Dr Steven Yip (Canada), Dr Alicia Morgans (USA) and Professor Yao Zhu (China) discuss the impact of HRR/BRCAm status on prostate cancer prognosis and the resulting implications for multidisciplinary team decision-making.
Meet the experts
Dr Steven Yip
Dr Steven Yip is a medical oncologist at the Tom Baker Cancer Centre (Calgary, Alberta, Canada) and Precision Oncology Experimental Therapeutics (POET) medical lead. He is also a clinical associate professor at the University of Calgary. His research interests include PSMA PET/CT imaging and novel r adiopharmaceutical drug development for advanced prostate cancer.
Disclosures : Financial support from AAA, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Hoffmann-La Roche, Ipsen, Janssen, Merck, Novartis, OncoHelix, and Pfizer.
Dr Alicia Morgans
Dr Alicia Morgans is a medical oncologist specialising in prostate cancer. She is an associate professor of medicine at Harvard Medical School, Boston, Massachusetts, USA. Her research primarily focuses on novel therapeutics and the impact of prostate cancer treatment on patients’ quality of life.
Disclosures : Financial support from AAA, Astellas, AstraZeneca, Bayer, Exelixis, Janssen, Lantheus, Lilly, Loxo@Lilly, Merck, Myovant, Novartis, Pfizer, Sanofi, Sumitomo Pharma America , and Telix.
Professor Yao Zhu
Professor Yao Zhu is a consultant urologist specialising in urologic cancers. He is a professor of oncology at Shanghai Medical College, China. His extensive research in urologic cancers, particularly prostate and bladder cancer, has led to significant contributions to the field.
Disclosures: Financial support from AstraZeneca, Bayer, and Janssen.
[Dr. Yip] Welcome. I'm Steven Yip, I'm a GU Medical oncologist based in Canada out of the Tom Baker Cancer Centre, and the medical lead of our Precision Oncology and Experimental Therapeutics, POET programme, and your host today. Precision medicine or targeted therapy approaches based on biomarker positivity is increasing in its use and revolutionising the prostate cancer care. Across this podcast series, we'll be diving into the world of diagnostics in prostate cancer, raising awareness on the importance of considering molecular testing for all patients with metastatic castration-resistant prostate cancer and addressing key knowledge gaps, all while providing a variety of perspectives from different specialties and regions of the world. Following this session, we'll have sessions covering current molecular testing techniques in line with updated guidelines and patient access to genetic testing. In the previous episode, we went through the genetic and genomic testing guidelines highlighting what each of the international guidelines recommend and the differences and similarities between them. So, for a comprehensive comparison of international guidelines, please go into podcast one. Today we're going to discuss what the impact of homologous recombination repair HRR mutation testing is and how identification impacts patient outcomes, and multidisciplinary tumour treatment decision making. I'm happy to be joined by Dr Alicia Morgans, Genitourinary Medical Oncologist and the Medical Director of the Survivorship Programme at the Dana-Farber Cancer Institute, as well as Dr Yao Zhu, a urologist based in China. And so it's a pleasure to speak with you both today. Yao, we'd like to dive right into it. What is the relationship from your perspective between homologous recombination repair gene mutations and metastatic castration-resistant prostate cancer?
[Dr Zhu] Yeah, thanks Dr Yip. Thanks for having me. We know that the mutations in HRR genes are commonly found in mCRPC patients and approximately 23% to 28% of patients with mCRPC demonstrate loss of functioning mutations in genes associated with HRR pathway in prostate cancer patients. And it's nearly 10 to 11% of individuals with primary prostate cancer exhibit such alterations and we know that the BRCA1, 2 and ATM mutation is the most common HRR mutations in mCRPC patients.
[Dr Yip] Excellent. That's great insight. And from your perspective, what do you see as the prevalence in the earlier setting in your field of practise?
[Dr Zhu] Yeah, in China, we know that there is no PSA screen, so we are facing patients with relative high risk and advanced localised disease. So, the prevalence of primary prostate cancer with HRR mutation is slightly higher than 11%. In our tumour centre, we found nearly 15% of our patients with high risk prostate cancer disease, they have HRR alterations. And I think that the data is slightly higher than Western patients.
[Dr Yip] Yeah, that's very interesting to see the regional variability. Alicia, how prevalent are HRR alterations especially BRCA1 and two, and in your experience in primary and advanced prostate cancer, both looking at real world evidence and clinical trials. And are there differences in these rates across your populations that you're seeing?
[Dr Morgans] I think it's such an important thing that you mentioned. You know, there can be different settings where we see these prevalence are going to vary pretty substantially. And I think in the US cohorts that I've seen in mCRPC, at least, the rate of HRR mutations is somewhere between 15 and 25%. And I think it's important as we think about that particular population that the number is going to be higher because it's certainly a group of patients that's enriched for patients with more aggressive disease. So, patients who have localised disease but don't have these alterations may never progress and hopefully never progress to mCRPC. Though of course we know some will. The mCRPC population is absolutely enriched. In our clinical practises, I think in the US, at least, in my practise in Boston, we have a much lower rate in localised disease of seeing these HRR mutations. And in my estimation, it's probably somewhere around say 6 to 8% or maybe you know, a little bit higher, a little bit lower. But in localised disease in the US, because we use PSA screening, probably we are catching people with lower risk disease. We've got many patients, 40 to 60% who end up going on active surveillance. And so this is not necessarily gonna be a population that has a high prevalence of HRR mutations. I think it's important to remember that in clinical trials we're often enriching these studies to enrol patients who may have more aggressive disease or for whatever reason, may actually have higher rates of genetic alterations than we might see in the real-world. So in some clinical trials we've seen rates of BRCA2 of somewhere around 9-10% of patients. When we're thinking about studies that enrol all HRR mutations, BRCA1 is much lower than BRCA2 in prostate cancer. So you know, I usually imagine that to be somewhere around 1% in clinical trials. When I think about rates in real world of BRCA2 in general populations, usually this is going to be somewhere closer to maybe 5% somewhere around there. If we think about that more broadly, including BRCA1 and ATM, but somewhere around 6 to 7%. But, I think we just have to remember that the rates in clinical trials don't necessarily reflect the rates that we see in our practises. And further, depending on where we practise, depending on the population of people we see, we also may see differences even within our practise catchment area and rates that might be reported from real-world studies from other areas.
[Dr Yip] Yeah, excellent points. Certainly the stage of disease will impact this region. Access to testing, certainly in a public pay system in Canada, we can see great variability in our access to be able to offer testing for our patients. And then even more so we can see variability in ethnicity disposition and so certainly this impacts a lot, you know, even just comparing Western Canada to Eastern Canada, larger city populations versus community populations, so, excellent insights from the group there. And moving on, based on your experience, how prevalent are these HRR alterations including BRCA in your practise, specifically Yao?
[Dr Zhu] Yeah, so in our clinical practise we have genetic testing centre in our cancer hospital. And we are referred by patients with advanced disease. So, we have in primary prostate cancer, nearly 3-5% of patients were presented with BRCA mutation and BRCA2 I think has the highest rate in our patients. For patients with de novo metastatic prostate cancer, the incidence of germline BRCA mutation is increased to like 6-8% and thus, the prevalence of HRR mutation is increased to 11% in our de novo metastasis prostate cancer patients. And we also test the somatic genetic alterations in our patients with diagnostic biopsy specimen and we found nearly 20% of patients were present with HRR mutation, including like 8-10% patients were present with BRCA somatic mutations in the tumour specimen.
[Dr Yip] Excellent. I think you've alluded to the fact that there's great variation not only from a germline perspective, but also somatic. Alicia, maybe you can share your insights into the same situation of how prevalent HRR alterations including BRCA are in your practise.
[Dr Morgans] Thank you. So, I think when I consider all HRR mutations in my practise, it's actually probably somewhere around 20%, especially thinking about advanced disease and that includes both germline and somatic testing in my practise. I think that if I really focus on BRCA2 it's certainly lower than all HRR mutations, but it's probably somewhere around 5%. What I think is interesting is that in other real-world data sets, it might be that 5% of patients might have germline BRCA2 identified. 5% of these BRCA2s are gonna be identified in somatic testing. And so it just reminds me that you really need to use both of these methods of testing to really identify all patients that might have these particular alterations. The rate of BRCA2 in Boston is probably a bit lower than it is from practises that I've seen from New York where I have colleagues who have what seems to be much higher rates of BRCA2 when they get to advanced disease settings, maybe around 8-10%, which is not what we see at least in my practise in Boston. And that could be due to founders effects where we see certain populations that might inherently have higher rates of these alterations and they go to an area, they stay in an area, they marry and have children within that community in an area, and so rates can stay relatively higher in certain geographic regions.
[Dr Yip] Yeah, certainly I've seen that in small pockets of regions and that can have a big impact. And I think as you've underlined, it's really important that we have access both to germline testing and some form of somatic testing, whether we're looking at tumour tissue, which is being more common place, but perhaps where liquid biopsy can also augment in that space would be quite beneficial. Certainly from my experience, I have a bit of a bias in collecting this data and the patients who are referred to me, so I see higher prevalence because they're patients who are clinically suspicious and we certainly do see that there are some clinical variables that are more associated with harbouring these alterations. So I do see them probably at higher rates, but I would estimate similar rates in Canada that we're likely dealing around 15-20% of patients being impacted by HRR alterations in the general group of mCRPC at the very least. And moving on, can you share and discuss a case study that specifically illustrates how you identified an HRR alteration or lack thereof, and how would this influence your management of a patient with metastatic castration-resistant prostate cancer, Alicia?
[Dr Morgans] Sure, so this patient that I'm thinking of today actually had no family history of prostate cancer, no family history of breast cancer, ovarian cancer. His family was quite healthy with no cancer history in general. And he came in and had high risk localised prostate cancer at the time of diagnosis, and we decided because he was a bit older that he wanted to really undergo treatment with radiation and long term androgen deprivation therapy with curative intent. So, he started on treatment, he had a nice response in terms of his PSA and was tolerating things quite well. But before he finished his two years on hormonal suppression, he actually started to have a rising PSA suggesting resistance. He also noted that he was having more fatigue and had some sternal pain. He underwent repeat imaging so that we could determine what was happening. And this demonstrated a sternal lesion on a bone scan and enlarged pelvic lymph nodes. So we knew that we were dealing likely with metastatic castration-resistant prostate cancer. We did get tissue from a pelvic lymph node and performed somatic testing on that tissue that demonstrated that he had a somatic BRCA2 mutation and we also did germline testing and that demonstrated that there was no germline BRCA2. So, this perhaps was certainly important for his family to understand that difference in distinction. So, at that point in time, his cancer was actually somewhat rapidly progressing. We had a shared treatment decision around what he could do. He had just had ADT, so certainly could use novel hormonal agents in combination with PARP inhibitors or on their own he could consider chemotherapies. So at that point in time, he decided because he did want to be more aggressive in getting a response, especially because he had quite a bit of pain and fatigue, ended up getting a combination of a PARP inhibitor and a novel hormonal treatment as his first line treatment for metastatic castration-resistant prostate cancer.
[Dr Yip] Excellent. And Yao, can you also share with us a case that would illustrate such testing and how that impacts your management in the mCRPC setting.
[Dr Yao] Yeah, so this Chinese gentleman is diagnosed with prostate cancer and the metastasis to bone two years ago. He did not have any family history and the treatment with castration lead to a decrease in PSA from 150 to an 80 or 1.2, followed by an increase to 28. Then the patient were treated with abiraterone, the approved novo anti-androgen in China and the late docetaxel. The PSA decreased, then the PSA rise again to 70 and that the patient feel mild pain in his back. Upon testing of the metastasis progression, we have a radiological assessment of this patient and showed that the patient had numerous metastasis in both bone and the lymph nodes. So, this time the patient is... I think that it's a third line mCRPC patients and he underwent a ctDNA testing and the liquid biopsy showed us the patient had a germline mutation in BRCA2 gene. And the patient then advised to consider PARP inhibitors as well as chemotherapy. And he select PARP inhibitor for his treatment. And also a genetic consultation for his family was planned. And I think the patient just benefit from the liquid biopsy for genetic assessment and a family planning of his cancer risk increased the likelihood of the family risk prevention in his family members.
[Dr Yip] Very interesting. Thank you very much for sharing that with us. From my insights in Canada, as I've alluded there is many different regional differences. And so I actually saw a gentleman who was originally from a different region in Eastern Canada, 62-year-old gentleman with metastatic castrationresistant prostate cancer when I met him. But initial presentation in 2020 with de novo metastatic castration sensitive prostate cancer and no biopsy available, it's quite difficult to be able to get access to this from other regions. Had high volume of disease with visceral involvement of liver and lung. And he also had a Caribbean ethnicity and two first degree relatives with prior cancer, unknown primary, so certainly very concerning for potentially harbouring an HRR alteration. He previously had had an ARPI in the mCSPC setting before I'd met him. And then when he developed metastatic castration-resistant prostate cancer, he went on to subsequently receive taxane based chemotherapy and subsequent taxane therapy after that. When I had met him, there had been no testing and I didn't have any tumour accessible. So, by research basis at the time, we were able to get access to a liquid biopsy circulating tumour DNA testing. He wasn't extremely keen to undergo an invasive tumour biopsy, although I think it would be quite ideal in this gentleman to consider a liver biopsy. But the ctDNA fortunately was very high and reflected a BRCA2 deletion. And so as a result we did refer for hereditary testing and this seemed to be a somatic alteration. He ended up getting access to a PARP inhibitor and subsequently after the PARP inhibitor had had a platinum plus taxane based chemotherapy. So you can see how this illustrated his overall trajectory, his treatment options, and how we tailored this not only with targeted oral agents, but also chemotherapies after the fact there. So many important pearls to gain from all of these cases. So moving on to your insights, how is molecular testing integrated in your practises and how is this achieved through multidisciplinary tumour board interactions. And how could the addition or involvement of multidisciplinary tumour board improve testing rates?
[Dr Zhu] Yes, so in our centre, we routinely hold MDT meetings and during the meeting we have molecular testing results discussed. And I think these results play a very crucial role in guiding treatment and the prevention strategies. The first is because there is various treatment options available for prostate cancer. So we discuss this genetic results in our MDT team is a very essential step to provide a thorough understanding of genetic testing and the different treatment alternatives. And the second point is that we know we are moving more intensive treatment options in the mHSPC stage. And I think in mCRPC patients, the treatment should be more selective and really depending on the genetic results. For example, if we have HRR mutation, we may recommend the PARP inhibitor or platinum chemotherapy. If the patient have mismatched repair gene alteration, we may recommend the immunotherapy. So, in mCRPC stage it's really dependent on different tumour markers and the tumour targets. So, we are routinely include some molecular tumour testing results in our MDT meetings.
[Dr. Yip] Excellent. And Alicia, do you have similar experience?
[Dr. Morgans] Yeah, this continues to evolve, but so many of our centres and currently we have a multidisciplinary team that helps support genetic testing. And when I meet new patients, I'm always evaluating them for whether or not they're eligible for testing based on our current guidelines in the US and I send them to a rapid genetic testing for germline testing if I can, that first day when we meet. In terms of somatic testing, this can be harder as we've heard in our patient cases that we don't always have access to an easy prior tissue or a new biopsy site. So sometimes we're able to send and use our multidisciplinary team meeting to send off tissue that either is from a prostatectomy in the past or is from a recent biopsy that may have been performed. But sometimes we just send from clinic circulating tumour DNA, liquid biopsy assays right at the end of that first visit. If there's not going to be any available tissue or if the patient is unable or unwilling to have an additional biopsy, we need to make sure that a patient has disease progression and is not actually responding to therapy very well when we're sending off these liquid biopsies because if they don't have high levels of circulating tumour DNA, we'll just have an inconclusive assay that's not gonna be really additive. But the other thing that I wanted to mention when it comes to the multi D team is that we use this as an opportunity to educate ourselves around other patients who are being seen and treated, but also around data that's coming out, which can be really important because this is so rapidly evolving. We also use it as an opportunity to consider patients who might be eligible for clinical trials based on their tumour testing, which is something that I know all of us on this podcast are extremely dedicated to doing that and it's really important and helpful for our patients as well.
[Dr Yip] Yeah, excellent points. It is so complex and we do see a major amount of variability across Canada, let alone within our province. This is very much influenced by the very shifting testing landscape and currently that does shift based upon what test is available to what patient, what specific stage. But overall the engagements of scientific lead in our Precision Oncology and Experimental Therapeutics group, Dr Bose and I from the medical side, we meet from a clinical perspective especially supporting those patients with prostate cancer whenever these difficult cases do come about. And I think it's really important to emphasise the need to consider all treatment options and management around patients who have other HRR alterations. The RCa I think oftentimes we can think largely around PARP inhibitors, but it has been emphasised there are many other treatment options, many other implications, other tests that need to be offered and we need to foster greater access. So it's important for us to all come together with pathology, molecular pathology experts in the clinical setting to help support these difficult cases. And consider whether or not tumour tissue is a possibility, whether a liquid biopsy is appropriate. Oftentimes, I get referrals or access to this and the patient is already on treatment. As you've mentioned, your CTDA level is likely going to be low with a a good response, so it is so nuanced. And that we all are working to try to keep up and push the pace in this setting. Firstly, I'd like to thank my fellow speakers for their time and fantastic inputs. Alicia and Yao, thank you so much. Following these discussions, I think we will all leave this episode today with an increased awareness of the early occurrence of HRR alterations in prostate cancer. And their impact on outcomes really showing the importance of genetic testing. As my final remark today, thank you to all of those listening to this podcast. If you've enjoyed listening in on our discussions, be sure to tune in next time to listen to some more fantastic experts who will be discussing molecular testing techniques in metastatic castration-resistant prostate cancer. And if you missed the previous podcast, you should definitely go back to listen to that one, too.
