Kim Thiboldeaux  00:06
Welcome to The Cancer SIGNAL, a new podcast presented by GRAIL where we discuss the impact of early cancer detection, the science behind multi-cancer early detection and insight into how this approach has the potential to shift the cancer paradigm. I’m your host, Kim Thiboldeaux. On the episode today we’ll discuss the process that a Galleri test sample goes through from beginning to end, so we can better understand the science behind this new technology. And while the process is quite complex, we’ll try to keep it basic. I think we’re all gonna go back to our sort of sixth grade science class today. And to help us do that is Dr. Rita Shaknovich. Dr. Shaknovich is the vice president of medical affairs, and clinical laboratories at GRAIL. She is a physician scientist with more than 10 years of leadership experience in senior executive roles in industry and academia. She has directed several clinical laboratories and developed molecular diagnostic tests. Dr. Shaknovich is a key contributor to the development and launch of the Galleri multi-cancer early detection test. She has published more than 40 scientific articles in the field of genomics, epigenetics and cancer biology. Welcome to the show, Dr. Shaknovich. 

Rita Shaknovich  01:22
Thank you, Kim. I’m very excited to be talking about the MCED test and Galleri in general.

Kim Thiboldeaux  01:29
Excellent. Before we sort of walk through that process that the sample goes through from beginning to end, tell us a little bit about you. Tell us more about your role at GRAIL. What drew you to GRAIL, and sort of what excites you about this technology?

Rita Shaknovich  01:44
Yeah, no, thank you for the question. So I joined GRAIL four years ago. And again, my life at GRAIL also evolved from being involved in the clinical development programs very early on. And I joined four years ago to currently being vice president of medical affairs, and overseeing and heading the clinical labs. So when I joined GRAIL, I really joined because of the mission of GRAIL, it really touched my heart, the mission of detecting cancer early, when it can be cured. I really believe in that mission. You know, I went through the long medical training, being MD PhD. And early on in my training, I came to care for patients, some old and some young, who unfortunately succumbed to cancer. And that really impacted me and sort of stayed, their stories, their life stories stayed with me, for the rest of my life. And so my research work was focused from then on, on cancer biology. And when I learned about, you know, the strides that…that molecular diagnostics was making, I understood in what Galleri was developing, what GRAIL was developing, the Galleri test, I really understood that that can be a game changer, that it really can change outcomes for millions of patients and so I wanted from then on to join GRAIL.

Kim Thiboldeaux  03:09
I appreciate you sharing that sort of personal background and your…you’re passionate about the work, it really comes through. Let’s walk the listeners through this process. So we’re told that the Galleri test is a simple blood draw. So after a person gets their blood drawn, it could be at the doctor’s office, it could be at a laboratory, what happens next?

Rita Shaknovich 03:29
Simple. So the blood test after it’s drawn, the tubes are packaged and shipped to GRAIL. The test is processed at the GRAIL labs. And so we just receive the package and get to work.

Kim Thiboldeaux 03:43
Excellent. So once that sample does get to the GRAIL lab, then what happens? What’s the…what’s the process that happens with that sample?

Rita Shaknovich 03:55
Yes. So, as I mentioned, the kit and the sample is shipped to GRAIL lab where it is received and there is a standard process, we have qualified technicians who are trained at receiving and beginning the processing of the sample. So the kits are unpacked and the blood tubes are examined for integrity, stability, for the expiration date, it’s very important to have the correct labeling on the tube. So we are comparing labels on the tubes to the labels on the paperwork that arrived with the test, with the test requisition form. And then the sample is accessioned into our electronic system in the lab and the processing starts.

Kim Thiboldeaux 04:40
And so in the lab, what is it exactly that your scientists there in the lab are looking for in the sample, just to remind our listeners to go back, you know, this is…it’s called MCED. It’s multi-cancer early detection. So what’s happening in the lab that helps us identify whether there might be an early cancer present.

Rita Shaknovich 05:01
Yeah, it’s amazing technology. So Galleri test is based on examining and studying the cell-free DNA, so fragments of DNA that are in the sample, in the blood sample. And so what we are looking for in Galleri specifically in identifying those circulating cell-free DNA and looking at the methylation pattern on DNA. So just to remind everyone that where does DNA come from in the blood, so all cells, whether they’re normal cells, or cancer cells, shed either secrete various proteins, enzymes, and so on. But also when they die, they shed DNA material into the peripheral blood. And so the technology now allows us to isolate that cell free DNA, look at the secondary modifications or methylation patterns. And then, you know, learn a lot like learn whether those fragments are abnormal or normal. And we can expand on that.

Kim Thiboldeaux 06:05
Yeah, let’s expand on that a little bit. So looking for what’s…what’s referred to as cell-free DNA, or cfDNA, and then identifying you said, identifying methylation patterns again, past sixth grade here. So talk to us about what are those methylation patterns that you’re looking for? What does that mean? 

Rita Shaknovich 06:26
Right. So, yes, so DNA, and various enzymes and proteins are dissolved, or are circulating in the plasma of the blood, and the plasma is the liquid sort of translucent part of the blood, everything besides the cells that we are, you know, used to talk about in the blood. And so the DNA fragments themselves, they of course, we know that they have certain nucleotides, patterns, right. And sequences, they also do sequences and and nucleotides also have secondary chemical modifications. So what we learned in the last couple of decades that not just the nucleotide pattern, but also the methylation of some of the cytosines, one of the nucleotides, and the way it is done, how much of it there is, and what is the pattern of methylation, it really reflects whether the cell that it comes from, that DNA comes from is normal or not, healthy or not healthy with its associated with cancer. And so the advent of science in the last decade allowed us to learn what is the abnormal pattern of that DNA methylation that is specifically associated with various types of cancers. And so what GRAIL learned through just a very large library of reference material and clinical trials, many, many samples that were processed, you know, what is that abnormal common shared methylation signal? So GRAIL was able to identify shared cancer signal in circulating cell-free DNA.

Kim Thiboldeaux 08:10
And so, again, to remind our listeners, so it’s not… it’ll show with a fairly high level of specificity what type of cancer potentially you could have, from a list at this point of 50 different cancers? Is that correct Rita?

Rita Shaknovich 08:22
Yeah, yeah, no, it’s exactly correct. So that is the unique feature of the Galleri test that not only we’re looking for the abnormal…for the cancer signal, right, or abnormal pattern of methylation associated with cancer signal, but also based on that pattern, the algorithm that GRAIL developed, it is able to identify the source, potential source, of that abnormal signal. So for example, you know, as you said, there are many cancer types that share certain features. And so based on that shared abnormality, we can actually we, in our clinical trials, we have identified more than 50 cancer types with a huge potential to identify, you know, all cancers. And so, you know, the test detects what we report is whether the cancer signal is present, but also where it may be coming from, or cancer signal origin, whether it may be coming from the lung cancer, or liver cancer or lymphoid lineage, or head and neck cancer, etc. 

Kim Thiboldeaux 09:24
Okay, so now, take me into the lab with you. All right, I’m standing next to you. I’ve got on the white lab coat. I’ve got my goggles on right in the lab. What what are the machines? What are we looking at in the lab? What are the machines that are used to analyze this cfDNA? What are we looking for? What are we looking at? 

Rita Shaknovich 09:43
Yeah, very good question. So there are there’s a lot of technology. There’s involved many machines as you’re saying. It’s a semi automated test. So we still need our skilled, you know, technical personnel to operate the machines. They don’t do it all by themselves. But, you know, one of the…because it’s a test that includes, involves many steps, we are using many liquid handlers. So that is to move plates around to aliquot things, to wash the material. So liquid handlers is one of them. And then the key instrument that is utilized is the high throughput next generation sequencer. And this is really to sequence the cell-free DNA fragments. As a result of sequencing, we get that important data information about, you know, where in the genome DNA is coming from, so we can identify circulating fragments and link them to specific areas in the genome. But also, because it’s methylation sequencing test, we’re able to determine which of the nucleotides, which site is methylated, so the pattern of methylation. And then important part, in addition to machine is the classifier or the software algorithms themselves.

Kim Thiboldeaux 11:03
So you talked about sort of cancer related or cancer associated fragments, can you…can you break that down a little bit more? What are you looking for, you know, in the fragments at this point, how are those analyzed?

Rita Shaknovich 11:18
Yeah, so the result of this, as a result of the sequencing, we get a lot of data or information about the sequence of DNA. And again, as I said, you know, when the genome, the sequences are coming from, and the methylation patterns, so the critical step after that is really to utilize Galleri classifier, and that’s the algorithm that was developed to, to read out the methylation pattern on the DNA, and then to determine whether that pattern is abnormal. So, what we are looking for is specifically that…that result, whether the fragments that are in circulation, DNA fragments, represent abnormal or normal fragments, and when the abnormal fragments are detected, you know, whether they…where they may be coming from what type of cells or tissues, organs.

Kim Thiboldeaux 12:11
Okay. All right. So my doctor calls for the tests, I get the…I get the blood draw, they send it in. I’m nervous, right? I’m a little worried. Yeah. Does it come back positive? Might I have cancer? So I’m sitting around maybe pacing a little bit for how long? How long until I get the results of the test back?

Rita Shaknovich 12:33
Yeah. So the turnaround time, or the time that it takes to get the result is 10 business days. Most of the time, though, because we’ve launched already and delivered this test for more than a year, it takes six to seven business days for patients and their providers, most importantly, to get the result first.

Kim Thiboldeaux 12:52
Okay, well, not terribly far off from wherever you are, these days, waiting for results and things like that. So reasonable, a reasonable period of time. The other thing that’s going through my mind is okay, now my sample of my blood has been sent off to this lab in a faraway place. So how do I know or how could I be assured as a patient, that you’re taking the steps to maintain my, the integrity and the privacy of that sample, and it’s not being used for anything beyond what I’ve sort of agreed to?

Rita Shaknovich 13:25
Yes, very important aspect of the clinical laboratory is preserving the patient privacy. So, of course, GRAIL and our, you know, clinical labs are CLIA and CAP certified. And we, everyone at GRAIL organization is required to have up to date HIPAA training, and that ensures that everyone knows how to handle patient health information. So the electronic system where pat…in the lab where patient health information is stored, is under access control. So only people who need to have access to it have access, and it’s password protected. And, you know, and is restricted. So that is very important. In addition, some of the actually, documents like paper documents are stored actually also in the, you know, secure location with a physical lock and restricted access. So, you know, the privacy is of course, of all patients, is protected.

Kim Thiboldeaux 14:27
So let’s unpack a little bit of the alphabet soup of healthcare that you just mentioned, a couple of things you talked about. The the test is CLIA and CAP certified, and the labs are as well. What does that mean for our listeners, what does that mean?

Rita Shaknovich 14:39
Yeah, so there are organizations that ensure that the clinical labs are compliant with all of the regulations that they need to be compliant with and so there are several agencies, CLIA is one of them. It’s a…and you know, for the lab in good standing, it’s necessary to be certified by CLIA or to be compliant with their rules, which we are. And then CAP is our accreditation agency. So we get actually, you know, we get inspected by CAP, that comes every other year, and then we self inspect, you know, on the alternative years to make sure that we are up to date with all of the regulations for the clinical labs. So those are the agencies that safeguard the quality of the operating clinical laboratories.

Kim Thiboldeaux 15:35
Right. And then you also referenced HIPAA and HIPAA compliance. And again, for our listeners, HIPAA is the federal law that protects patient privacy, correct? And you’re subject to that?

Rita Shaknovich 15:44
We are subject to that, even though there’s a little bit of their complexity in terms of when the company or the lab becomes, you know, HIPAA regulated based on the billing practices, but we are certainly adhering to all of the federal laws that are HIPAA regulations.

Kim Thiboldeaux 16:04
To protect the patient’s privacy. That’s great. So let’s, let’s talk about, okay, I’m waiting for the results, I get the results, in the vast majority of cases, it’s negative, I don’t have cancer…I can feel pretty good about that, I’m sure. But in a small percentage of cases, we’re going to detect a positive signal, which means that the lab has detected the potential of sort of early and early cancer, again, specificity around what type of cancer, what happens next, then what…what can the patient expect? What’s the next part of that pathway for them, for that small percentage of patients?

Rita Shaknovich 16:45
Yeah, so the, what we saw in our clinical trials is you’re absolutely right, only 1% of patients gets the positive result. But those are the cases that we particularly want to, you know, support very closely, and work very closely with the with the physicians who have patients with positive results. So the results, go back to the health care providers, who share them, you know, those results with patients, we have to, you know, our response is very quick. First of all, I want to remind listeners that this test can only be ordered by licensed physician. And so that is an important part of having that inherent in build support, because we understand the result is very important, and impacts the patient significantly.

Rita Shaknovich 17:34
So if the provider gets the positive result, Galleri positive result, we as a company, we have a large team of medical science liaison. So those are the trained, support sort of personnel that reach out to physicians, and provide an end user, our reach out time actually is incredibly fast. It’s within several hours. And what they offer is discussion of the result, answering questions that provider may have, you know, helping providers sort of frame that in, the frame that result and help them think through, you know, to the cases that we can share with them from our clinical trials, and how those were worked up. We also talk with providers about, you know, the guideline recommended ways of, you know, of working patients up for cancer, there is also in addition to that, we have peer to peer consultation, that we are supporting as a company.

Rita Shaknovich 18:35
So there is there are some key opinion leaders and doctors who have experience with Galleri, who actually can provide peer to peer consultation for the Galleri users. I have to mention also that, you  know, we have customer service, we have patient advocates and navigators, who can help patients directly. So every report has our website, which has the information about you know, how to navigate Galleri, and also the medical information team. So if there are questions, patients also are put in contact with medical information to answer you know, at GRAIL, to answer the questions. As a lab director, I get calls, you know, and I speak with providers and with patients very early on.

Rita Shaknovich 19:23
After the launch, I got, you know, a little bit more of the patient calls because it was such a novel technology, and every conversation is special because it’s about that person’s health journey. So, so yeah, I think there is a lot in place currently. What we also remind patients, I think it’s very important is to continue the recommended screening, recommended screening for cancer as they are doing with their annual sort of health checks, or what you know, or based on their risk profile. So Galleri currently is not intended to replace any of the USPSTF recommended screenings, it’s really in addition to those. So that’s an important point that we emphasize with patients and with doctors.

Kim Thiboldeaux  20:11
So it doesn’t replace things like a mammogram, things like a colonoscopy for example – those should be taken. Okay, so just to summarize, so again, our listeners are clear. If there is a positive signal, then…then the company will inform my doctor about that. And then my doctor will be in touch with me. And typically, then what would happen at that point is there would be what’s called a sort of a diagnostic workup. So that may include more bloodwork, it may include scans, it may include a biopsy where they take a tissue sample, because we want to confirm that I do have cancer, I want to confirm the stage of the disease. And then that will inform then how we go ahead with with a treatment plan, am I getting that right?

Rita Shaknovich 20:53
Exactly. That’s exactly right. That is exactly right. Yeah. And again, to remind that the test has because it’s intended, for intended use with, for patients or for the asymptomatic individuals with elevated risk of cancer, the test was designed to have very, very high specificity. So we get a few positives, as you pointed out, so we’re not detecting just any signal, we’re really detecting signal that is likely to be associated with cancer.

Kim Thiboldeaux  21:21
And it may go without saying Dr. Shaknovich, but I want to emphasize for our listeners, that at this point, for the most part, the best way to cure cancer is to find it early, before it has spread, before it has metastasized. So the idea that we have this test that could detect cancer early in the stage when it can be treated, and cured is a pretty big step forward in the whole sort of cancer continuum, correct?

Rita Shaknovich  21:45
It’s a huge step forward. That’s exactly it. Because survival at early stage one and two is much higher, it’s closer to 90%, versus, you know, survival of 20% in stage three and four, there is just, you know, easier cure, there’s less toxic cure, there is much better survival at early stages. So as a company, that’s what we can do, because we have the tools, and we can offer this test. Of course, prevention is always best, we want to prevent cancer. But you know, at this stage, what we can do as a company, and what we think we can really how we can change the cancer battle is to allow early diagnosis, better quality of life, and you know, and lower mortality, or, you know, the better survival for patients.

Kim Thiboldeaux  22:32
Right, and I just want, you know, I want to address, you know, the fears that consumers and patients have, and I don’t want to know, I just put my head in the sand and I don’t want to know, and I, a lot of  times as a, you know, patient advocate working in cancer for 27 years, people say to me, when are we going to cure cancer, and I say, we’re curing a lot of cancers. And the best way to do that is to get out, you know, get your screenings, get your testing, and of course, engage in, you know, behavior that will help with prevention as well, I think those pieces are really important. As we start to wrap up, I could talk with you for hours about this, to me, it’s just so also interesting and enlightening. But um, so just to confirm the test is available, the test is on the market. The circumstance at this point is that it’s generally not being paid for by insurance, by Medicare, by others. So if I wanted to get the test today, right now, is there a way that I can do that? 

Rita Shaknovich 23:29
Yes, no, absolutely. Yes, it’s important to emphasize that the test is new. And so it’s not yet covered by most insurance companies. The cost is approximately $949. So it’s not a cheap test. But as a company, we understand that to make, you know, impact on on the population, right, we need to achieve reimbursement policy. So that’s what the company is working on, we hope that we get reimbursement and that, that becomes accessible and available to everyone because it is a blood test. It’s an easy way to get multi-cancer screening, it’s going to impact a lot of people. And the test, nevertheless, for those who have either employer benefits or and that may cover this just through their spending accounts or who are willing to pay out of pocket at this point, you know, they can go to their providers to their healthcare, primary care or their health care providers and ask for the test. The information can be found on our website www.galleri.com. It’s also patients who are very proactive and want to educate the physicians, they can go to the website and actually initiate you know, the inquiry into the test. So, yes, galleri.com has a lot of information for patients and physicians.

Kim Thiboldeaux 24:52
Right. And I know the company is doing a lot at this point to get the test out there through many partnerships with the Veterans Administration with health systems with the employers, as you mentioned. And I know there’s a team that are working on reimbursement as well, which is going to be an important, certainly important step forward for bringing the test. You know, out to more folks. I know you’re also working with underserved communities to get the test out there. So really exciting technology. Dr. Shaknovich I want to thank you so much for joining us on the show today and walking us through this process helping us, helping us understand. This is the cancer signal presented by GRAIL. I’m your host Kim Thiboldeaux. Tune in next time to learn more about the impact of early cancer detection.

Important Safety Information
The Galleri test is recommended for use in adults with an elevated risk for cancer, such a those aged 50 or older. The Galleri test does not detect all cancers and should be used in addition to routine cancer screening tests recommended by a healthcare provider. Galleri is intended to detect cancer signals and predict where in the body the cancer signal is located. Use of Galleri is not recommended in individuals who are pregnant, 21 years old or younger, or undergoing active cancer treatment.

Results should be interpreted by a healthcare provider in the context of medical history, clinical signs and symptoms. A test result of “No Cancer Signal Detected” does not rule out cancer. A test result of “Cancer Signal Detected” requires confirmatory diagnostic evaluation by medically established procedures (e.g. imaging) to confirm cancer.

If cancer is not confirmed with further testing, it could mean that cancer is not present or testing was insufficient to detect cancer, including due to the cancer being located in a different part of the body. False-positive (a cancer signal detected when cancer is not present) and false-negative (a cancer signal not detected when cancer is present) test results do occur. Rx only.

Laboratory/Test Information
GRAIL’s clinical laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and accredited by the College of American Pathologists. The Galleri test was developed, and its performance characteristics were determined by GRAIL. The Galleri test has not been cleared or approved by the U.S. Food and Drug Administration. GRAIL’s clinical laboratory is regulated under CLIA to perform high-complexity testing. The Galleri test is intended for clinical purposes.