ASCO 2018: Integrating genomic data throughout treatment for prostate cancer

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Published: 2 Jun 2018
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Prof Kurt Miller and Prof Bertrand Tombal

Prof Kurt Miller (Benjamin Franklin Medical Centre, Berlin, Germany) and Prof Bertrand Tombal (Cliniques Universitaire Saint Luc, Belgium) share their thoughts on the genomic data and its implications for prostate cancer treatment presented from day 1 at ASCO 2018.

They emphasise that taking a detailed family history of any breast cancer, ovarian cancer as well as prostate cancers is a vital first step for new patients.

Genetic counselling for ‘healthy’ family members needs to be considered alongside the role that geneticists versus urologists/oncologists play to ensure robust pathways and local working practices.

Emerging data indicates that 40% of BRCAm patients may not have a family history therefore somatic and liquid biopsy testing needs to be integrated into treatment pathways for new and existing patients who may progress whilst on treatment with abiraterone or enzalutamide. Currently patients may be screened for genetic mutations for clinical trial entry (BRCA and MSII), however with the future introduction of PARP and checkpoint inhibitors this will become more routine and will be an important consideration for all specialists to start to consider for prostate cancer patients.

 

Genomic counselling for prostate cancer risk
Somatic testing and liquid biopsy
Tumour biopsy v liquid biopsy
Who and when to genetically sequence


This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

 

KM: Hello and welcome to our first prostate cancer session from this year’s ASCO here in Chicago for the ecancer community. I’m happy to have Bertrand Tombal here beside me to discuss the first news because many of the prostate cancer sessions actually are starting this afternoon and are on Monday. Bertrand, what we discussed is yesterday there was a session, I think it had the headline ‘Genomics and Genetics of Prostate Cancer.’ This is something that has been around for quite some time but it’s now more and more getting into mainstream. I would suggest we could start with let’s call it genomics. If today a guy comes into your office with metastatic prostate cancer, newly diagnosed, what role plays actually genomic counselling, genetic testing and all this type of stuff? Can we start with that?
BT: I think that indeed what we learn is that we should basically behave like breast cancer or ovarian cancer doctors, that if it has not yet immediate therapeutic implication it may have family implication and especially all the reports on the quite high, although we understand what it means, incidence of DNA repair mutation. I think it’s fair that we go back to the clinic, that we teach our colleagues to do a proper family history of cancer. Indeed, if you look at prostate cancer guidelines they’re going to say that hereditary prostate cancer exists and as urologists we tend to limit our anamnesis to, ‘Does your father have prostate cancer?’ So I think that we have to move beyond that and really start implementing a true cancer genealogy of this guy about breast cancer, ovarian cancer, prostate cancer. That’s really the first step although in the very famous paper from London 40% of the patients had no family history.
Then the question is when do we look for germline mutation and especially as this regards the DNA repair mutation germline. We have no good argument to start thinking about doing it in newly diagnosed metastatic prostate cancer, especially those occurring at a young age. It may not have a direct impact for the patient, no, still it’s going to come soon but at least for family education, genetic counselling it’s important. So I think that these are two small steps. These technologies do exist everywhere in Europe and everywhere in the world so we should think about doing them.
KM: Let’s just get one step more upstream, let’s say a guy is coming to you and saying, ‘Look, my whole family has different sorts of cancer. My mother had breast cancer, my father had prostate cancer,’ and whatever comes up. Is that something where you would say, and the guy doesn’t have prostate cancer yet, would you recommend him today to undergo genetic testing and genetic counselling? Is that something we should consider?
BT: I would say yes. The question is are we going to do that ourselves or are we going to hand it over to a genetic counsellor because then we may immediately use all the resources of genetic counselling. So that’s where we’re going to have to find do we do the test ourselves. You can get quite cheap DNA repair gene panels and if the patient is negative that’s OK. So that we still have to sort out. What we do now is that we have an agreement with the geneticists that we request a DNA repair mutation panel and if the patient is negative then we carry on as a normal patient. If not, then we’ve got the discussion with the genetic counsellor because you understand that we don’t want either to harm patients, everybody knows the Angelina Jolie syndrome, you don’t want that guy who has no prostate cancer to end up with a radical prostatectomy before…
KM: Prophylactically, so to speak.
BT: Prophylaxis. So we have to be careful not to harm the patient. But thinking about it, discussing with the patient, discussing with your genetic counsellor in your institution to find a common care pathway, I say now that should be done.
KM: Yes, currently it’s a couple of steps away from mainstream, specifically if you think about some office urologist or some peripheral community practitioner. They will definitely not offer this, they are doing PSA tests and they never think about family history and this data. But, as you say, the technology is available and it’s a matter probably of education to get people closer to that. So that is one thing, that’s germline testing, and we also discussed about somatic testing. The question would be in the career of a patient with advanced prostate cancer where would you think somatic testing, which kind of includes biopsies either or doing it from a liquid biopsy, comes into the equation?
BT: I think that’s getting clearer with time. There are first a few observations. I think that we can say now that the standard treatment of prostate cancer patients is somewhere androgen deprivation therapy plus/minus local treatment plus at least one of abiraterone or enzalutamide and probably soon apalutamide. Then we really see that the complexity is appearing when these patients are progressing, especially the 30-40% of patients that progress quite rapidly. So do we have therapeutic intervention available right now? Not ready yet but olaparib and other PARPs and in a good way to be approved in patients with DNA repair mutation. Some IO agents, especially pembrolizumab has been FDA approved for patients with MSI high or MSH mutations. So these are all ready too. So the question for us practitioners is when do we recommend a solid or a liquid biopsy and that’s where we need to learn. We need to integrate exactly like we discussed the family history. I think that doing more biopsies, including liquid biopsies, in patients progressing on abiraterone enzalutamide will become routine because that’s where we’re going to have opportunity for these patients. What we don’t want is that the drug is approved, the drug is reimbursed and we have no way to look at the target. So I would rather say let’s learn to screen, maybe not having other options for the patient, that to give the access to a clinical trial. But we should do it because the way the screening is done right now it’s done within clinical trials meaning that you have a clinical trial open with a PARP inhibitor, you screen your patient, if your patient has a DNA repair mutation you put the patient on the PARP inhibitor. But if the patient is MSI high, for instance, you don’t know it because it’s not an IO study. So it’s better that the screening comes back to the physician so we can allocate. So really, for the patient progressing on enzalutamide abiraterone, instead of giving abiraterone or enzalutamide after that or discussing endlessly about what drug is the best, which we don’t know, we should start by learning to do solid biopsy or liquid biopsy and the technology is evolving very rapidly. Tomorrow they’re going to show a nice paper where they can pick up DNA repair mutation on liquid biopsy using modern technologies that are commercially available. So we need to get organised at this level also. For a primary care urologist, those who see the patient, 80% of urologists will get their hand in with these patients, they need to learn that strategy of getting more tissue, more blood.
KM: Yes, as a matter of fact, you mentioned PARP inhibitors and you mentioned checkpoint inhibitors and, as an example, pembrolizumab is in the United States only, kind of unfortunately, approved for a number of tumour entities which is not dependent on where the tumour comes from but has certain properties like, as you say, microcellular instability, like mismatch repair deficiency, high mutational load and all these types of things while we know that the likelihood of having an effect with this type of new drugs is pretty high. So the question for me, and what I have learned in our setting which is again a university setting, we’re still not having that in the mainstream organised that I say every patient that is, let’s say as you just mentioned, is failure of first line treatment in CRPC has a structured way of getting this type of testing. So it’s still a matter of education and a matter of resources. You mentioned, and that’s probably something we could discuss, you mentioned a biopsy which is still invasive and it’s, again, far from being a routine procedure in metastatic prostate cancer whereas liquid biopsy… What is your feeling, is one better than the other? Do we need both? Is it still too early to say we get the same information from liquid biopsy which is much easier for the patient, of course?
BT: I think the heavy trend is to move to liquid biopsies. So hopefully solid biopsy will be more and more like a validation step for the new liquid biopsy to come. They are emerging technologies so I think that in the future it will not be a question anymore. But at this point in time, even in the setting of doing that kind of validation work, if you look at metastatic CRPC patients and you do simply a bone scan you would see a lot of these patients having metastases in the pelvis. Any urologist can do the biopsy itself so it’s not that difficult. It’s much like you mentioned about how do we organise this? Because we should not forget that one of the problems of precision medicine is that we have probably drugs of exceptional activity but in a very limited…
KM: Yes, in a small niche of patients.
BT: A small niche of patients, so we’ve got to do a lot of biopsies to tell patients unfortunately there is nothing for you. So these are important problems. Basically you can take two attitudes – the first one is to say, ‘I don’t biopsy anybody and I see what’s going to happen’, ‘I biopsy everybody,’ or we start to understand. You know, if you have an 85 years old guy which is in poor performance status which has been on abiraterone for four years and is now progressing indeed I wouldn’t do any biopsy in that patient. But if you have, like we all have, a 55 years old guy who had a prostatectomy one year after he’s progressing, stays six months on enzalutamide, we need to find a way to put this patient in a system we can get genetic information. That’s probably the technology will be liquid biopsy but keep in mind that the earlier we’re going to be the less contributive it’s going to be. So we’re still going to get to do biopsies.
KM: That’s probably the message that we should get across to the front line guys who are treating these patients. Yes, you say treating CRPC patients with abiraterone or enzalutamide, this is now bread and butter, everybody can do it. So then, of course, when the patient is progressing then these guys are puzzling what should I do next. Then we need some information to say, well, you should take this step and where can you take this step and what should you do exactly for that. That would be actually one of the tasks for tertiary referral centres to say, well, we offer you this and we get the information across. Then you can send the patient to us and we do all the work for him. Because, as you say, you need to test a lot of patients to really see this could be a candidate for this and that and you need to think about what to test. That’s what we are currently discussing with our pathologists – what exactly should we test? And what is something that is targetable and what is useless in this huge amount of information that we get across when we’re doing next generation sequencing. So that is one thing and currently my understanding is for liquid biopsy we’re probably still…
BT: Another two years.
KM: Yes, another two years doing biopsies for [?? 14:29] or whatever. That’s a little closer to what we can do.
BT: I would fully support the fact that now we basically have two jobs with abiraterone enzalutamide. The first one is that we need to train the referral doctor to give abiraterone enzalutamide because we can’t absorb the whole resource. Then also say, OK, if you treat with abiraterone enzalutamide this is what we expect from you when the patient is progressing. Once again, in five years from now when liquid biopsy will become broadly available we’re going to transfer this liquid biopsy to them and then select another source. That’s what we see in renal cell carcinoma – we barely see people who haven’t received two or three lines of treatment now in the referral centre because the first and the second line have become so usual. So that’s the same question.
KM: That’s correct, yes. So currently the word precision medicine is all over the place but, to be honest, in prostate cancer we don’t do precision medicine at this time.
BT: No.
KM: We’re still a couple of steps away from that. But as we discussed before, the general tools are there, we just need to start using it and then probably a couple of years from now, it’s always hard to tell is it one, two or three years from now, we’re going to treat prostate cancer probably differently than we do now.
BT: Yes, I think that when we look at genomics and genetics we spend too much time maybe discussing about who should get chemo, who should get abiraterone, who should get enzalutamide because the bottom line is that everybody’s going to get chemo and abiraterone enzalutamide or most of these. So at this point we have to focus on that population and not about who should get chemo or abiraterone or enzalutamide but are we going to feed in the new drugs that will slowly come on. So that’s the most important thing.
KM: OK, nice closing remark.
BT: Thank you.
KM: Thank you very much, an interesting discussion, and goodbye everybody.