Rae Woods (00:02):
From Advisory Board, we are bringing you A Radio Advisory, your weekly download on how to untangle healthcare's most pressing challenges. My name is Rachel Woods. You can call me Rae. And there's someone else here, too. Devin, do you want to say hi?

Devin Airey (00:18):
Hello. Devin Airey, here.

Rae Woods (00:21):
Devin, what do you do on Advisory Board?

Devin Airey (00:24):
Which hat am I wearing today? My main job is a managing director on our executive services team. That's the arm of Advisory Board that works with our largest relationships. So my true day-to-day is bringing research and insights to some of the large organizations that Advisory Board works with, and helping them apply the work that we have published or the insights we've gathered, to their strategies and operations.

Rae Woods (00:56):
I don't want to hide the ball. One of those organizations is Quest Diagnostics. And you came to me, Devin, I'm not kidding, months ago. More months than I think I am willing to admit in exact to the ones digit on this podcast. And you said, "Rae, we have got to get Quest on the podcast." What was the story that you were really hoping that Quest would tell through this channel?

Devin Airey (01:26):
As a person who's worked with Quest for a long time, one of the things that I pay attention to are the stories that they are putting out to market. And a big milestone of that every year, a couple times a year, is investor day. And so I listened to Mark Gardner present around the third era of genomics, really bringing genomics to scale. And as a bio-nerd who started following genomics in the nineties when the Human Genome Project started, really hearing about this coming to scale as a hundred dollar whole genome sequencing or as the ability to really detect very small minute cancer cells that could actually change treatment and diagnostics. I was just so excited, emailed you immediately with all of my notes and said, "We've got to do this."

Rae Woods (02:11):
And so I think that you are actually the right person to have this conversation. So you mentioned Mark Gardner, he's the SVP of Genomic Medicine and Oncology at Quest, and you kind of heard his initial take on genomics at scale, but there's another person who we ended up wanting to involve in this conversation. Who's that?

Devin Airey (02:31):
Yeah. So over the spring, Quest announced an acquisition of a company called Haystack Oncology, really looking at very sensitive precision liquid biopsies. Liquid biopsy is not new to oncology, but it is this kind of early detection, very sensitive MRD, minimal residual disease testing that Haystack does that brought Quest's interest. And so with that acquisition, we wanted to have Dan Edelstein, GM of Haystack Oncology, formerly the CEO, but now on Quest onto the conversation as well and hear from him while he's excited about working with Quest and through that relationship, bringing some of this work to scale.

Rae Woods (03:12):
Well, I feel like my job is actually to let the three of you just nerd out. So I expect that you're going to talk a lot about the science, but you're also going to of course get to the business implications, not just for diagnostics and testing, but for every stakeholder in healthcare. So Devin, I think I'm going to let you take it from here.

Devin Airey (03:29):
Thanks, Rae. Mark, Dan, welcome to Radio Advisory. Happy to have you on today.

Mark Gardner (03:35):
Thank you. It's a great pleasure to be here.

Dan Edelstein (03:37):
Thank you, Devin. Good morning.

Devin Airey (03:39):
Mark, you spoke recently about how we're moving into the third era of genomics. The first era was around single gene testing. There was a next era of innovation looking at whole genome sequencing. Those are only getting cheaper and easier and more accessible. And now we're in this third era or moving into it looking at genomics scale. What does that mean to you and how would you describe this new third era to our listeners?

Mark Gardner (04:05):
Yeah, I think it's an important concept for people to understand because sometimes when you look at change over time, it's kind of difficult to know when you've hit an inflection point. The hundred dollars genome really does represent a huge inflection point in the industry because essentially the cost of everything other than sequencing is a lot more than a hundred dollars. And so you're now at this point where when the cost of sequencing represents a minority of the overall cost of what you're doing, then the impact of everything else has to matter a lot more. And we've not been at that era until really just these last few months.

Devin Airey (04:44):
When I talk to healthcare leaders about scale, they think, maybe this is right or wrong, you can tell me, that that means that we should all be at scale together. So everyone who has a hundred dollars should get their whole genome sequenced. Is that the right way to think about scale and how does Quest play in here?

Mark Gardner (05:00):
This requires probably a longer answer than our listeners wanna hear. Well look, for most laboratories it's very difficult for them to even acquire a sample. It can cost well north of a hundred dollars to get blood drawn, to put it in the right container, to ship it, to so-called accession it, which is a fancy word for to make sure that you have the right sample and that it can be tracked in the system. And if it costs a hundred dollars to do that for an average sample and it costs a hundred dollars to do the sequence, well, why would you keep accessioning a sample if the endpoint of germline genomics is the whole genome? Your genome doesn't change. It's the same from womb to tomb. And so why continue to repeat something that you've already done once?

(05:52):
When it comes to areas like cancer, there's an added element to that where a lot of the same things we talk about in genomics don't necessarily apply because cancer is always a subsection of the entire genome that you're trying to measure because if the majority of you was cancer, then you would be dead. So we are constantly looking at the so-called needle in the haystack because the cancer represents the needle and the body represents the haystack.

Devin Airey (06:25):
I think that's a great tee up to Dan here, leading Haystack Oncology for several years and then coming into the Quest Diagnostics family very recently, how are you all bringing other innovations like liquid biopsy in helping those integrate genomics into oncology care, cancer care specifically?

Dan Edelstein (06:45):
The innovation with Haystack Oncology is not only liquid biopsy and the approach to measuring, as Mark just mentioned, identifying that needle in a haystack. Those rare molecules that are in circulation that are derived specifically from the tumor, but using those molecules to help the physician and the patient better understand information about their cancer. For example, many of the patients in the clinic today who have been diagnosed are asking some very basic questions about whether the treatment they have been on has been successful and whether their cancer is responding to treatment and if they have responded, if the cancer has returned. So I think it's kind of an application where we're looking at the genomic information that Mark just mentioned where it can be used for therapy selection, so identifying specific variants that are useful for a specific therapy or sensitizing to a specific treatment.

(07:46):
And then there's the general concept of looking at fragments of DNA derived from the tumor to better understand how patients are responding. Traditionally that's done with radiography. It's done with protein biomarkers, both lack a certain sensitivity that we've seen over the last decade or so. Protein biomarkers are associated with cancer, they're not causative for the cancer so sometimes they're elevated in patients that don't have cancer. We know, for example, that ctDNA is a specific marker for the cancer, and when we measure it, the innovation at Haystack is doing so with really a refined sensitivity and specificity.

Devin Airey (08:25):
I do want to back up for a moment though and make sure that we're clarifying some of the concepts and definitions language that we're using for our audience. So could you describe briefly what a liquid biopsy is?

Dan Edelstein (08:39):
If we think about what a biopsy is, biopsy for a patient with cancer would be some mechanism to access the cancer. So typically it can be done with a needle, it can be done through a surgical biopsy. It's a pretty invasive procedure where the patient has to basically go into surgery of some sort or interventional radiology to access the cancer. What we know about a liquid biopsy is these can use this technology to access the tumor through a blood draw. So it's not necessarily non-invasive, minimally invasive in that the patient has to go into a blood draw center and have submit a few tubes of blood for analysis. And in doing so, we're able to measure molecules that are shed from the cancer in that blood tube.

Devin Airey (09:20):
So if I summarize here, liquid biopsy is an example of an innovation that can enable this genomics at scale, this third era of genomics. You were starting to talk about the ability to bring more information to the patient. So I want to pause and talk a little bit about how these innovations can help and drive the context for our patient individually, and then of course across their entire cancer journey. How does genomic testing fit into a patient's cancer journey?

Mark Gardner (09:49):
There are a lot of things that can be tested for, from everything from what is your risk of getting cancer that you may have inherited from your family background. For example, everyone's familiar with the BRCA gene, which confers a risk for breast cancer. It actually confers a risk for other cancers as well, but nonetheless, it's most associated with the breast cancer. And so you can measure everything from genomic risk to... Cancer in and of itself is a disease of damaged DNA. That is one of the hallmarks of what cancer is.

(10:27):
And so all cancers have variants between the cancer cells and the rest of your body. And so these technologies, as they've advanced, enable you to separate those variants that are occurring in the cancer and contrast those with those that are in the rest of the body. And that's a very specific personalized marker of the presence of cancer in the body.

(10:55):
And so at its core, that's what a lot of these methods of trying to do early detection or early screening are trying to do. Some of them are more focused on methylation, which is not quite the same as a variant in the classical sense, but it is a marker of something is going on to change the original DNA. To what we're doing with MRD testing or minimally residual, minimal residual disease or molecular residual disease. People use both of those terms where because the half-life of cancer DNA is only about two hours once a cancer cell dies and its DNA is shed into the bloodstream, it's only with you for a couple hours.

(11:40):
So an MRD, if you're measuring something and you know what to look for between the baseline of what that cancer fingerprint is versus the rest of the body. And if it's still there after a few days post-surgery then this person still has some cancer somewhere in the body. It doesn't isolate exactly where it is, but that they still have something going on.

Dan Edelstein (12:04):
Add just kind of to summarize, it's basically an excellent biomarker to kind of provide that level of precision for patients that are undergoing surgical resection. Just to kind of put it in the context of the patient physician after a patient, let's say with stage two colon cancer has undergone surgery, there's a very open question as to whether or not that patient should undergo treatment with additional chemotherapy to potentially eradicate disease. That decision is made based on pathological staging.

(12:37):
And what happens in a pathology lab is somewhat of a static entity, but it informs the recurrence risk to some degree for patients, and it informs to a degree, but lacking some precision, how much chemotherapy a patient should receive. And so what we can do as Mark mentioned, is measure a few days, couple weeks after surgery, the presence of circulating tumor DNA, and if we don't see it and the appropriate test is used, we have more certainty that patient's surgery was successful. If we do see it, then that patient would benefit from additional treatment to eradicate any of the residual disease in their body.

Mark Gardner (13:21):
I think it's very exciting because historically we've been limited to... A tumor has to be about one centimeter in size to be able to see it via imaging. Well, by the time a tumor gets to be one centimeter in size, there's literally billions of cells. You're not fighting against a lone ranger out there. And remember, one of the hallmarks of cancer is unconstrained growth. So a billion cells can make a billion copies in a hurry. And I think just because it's small to the eye doesn't mean that it's not dangerous. And that's why cancer frankly has been such an incredible foe to humanity because these things that start as one centimeter in size can be lethal within a matter of just a few months. Having to wait until something gets to be one centimeter in size, it's just too close to lethality.

(14:21):
Whereas through this liquid biopsy method where we're able to pick up even just trace amounts of recently deceased cells, that enables you to measure much lower levels of cancer size than one centimeter and sometimes can give you months of time of a headstart to treat that patient. And there's an old saying that I learned from Dr. Dan Van Hoff, although frankly I think a lot of people use this expression, but I'm grateful to him for it which is, the patients are waiting. The second somebody finds out they have cancer, their whole life is consumed with worry over this. Their family's whole life is consumed with worry over this. And so having real time data is incredibly valuable for these folks.

Devin Airey (15:15):
We have early diagnosis, faster results, more confident results, fewer unnecessary treatments that all sound like a slam dunk for the patients. Kind of a no-brainer, but I look back on all my years in healthcare, I know there's not a whole lot of slam dunks that exist for real. And so what barriers come up when you work with providers and organizations bringing this to the patients, using this in their workflow, and what's Quest's role in removing those barriers on behalf of those providers to make sure that they can actually use it for all the patients that need it?

Mark Gardner (15:49):
The largest role we have is 92% of all covered lives in the United States have a contract with Quest Diagnostics. So one of the main barriers is, do I have insurance? Who's going to pay for all this? Obviously, cancer is a very expensive disease to treat, and nobody wants to go through this uninsured. Nobody wants to go through this where somebody's asking you, "Hey, we have this really important information for you, but you're going to have to pay for it yourself."

(16:22):
And so the thing that I'm super proud of with Quest is that we have built a relationship with payers over the years where they know that we give good value for appropriate testing. That's one of the hallmarks of our brand as Quest Diagnostics. And payers trust us. So we're not covered yet for MRD, but we're obviously in the process of working on the steps to get that done. But I'm confident that Quest will be able to get private payer coverage and Medicare coverage for this type of testing wherever it's appropriate.

Dan Edelstein (17:05):
Yeah, I'd say back to Devin your question with the barriers. There's two, right? There's two general barriers. One is logistics and kind of ease of use on the patient physician administration side for a health system and the other is confidence in the test. And so the physician and the patient both feel confident that this is the right test because there are a number of tests out there. Back to Mark's point, Quest's integration with pathology, and the fact that there are, how many pathologists are at Quest processing tissue, Mark?

Mark Gardner (17:38):
420.

Dan Edelstein (17:40):
420. So that is a heck of a number. And that means that Quest is processing a number of tissue pathology samples in patients that have cancer. And that we've heard over the last five, six years is one of the biggest challenges in just easing the logistics because what we do, as Mark mentioned, is we first sequence the patient's primary tumor or metastatic tumor site. And that informs the liquid biopsy test that we design for each patient. So in some scenarios, that first tissue sample can be a bottleneck. I think that's where Quest has great access and can enable this to move in a much more streamlined fashion.

(18:23):
The other piece is this the appropriate or the right liquid biopsy test? And having been in this field for over a decade, over 15 years, there was a lot of proving that needed to be done let's say in 2010, 2011, that liquid biopsy, that you could actually detect ctDNA and that ctDNA was representative of the patient's cancer. There was a huge burden of proof about a decade ago, and that's been largely demonstrated. So now where we are is in a space where there are multiple different options available to the patient and clinician, and it really comes down to the performance and then the level of clinical data supported by the performance of a particular assay.

Devin Airey (19:08):
So should every payer be covering this? Should all employers make sure that liquid biopsy is a part of their benefits?

Mark Gardner (19:15):
Well, I think that really depends on the cancer type right now. The clinical utilities proven pretty well for colorectal cancer. It's been proven pretty well for breast cancer. It's been proven in some bladder cancers. We're obviously committed to making sure that it's proven in other cancers as the science allows it. But I would say that as Dan mentioned, there are other competitors out there. If you kind of look at the analyst reports and what's being said, this is probably the most rapidly adopted technology I've ever seen in the world of the intersection of genomics and oncology. I think about a third of all oncologists are using this today, and so usually it does take payers a little while to catch up with the clinical practice, but I think that they're doing so.

Devin Airey (21:01):
Dan, you mentioned that you are focused on logistical barriers. This is most important to patients and to providers. To Mark's point, there are other strategic considerations for purchasers, employers, payers, and they care most about cost. What is your approach to talking about how liquid biopsy and other innovations in the space will really work to reduce spend?

Dan Edelstein (21:23):
It does depend on the audience and, for payers in particular, where we're focusing is reducing the unnecessary spend on unnecessary treatments, in some cases, because those treatments are not without side effects. And there are ... if you just take Stage II colon cancer, it's maybe 30, 35,000 Stage II colon cancers newly diagnosed every year, depending on where you go in the United States, 50 to 60% of those patients might receive adjuvant therapy.

(21:54):
We know that that number is too high, so we could essentially reduce that potentially by half. And so there's a spend there that could be offset by the use of a liquid biopsy test. We also know that there is a certain threshold for detecting disease that radiography can perform reliably at. And then there are standard of care circulating biomarkers like CEA, CA 125 protein biomarkers that can provide some information but are not that useful generally speaking. They're not as sensitive or specific as a liquid biopsy test. And radiography, depending on the type of test, can be very expensive.

(22:35):
So right now, liquid biopsy is sitting in between those two modalities, and we know that it adds a level of sensitivity and specificity that is much greater than a CT scan. In some cases, we see a lead time of sometimes six months to detecting residual disease or detecting progression in a patient. I think the question is when the clinician and the patient feel comfortable acting on that information. And we're getting there in terms of the studies that are being designed and the evidence that's coming forward.

Mark Gardner (23:03):
And Devin, just to add, there's also been a number of approvals in the case of monitoring, for example, the use of immunotherapy. Immunotherapy, it's great. It's clearly lifted the tail of survival. Jimmy Carter obviously went from death's doorstep to living much longer as a result of KEYTRUDA and, or OPDIVO, but those are very expensive drugs. They could be $150,000 a year.

(23:33):
And so one of the benefits of this technology is that it's been proven that you can actually monitor how well a patient is responding to therapy with this technology. And to Dan's point around current standards, mostly imaging, unfortunately in the world of immunotherapy imaging actually gets confounded because the tumor mass appears to actually swell in some cases, some call it pseudo-progression because there's so many T-cells that infiltrate the tumor microenvironment that the mass itself appears to get bigger when in fact the patient is responding to immunotherapy.

(24:12):
So imaging's going to send you the wrong way potentially whereas liquid biopsy gives you a very accurate count of is this patient responding to this very expensive therapy or not? And so we're committed to proving out that not just in the case of surgery, but also in the case of the use of drugs, that minimal residual disease testing has a clinical benefit and cost benefit.

Devin Airey (24:37):
So to summarize, the clinical benefit is there and the patients and clinicians are seeing that, they're using it today. The logistical barriers are being worked on, and you all are focused on doing that as a partner, the organizations you work with and will work with in the future. The coverage landscape is going to be complicated as purchasers are navigating their own goals. But we all are seeing the stars align for a few cancer, a few tumor site areas today and are hopeful for the future.

Mark Gardner (25:04):
I think that's a great recap, Devin. And look, this is why people anticipate that a market that is maybe two, $300 million in revenue this year people expect will be in the billions of dollars in the future. Having said that, I really do believe that this is one where... Look, you got to understand chemotherapy started out as mustard gas. So the fact that we're able to tell people, "You, with great confidence, should not be receiving chemotherapy because you don't have any circulated free DNA from the original tumor," that is a huge benefit. It's not just a cost benefit. It's a huge benefit. Dr. Farber wrote about the use of mustard gas in order to invent the initial use of chemotherapy. This stuff is not like taking your vitamins. Chemotherapy is extremely dangerous and very toxic. And so a technology that can come along and tell you with confidence you don't need adjuvant mustard gas is a big deal.

Dan Edelstein (26:19):
And to Mark's point, just to add on, patients that do receive a benefit from immunotherapy, they're still open questions around how long they should receive treatment. And liquid biopsy or an MRD test can certainly help to determine when that patient's cleared ctDNA for a period of time. When, if side effects become to the extreme point, when they could take a potential treatment holiday. And if they do discontinue treatment, liquid biopsy can be used during that period to inform whether the tumor has relapsed at some point so that they should restart. So I think we have a lot to learn over the next five, six years, but there's definitely approach that will come forward to fine tune and add a level of precision to the application of immunotherapy in patients that are driving benefit in a very big way.

Devin Airey (27:10):
It's exciting to me, and I think there's an incredible opportunity if we're going to spend billions on this, we're going to spend the right billions. If we are going towards a future where there's confidence in the testing, confidence the diagnostics, confidence in the treatment, that means that the appropriate care is happening and we are ideally cutting out some of the unnecessary care, unnecessary spend.

(27:34):
So far, we've focused a lot of the conversation on liquid biopsy. Are there other technologies and innovations that you're watching to kind of bring this industry to reach true scale? Anything that you're excited about? Anything that makes you nervous?

Dan Edelstein (27:49):
Yeah, for better or worse, this is still in the realm of liquid biopsy, but I'm very excited about the potential, and this is where some of these technologies started, right? Way back in the late nineties with Bert Vogelstein's group at Johns Hopkins. And that is the concept of early detection of cancer.

(28:11):
So that's manifested itself in some ways in stool test to detect colon cancer early. But what we're seeing is a transition to liquid biopsy tests. And I think that's going to greatly transform hopefully the number of patients that are detected with early stage disease that can be essentially cured of their disease rather than waiting for symptoms to manifest themselves.

Devin Airey (28:34):
Yeah, it's huge.

Dan Edelstein (28:35):
So I'm really excited about that potential because essentially over the next 20 years, there should be a transformation and a great reduction in the number of new cancers and the stage of those cancers being diagnosed. And that's what makes it extremely important for minimal residual disease tests to enter the clinic. Because if more and more patients are diagnosed with early stage disease, those patients are going to need to understand whether those surgical interventions have been successful. And that's exactly where MRD tests are going to come full circle with multi-cancer early detection and other tumor specific early detection modalities.

(29:17):
So that's going to be a very exciting space that is really a great compliment to MRD testing. And also moving some of the later stage treatments to earlier stage diseases. There's an entire burgeoning field of immunotherapy that's shown great success in specific tumor types, and I can see those being very effective in early stage cancers.

Devin Airey (29:39):
Mark, I'm going to have you take the other lens, if you don't mind. What makes you nervous about bringing genomics to scale?

Mark Gardner (29:46):
What makes me nervous is that there's a lot of excitement about this, and I call it the daughter problem, where the daughter finds out mom or dad has cancer and the daughter's a lot more aware of how to look things up online. And they start investigating what can be done because this is somebody they love. And at the end of the day, I'm worried that if we over hype this, that it's not going to live up to the promise that it should have. And so our obligation is to be looking towards the future, but also focused on the here and now.

(30:36):
We have to be focused on if somebody entrusts us with their sacred precious sample that we have to take care of it. We have to do the best job we possibly can because the other end of the line here is somebody that somebody really loves and they're reading about this stuff online and they want to make sure that it really works.

(31:02):
Look, I'm super excited about the future. I'm a technologist. I love technology, but at the end of the day, if it doesn't really impact patient care in the ways that we're promoting it to, then shame on us. So I'm afraid that I get so excited about the technology that sometimes I let that excitement get ahead of me, but I believe that we can really do something for patients, and that fear has to stay in the back of our minds so that we stay on task.

Devin Airey (31:34):
I think it's a good fear. I'm glad that you're fearful about that so that you can stay focused. So I have to tell you a personal story. I was telling some friends last week I was doing this, and one of them is a child of a parent that's going through cancer treatment and he immediately said, "Can I use this? Can I ask her doctor about this? Can we use this technology to help make sure that she feels confident in her treatment course?" And I said, "I don't think it's approved for her tumor site yet." And try not to be Dr. Google when you go into those conversations. But people are excited and I think it's an important step to make sure it goes right.

(32:12):
All right, well Mark, Dan, I just really appreciate you joining us on Radio Advisory. This is an excellent conversation. It's gotten me really excited about learning more about what you are doing.

Mark Gardner (32:22):
Thank you, Devin.

Dan Edelstein (32:24):
Thank you, Devin.

Devin Airey (32:29):
We spent a ton of time today talking about the science and we thought that was important. I thought that was important because the technology is here. We also got through some of the barriers like logistics and some of the important ways to partner on some of the decisions here. We know that patients are excited, clinicians are excited. I'm excited about this, but we haven't figured out all the details. There's still so many things on the table, like clinical decision making, purchaser strategies, even more logistical issues I'm sure we'll run into. You probably also have a lot of questions left on the table. Remember, we're here to help.

Rae Woods (33:07):
If you like Radio Advisory, please share it with your networks, subscribe wherever you get your podcasts and leave a rating and a review. Radio Advisory is a production of Advisory Board. This episode was produced by me, Rae Woods, as well as Devin Airey, Katy Anderson, Kristin Myers, and Atticus Raasch. This episode was edited by Josh Rogers with technical support by Chris Phelps, Joe Shrum, and Dan Tayag. Additional support was provided by Carson Sisk, Leanne Elston, Erin Collins, and Rachel Peroutky. Thanks for listening.