The Evolving Role of NGS and Germline Sequencing in Patients with Advanced and Metastatic Cancer - Episode 6

Operational Processes and Challenges

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Mark Robson, MD; John Henson, MD; Ashley Ross, MD, PhD; and Dana Farengo Clark, MS, LCGC, discuss operational processes and techniques for counseling patients about germline testing.

Mark Robson, MD: Let's talk about process a little bit.Dr Hanson and Dr Rush, you are doing simultaneous tumor-normal testing. How do you counsel patients about this? Traditionally, we'd go through this whole formal pretest counseling process for germline testing. How much of that do you incorporate?

Ashley Ross, MD, PhD: For good or bad, what I tell my patients is at a fairly simplistic level. It actually starts with me; I don't usually refer them to the genetic counselor to have the discussion about whether they should test or not. It's usually happening with my newly diagnosed patientI mostly do prostate cancer. I do this for all the men whom I deem incurable, so basically all my patients with stage IV cancer at diagnosis. For all my patients with locally advanced disease, I encourage it as well, so it is discussed with some of the men diagnosed with higher stage III cancer. I tell them, “You have this cancer. It's definitely a lethal cancer. It is your major life problem. The goal is going to be containment. Cure is a hard word here. What we want to know is everything that led you to develop this cancer, and we want to know everything that drives this cancer. My feeling about the best way to do that is to understand your genetics.”

Prostate cancer is common among the population, but there is at least 12% germline variability.I would say to the patient, “We want to understand your genetics, not just for yourself and opportunities for yourself, but this can affect cancers of the breast, ovary, pancreas, and even male breast cancer. We also want to know everything we can about the tumor.We want to send off your tumor for comprehensive analysis to understand what's coming from your tumor, what's coming from you. They're going to do a hygiene panel of the tumor and of your germline. But we also want to drill down deep into those genes that we've known over time, about 50 genes that are related to multiple other malignancies, and screen you for them. If we identify something, we will send you to a genetic counselor to talk about what the implications are and find the malignancies in you and in your family.” That's the way I lay if out, for good or bad. I don't go too detailed into anything like, “Look, we're going to test for this large expansion of genes, and that means that we might find more things, not just incidental, but some things of questionable significance.” We don't really go deep into it.

Again, I don't know if that's the right approach or not, but, logistically and pragmatically, I find it to be a very good approach. They're usually very engaged at that time. There are some minor things with younger men that I talk about for the germline testing, because they'll sometimes ask me, so I bring up life insurance and things like that. But that's the way I approach it. It's not as ideal as sending them to someone like Dana, a genetic counselor. It's certainly not as ideal as having a dedicated tumor genetics program, where there's someone who's a tumor geneticist looking at that, as well. But it's the only way to make the workflow work for me. Then I see the genetic counselors afterward.

Mark Robson, MD: How about you, Dr Hanson? How do you deal with it?

John Henson, MD:Basically, our hereditary cancer clinic deals with all cancers.Unlike what Ashley's doing, we don't come from the standpoint, “I'm your oncologist for this, and I need to figure out what we're going to do here, particularly from a therapeutic angle.” We kind of start more from the germline angle. Just to back up a little bit, I find that patients are about equally invested in what this might mean to their family—that they have this cancer and what this means for their treatment. We talk about the germline, and then I tell them that adding the tumor has really important added value. It can help us figure out if we get a funny result on the germline testing. It can help us figure out whether that's important or not. Sometimes, I tell them the story about a recent patient that we had. We did testing on both the tumor and the germline, and, lo and behold, there was a BRCA1 mutation in the tumor and not in the germline. We knew exactly what the spelling error was in the BRAC1 mutation, and it was not in the germline. It was the best of both worlds. Now the patient had a treatment option that arguably there is a stronger argument for, and she didn't have to worry about the fact that this could affect her family. It's a really, really powerful example of how doing the paired testing helped this one particular patient so much.

We start from the germline, we talk about it, and then I add in the tumor conversation immediately thereafter. It's always very seamless. I do talk to patients about whether they want to do it or not, but I have yet to have a patient tell me, “I don't want to do this.” These people are invested in this issue. You can argue that I'm too direct about it, but I don't think so.

Mark Robson, MD: Well, you wouldn't. Dana, you're on the other side. You have this challenge, because you're coming from a conversation about a tumor only and then you're being asked to confirm. Do you find difficulties getting reimbursement for that if the people are not actually meeting criteria otherwise?

Dana Farengo Clark, MS, LCGC: We used to when we first started this program. It was, I want to say, 2016, and for noncanonical tumors, people were certainly paying out of pocket. I remember a woman had anaplastic thyroid cancer, and they found a BRCA2 mutation in her thyroid cancer. She had no real significant family history that would meet any sort of criteria, she had Medicare, and she was considered unaffected. Her daughter actually paid for her to get germline testing, and it did, amazingly enough, confirm in the germline. So, yes, in the beginning we did. At least for the BRCAs that have been added to NCCN [National Comprehensive Cancer Network] guideline, if you identify a somatic BRCA, some of the insurance companies are covering it. Medicare is still a real sticky wicket. Luckily, the cost of genetic testing has decreased enough that people generally agree to pay at least no more than $250 out of pocket. But we still have to deal with insurance considerations.

I do counsel people a little bit differently when we're dealing with someone with advanced metastatic disease versus someone who's having predisposition testing. There are certainly a lot of different conversations but we definitely have to have those conversations. The interesting thing—getting them on the back end, too—is that they knew something was going on with somatic testing. I don't think they clearly had a great understanding of what it was, sometimes. They're more concerned about their cancer. Then they say, “What does that mean for my cancer? Are you going to treat me with anything?” “Well,” I answer, “your oncologist has to talk to you about that, and then I'll talk to you about this.” There is a little disjointed conversation there. I, unlike Dr Henson, because maybe he's a better salesman than I am, have had people say, “No, I don't feel comfortable with this. I didn't know that that was being done, and now I'm not sure about it.” Eventually, the oncologist may say, “Can you just talk to his daughter? He's not budging.”We talk to the family members sometimes. But we've definitely been rejected. I think that's one of the pitfalls of tumor-only results—you're sitting on a BRCA mutation, and the patient just will not, for whatever reason, come in, and it's tough.

Mark Robson, MD: Anxiety provoking. We have 2 questions that I just want to ask. One is probably pretty quick. What was the name of the website that you used, Dr Henson, to look at the United States?

John Henson, MD: VarSome. You don't have to sign up for it, but it's good to register. It's free. I find it to be quite powerful. It actually calculates the American College of Medical Genetics and Genomics risk or variant classification for you, based on the rules. It's quite helpful.

Mark Robson, MD: Thank you. Then the other is sort of an EMR [electronic medical record] question. This person has Tempus [Tempus, Inc] fully integrated into Epic [Epic Systems Corporation], so everything's coming right in. Universal testing with Ambry [Ambry Genetics Corporation], and those come right in, and they have a genetic module where everything comes together. Can you share your experience in bringing discreet genomic variants from multiple sources labs in the EMR? I cannot.I don't know if any of you have experience with that? We don't have direct feeds at our place.

John Henson, MD: Yes, Tempus does offer direct transmission into Epic. I don't know what other programs they offer. I'm pretty sure they do anyway.

Dana Farengo Clark, MS, LCGC: Yes, we do. We have the same. We have Ambry coming right into the EMR. We're working with other labs, so some of our gynecologic oncologists are using Myriad [Myriad Genetics, Inc] for HRD [homologous recombination deficiency] testing, so we're working with them. I know we're working with GeneDx (GeneDx, Inc]. Invitae Corporation just launched from a germline standpoint. I'm not sure about Guardant [Guardant Health, Inc] or anything else. I don't think we've had any success there yet. But a lot of the germline labs are now wanting to feed anything to make it easier to make their company more attractive.We just launched Invitae, we have Ambry, and we're working with Myriad right now.

Mark Robson, MD: Clearly, this idea of more transparent integration, ever-closer union, is part of what everybody's trying to do. It makes sense. We don't actually have a disclosure slide, so I don't know if any of the speakers would like to make any disclosures? I personally don't, but I wanted to see if anybody wanted to disclose a conflict.

Ashley Ross, MD, PhD: I speak for, have spoken for, and have worked with Tempus for many years, either collaborating with them or speaking for them in the last year or so.That's my only relevant disclosure. Then I partner with a lot of pharmaceutical companies that make targeted therapies that can be matched to patients through genetics. That would be my second disclosure.

Mark Robson, MD: I certainly do that, too, for a number of pharma companies that use genetic information. I just feel like that's an important thing to get out there.

John Henson, MD:Mark, I have a research project with Tempus looking at HRD in nonsyndromic tumors. I haven't spoken for them.

Mark Robson, MD: OK, very cool. Thank you. Dana, anything?

Dana Farengo Clark, MS, LCGC: I'm on the speaker’s bureau for AstraZeneca [AstraZeneca Pharmaceuticals, LP]. That's about it.

Mark Robson, MD: Cool. We are out of time. Thank you all for your participation. It was really energetic and enjoyable. Thank you for engaging.

Transcript Edited for Clarity