Beyond the Slide is dedicated to exploring diagnostics in oncology. The prostate episodes are focused on BRCA testing in advanced prostate cancer.

In Episode 4, we're tackling one of the most debated questions in advanced prostate cancer: Is tissue an issue when it comes to BRCA testing?

Joining our Host Rachael Babin are two leading voices in the field - anatomical pathologist Professor Fiona McLean and urologist Associate Professor Matthew Roberts. They'll be sharing their expert insights into tissue stewardship, the challenges of obtaining quality specimens and how evolving testing requirements are shaping clinical practice, especially in regional and resource-limited settings.

Together, we'll unpack the complexities of genetic testing in prostate cancer, discuss practical approaches to specimen collection and explore how multidisciplinary collaboration can help ensure patients have access to timely and meaningful results. So, whether you're in pathology, surgery, oncology or somewhere in between, this one's for you.

We hope you enjoy listening.

This podcast has been commissioned and funded by AstraZeneca. This podcast is intended for Health Care Professionals only and contains discussion of AstraZeneca Products. The thoughts and opinions expressed are the speaker's own and may not represent those of AstraZeneca.

EPISODE 4

[ANNOUNCER]

Welcome to Beyond the Slide, an AstraZeneca podcast series proudly produced by the Oncology Podcast. In this series, we go beyond the data to explore the evolving role of diagnostics in cancer care. I'm your host, Rachael Babin, and in today's episode we're tackling one of the most debated questions in advanced prostate cancer: Is tissue an issue when it comes to BRCA testing?

Joining me are two leading voices in the field - anatomical pathologist Professor Fiona McLean and urologist Associate Professor Matthew Roberts. They'll be sharing their expert insights into tissue stewardship, the challenges of obtaining quality specimens and how evolving testing requirements are shaping clinical practice, especially in regional and resource-limited settings.

Together, we'll unpack the complexities of genetic testing in prostate cancer, discuss practical approaches to specimen collection and explore how multidisciplinary collaboration can help ensure patients have access to timely and meaningful results. So, whether you're in pathology, surgery, oncology or somewhere in between, this one's for you.

Before we begin, please note this podcast has been commissioned and funded by AstraZeneca. It is intended for healthcare professionals only and may contain discussion of AstraZeneca products. The thoughts and opinions expressed are those of the speakers and may not reflect those of AstraZeneca.

Let's get started.

[EPISODE]

Fiona Maclean 01.43: Hi

Matthew Roberts 01.44: Hi

Fiona Maclean 01.45: Thanks for having us.

Rachael Babin 01.46: So today we're here to talk about BRCA testing in advanced prostate cancer. Over the past two years, we've seen significant therapeutic developments in this space, particularly with the growing role of PARP inhibitors and molecular tumour testing in the metastatic setting. All of this brings new challenges and opportunities in how we approach tissue requirements in clinical and diagnostic practice. So, Fiona, I'd like to start by asking you how has this impacted the specimens required and available for testing?

I think pathologists always want more. You know we always want as much as we can have and I think it's this whole issue of the tissue is the issue. Do we actually have enough tissue to do what we need to do? And I think, as stewards of the tissue because we hold that material, we hold those blocks we need to be sensible about how we're actually using them and use the appropriate material. And each test we do costs money and it's time consuming. So we actually want to test correctly the first time.

Rachael Babin 03.42: Matt has downstream testing changed your approach to collecting specimens for testing at primary diagnosis?

So, in answer to your question, I don't think it's really on our radar, because urologists are focused on doing the biopsy and doing the surgery and treating patients, and poor, smart people like Fiona are stuck with biopsies from 10 years ago to do their molecular testing on, and so I think we have a long way to go and I think, at least for me personally, I now strongly consider primary tumour biopsies in people with metastatic disease, when we wouldn't have previously.

We would just say that patient has a PSA of 100 and metastases, let's just give them ADT and see what happens, whereas now I think we really need to think beyond that and think downstream of that.

I think this is where a lot of learning with urologists and also radiation oncologists need to go, and I think you know the way that I sort of envisage it is that if we take from other tumour streams, we should be molecularly testing up front and if the patient has, for instance, a BRCA mutation, well their pathway is different to those that don't, right from the outset. That way the patients don't get disappointed at the end if their testing fails or they're tumour negative. They know that from the start. But we also have to be mindful, as Fiona said, of over-testing and all of the implications with that. So it is tricky and a lot more research is needed.

Fiona Maclean 05.35: Yeah. So we've got a few options in that space we need to think about what tissue we've actually had already on this patient and it may not have all come to the same lab. So, if you're asking one lab, they may only have the biopsy and not the radical, or they may have a TURP specimen, they may have a metastatic deposit. As Matt was referring to, bone is a problem because we know that prostate likes to go to bone, right, and it's fairly easy to get to because it's peripheral and you can biopsy it. There you go. But the problem is if we actually put bone in our decalcifying solution, which is a strong acid solution, it actually denatures the DNA. So you really don't get anything back from those bone specimens. So the bone, if it is a bone biopsy, it needs to be placed in a slower decalcifier, an EDTA based agent, but still that's not as optimal.

But actually it's counterintuitive. The radicals actually are a better specimen to use for testing or TURP specimens than the cores are. The cores have less cells in them, and sometimes we have to combine a couple of cores, and so that means that you can actually get contamination the more tissue blocks that you can combine Although we can do it, it's not optimal. So you're better off using the radical or the TURP.

And with the radical obviously you want to use the index malignancy, because a man's going to have often multifocal disease. You don't want to be testing the disease, that's not so relevant. You want to be testing the index carcinoma. So when I'm reporting a radical, I will actually write down a couple of blocks on my report which would be optimal to test. So if you need to come back, I don't have to go back through 60 blocks of a radical to try and find the best slide. I've already done that at the time of reporting and that's already recorded in the patient's report, and so it's much easier to identify.

So in summary, avoid bone if possible. Avoid old things. If possible, use the radical rather than the core biopsies, if you're using the primary tumour. You can think about a metastasis that's non-bone. So if you had a lymph node metastasis that could be quite good, as long as it's large enough.

Fiona Maclean 9:25: The skinny chips are fine because we'll actually put them into a block together. So we pack them in the blocks actually a lot more. One block will have quite a bit of tissue in it. The core biopsies because we're trying to grade quite carefully on the core biopsies, we do try and spread them out so we don't put so many per block. So I think your channel TURP should be fine as well, as long as it's got tumour in it basically. Some men they tend to have tumour more at the periphery as well. It really depends on where the index is. So as long as there's index tumour in that specimen and it's enough, five millimetres squared of tumour is enough.

We need at least 200 cells or five millimetres squared is the area that we usually look for and it needs to be about 20% tumour. So we have to be careful because sometimes when you think you're getting a biopsy of tumour, the tumour may be necrotic, there may be mucin, there may be lots of fibrosis, there could be haemorrhage. There's lots of reasons why something that when you biopsy it feels like it's got a lot of tumour, it doesn't actually have good tumour volume. So we need to have at least 20% tumour within the tissue that we're submitting. So I think the most important thing is to think about all the tissue that you have, like where is it and what is it, and plan if you need to do a biopsy at that stage, so if you're actually going for a metastasis.

But changing that within a hospital setup or changing it between patients would be really challenging. Say, it's a patient with metastatic disease, do you do that under a local anaesthetic which has more discomfort? Maybe they're not fit for a general anaesthetic because of the burden of their disease and also, as Fiona said, with the index lesion. But whereabouts do we get it? So if, for instance, we aimed for the centre of the tumour, there might be necrosis and maybe we should be aiming for the periphery and I think this is where imaging really plays an important part, looking at PET scans and the MRI for the avidity and also, you know, the role of systematic cause, because sometimes the index tumour is actually not imaging visible and so that that becomes challenging.

But I think also thinking of the radical specimens, with the increasing use of robotics. We put the specimen in a bag and leave it in the patient. For some people they leave it in the patient for an hour, hour and a half and then it gets taken out, put in the pot to just sit there. And I would say the time from being put into the formalin pot to formal processing would be highly variable and I'm sure there's been studies done on time to that as to what the outcomes might be. So that would be another major part. I think also, people probably do the surgeries slightly differently, so some may devascularise the prostate at the start, some may devascularise it at the end. So there would be many aspects to that. But I would say that the biggest challenge will be trying to change what's been effectively 50 years of practice in terms of how a prostate biopsy is done or how a prostatectomy sample is processed from a surgical perspective.

And I would say, outside of the pathology aspect, you know even access to specialist services. So for instance, in urology in Queensland there's really not much regional urology available and those that do work regionally are very busy. So specialist training and presence in those areas is really important, I think, across urology, oncology and probably pathology as well. So I think public and private have similar themed but slightly different issues in that a private turnaround time for a specimen wouldn't be more than two or three days, whereas in the public it can be three or four weeks. And another issue I think that affects all of them is the time from biopsy to say the molecular testing being done, in that if the turnaround's quick or the retrieval is quick, then presumably the molecular results would be better, whereas if they're in some warehouse interstate that takes a long time to get, then that would presumably affect results as well.

So I think that's something people don't think about the timing of their biopsies. And I think a lot of surgeons have got the message that we want more. Especially when you're going for an index area, you might take extra biopsies of that site. Most surgeons will put extra in the index pot or they might give you a couple of index malignancy pots with some extra specimens in them. Sometimes, I appreciate in rural areas you might not have a surgeon that can come and do the biopsies and it might get done in radiology, and sometimes radiology are still taking a lesser number of biopsies, and so that can be a problem as well if you're not getting as many biopsies coming through. And especially if you've got the radical, then that's good. But if the patient ends up having radiotherapy, not surgery, and then the tumour's been irradiated, therefore you know you might find that you've not got a lot of tissue to actually test with. It might only be the biopsy material and then the metastasis, and if that's a bone metastasis, that could be an issue.

Matthew Roberts 18.16: And if I could also look to the future, I think that some people will say what about liquid biopsies? We'll just use the DNA from them? But at least the current data that I'm aware of is that that's kind of dependent on tumour volume, and so if you don't have enough tumour to make free floating DNA, then you're not going to be able to do the testing. So I think we have to consider all aspects of the material for the testing. It might be someone that has diffuse metastatic disease and their ctDNA levels are really high, or then maybe we don't need to get all of these biopsies and things. But yeah, we'll need to consider the individual patient.

So we have to wait till they've actually had a metastasis, then go back and test, and that could be quite some time. That's where the time delay happens, with the specimens getting old and the blocks aging, and so at that stage you might think well, it's been a while since we've had the primary diagnosis. Maybe it is better to test the metastasis and think about what you've actually got. Have we actually got a soft tissue metastasis, a lymph node metastasis that we can use.

And then, as I mentioned also, was the decalcification situation. So you know we should put it in some EDTA-based solution, which is going to take a little bit longer. So I actually do get clinicians ringing up saying why hasn't this result been released? You know why you've had it for two days, why haven't I got my result from my biopsy? And understanding that I've actually opted to put that into these slower decalcifiers that take a few more days, so that we will slow down the turnaround time for the diagnosis part this is metastasis before we then move along to sending it off for molecular.

Separate out the index or the target lesion so that we know which one that you feel that that is, and we will determine the grade as well from that. But take extra of those biopsies that radiologically on MRI look like they're going to be the target lesion, so that we've actually got more tissue if we need to use it.

Think about when you're doing the radical specimen, not having such prolonged cold ischemia times, and if you think that this patient's going to need to have biopsy testing of metastases, we'll plan that. What metastases are we going to test? If they've got multiple metastases, do I have a choice of a soft tissue metastasis? Can I biopsy that if the other material is probably going to be too old? So think about how long ago the primary diagnosis was made. Can the material be found somewhere else? So has one lab got the cores, but has another lab got a really nice specimen with the radical, with quite a lot of tumour, that's easily accessible.

Thinking about patients who have a germline BRCA mutation is a little bit different, because those patients, you know, we think are going to progress faster and are much more likely to have a metastasis. But when we think about those ones with a somatic mutation which we want to be able to treat as well and there's a significant group of patients we're not going to know who is going to need treatment until they've actually metastasised. I think the difficulty with knowing when to test is all related to the rebate being available or not, and I think, as Matt was alluding to, we really need to be advocating for patients that if they have got high-grade disease, maybe the time to test is earlier. And as testing becomes cheaper and easier, I think over time molecular testing is actually decreasing in price. It's easier to apply.

In the future perhaps it's going to be available to do this straight up with men who actually have high-grade disease. But currently we can't practicably do it right now. So right now we can't test the primary unless they've actually got a metastasis at that time. We're kind of a bit stuck really. What would be ideal is not exactly what the situation is.

So I was at the APEX meeting last year where a prominent person from the US got up and said every single patient with prostate cancer should get molecular testing, and then I walked up to them after the session and said well, that's all well and good, we can't afford that. But every single patient in our jurisdiction gets a PSMA PET, but you can't afford that. So everyone has their strengths and weaknesses, but the access as much as we can get access is important because another aspect is that I think of all patients eligible for PARP inhibitors, half are somatic and half are germline, I think to that degree. So if you only treated germline people, then the somatic people would miss out, but you just got to test a lot of people to find both of them. So a lot of aspects to work through on many levels, that's for sure.

[ANNOUNCER]

Just a reminder this podcast has been commissioned and funded by AstraZeneca. It is intended for healthcare professionals only and may contain discussion of AstraZeneca products. The views expressed are those of the speakers and may not necessarily reflect those of AstraZeneca. If you found today's episode valuable, please share it with your colleagues.

Thanks for listening. This is Rachel Babin and this is Beyond the Slide.

[ENDS]