicated [12]. In addition, and as highlighted earlier, repeat somatic testing may be warranted at disease progression since newly actionable HRR gene alterations can be identified that were not present during initial testing [25, 28].

From your perspective as a genetic counselor, Brittany, what else should a healthcare professional consider if a patient is found to have an HRR gene alteration?

Dr. Szymaniak: The NCCN® guidelines recommend genetic counseling for patients if a germline alteration is identified [12], and the ASCO guidelines note that patients expressing concerns regarding germline testing, including significant anxiety, or who prefer to see a genetic counselor or genetic professional, should be referred accordingly [30]. Additionally, cascade testing is recommended for relatives to inform their risk for specific familial cancers [12]. As counselors, we can offer psychological support for patients with positive germline HRR gene alterations and discuss next steps for themselves and for their family members.

Dr. Morgans: I agree. As healthcare professionals, we have to perform our due diligence and work together. We need to offer testing for HRR gene alterations as early as is appropriate and collaborate with our multidisciplinary teams to bring all the patient information we have available into an optimized and personalized care plan. Neal, what are your thoughts?

Dr. Shore: Overcoming the barriers to genetic testing for HRR gene alterations will not only help to add precision when informing a patient’s treatment care plan but it will also impact a family member’s understanding of their risk of developing inherited cancer. We have discussed multiple implications of genetic testing for HRR gene alterations and how that can impact patients and many ways that healthcare providers can overcome obstacles with genetic testing. From my perspective, there is no reason for healthcare providers not to offer genetic testing as part of their routine clinical practice. We simply must do better.

Dr. Szymaniak: Alicia, Neal, thank you so much for sharing your insight and experience with our listeners. Indeed, testing for HRR gene alterations is guideline-concordant care and should be implemented in clinical practice. Criteria for genetic testing will likely broaden with future developments in treatments and we are moving towards an approach where all patients will eventually be tested. So, it is important to ensure it is incorporated into routine clinical practice now with no more delays.

Thank you all for listening to our podcast and we hope these discussions allow you to further consider how your own multidisciplinary teams can help to increase the rates of HRR gene alteration testing for patients with prostate cancer. Please note that we have an accompanying infographic that provides a visual overview of the topics we have discussed in this podcast.