Role of molecular diagnostics in prostate cancer

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Published: 2 Oct 2019
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Dr Elena Castro and Dr Shahneen Sandhu

Dr Elena Castro (Spanish National Cancer Research Center, Madrid, Spain) and Dr Shahneen Sandhu (Peter MacCallum Cancer, Melbourne, Australia) discuss the role of molecular testing in prostate cancer at ESMO 2019

Dr Sandhu discusses the personalised treatment of prostate cancer, including the use of molecular testing using archival tissue in the PROfound study.

The experts question how molecular testing can be implemented into clinical practice and describe this as a technical challenge.

The experts conclude by discussing the Australian and ESMO guidelines surrounding the use of molecular screening for prostate cancer patients.

This programme has been supported by an unrestricted educational grant from AstraZeneca.

 

EC: Good morning. My name is Elena Castro, I am a medical oncologist from the Spanish National Cancer Research Center in Madrid. I am here in this ecancer conversation with my colleague Shahneen Sandhu from the Peter MacCallum Cancer Centre in Melbourne. We are going to discuss about some of the abstracts presented at the ESMO 2019 congress. We want also to see how this is going to be incorporated into the new ESMO guidelines.

SS: It’s been a very exciting ESMO for me and I’m sure for you as well and for most of us that treat prostate cancer because there’s been a lot around molecular diagnostics and also imaging as well in terms of trying to molecularly dissect the prostate cancer. For the first time I believe we’re starting to stratify the disease space on underlying molecular biology and being able to translate that information with new therapeutic agents that are coming into the pipeline for our patients. In particular, I find that the understanding that a significant proportion of men with prostate cancer actually do have an underlying homologous recombination DNA repair defect that could potentially be targeted, offering these men a new treatment, is exciting. Again, one of the challenges we are faced with is how do we find this subset of patients who would benefit from some of these new treatments. Of course, as you know Elena, one of the challenges we face in the clinic all the time is tissue and getting tissue for our men. It’s not as straightforward for men with prostate cancer. But it was instructive to see the molecular data from the PROfound papers. There was a molecular poster that was presented which looked at the landscape of mutations that they found. I found it quite instructive that we were able to use archival tissue, both primary as well as metastatic tissue, to identify some of these genomic changes that could be targeted. It was intriguing that, of course, with the metastatic tissue the yield was slightly higher but primary tissue was also valuable. Hopefully the assays will improve. There are about a third of patients who did not have a result and we need to do better. Hopefully over time technology will improve as well.

The other area that is really quite exciting but also raises lots of issues is around novel imaging. Particularly we know that prostate specific membrane antigen is ubiquitously expressed on most prostate cancers, both treatment naïve as well as hormone resistant prostate cancer. In fact, the expression gets increased over time and they have been able to develop what they call theranostics, which is looking at identifying the target in men with prostate cancer. Then also creating a therapeutic, looking at lutetium PSMA and also other agents like BiTEs that target CD3 and PSMA that actually get to this target. So being able to, again, identify patients with this therapeutic strategy of targeting the vast majority of men with prostate cancer is also very exciting but I really feel that we need to learn a great deal more about the implications of how we incorporate some of these novel imaging into our standard practices as well as the molecular testing as well which we don’t fully understand. I think the technology has moved well in advance of us as a community thinking about how we implement some of these new things into clinical practice. But it is exciting times and lots of work to be done.

EC: Yes, I complete agree with you. I think in this ESMO we have finally entered the role of precision medicine for prostate cancer. I completely agree that the challenge we have ahead is mostly a technical challenge, so how are we going to do this testing accessible for all the centres and therefore for all the patients. What do you think will be the way to move forward? Will it be tissue testing or will it be plasma testing?

SS: I think there’s probably a role for both. Certainly if we are able to use primary archival tissue for men with metastatic prostate cancer, we know the yield is reasonable. But, as I said, technologically we need to improve the subset of patients who don’t have those results.

Understanding which proportion of patients actually harbour a germline mutation in addition to a somatic change within the tumour is important. Particularly relevant for cascade testing, more broadly for the men with prostate cancer who might have female daughters, identifying a BRCA mutation in a female daughter has significant implications. So how do we start to look at some of these things? Really probably it would be archival tissue and plasma is very useful in that it allows a global representation but perhaps the limitation there can be sometimes the sensitivity if the tumour burden is very low. These platforms are not well established globally. They so far have been established at academic centres and so the challenge of how do you roll this out so that it becomes broadly available for men with prostate cancer, which is what we ultimately want.

EC: What is your impression on how all these new results and advantages are being implemented in clinical guidelines? For instance, in Europe the updated clinical guidelines now recognise the utility of PSMA-PET but they also acknowledge that this is not available for all institutions. These guidelines also recommend germline testing for all patients with metastatic disease but we will need to see whether this is affordable for all the national health systems. There’s also always the discussion on whether, of course, tissue screening is relevant for patients and is recommended but obviously how are we going to do that. How are the guidelines in Australia or in other…?

SS: One of the challenges, you’re completely right, first tackling the germline question, I certainly believe that when the incidence is about 10% or 12% finding a target that could potentially benefit patients there is significant value in offering patients germline testing. The costs of these tests have gone down considerably and there must be significant clinical and economical benefit of identifying patients’ family members who might also harbour some of these germline changes and impacting their cancer care. So there’s significant value, the challenge we’re faced with in Australia is how do you reimburse it. Again, it has largely fallen on academic institutions where we’ve set up panel testing for a subset of men but how do we more broadly implement this? Also how do we integrate with the genetic counsellors because I think they would be overloaded if we actually sent them every single man with prostate cancer ahead of screening? So working with them to create some national guidelines is going to be critical as increasingly these sorts of things are implemented. So that’s the challenge with germline testing.

I feel that if we are testing archival tissue and we find a biallelic deletion then I think we have an obligation to make sure that there is a component of follow-up in making sure that that germline component is followed up because it has got such clinical significance, both for the individual patient but also for the broader family members.

So that’s the germline aspect of it. The PSMA imaging is more challenging at the moment because it’s not routinely available. Certainly in Australia it has certainly been taken up very broadly and it’s not uncommon to have a patient turn up to clinic with a PSMA-PET scan that has been done already, often by the urologist. So what we’re starting to see is patients who we previously would have said were M0 but now we are defining evidence of small volume PSMA disease and trying to understand the biology of that and how we are impacting treatment is important. Because there’s the possibility we are creating anxiety but maybe offering these patients earlier treatment may or may not be useful. Certainly the clinical trials and the evidence have not actually incorporated any of these imaging technologies at the moment. So lots of work needs to be done. Some of my colleagues in Australia, Professor Michael Hofman in fact, is leading a very exciting imaging study looking at comparing lutetium PSMA imaging versus conventional imaging in high risk men prior to surgery. So, really trying to optimise the patients who undergo surgery and not offering surgery for patients who have actually got metastatic disease. So that’s one place where there is a role.

Certainly, for me, there’s a very important role of PSMA imaging as a way for signal seeking studies. If you have got a new target, one of our challenges with drug development in prostate cancer has been always to try and identify the activity of the drug. Now we’ve got this exciting functional imaging and we might be able to look at that signal in a more robust way. I would encourage pharma to incorporate some of these imaging technologies into their studies. They are always going to be exploratory but that’s how we learn.

So, Elena, there’s been such excitement and so many changes in the field, both in terms of molecular imaging and also molecular testing, both germline and increasingly we’re seeing that somatic testing is also valuable in men with prostate cancer to personalise treatment. Of course I’m very intrigued about how these new changes that are actually evolving are going to be incorporated into the ESMO guidelines.

EC: Yes, the ESMO guidelines have been recently updated precisely to include all these changes in the management of prostate cancer, of course, but also in the diagnosis, both imaging and molecular diagnosis. So these guidelines now recognise the utility of PET-PSMA, particularly after disease relapse in patients who have previously had radical therapy for localised disease. But we also have to acknowledge that the PET-PSMA is not widely available. So in some institutions they are using it routinely whilst in others the penetrance of this technique is still poor.

The PARP inhibitors have arrived to stay and now we need to identify who are the patients more likely to benefit from these therapies. Therefore the guidelines recognise the need for molecular screening in these patients. These guidelines have an entry which will be the more accurate technique, whether we should be using tissue or circulating DNA, obviously, because we understand this is something that will evolve and may change rapidly. But definitely this is something that in all healthcare systems should be provided for our patients. We need to put in place a strategy to provide this type of molecular screening for all prostate cancer patients. With regards to germline testing, there’s a clear benefit for patients with prostate cancer to be tested. As you know, we cannot identify up front which patients are likely germline mutation carriers but the benefit, not only for the patients in terms of therapies or follow-up but also for their relatives is great as it could help to prevent or in some cases could be helpful for the early diagnosis of breast and ovarian cancer in the relatives. So the guidelines now recommend germline testing for all patients with metastatic prostate cancer.

SS: It’s a good time in prostate cancer and lots of advances.

EC: Yes, lots of excitement. Thank you for listening to us, I hope you have enjoyed this conversation and hope to see you soon.