Chapters Transcript Video Circulating Tumor Tissue Modified HPV DNA in HPV Mediated Oropharyngeal Carcinoma All right, welcome everyone to our Tampa General Hospital um virtual CME webinar with Doctor Nichol today. Um Before we go ahead and get started, I wanted to run through a couple of housekeeping items. Before I turn it over to Doctor Nichol, we do have a question and answers box at the top of the screen. Please utilize this throughout the presentation if you have any questions and we will answer them at the end of the presentation. Also to claim CME credit today, you must stay logged on for the entire presentation. Claim credit information will be emailed to you after we are done with our session. And without further ado, Doctor Nichol, thanks Isabel. Hi, everyone. Thanks for joining us today. I know uh lunchtime CME meetings are always uh you know, crunched for time. So I will do my best to deliver uh pertinent information as, as uh efficiently as possible and let everyone uh get on to lunch and back to their day. Uh I'm here today uh to talk about tumor tissue matter. I had viral HPV DNA testing in HPV, mediated or pharyngeal carcinoma. Um That's obviously uh quite a mouthful. Um We'll try to distill it down um in, into uh some kind of basic tenants, um strengths and weaknesses and how it fits into our, uh our practice. Obviously new testing for oropharyngeal carcinoma uh that's HPV mediated is, is uh a really exciting modality. And that was the reason, uh you know, I decided it would be a good topic to, to discuss with our community partners uh to begin today. Uh I want to show that I have no disclosures and make this disclaimer. So there is a product out on the market um called NAV DX. Um NAV DX is made by a company called NAVAIS. Um I'll refer to this uh test um specifically because it is the test that I use. It is the only clinically validated test available. Um But references to this modality are not construed as an endorsement of the product or uh uh an endorsement of this product over any future alternative products that may become available, which we do anticipate um objectives of the talk. So first, we'll discuss applications of the TT MV HPV DNA testing and HPV mediated or Ph Pharyngeal Carcinoma will review some strategies for implementing this testing into clinical practice and we'll briefly identify some exciting ongoing areas of research uh that may lead to future applications of TT MV HPV DNA testing. So first, what, what is the test and how does it work? Um So as HPV cells uh degenerate uh tumor tissue modified viral DNA fragments are released into the bloodstream. Um This test is essentially a PC R based assay designed to quantify the fragments of a ATT MV HPV DNA that are released. Um And the nice thing and the reason that this uh uh um blood marker is so particularly useful is that uh TT MV HPV DNA is specific to HPV, malignancy HPV related malignancy, nonmalignant HPV infections do not release TT MV HPV DNA into the bloodstream. So when we are able to quantify this type of marker, we know that it's specifically related to a malignancy mediated by the HPV virus, making it an ideal biomarker briefly about N AD X. Um It's commercially commercially available, it's widely distributed. Um It's like I said, currently, the only clinically value validated test, there have been several similar research grade TT MV HPV DNA assays developed where none are, are commercially or broadly available. So for right now, the NAV DX product is the most uh widely available uh uh product out there. And the one that, that I personally use my, my clinical practice talk a little bit about uh the test features. So there's evidence to support TT MV HPV DNA as a marker of HPV mediated squamous cell carcinoma, the oropharynx. But it's important to note that HPV DNA in the bloodstream is not specific to an atomic subsites. So there is the possibility that cervical or anal rectal carcinoma that can also be mediated by the HPV virus can cause positive results that becomes relevant when we're relying on um oropharyngeal or, or, or, or this test to diagnose specifically an oropharyngeal malignancy. One of the major benefits and really the highlight of, of the uh the test is that it can detect clinical recurrences in folks that are treated for oropharyngeal malignancies mediated by the HPV viruses. In fact, there's evidence to say that um TT MV HPV DNA as a median lead time on traditional surveillance modalities, whether it be pet scan or physical exam, uh that uh ranges from a little under a month to up to uh almost 13 months with an average of just about four months. So this is a uh a test that's sensitive and specific, that also gives us um statistically proven lead time uh benefit when compared to standard uh surveillance techniques. As you can see here, the positive and predictive negative values um are both 95%. Um and that's been validated with little variation over several studies. So it's a test that we can have some confidence in. Let's speak a little bit about applications. So I think there are are really five main applications uh of this test and potentially down the line. Um several more um in the pretreat time frame. Uh This test helps confirm the diagnosis of an HPV mediated tumor. And in a minute here, I'll present a case where I was able to utilize this uh testing modality to confirm the diagnosis of an HPV mediated tumor. It helps us establish the genotype and establish a baseline TT MV score which I'll speak briefly about in a bit. Um In the post treatment space, it helps us assess response to treatment whether that be upfront surgery plus or minus, adjuvant therapy or definitive radiation plus or minus chemotherapy. A posttreatment TT MV HPV DNA test helps res helps test our response to that treatment. Uh And then the most well documented and well studied uh application is in the surveillance space. How do we surveil our HPV, mediated or referring patients long term? And, and where does this test sort of fit in, in that surveillance paradigm? We'll discuss that a bit more as well. So let's go on to a case study where we talk a little bit about how I implement this, how or how I implemented this into my clinical practice in a very specific uh case. Um That really touches upon all five of those uh applications that we discussed. So this is a pretty common, at least in my clinic, a pretty common uh presentation. A uh 61 year old male presents with a left neck mass, mass had been present for about three months. It was incidentally noted he was treated with several rounds of antibiotics uh without resolution. Um He's essentially completely asymptomatic. He's a lifelong non-smoker. He's told by his PC P that it, it a mass looks like a branchial cleft cyst presents to my clinic with this, uh you know, clinical presentation exam reveals uh a 2.0 times 1.5 centimeter left level two mass, somewhat cystic well circumscribed without obvious invasion into the SCM or surrounding vascular chair. The upper air digested tract including a scope is unrevealing. Uh The FN A is nondiagnostic. Unfortunately, a lot of times with these cystic neck masses, uh you know, I perform FNAs in clinic under ultrasound guidance and uh we occasionally have positive cellular nondiagnostic um FN A results which leaves us in a, in a conundrum. Um The question here becomes, you know, what do we do with this patient? Do we take them for an excisional node biopsy and then complete a neck dissection? If the uh if the node turns out to be positive, do we treat it like a branchial cleft cyst? Uh that's certainly not advised, but that's something I've seen. Um Do we get a pet scan? Well, unfortunately, without a diagnosis of a malignancy, a lot of times it's very challenging to get that pet scan approved by insurance. I I run into that problem all the time. Um repeat biopsy with an FN A or a core is is feasible but takes time, takes another, you know, effort by the patient to, to undergo rebiopsy. Um So we, we needed a solution to this problem. Here's a uh a review of, of that CT scan that I mentioned pretty classic presentation for an unknown primary oropharyngeal cancer. But you know, the tumor is on the anterior border, the SCM, it's well circumscribed. It's small. This was the only lesion that this patient had on his imaging. And as you see here, the insurance won't let me get a pet. So I I'm kind of stuck. Do I biopsy again? Do I take him for the, to the or? Um, so when, when the uh TT MV testing came online, we we got another modality uh that we can use to, to assess the patient in the pretreat space. So here HPV, uh DNA testing, excuse me, confirmed HPV mediated disease. Beyond that, it identified the genotype, you can see that up on the top left corner of the uh of the results page. Uh it's identified as HPV 33 and we get a baseline TT MV score. Now, the baseline TT MV score is a little bit of a black box. Um uh briefly the score is calculated by comparing the patients um you know, fragment count against a essentially a, a normalized database of hundreds of thousands of tests performed by NAV DX and the virus. Um It unfortunately is, is somewhat of a proprietary uh uh calculation. So we don't actually know what that score means. And I often have patients ask me what is 91 mean? Is that better or worse than 100? Is it better or worse than 1000 these are questions we don't have clear answers to yet both because we don't know how the score is really calculated. And secondly, because we don't know how to take those calculations and apply them, uh you know, to clinical scenarios in real ways, there is some emerging data that higher scores is indicative of a greater nodal burden. Um but there's more study to be done there to figure out if the actual quantitative data means anything. And if so how do we apply it? Either way? In this case, the patients diag diagnosed with a HPV, mediated squamous cell carcinoma, the oropharynx with nodal metastasis to the left neck, uh CT zero and one M zero. I'm able to get a pet after this because I've diagnosed cancer. And uh you know, we prove that there's no metastatic disease. So, uh I am a surgeon that does transoral robotic surgery. So that's uh what I did for this patient. I feel uh uh I, I had to kind of push back against the notion of making this a torus talk. It's not a tours talk. And I think there are applications for this test in surgically managed and non surgically managed or pharyngeal cancer patients for sure. But in this particular case, uh uh I did operate on the patient. So uh the patient undergoes transoral robotic resection. There's a 1.2 centimeter tumor found in the ipsilateral base, the tongue which was resected to a negative margin. Now, in this case, the patient surprisingly found that five positive nodes, uh the largest node was uh 3.0 centimeters and had a uh what we could would consider macro ec. So he's actually quite high risk of failure, at least in the neck. Um So he's upstage to PT one N two M zero HPV, mediate squamous cell carcinoma of the left basic tongue. Um after surgery, another uh NAV DX TT MV HPV DNA test was performed which showed an incomplete response to treatment. Now, this isn't necessarily surprising given his E ce the fact that he has five nodes. Um and this most uh medical and radiation oncologists, I think would agree that despite uh whether or not we had this test, this patient needs adjuvant chemo radiation. But this further confirms that notion uh that the patient uh needs to go under uh needs to undergo adjuvant chemo radiation because we don't have a complete response. Now, there is more study to be done here. Like I said, quantifying this, what is a indeterminate designation mean? What does the actual score mean in the setting? That those are all, all questions that we don't have clear answers to. But as you know, a patient like this gets presented in front of a tumor board, it's natural to be concerned, you know, when the first modality of treatment does not result in resolution of uh uh tumor tissue modified DNA. Uh This patient underwent pharyngeal sparing, adjuvant chemo radiation did quite well uh through treatment, he is able to speak and swallow uh his G tube and tr free. So he was a success story. Um Here we see how HPV DNA is used for surveillance. So he was initially treated in February 2022. And you can see several additional data points as recently as a couple of months ago that uh uh show that he uh is disease free. So he remains disease free on exam pet and TT MV HPV DNA testing. Uh So this to me, you know, gives us and we'll talk a little bit more about surveillance, but just gives another modality uh that we know is sensitive and specific uh you know, for this disease. Um And uh I think patients, physicians have all found this to be a useful tool in the surveillance space that doesn't leave us without questions about where it fits in. But it's certainly, you know, a, a another good test to help reassure our patients. So let's talk a little bit more about the surveillance space. Um As we know, 10 to 25% of HPV mediated or pharyngeal squamous cell carcinoma patients experience a recurrence within five years of treatment um 33 to to 50% or so of those first recurrence or distant metastases, excuse me. And this test does, does like we talked about AAA good job picking up these recurrences even before some of our uh imaging modalities may the challenge or one of the many challenges with uh this testing modality in the surveillance space is we don't quite know how to use it. Um The specifically the, the ideal interval is not very well established. Uh NAVAIS recommends testing every three months for 1 to 3 years, six months for years, four and five, once a year in perpetuity. Um Iommi that they'd recommend testing every week if they could. But uh I've found this to not be uh pra practical in my, in my practice. Um I've found it to not be particularly cost effective both to the system and to the patient. And I don't see any um firm evidence available to show that this is truly uh been studied and is a uh evidence based recommendation. This is sort of expert opinion and it's not how I practice in my practice. I've integrated the, the NAV DX test into the, into the uh surveillance testing at three months. I'll often get uh a pet scan in six months. I'll often get a NAV DX and then alternate imaging exam and NAV DX going forward. Um You know, so the patients at least being touched once every three months or so with either, you know, one of those modalities and I depending on patient preference, patients ability to pay some cost out of pocket to the test, which generally runs 100 to 100 and 50 bucks. Um we, we kind of work out uh the patient's best plan for surveillance. I think that does highlight the need for um more research into the uh integration of uh TT MV testing into the surveillance space to look for, you know, um evidence based ways to move forward and to, to, you know, offer our patients and third party payers real evidence on, on how often this should be used and and why we should take the time to, to implement it. Um Several questions beyond just the surveillance uh time frame remain. Um One question that's been posed is whether TT MV HPV DNA testing augments or eliminates the need for regular testing. Um The question really is, is this a replacement for the pet scan, the CT scan uh going forward um to be clear, there's no evidence out there that says that that HPV. Uh DNA testing obviates the need for traditional surveillance uh modalities like exam and imaging. And I think that's very important because I have personally had patients come to me and say, well, I don't need that pet scan. Uh you know, my tumor marker looked great and my uh my, you know, TT MV score zero. And I just wanna get this blood test in a year and call it a day. And I do have to tell them that while that's, you know, um your choice, it's not something that I can, you know, recommend based on the body of literature that's available. We still don't know how patients would do without our traditional uh surveillance modalities. And there's no been no uh uh study that's directly compared uh you know, blood tests or liquid biopsy alone verse standard, you know, imaging based and exam based testing modalities. So I think it's important to be very clear that that's a limitation. Um The other challenge that we have and one that's been raised in several different forums is uh you know, we tout the TT MV HPV DNA testing um in the surveillance space is is beneficial because it gives us a lead time on uh detecting a recurrence. The question becomes, what do we do with that time? So the range, like I said was from a little under a month to a little over a year where, you know, studies have reported that NBDX testing has been positive before a clinical recurrence has been uh detected. And like we discussed, the positive predictive value is 95%. So that's generally a real finding. But without clinical evidence of recurrence, we have a hard time knowing how to treat our patients. Um This can be a uh considerable source of patient stress. Um The question becomes, do we scan them more frequently? Do we take them to the or for for biopsies? Do we empirically treat them? Do we talk about systemic therapies? Because we know a lot of the failures are distant distant, excuse me. Uh There are no answers to these questions. And I have been in this scenario, um where, you know, we had a positive test after, you know, several negative tests in the surveillance base. And uh you know, we don't know what to do with that, that lead time and, you know, we, we keep repeating pets every three months until something becomes apparent and, and we can go on to treat, but we, we don't really know how to counsel our patients in that space. And that's AAA real serious challenge. Um The overriding question of does early detection with TT MV HPV DNA testing lead to better survival and that that needs to be answered. The final question. Surveillance. Uh use of this tool is, is whether or not it's cost effective. Now, there is a study out there from the laryngoscope last year uh that compares standard surveillance, which is serial exam plus imaging versus quote unquote modified surveillance, serial exam plus serial TT MVHP DNA testing without imaging, there was a cost reduction noted but there are several caveats. One being we don't know how safe the modified surveillance regimen is and two in different payer systems with different uh um rates of reimbursement and cost to the patient. It it's difficult to, to apply this retrospective uh review of of cost uh to you know, broadly to our practices. So there does need to be some perspective, look into what the true cost is to the system with modified surveillance and and how does that compare to standard surveillance? The big overriding criticism of, of this paper in my mind is is that I think very few providers at this point are going to be comfortable completely eliminating imaging from their surveillance regimen. So we end up with a hybrid of both the standard surveillance and modified surveillance uh designations that this study laid forth. And it's hard to know in that real world setting if we get a cost reduction or not. So, as I said, further perspective, research, I think is necessary to assess cost reduction and safety of these modified surveillance paradigms. Uh This is my last slide. It's a uh major topic, um uh ongoing research and future applications. And I didn't want to get into the weeds too much. But I did wanna talk a bit a little bit about where I think this uh where we're testing uh as as future applications and give one example of a, a clinical trial that's out there now. So kind of the holy grail for TT MV HPV DNA testing is help or finding ways to use it to guide our adjuvant treatment therapy in patients that are managed with upfront surgery. As a tourist surgeon. I would love, absolutely love to be able to go to my patients and say I did trans or robotic surgery and a neck dissection on you your intermediate risk. Uh whether it's because of, you know, you had multiple nodes or one node was, you know, over three centimeters, whatever it puts them in the intermediate risk category, but rest assured you your N AD X uh score is negative. Um So we don't need to give you adjuvant therapy to be very clear. That's not my practice, that's not evidence based. And I don't think that's safe. I think most people would agree that that is not safe at this time, but that is the holy grail. We do want to find ways to integrate this testing paradigm into our adjuvant treatment decision making. Um The Mayo clinic picking up on this, this, you know, kind of obvious uh goal um is currently recruiting a phase two trial that evaluates several de escalation strategies based on in part uh response uh or TT MV HPV DNA response to ongoing treatment. So I think um in the, in the upfront surgical patient down the line, we will get some guidance on where uh TT MV testing fits. I think it's really, really important to talk as surgeons, as medical oncologists, radiation oncologists to talk to our patients and tell them that we are not able to use this test to guide adjuvant therapy de escalation. I feel strongly about this because I've, I've been in several situations. I even had one patient call Novais and say I have a negative score after surgery. I don't think I need adjuvant therapy. Does your data support this? There's a lot of pressure from our patients or from my patients that they had operated on to deescalated aggressively. That's what patients want. And that's why they buy into surgery in the first place. It's been a red line for me. I've always told them that, you know, up front when we do surgery, we have ways to decide how we uh administer adjuvant therapy. We deescalated when we think it is safe. But we don't use this test for deescalating because it hasn't been studied in that capacity yet. So we're still working towards that as a group. But at this point, um it's really just an adjunct and a surveillance tool with that said uh here are my references, here is our referral side where you can see uh ways to get patients uh to see us in clinic, whether they're surgical or non surgical. We are happy to see them and uh we uh see folks both in our uh North Tampa location at the MSA Center and downtown on the TGH US F campus in on Davis Island. Finally. Um If there are any questions in the chat, uh Isabel, maybe you could relay them to me and we could go ahead and answer any questions. Yep. Um Yeah, no problem. Great presentation, Doctor Nichol. Um Can you talk a little bit more about your multidisciplinary team and who you work with and how things get accomplished in your clinic? Sure. So here at US F and TGH, we have a multidisciplinary head and neck tumor reward. So when a patient comes to me with an oropharyngeal cancer that's HPV mediated. Uh I put that patient before our board, which is uh comprised of, as you can expect uh the uh surgical group, um radiation Oncology Group and medical oncology group. We also have ancillary support staff like of speech language, pathology, physical therapy, dietician, all of those folks are, are available and at our tumor boards to varying degrees, but the bulk of the decision making is obviously uh uh comprised, you know, between the opinions of the uh the radiation oncology, medical oncology and surgical teams. So this has helped me in a few ways. As I obviously, I'm, I'm, you know, a younger surgeon coming into my third year of practice. Um as I've, you know, built out uh our robotic surgery program, I've wanted to proceed cautiously and I think the way to do that is to have uh partners in medical and radiation oncology that are uh you know, willing to, to discuss each patient on a, on a multidisciplinary basis. So, uh with that uh system in place, I think we're able to uh you know, give patients, you know, when they see me back in clinic, um you know, they get the opinion of, of our multidisciplinary group as to how to proceed and we can facilitate further interdepartmental referrals as necessary. So that's been a real benefit. I think to my patients. Excuse me? Yeah, we can definitely see that a lot of our multidisciplinary teams feel the same way. So it's really important to know that we have that to lean on within our network. Um That was all that was in for questions. Is there anything else you would like to mention before we turn down? No, great. Thanks everyone for joining. I appreciate you taking a half hour to spend some time with me. Thank you. Yep. And this is no man. Can you hear me? Yeah, excellent talk. Thank you very much for doing this. Yeah, I mean, I I think cost is the major issue. II, I have heard this costs about $5000.03 to $5000 per test. I mean, that's ridiculously high cost. Um It's an excellent test but I think until the cost is uh better, I mean, it's gonna be difficult as you mentioned earlier. This is doctor, he's our, our medical oncology partner here. He's utilized this test in, in his clinic as well. Um Cost is definitely an issue and as we know, Doctor Ashraf, that's been a little bit of a moving target when, when NARRE first came online, they were deferring most of the costs um just because they wanted the data points, but now now they've, they've kind of reneged on that and, and because they, they have what they need, I have had decent luck getting to help pay for this Um, I've seen quotes from NARS saying that the average patient pays 100 and $50. I've seen a lot of variability there with my patients, different patients reporting different fees. I know. And I've only used this on a handful of occasions. There are some internal, uh, options with the NARS company to help defray costs, but those aren't very easy to together. So cost you and, and, you know, efficient utility is, uh I think a, a big um question mark going forward because like you said, it is a good test. We do want to use it, but it's, it's a challenge. Um if it's, and it's not just the patient side of cost. I mean, just as uh for the health care, if I start doing this on all my patients, like every time, every three months that I see them, it's just that the, every three month uh recommendation I think is, is way off. Um, you know, out in left field it's not reality. Exactly. And I think we have to have and I do have this discussion. I'm sure you do too with patients. The cost can be a little bit unpredictable. Um, sometimes it's easier to, uh, you know, and, and tailor the, the surveillance plan to the patient, they need to defray cost. There's sur in traditional surveillance modalities that we've used, you know, up until, you know, 18 months, 24 months ago that are, are sensitive and specific as well. So it's an ongoing discussion, an ongoing issue and something that I think we need to uh look at as a group more and more going forward, right? And one other utility uh kind of in the same lines of deescalating of therapy. Um That might be interesting is that I have a handful of patients who are on immunotherapy and imaging does not show evidence of disease, they wanna come off treatment. So now for those patients, uh like the decision whether to come off or not. Um I mean, like, um I find sometimes like, oh, you're, you're uh this NDX came back positive. So I don't think it's a good idea to come off treatment or if it's negative, it gives me one more thing to say, ok, well, maybe we can uh stop the treatment at this point because as you know, with immunotherapy, there's really no end point on those studies. So, you know, and then I think it becomes, you know, if you can swing it a useful treatment modality or, or testing modality going forward for patients that can, but I'm sure that's a constant challenge in your practice. When, by the way, yesterday I saw a patient, his number was the highest I've seen. It's 3.9 million on this. Now, I've, I've had one or two of those that are usually distance failures, but again, hard to know really, you know, scale that they pour. We don't know what it means. Well, thanks for your input, great discussion. Um Thank you everybody for joining us this afternoon. Um Friend friendly reminder that your CME claim credit information will be emailed to you following this presentation. And if you do have any questions for Doctor Nichol or our team, um please reply to that email and we'll get you in contact with the correct department. Thank you everyone for joining us. Have a great rest of your day. Thanks everyone. Published Created by
