Alicia Morgans: Hi, I'm delighted to have here with me today, Dr. Panas Vlachostergios who is here with us today as an Assistant Professor of Clinical Medicine for Weill Cornell. Thank you so much for joining me today.

Panagiotis Vlachostergios: Thank you for the kind of invitation.

Alicia Morgans: Wonderful. So, Panas, you have done work in multiple areas of GU medical oncology, but we wanted to talk today about germline testing, somatic testing, and really how we think about integrating genetic genomic material into treatment decisions for men with prostate cancer. So what do you think about when you're seeing these men in your clinic?

Panagiotis Vlachostergios: Absolutely. So it's a very, very interesting and very active topic of investigation right now. We're learning more and more about, it's not just family history that we should always take from our prostate cancer patients, for example, when we see them in the clinic. But there's more and more evidence now that there are several rare high penetrances, and also moderate penetrance genes, that are involved in genetic predisposition to prostate cancer. There are several studies that have worked on this, including our institution. So it's really important also following the current guidelines, the updated guidelines, to really talk about this with our patients, and besides family history, really try to educate them and highlight the importance of genetic germline testing, even at earlier stages.

So that's slightly different from what used to be the case, just for metastatic patients, based on earlier data published in the New England Journal of Medicine from Pritchard and coworkers. So now we know that even high, and very high risk, patients would benefit from germline genetic testing, and that might have implications both for these patients in terms of their treatment options, for example, with PARP inhibitors later on, but also for their families for more intense genetic counseling and screening.

Alicia Morgans: So when you're seeing a patient with metastatic disease, for example, in your clinic, how do you operationalize germline testing for these patients?

Panagiotis Vlachostergios: So we emphasize the importance of, again, assessing this information irrespective of their family history, emphasizing that this may have treatment implications for them. But also, we always try to get some somatic testing as well particularly in patients that are not new or in progressing on prior therapies. And that's very important because we may detect the same genes either as somatic alterations or as germline, but if we only get somatic, that should also prompt germline genetic testing in most cases.

Alicia Morgans: Absolutely. So really important point that if you were doing tumor testing, so regardless of which stage of disease, but if you're doing tumor testing and doing next-generation sequencing, for example, to identify targetable or actionable mutations, and you find a BRCA2 mutation, you should, if you've not already done it, reflexively then test these patients for germline mutations that could lead to cascade testing for their family members if you do identify an abnormality.

Panagiotis Vlachostergios: Absolutely, and this is the current guidelines and the more and better we educate our patients about this, the more eager they are to get tested because there's a misconception that patients don't want to get biopsied, or don't want to get tested, and we can also offer them, especially for metastatic patients, liquid biopsies now. There's a high yield that they will present some alterations in their circulating tumor DNA.

Alicia Morgans: Absolutely. But if you find it in that DNA, you should always go back to the germline as well.

Panagiotis Vlachostergios: Absolutely, yes. Correct.

Alicia Morgans: So for metastatic patients, regardless of family history, all patients should undergo germline genetic testing, as you mentioned. And then even those high-risk patients, particularly with certain pathologies, and all of that is outlined in the latest and greatest NCCN guidelines that were just updated, these patients also should undergo testing. How do you think about talking to patients and providing counseling if you do find a positive mutation in a patient? So for example, if you did testing in the tissue, and in the germline and found a BRCA2 mutation, do you engage with genetic counselors? Do you use online programs or telemedicine, or do you counsel patients yourself? What do you do with positive information?

Panagiotis Vlachostergios: So, absolutely. I was fortunate enough to get some training in cancer risk assessment from the intensive course in genomic cancer risk assessment by City of Hope. But we also definitely have available genetic counselors, and we usually work with them all the time in these cases. So when we see a patient in order to discuss their results, we talk about three different tiers, or sections, or types of results. One would be a negative result, so that wouldn't have any implications for the patient, and in terms of their family, their screening should be dictated by the family history. Meaning that patient, or any other relatives, first degree particularly, with malignancies.

Then the other extreme is there is definitely, a definitively positive result which we know as being either pathogenic or likely pathogenic mutation in one of the high-risk genes. Definitely most of which are within the homologous recommendation repair and absolutely number one BRCA1 and 2. So, in that case, we discuss the direct implications for the patient, that they may benefit from PARP inhibitor therapy depending on the finding. Or for example, from a PD-1 inhibitor, if this is a mismatch repair mutation, although they're rare in prostate cancer.

And also the implications for screening for the family at an earlier age. And there are clear recommendations for breast cancer screening and ovarian cancer screening, less clear for others, for example, if we're talking about BRCA, for other BRCA2 related to cancers like pancreatic or melanoma. But these things will evolve, obviously, in the next couple of years.

And we also discuss a third category, which is a little tricky, but as long as we educate them, they will understand. So in this third category is the variants of uncertain significance. That means we find a mutation in one of the high-risk genes that is not really known to cause a particular defect in the protein and leading to significant risk, as far as we know right now. But the more we study, and the more functional work we do in all of these mutations in those high-risk chains, the better we'll be able to inform these patients later on in their treatments whether this VUS, which is how they're abbreviated, ends up being reclassified to either a nonpathogenic mutation or a likely pathogenic or pathogenic.

Alicia Morgans: How are you in your clinical practice following up on those VUS's? Are you giving the patient his report and then having him engage? Because a lot of companies will provide updates to whoever is engaging if that's the patient or the clinician, or do you have a system in place where your clinic is monitoring VUS's, and reporting back to patients? How do you tackle that?

Panagiotis Vlachostergios: So we try, myself as a clinician, with some particular training in cancer risk assessment, to follow this evidence moving forward. But also we definitely provide the services of the particular company that is providing the multi-gene panel test that we use in that particular patient. There's no real direct comparison between the different multi-gene panel tests across different companies. What we know, for sure, that there's this particular group of genes that are high-risk and they're included in all of them. And then it's an à la carte additional inclusion of a few more genes, or fewer genes, depending on the company.

But yes, absolutely. We try to do this at both angles. So we engage the patients, so they definitely get, in addition to our genetic counselor visit and information, and contact the online genetic counselor from that company that's providing the test, but we also ourselves, like myself, follow up on the data and update myself on everything that's coming up.

Alicia Morgans: So for clinicians who don't have a counselor, I think, whether they are chat boxes, or telephone counseling, or online web-based counseling that the companies provide, can be very, very valuable. So as clinicians are thinking through which test to use, understanding the support services that they may have available can be really helpful particularly again for those clinical practices that do not have access to a genetic counselor-

Panagiotis Vlachostergios: Correct.

Alicia Morgans: ... And that's going to be many, many practices.

Panagiotis Vlachostergios: Absolutely.

Alicia Morgans: So understanding those supports can be very, very useful when choosing a test. So if you had to give just an overall message to urologists, medical oncologists, or even primary care if they're really engaged with men with either high-risk localized or metastatic prostate cancer who are undergoing germline testing, what would that be?

Panagiotis Vlachostergios: I think the message and what's the spirit of the recent guidelines, and this is what has dramatically changed from the previous guidelines, is try to get your patients to get access to more testing. You may detect more genes, or moderate genes, that we are not very clear about their exact contribution to heritability of prostate cancer. However, it is important to broaden and use multi-gene panels as opposed to single panels, because you may, first of all, incidentally discover some genes that would not have been otherwise tested.

And most of the available evidence on several patients in different stages in prostate cancer agrees and supports this notion that there is a proportion of patients that would have never been tested if only based on family history, particularly for hereditary breast, ovarian cancer syndromes. And this proportion can be pretty significant in one fourth, or even one-third of patients. In a recent study published in JAMA Oncology by Oliver Sartor and coworkers showed this. So it's really important to give the message that we should test as many patients as we can. Again, guideline-based, but definitely high-risk, and very high-risk, patients are eligible and are candidates for genetic testing.

Alicia Morgans: Absolutely, and when we think about metastatic patients, we should also be thinking about somatic testing as well.

Panagiotis Vlachostergios: Absolutely.

Alicia Morgans: If 5% of patients actually end up having a germline BRCA2, for example, we'll actually see an additional 5% of patients who may have that in their tumor, but not in their germline. Giving them access to potentially life-prolonging and palliative treatments that may be useful to them. And certainly, if you find a mutation in somatic testing and tumor testing, that is a potential DNA repair defect that could have connotations, or could predispose someone to a heritable risk syndrome, you should always then-

Panagiotis Vlachostergios: Go back to the germline.

Alicia Morgans:  ... Reflexively go back and do the germline if you haven't already done that.

Panagiotis Vlachostergios: Absolutely.

Alicia Morgans: So thank you so much for talking all of this through with me. I really appreciate your time.

Panagiotis Vlachostergios: Thank you. Absolutely. It was great.