Bobbi Pritt, M.D. (00:04):

Hello, I'm Dr. Bobbi Pritt, a clinical microbiologist and laboratory leader at Mayo Clinic and your host for today's episode. I'm excited to be here today with Mayo Clinic Laboratories' CEO and president, Dr. Bill Morice, to get the latest news. And then we'll go to Dr. Ann Moyer, who will join me for the deep dive to talk about how pharmacogenomic testing solutions are improving cancer care. But first, we'll start with Dr. Morice. Bill, welcome back.

William Morice II, M.D., Ph.D. (00:32):

Hi, Bobbi. Great to see you as always.

Bobbi Pritt, M.D. (00:35):

As always, great to have you here. Well, you know, I think there's a lot of things we could talk about, but I think, let's visit what's new and noteworthy in terms of payment reform. You know, our last episode we talked about outbreaks of hantavirus, Ebola, and the critical role laboratories play in protecting public health. And you know, as part of that conversation, we briefly touched on how payment reform supports a strong laboratory test infrastructure. We have to get paid to be able to perform these tests for our patients to keep the infrastructure strong. So, maybe we could take a few minutes to talk about what's new with things like PAMA and the RESULTS Act.

William Morice II, M.D., Ph.D. (01:13):

Yeah, it's a great question. A good, very important topic to cover. It's interesting, as you were talking, I was thinking back to the days of COVID when we really started doing these in earnest and what a great kind of outgrowth of that was us having these regular conversations, which is awesome. And there are some important things happening. It's important for us to advocate for our profession and for our patients because during COVID we were all like, "This is it. Now everyone recognized the importance of diagnostics." And then of course, now people want to forget about COVID, which I get. But also, we have to remember that the critical part that diagnostics play to our healthcare infrastructure and the fact that even though they do, they constitute a very small percentage of the overall healthcare spend. And the laws that's currently written, the Protection to Access to Medicare Act, or PAMA, actually will probably lead to further cuts, decreased payment for many commonly ordered tests. That's why it's important right now, we're in a data collection period as it's stipulated by that law. It's now I think through June. And then, that data will be collected and then it'll be used to set rates either higher or lower for I think in 2028. But again, that data was skewed towards lower payments, labs which tend to get lower payments, like independent reference labs. And so, the bill that's been introduced would take a different methodology to do that rate setting. Looking to actually the same principle, but I mean look, it's so hard for us in the labs to collect all that payment data. It's a big, big task. So now, there are other data sources out there and legislation that's been introduced would apply some of those principles but to an actual, very much more fair and holistic database so we can really get and understand what the pricing of tests should be. I think it also has some barriers in terms of how much they can go up or down. So, hopefully that will get passed because the last thing we need is fewer laboratories or less investment in clinical laboratories in this country or really across the globe.

Bobbi Pritt, M.D. (03:09):

Yeah, it's so important. So, really two things right now, reporting period for PAMA. It's really important for laboratories to submit data, to submit accurate data, but as you said, it's a real burden to do all this. It's not something that really could be sustainable. And looking at the RESULTS Act as a way to fix some of the problems with PAMA in addition to just reporting the data and adjusting the reimbursement prices.

William Morice II, M.D., Ph.D. (03:33):

That's right. And just to be clear for the listeners, the next step with the RESULTS Act. It has over, I think, a hundred co-sponsors, so it has a lot of backing, but there will be a score from the Congressional Budget Office, CBO, which basically says how much this is going to cost Medicare. And then in the legislative process, they have to decide, "Well, if this costs us $2 billion more to do this, where do we take $2 billion out of spending someplace else?" So, it needs a lot of support. The American Clinical Lab Association has a lot of tools. I'm sure CAP and others do, maybe ASM. But yeah, reach out to your professional societies. It makes a big difference when you do that.

Bobbi Pritt, M.D. (04:09):

Absolutely. So, that's ongoing and we’ll continue to look towards advancements and new news in those areas. The other thing I thought would be worthwhile bringing up is some new news from the American Cancer Society regarding colorectal cancer screening. And there's also a reimbursement aspect to this as well. So there's been some major changes. The American Cancer Society has updated their guidelines for colorectal cancer to emphasize blood-based testing and at-home stool testing. And of course, we know colorectal cancer deaths are an important cause of mortality in the United States and morbidity as well. So, this should hopefully help in catching cases. And you know, really it comes down to the best way to screen for colon cancer is the method the patients will actually use. So, this will actually provide additional options.

William Morice II, M.D., Ph.D. (05:02):

That's right. And it also has a connection to the federal government. PAMA's not the only thing going on. Just recently this year, there was a bill passed in Congress that allows CMS to cover blood-based cancer screening tests. And also to set the reimbursement, which I think was actually set around the Cologuard price. They use that as sort of the benchmark. Why is that important? Well, it's important for a number of reasons. Number one, people will be able to get this test and not have to pay out of pocket if it's covered by CMS. Number two, it will make the test more widely used. And so hopefully, start to get incorporated into guidelines and allow us to really understand the best ways to use them. You know that coming out of ASCO is this week, the American Society of Clinical Oncology, it's not clear yet exactly the role of these multi-cancer early detections, you know, the blood tests that can detect any cancer. So, I think what we've seen with colorectal is what we'll see in other cancer types where we know circulating DNA in particular is very effective for screening, that these will be incorporated into guidelines around specific cancer types. And over time, these multi-cancer tests will get more and more use and adoption.

Bobbi Pritt, M.D. (06:08):

It's a really interesting area, and it's great to have more options. Of course, it's important for people, patients, to talk to their doctors about these different methods for screening. They're not all created equal. So get the information from your physicians if you're listening to this, but having these additional options is going to be important. And then as you mentioned, Bill, getting reimbursed so patients don't have to pay out of pocket for these valid methods is also very important.

William Morice II, M.D., Ph.D. (06:33):

Exactly. And then, last but not least, there was introduced recently a bill about modernization of CLIA, which is another thing we should pay a lot of attention to. I think the chances that it'll get much traction this year is pretty low. But that's often the way with these future bills that get introduced just to build momentum. But really, we haven't talked much about FDA really since the LDT final rule was overturned, but CLIA modernization really raised some important questions about what's in the jurisdiction of CMS, which is the agency which issues CLIA licenses, particularly around algorithms and modernization around what constitutes good evidence for lab developed tests. And so, really important that we pay attention to that and weigh in as it starts to get socialized through Congress.

Bobbi Pritt, M.D. (07:17):

Absolutely. That is a very important issue that we'll have to keep eyes on because CLIA, of course, is the law by which we all operate as clinical laboratories and opening up CLIA and making changes could impact everything from lab director roles to who can perform different types of testing. It's very complex.

William Morice II, M.D., Ph.D. (07:35):

Indeed. Yep. And important.

Bobbi Pritt, M.D. (07:37):

Great updates. Well, thank you Bill. Have a great day. Until next time, I'll look forward to it.

William Morice II, M.D., Ph.D. (07:43):

Yeah, I will look forward to it like I always do as well. Thanks Bobbi.

Bobbi Pritt, M.D. (07:51):

Welcome to the deep dive. We're going beyond the headlines with Dr. Ann Moyer, a molecular genetic pathologist and chair of the hereditary genetics practice. Today, we'll focus on how precision therapeutics are improving cancer treatments. Dr. Moyer, thank you so much for being with us today.

Ann Moyer, M.D., Ph.D. (08:08):

Well, thank you for allowing me to join you and talk about this exciting topic.

Bobbi Pritt, M.D. (08:12):

It's a very important topic. And so, you know, a lot of what we'll be talking about today is possible because of pharmacogenomic panels. So, maybe we'll start there. Can you define pharma, pharmacogenomics, see even I have a hard time saying it, and explain why it's important to our listeners.

Ann Moyer, M.D., Ph.D. (08:29):

Yeah, absolutely. So, pharmacogenomics is a really exciting area. It's really at the intersection of pharmacology and genomics. And so what you can do is clinically a genetic test can be performed and with that we can identify genetic variants. And they're typically in genes that encode drug metabolizing enzymes. Though we do have a few other examples as well. And the genetic variants that we identify help predict how a patient will actually respond to a medication. So, this helps the clinician select the right drug at the right dose at the right time for each individual patient. So, the one caveat at present, we aren't at the point yet where we can tell the clinician exactly which medication and exactly which dose will provide optimal response, but we really can help cut down on trial and error. And there are quite a few examples where drug toxicity can be predicted as well, such as fluoropyrimidines and thiopurines that are both used in the treatment of cancer.

And so there's a few good examples too where we can actually predict lack of efficacy. I think a really good example there being clopidogrel, which gets activated by CYP2C19 and is used for patients who have had a recent myocardial infarction or a stroke. And so just in general, it's been really exciting to see the field of pharmacogenomics grow in recent years because research has been ongoing for many decades now. And at this point, it's just important to translate all of that great work into clinical benefit. So, why does it actually matter for the average patient? Well, most of us are going to take medications during our lives, and I think the latest figure I saw was maybe about 60% of adults will take a daily medication. And in general, that ends up being important because we really want those to be helpful for patients. But in about 2022, there was a statistic of a little over 1.25 million serious adverse events were reported and nearly 175,000 deaths. But those might even actually be an underrepresentation. So, is there anything we can do to help predict those adverse events and then hopefully prevent them? Well, we know that genetics is one of the multiple variables that's really important there. And so, anything we can do can help. And that's where pharmacogenomics comes in.

Bobbi Pritt, M.D. (10:29):

Well, that's a great introduction and you had mentioned briefly some of the medications we use for cancer care. So, I get the sense that that's one area where pharmacogenomic testing has become increasingly common. What benefits do these tests offer for cancer care and what's contributing to their growing adoption?

Ann Moyer, M.D., Ph.D. (10:48):

Yeah, so especially if you're thinking about the setting of cancer, the goal is we just want to always find better ways to treat our patients. And there are all of these really new and exciting medications that target very specific tumor mutations. But what's kind of interesting is there are also a lot of older medications that are quite effective, but one of the limitations has historically been toxicity. And so, if we can understand how those medications are metabolized, maybe that's where we can predict some of that toxicity. So, I've got two specific examples for you. So the fluoropyrimidines that I mentioned before and then I thought I would touch on tamoxifen also. Thinking about the fluoropyrimidines, they are drugs like 5-fluorouracil, or sometimes they just call it 5-FU for short or capecitabine. And they're used for the treatment of solid tumors, so things like colorectal cancer, breast cancer. And in general, these medications have been around for many years, like since the 1960s. But the problem is that when the patient takes a dose of the medication, there's this enzyme dihydropyrimidine dehydrogenase, or DPD, and it's present in the liver and it metabolizes about 80% of the dose to an inactive form. So when the patient takes that medication, they're really only getting about 20% of the dose to go kill the tumor cells. And so, that's how the dosing is all set up for this to happen. And so the gene that encodes the enzyme is called DPYD. And we know that patients can have genetic variants that can decrease the enzyme activity or some people can have a non-functional copy of this gene. And so when that happens, a lot less of the medication is metabolized and eliminated.

So basically, the patient ends up with way too high of a concentration of the fluoropyrimidine medication. And then the sad part is this can result in some very severe toxicities. So a big one that's problematic is mucositis, which is basically ulceration of the mucus membranes. It can make it really difficult for patients to eat and drink and be horribly painful and they can develop severe nausea and diarrhea, myelosuppression, cardiac toxicity and other toxicities. And as a whole, they're not just annoying toxicities, they can be very severe and life-threatening. And so really at the end of the day, your goal is to treat the cancer, but we don't want our patients to suffer and ultimately die from the treatment rather than the disease. So unfortunately, it's still possible to develop toxicity with the negative test, but the testing can help identify many patients who would be at risk.

And then the really good news though is that recently there have been some studies that have come out that have demonstrated that if a patient has one of these genetic variants in DPYD that results in decreased DPD activity, if you just give them a dose reduction, you'll still be able to treat their cancer and they'll still do fine from that, but they can avoid the toxicity. And so that was really one of the big questions, "Well, what if we reduce the dose for these patients to avoid the toxicity, but now we're not adequately treating their cancer?" And so, these studies have been really transformative and that guidelines have been updated. The FDA labels have been updated. And I think really at the end of the day what prompted a lot of the studies though was the patient advocacy groups. They were out sharing their stories, talking about the bad experiences that they or their loved ones had had.

And at the end of the day, the impact on the patient is really what ends up being the most important. And so, I think that's really driven forward a lot of pharmacogenomics as a whole. I mentioned though I wasn't going to just tell you about DPYD, so I'll give you a different example where I think we still have some work to do. So another example being tamoxifen, and this one gets used in the setting of breast cancer. It's metabolized by CYP2D6 as well as CYP3A4 and CYP3A5. And what's really interesting is that this one is actually a story of efficacy rather than toxicity. So when the patient takes tamoxifen, it's not actually the active medication. It has to first be metabolized to a different metabolite called endoxifen. And CYP2D6 is probably one of our favorite pharmaco genes around in that it's very highly polymorphic.

So what I mean by that is there are a lot of different forms of CYP2D6, and they're all pretty common. And so some of the genetic variants that we can find in CYP2D6 can result in absolutely no enzyme activity at all. So there's people walking around living their best lives with no copies of CYP2D6 in their genomes, and they're fine until you give them the wrong medication. So if you give one of those people with very limited CYP2D6 activity tamoxifen, they won't make endoxifin, they won't benefit and they really need an alternate treatment strategy. There are other medications out there, but without the testing, we don't really know which patients would benefit. And so this is an example where I think we probably are still underutilizing it today, but there are many more examples where pharmacogenomics is important in oncology beyond just these two.

Bobbi Pritt, M.D. (15:22):

Oh, those are great examples, Dr. Moyer, and also wonderful examples of how laboratory testing can really guide patient care. And I think a lot of people will probably resonate with the tamoxifen example because we hear a lot about breast cancer and a good number of people are on that medication. So, I know you've been working on targeted approaches and I know Mayo Clinic Laboratories takes a medication targeted approach to this type of testing. What would be the benefit of that type of approach?

Ann Moyer, M.D., Ph.D. (15:53):

Yeah, there are a couple of different ways you can do pharmacogenomic testing. And there are laboratories out there that end up basically having a really big multi-gene pharmacogenomic panel with every pharmacogene imaginable. But we've really taken intentionally a different approach for a couple of reasons. So we really want to focus on the genes that are very well established, that have a very high level of evidence for clinical use. And so one of our panels is a focused pharmacogenomic panel that includes genes that are fairly broadly applicable across many medications that patients will commonly encounter throughout their lifetimes. And so for some of the medications though that are less commonly used, like some of the examples in oncology even, we typically offer the corresponding genes separately or as a smaller panel. And the reason for this is that some of these genes pose some interesting technical challenges, such as some of the HLA alleles that we test for and we utilize a different method.

And so it'd really drive up the cost of the test for everybody if we included them on every single panel, especially when not everybody is going to need those medications. And in other cases, if you're thinking about the genes associated with cancer therapies, these tests just keep getting better and better over time. We've realized that there are a lot of genetic variants that are really important, but might not be common in all patients of all different ancestral populations. And so we've worked to be more inclusive in our testing and we've included more alleles over time. So, if someone is going to be getting a very toxic medication and we're doing a test to predict who might be developing toxicity, I think it's really important to have a current result at the time of treatment rather than potentially relying on a result that might be a few years old and maybe the test didn't include as many variants at that point in time or sometimes the interpretations can change as we learn more. And so really by focusing on what medications the patient might take and designing our panels that way, we think that our approach supports more confident prescribing and dosing decisions and it should hopefully help reduce adverse effects while still preserving the treatment effectiveness for our patients.

Bobbi Pritt, M.D. (17:47):

Yeah, that makes a lot of sense. And definitely I like the idea of really targeting it on the information that you specifically need. And this kind of gets to my next question. How do you anticipate precision oncology therapeutics will evolve in the coming years?

Ann Moyer, M.D., Ph.D. (18:02):

So, I really anticipate that pharmacogenomic testing is going to continue to improve and it's going to become mainstream with the results incorporated into the tests that report out tumor mutations that also are driving therapy rather than those being separate tests. And in the future state, I think it's going to be really important though to make sure that for our pharmacogenomic testing, we're performing that on a sample that represents the patient's germline. Since we know the tumor can develop somatic mutations over time, that won't reflect drug metabolism. And the other thing that I think will happen hopefully over time is we'll really see a change from targeted genotyping to sequencing. So as I mentioned before, with targeted genotyping, you're really only able to detect the very specific variants that you designed your test for. And so it's possible that patients with a rare variant may have a false negative. And so, our lab has already had some experience with sequencing based pharmacogenomics through some previous studies as well as a few sequencing based tests that we offer today. So I think it's going to add a lot of complexity to the interpretation, classifying all those rare variants. But we see those in our testing. We know that they're important. And so I think that's something that I'm really excited to see change in the future.

Bobbi Pritt, M.D. (19:04):

Well, that's great Dr. Moyer. So, if I'm getting this right, there are some instances where you really want a targeted approach, but other instances you want to capture as many potential mutations or variations, pleomorphisms, as you would, as possible. So I guess really, that's where your expert knowledge comes into play of helping to guide which of these tests and approaches would be most appropriate.

Ann Moyer, M.D., Ph.D. (19:26):

We're always happy to help answer those questions when people call with them, because it's absolutely essential to make sure you get the right test for the patient.

Bobbi Pritt, M.D. (19:34):

That's wonderful. Well, thank you again, Dr. Moyer, for joining us today and sharing your knowledge with us.

Ann Moyer, M.D., Ph.D. (19:38):

Thanks for having me.

Bobbi Pritt, M.D. (19:46):

Let's wrap up with the top takeaways and how to learn even more on the topics we discussed. In the news summary, Dr. Morice began with an update on laboratory payment reform and other policy changes that have the potential to impact laboratory medicine in many different ways. In the show notes, you'll find a link to a CMS webpage with resources for laboratories reporting data to CMS. Then we went into the deep dive summary with Dr. Ann Moyer, who joined us to discuss the therapeutic tools enabling more precise cancer treatments. In the show notes, you'll find a link to an overview of Mayo Clinic Laboratories' precision oncology therapeutic options, along with links to past episodes covering specific genetic tests in oncology care. Thank you for joining us today. If you haven't already, be sure to subscribe so you never miss an episode. In our next episode, Dr. Bill Morice will stay on for the full discussion to explore the future of personalized medicine. I hope you will join us.