Genetic, Genomic Testing in Heavily Treated, Metastatic Castrate-Resistant Prostate Cancer

Raoul S. Concepcion, MD, FACS: So this next case is gonna be a heavily, uh, heavily pretreated metastatic, uh, castration-resistant prostate cancer patient, who is a 62 year old and under-, that again, experienced a, uh, episode of urinary retention about five years ago. Had a markedly elevated PSA at 55. Staging TURP showed a poorly differentiated adenocarcinoma Gleason grading group five. Staging workup showed a, um, CT scan of the abdomen pelvis with the large nodule, uh, heterogeneous mass with, uh, in the prostate borderline enlarged no-, lymph nodes. No, um, sclerotic lesions in the pelvis and sacrum. Bone scan the same day showed multiple areas of uptake in the left shoulder, clavicle, multiple ribs TL spine, pelvis.

Um, obviously, would've, you know, this patient, you know, fits the do-, fits the, uh, fits the classification of metastatic castration-sensitive high-volume disease based upon the charter trial. Uh, especially with this, um, an in- increase in, uh, intake, uptake, excuse me, in the right femur. Uh, past medical history here is listed. Had, had a colectomy, um, what turned out to be a benign polyp. Uh, family history of colon cancer. Didn't go really past beyond that. At least what's documented. So let's go to the next slide.

This is a representation of the technician-based bone scans. And as you can see, multiple areas are lighting up, uh, in the axial skeleton, as well as, uh, in the clavicle. And you've got that one potential spot there in the femur. Next slide, Jason. This is representation of the, of the, uh, of the, uh, CT of the abdomen pelvis. And as you can see, we've got some adenop-, some, uh, adenopathy there. And that p-, um, so this is part of the t-, the, your typical staging workup, which was, as we all know, could potentially change big time over the next year with the advent and the approval of PSMA testing that, that is probably gonna be approved for staging.

Um, so treatment course. So again, this patient, um, presents, uh, with, uh, castration sen-, metastatic castration-sensitive prostate cancer high-volume disease. He was offered docetaxel based upon charter. He declined. He instead of-, uh, opted for a clinical trial, uh, using androgen deprivation therapy plus apalutamide, which as many of you know, is a androgen receptor targeting agent.

Um, also received, uh, bone targeting therapy, including deneme-, uh, denosumab 120 milligrams, SubQ monthly supplemental calcium and vitamin D. Patient then, when he came off trial, got sipuleucel-T and, uh, and he got delivered all three cycles of sip-T, as well as some radium 223. Follow-up bone scan shows interval improvement, um, with, but, however, persistent uptake in the left humerus clavicle, hemipelvis. Um, he had some, uh, palliative radiation to the pelvis. Also, however, unfortunately, showed it came up with a lec-, left neck mass, which had interval increase in size. And, um, also again, got some more palliative radiation.

So for the polling question on this particular patient, again, we've got a patient who presents with metastatic castration-sensitive disease. Gets treated, is progressive. Uh, polling question one, I would order germline testing, somatic testing, both, or unsure. So go ahead and please vote. Kerry, progressive patient, obviously multiple lines of therapy, including androgen receptor targeting agent. Did not, uh, get a [inaudible 00:34:59] yet. Has some sip-T radium. What are your thoughts relative to testing for this patient as it relates to potentially, determining the next line of therapy?

Kerry Schaffer, MD: I think this is definitely a good opportunity to take the time and do, um, somatic testing. If they've not had germline yet, I would offer a simultaneous germline just ... Well, I guess I'll say germline if there are familial implications and they're interested. Um, but to be thorough, I would offer both. Um, and I would, you know, I guess I would probably, if they were willing to get a biopsy, try for the supraclavicular node, um, pretty easy to access.

Raoul S. Concepcion, MD, FACS: Jason?

Jason M. Hafron, MD: Yeah. I, I would, I would do both. You know, I think, uh, I would, uh, you know, I, I'm [inaudible 00:35:52] conditional. I want somatic and germline testing on all these patients. I think it's very informative and very helpful in how to manage those patients.

Raoul S. Concepcion, MD, FACS: Okay. So Jason, let's go to the next slide. So in fact, this patient did get somatic and germline testing. The primary, the prostate got tested. He's MSI, MSI high. Has a somatic mutation detected in MLH1 and BRCA2. So basically, has a mutation in the mismatch repair, as well as the homologous recombination, and also has a germline positivity for MLH1, uh, on germline. So, uh, Rachelle, what is this screaming out to you? What's, what are you thinking now if this patient gets referred to you for genetic counseling?

What are these, what, you know, what should the family, what should the patient be thinking about given these particular mutations?

Rachelle Manookian, MS, CGC: Mm-hmm (affirmative). Well, the patient has Lynch syndrome, based on the germline results. Um, that's what MLH1 is associated. It's one of the five genes, um, associated to Lynch syndrome. And so, um, obviously, has implications for the family, um, given that this patient's primary concern is obviously going to be their prostate cancer. So this is an example of where it might impact the family and patient at this ti- ... screening following for Lynch syndrome perspective.

Um, if you look at the Lynch syndrome risks for MLH1 and the NCCN, it's broken down by gene. [inaudible 00:37:28] question mark in Lynch syndrome. And, um, it actually, the risk number that it gives you for prostate and MLH1 is the exact population risk. Um, it doesn't show it to be elevated. So, you know, personally in my practice, um, if I were ordering genetic testing for a patient who has prostate cancer, I would never exclude the Lynch genes. In any case, we're ordering large panels these days anyway. Um, but I would never exclude the Lynch genes, but it's still, um, you know, a syndrome where we're not a hundred percent sure of the association to prostate cancer as an established cancer risk.

I don't know if Dr. Schaffer or Dr. Hafron, you have any i-, a different opinion on that.

Raoul S. Concepcion, MD, FACS: I mean, I think based upon the family history, which again, if you look back, all they, all they reported was a history of a colectomy for a quote "benign polyp." And it's, you know, I think to, you know, for us, it just goes to show how basically inaccurate family histories are in general, in general. And obviously, I think that's why there's this big push towards polygenic risk scores to maybe factor out, you know, these, these, uh, really not very of-, at times, helpful family histories that, that, that are, that, that are obtained.

But at the same time, we as, we as clinicians don't do a good job, um, with, with taking adequate, adequate family histories. Jason, if you can go to the next slide. So here's the actual, and I'm not su- ... So this was a pedigree, this is the pedigree that was actually obtained. Um, uh, and again, I think, you know, without going into too much detail, this is, uh, you know, as Rachelle knows, and as, as, as I know, having taken this, Rachelle's course, uh, at, at City of Hope, you know, this is, this is what we need to be getting used to as clinicians to, to really determine, uh, again, what the risk assessment is. What's, you know, what are the risks for the, for the family members?

Because again, as we do more testing, um, we are going to uncover, uh, more and more, and we have to know how to, you know, how to address, uh, some of these. And as Rachelle said, you know, basically, um, wi-, you know, with a mutation of, of MLH1, that is one of the five genes, along with PMS2, MSH2, MSH6 on EPCAM that are associated with Lynch syndrome. And, and obviously, that, that has an implication for GU tumors as well, maybe not prostate, but then obviously, there was an increased association with upper tract tumors, uh, uh, in, uh, in the urinary tract.

Um, Kerry, look at, taking, taking a look at that pedigree, what, you know, kinda what are your thoughts and, you know, how do you, you know, ho- how do you, uh, do a better job (laughs) than probably the urologists, hopefully in, in obtaining family histories? And, you know, what are your thoughts about how we should be incorporating more family history in pedigree building?

Kerry Schaffer, MD: You know, I think, um, first of all, medical oncologists are not necessarily any better than urologists at doing it.

It's very time-consuming, and that's why we need our hereditary counterparts. Um, so I would say, you know, ideally, if patients are able to give a family history, it's great to think about that in the context of testing. But, um, you know, if this patient had not had germline testing and had somatic testing, this would be the perfect reason to make sure to follow up on the mismatch repair gene, as well as the BRCA gene that's identified on the somatic testing. And make sure they get that formal germline testing. So I think it's a major challenge to get patients to report accurate histories. Um, and, you know, it d-, it doesn't look very striking anywhere else except their immediate sibling. Um, perhaps they don't know. Or perhaps it was, you know, a new onset Lynch syndrome in their dad who died of a heart attack. Or who knows?

Yeah. That was the other comment I was going to make, is the mom died pr-, young i-, you know, ish. Right? So MLH1 is pretty penetrant. We would expect by 57, they, that a person would have developed some sort of Lynch cancer, but she still did die young. Um, and so, could she have developed a colon cancer if she lived five more years, or 10 more years? Um ...

Raoul S. Concepcion, MD, FACS: So bas- ... Jason, let's go to the next slide. So basically, the patient, um, had a lot of shots in the CT scan in the abdomen and the pelvis in March of 2020. A large soft tissue mass in the left hemipelvis. Uh, pretty impressive in size, 14 x 11 centimeters, uh, involving the left obturator. Some soft ti-, additional soft tissue nodules, uh, throughout the groin, proximal thigh, retroperitoneale adenopathy, uh, left inguinal adenopathy, sclerotic lesion.

So basically, clearly progressing. Uh, based upon, based upon the mutations, um, uh, was, was pushed towards, uh, immunotherapy. And if we go to the next slide, pembrolizumab was initiated. Got some radiotherapy, and unfortunately, uh, ended up passing on, uh, 51, 54 months after diagnosis. So, um, but 54 months, you know, that's, that's four-and-a-half years. That's markedly better where we were. Uh, Jason, comment, if you will, about essentially, how you envision urology practices, especially as we start getting into the smaller percentages of patients that are gonna need immunotherapy.

Obviously, we're also gonna see neuroendocrine tumors that they might be candidates for, for platinum. Um, in, in a big practice, um, how are you handling these more advancing patients? 'Cause, as we institute therapy early on in the castration-sensitive space, we're, we're delaying their progression to castration resistance. These tumors are changing from a molecular standpoint. How are you managing that, uh, with, with all the new mechanistically different drugs? And also comment, if you would, on how the role of molecular imaging is going to be changing things over the next couple of years. ... believe molecular imaging is going to be changing a little bit of this, especially with the pending approval of PYL and PSMA.

Kerry Schaffer, MD: Yeah. So I think, I think molecular imaging is definitely going to have, um, a big impact on prostate cancer care. I think there's a lot of promising PSMA-directed therapies that are coming down the pipeline. Um, numerous, uh, radionuclide ra-, and numerous immunotherapy agents. So I, I do think they will be incorporated into care. Um, and of course, they're being studied in the late, uh, late stage now and moving up earlier and earlier. So I, I think that, um, uh, our imaging-directed therapies are, um, really exciting. And I look forward to seeing them get approval and, um, you know ...

It'll be interesting to see where they land, how early they land in prostate cancer care. Um, and then how we, uh, use our existing medication therapies, um, within the treatment, uh, scheme. So, um, regarding this with the immunotherapy, I, you know, I think one interesting point to bring up is the BRCA2 was there, as well as the, um, uh, tumor high, or I guess it was MSI high. So one question, you know, how did someone choose immunotherapy over a PARP inhibitor? But I, I would have probably gone with PARP, the immunotherapy as well, um, rather than PARP inhibitor. Um-

Raoul S. Concepcion, MD, FACS: And I'm sure there's m- multiple trials out there looking. I mean, I mean, I think that's the real challenge. Right? Is that, is that all these therapies we're looking at, all these definite, different combinatorial therapies, with all these mechanistically different drugs and ... You know, this is, you know, sort of the promise of precision medicine based upon treating, you know, treating the molecular drivers and trying to figure out exactly what is, you know, what's driving these, these, these tumors, and what's the best combination to use.

And obviously, the timing. Um, Rachelle, how, if you had to sort of, for our viewing audience, if you, 'cause again, um, uh, first of all, I appreciate your expertise and, you know, being with us. Is that, a lot of the viewing audience, a lot of our, uh, a lot of our audience doesn't necessarily always engage with genetic counseling. Um, maybe some of them don't even have access. And, and as you said, you know, relative because there's such a paucity, um, what are the f-, you know, what are the key points from your standpoint, um, how we can, you know, recommendations, how we can do a better job as providers, especially if they're not really well-versed on, on, uh, on genomic and germline testing?

Rachelle Manookian, MS, CGC: Mm-hmm (affirmative). Well, the ideal is obviously, the referral to a genetic counselor, which we all do a-, I, I, we try in genetics to accept that that's not always going to happen. A- at least I have come to accept that. Right? And so, whether it's the process that, you know, Dr. Schaffer and Dr. Hafron have taken in terms of initiating that own, their own testing. Um, but as you mentioned, some people might not be as comfortable in that. Right?

They're not familiar with the tests, or how to order and things like that. So I would kind of think that, um, genetic testing laboratories want these patients to undergo genetic testing. They've made it more accessible, and many of them have local regional, um, people who will come and talk with you and, and tell you how to implement this within your practice. Um, and some of them even have chat bots that will disclose negative NVUS results.

Um, it's gotten really advanced and accessible for not only patients, but providers who wanna provide this service. Um, the other thing I would think about is, you know, you may have in your clinic or local to you, a really, um, proactive nurse practitioner, or somebody who really wants to take this on and is very interested in that. And so, if you wanna allow them the time to either, you know, shameless plug, take the City of Hope course that, um, both Dr. Concepcion and Dr. Schaffer, um, are alum of, you know, things like that are really great opportunities.

And we're not the only ones. I know Jackson Laboratories and others have, um, shorter, more digestible courses, where I would encourage that if you have someone in your clinic, or you yourself really wanna be proactive about that, uh, do it. Um, take that extra time so that you're knowledgeable and feel more comfortable at least ordering the testing. And then, if you need to refer, you refer after the fact.

Raoul S. Concepcion, MD, FACS: Yeah. I mean, Kerry, I don't know about you. I thought that course was invaluable (laughs).

Kerry Schaffer, MD: I loved it.

And I think, you know, I think that it's, it is a responsibility if you're doing genomic or germline testing. It is a responsibility to make sure the patient is aware of their results. Especially if there's a hereditary component. It's really important, um, you know, if their son develops colon cancer at 30 and they're unaware, that's, um, that's a gap that, that was missed. So.

Raoul S. Concepcion, MD, FACS: No, I, I, you know, in fact, I was, I was, and, and for, you know, they, um, in the, in the audience, uh, basically what we're speaking of is that the City of Hope, um, offers a three-month online course. And feel free to reach out to any of us. And we can give you the, I think they're taking applications if I'm not mistaken. Correct right now, Rachelle.

Rachelle Manookian, MS, CGC: They are.

Raoul S. Concepcion, MD, FACS: For [crosstalk 00:49:35] November's course. Um, they've been doing it for, I think next year will be year 21 or 22. Uh, the course is not designed for you to come out to be the next Rachelle Manookian ... who is a certified genetic counselor, which is a, which is a master's degree. Um, it is a course designed, it's called the intensive course for cancer risk assessment and genomics. And it's specifically geared if you want a more in-depth knowledge and, uh, understanding o- of how to look at, how to determine cancer risk assessment only. You know, the problem is, as Kerry mentioned earlier in, in this discussion, is that there's only 5,000 Rachelles out there. And the majority of them are not necessarily geared towards medical f-, towards oncology.

And as we, as we get so much more information, and as somebody creatively said in the co-, in the course this last year, you know, we're exceeding cognitive capacity. Uh, the ability to understand this. And to me, I think it's about actually demystifying this. Because, once you get a certain mindset, it, it actually becomes pretty straightforward. But I think for those of you who are interested, there is a course out there. You can go to City of Hope. Uh, look up ca-, uh, intensive course for cancer risk assessment. And I will tell you, I don't know about you, Kerry, but I, had I not had the background that I had, I probably would've thought that course was very difficult (laughs).

Kerry Schaffer, MD: It's a rigorous course. It's very comprehensive. It is ... I think they still have an online-only option, which is great for, you know, working professionals and, um, but I, I loved the course. Yeah.

Rachelle Manookian, MS, CGC: Yeah. And I, I will also add, um, it's an in-, no pun intended, intensive course, uh, currently. And we are actually working on what we call a self-paced version. Um, so that it's not, you know, 12 weeks of every Friday being committed to being online and, and, and, you know, being in these Zoom meetings, but self-paced for providers who don't have necessarily that time or flexibility. Um, and those will be actually, for example, breast-focused. Or GU-focused. And so, you have a GU provider who maybe doesn't necessarily need, uh, you know, some, some of the other things that we go over in the course. Um, the pediatrics, the hematology, and so on. So that is to come, and I'm more than happy if anybody wants to reach out to, to talk about that.

Kerry Schaffer, MD: And I'll say too... just in case someone does not have the ability to set up stuff to take the course, or actually do it themselves. There's so many initiatives nationally to try to get access about genomics and germline testing in prostate cancer. Um, you know, your nearest academic center probably is very willing to serve as a sounding board for tricky cases. So, um, there's a lot of resources nationally, um, including City of Hope, uh, which are interested in, in collaborations.