Susanna  00:00
Welcome to The Cancer SIGNAL, a podcast presented by GRAIL, where we discuss topics relating to early cancer detection, including multi-cancer early detection testing, cancer genomics and risk, barriers to cancer screening and much more. I’m your host Susanna Quinn. Today we are going to hear a research update from Dr Eric Klein. Dr Klein has extensive experience in clinical trial design and execution, cancer biomarker development, medical device development and deployment and healthcare leadership and management. He is a distinguished scientist at GRAIL and is a returning guest on the podcast. He joined us on episode nine, where he discussed genetic testing, cancer screening and genomics. Welcome back to The Cancer SIGNAL Dr Klein.

Dr. Klein  00:55
Thanks. It’s great to be here.

Susanna  00:59
So as an ovarian cancer survivor and a carrier of the BRCA 2 gene, genetic testing is very important to me. Do you think that we could go back and do a high level recap of what you talked about in episode nine?

Dr. Klein  01:14
Sure, happy to. We’ve seen a real revolution in the way cancer is managed and the way we assess individuals for risk of cancer based on the development of a wonderful technology called next generation sequencing. That was the technology that was used to sequence the whole human genome, but it has many, many clinical applications, one of which you’ve alluded to already, which is to be able to sequence the DNA that people are born with – we call that germline DNA – to determine if they had mutations in cancer causing genes that increase their risk of getting specific cancers. So BRCA in particular, increases the risk of breast and ovarian cancer. That’s useful for identifying individuals who are high risk and who should be screened for those cancers, and it’s also useful in identifying therapeutic agents, drugs, that may work in a targeted fashion and work more effectively in those individuals than they don’t have than those who don’t have the mutation. NGS, next generation sequencing, has also allowed us to take people who have actually been diagnosed with a cancer and again, pick out what targeted therapy they might be eligible for, and to monitor their disease status. So after treatment in individuals who get standard of care treatment, who don’t have any evidence of cancer on X-rays or physical examination, sometimes we can see a cancer signal in the bloodstream, and that information called molecular residual disease, or MRD, is now being used to design new clinical trials and new treatment regimens. And the thing that I’m most excited about about NGS that has allowed us to develop the whole field of multi-cancer early detection or MCED.

Susanna  03:14
Terrific. Well, that certainly gives everybody more hope in this cancer research arena. So at ASCO this year, the American Society of Clinical Oncologists, GRAIL shared follow-up data from PATHFINDER on how multi-cancer early detection testing can help detect cancer recurrence and new primary cancers in cancer survivors. How did MCED testing add to other screening methods for those individuals? And what can we take away from those results? 

Dr. Klein  03:44
Let me talk a little bit about the unique challenge of cancer survivors. They are a group of individuals who are at higher risk of developing cancer than the general population simply because they had an initial cancer, and they’re at higher risk for a number of reasons. One is treatment related effects. We know, for example, that various forms of radiation and chemotherapy drugs actually cause mutations that can increase the likelihood of getting another cancer. They’re also at risk of getting a recurrence of the cancer that they had initially. They may have a genetic predisposition to cancer, and there are certain syndromes like Lynch syndrome, that predisposes to multiple different kinds of cancers, and they may also be immunosuppressed, which is also a risk factor for cancer. So altogether, the group of survivors cancer survivors at higher risk of cancer. And if you look at the literature and NCCN and other guidelines, it’s relatively vague how these individuals should be monitored for the development of either a recurrence or a new cancer. There aren’t really good guidelines, and there’s a general sense that detecting a recurrent cancer before it becomes clinically evident, really, there’s not a lot of clinical evidence that doing that is beneficial, although that thinking is changing. So MCED, multi-cancer early detection seems like a perfect application of a screening technology for a group of individuals who are at higher risk again, both for recurrences of their initial cancer and of second cancers.

So the data we presented is from the PATHFINDER study. This was the first prospective study we did in 6600 individuals in ambulatory primary care clinics, not, not, not under suspicion of cancer, who were tested with an MCED test, and a subset of them told us that they had had a cancer previously, and they’d been cancer free for at least three years. And so we wanted to answer the question, what value does MCED testing bring in this special population of people who are at risk of both of a recurrence of their initial cancer and of new cancers, and at a high level, what we found was that in this population, the performance characteristics, the ability to detect these cancers of the MCED test that was used in PATHFINDER was very similar, almost identical, really, to individuals who did not have a prior cancer history. And the test found recurrent breast cancer in five women and new cancers in four other cancer survivors. So it’s interesting, half of the cancers that were detected in these cancer survivors were not the cancer that they were originally diagnosed with. They seem to have been cured of that, but they were at risk of other cancers. And so we think there’s value in using MCED in this population of individuals who are at higher risk than the general population for getting cancer.

Susanna  06:57
Thank you. Thank you very much. At the American Association of Cancer Research, GRAIL presented the first real world evaluation of repeat multi-cancer early detection testing 10 to 18 months from initial MCED testing. What was learned from this study?

Dr. Klein  07:16
This also was an important study when you think about standard of care screening. So mammography, colonoscopy, colon cancer screening, the value that comes from that in a population of individuals is being screened on a repeated basis. So you know, mammography is recommended every two years, cervical cancer screening every three years, colonoscopy now is recommended starting at age 45 but on a regular cadence. And so we are developing evidence of what the appropriate regular cadence for MCED testing ought to be. And the available evidence that we have that was presented in a previous year, and at this meeting, was that screening individuals with an MCED test, a blood based MCED test once a year, makes the most sense. So in this report, we looked at the first participants who were in our real world cohort, people who got MCED testing with Galleri through the commercial channel, and sought to see how it performed when they had a second one a year or 18 months later, because that’s how we expect that this technology is going to be used in the future as part of routine screening. It will be roughly once a year, and it’s important to understand what we might find. So this was about 6,000 participants. Importantly, they all had no Cancer Signal Detected or a negative MCED test at baseline. So the question then becomes, if I don’t have cancer currently or in a negative signal, what’s my risk of developing a cancer in the future? And that’s how it works in the real world.

So what we found was that on second testing, a proportion of the individuals who were negative to begin with actually develop cancers in the interval, and again, we know that that’s how it works in the real world. The kinds of cancers we detected were very typical of what we saw from all the studies that we’ve done. And the important finding was, although it was a small number of patients, as expected, the cancers that we found on repeat testing tended to be earlier stage than the cancers that we found the first time we test the population. And again that’s exactly what we expect. That’s exactly what we expect the first time that we test a population of individuals using any screening test, we detect all the cancers that are present in the population at that time. Once those cancers are identified and those patients are treated and screened, if you then screen the same population a second time, you would expect a slightly lower rate of cancer because the existing cancers have already been culled from the population, and you would expect new cancers to have developed, and you would expect to detect them at an earlier stage. And that’s ultimately what we think will happen when MCED testing is used at the population level on a repeated basis.

Susanna  10:26
That’s fascinating. So Dr Klein, I’m an ovarian cancer survivor, as I mentioned, and I’m almost five years post diagnosis, so I’m doing my cancer screenings every six months, and I’m doing mammographies every six months. How do you see MCEDs as fitting into my screening program?

Dr. Klein  10:48
Yeah, the data that we presented on cancer survivors is relevant to you. And as a cancer survivor and as a BRCA mutation carrier, you’re at risk for multiple different cancers. So you know, breast cancer, pancreatic cancer, ovarian cancer, that’s what runs in the BRCA world, and you also potentially at risk for a second cancer because of the effects of your prior treatment. So that would put you in what we call either an elevated or higher risk category for cancer compared to the general population, and we think that MCED testing makes perfect sense in that population, because you’re at risk, you’re not only at higher risk, but you’re at risk for multiple different cancers. And our current screening modalities, you know, mammography does a great job screening for breast cancer, but it does nothing for screening for pancreatic cancer, and it does nothing for screening for ovarian cancer and individuals who start with breast cancer and so forth. But MCED addresses all of that. You know. Let me add another perspective on this, which I may have spoke about in episode nine, which is that most of the deaths due to cancer in the United States occur from cancers that we don’t screen for. And as one of my colleagues likes to point out, if you’re unlucky enough to get cancer, you don’t get to pick what cancer you get. So even if you’re compliant with recommendations about doing mammography and colonoscopy and all the other screenings, you’re still at higher risk of getting a different cancer than the one that’s targeted by that screening test, and you’re also at risk of dying from that cancer. So that’s where MCED comes in, because the technology allows us to detect multiple different kinds of cancers.

Susanna  12:37
Thank you so much. I think that’s really useful information for cancer survivors of all different types of cancer. Another highlight was the data that demonstrated the power of our MCED test to preferentially detect high grade, clinically significant prostate cancer over indolent cases. Can you share more about this, Dr. Klein?

Dr. Klein  13:01
Yes, as a former urologist who spent his career treating prostate cancer, this paper really resonates with me. So prostate cancer is unique among cancers, because the most common form of prostate cancer is low grade and doesn’t need to be treated. And the current screening for prostate cancer using a blood based test called prostate specific antigen, or PSA, is prostate specific, but it’s not prostate cancer specific. And so we have a problem in the prostate cancer world of what we call over diagnosis. PSA detects these low grade cancers which don’t need to be treated, and that can result in a number of what we call harms, individuals treated and experiencing side effects from the treatment, which are quite significant when they had cancer that could easily have been watched, one that was not going to threaten their life or health. The MCED perspective on this is important because the prevalence of prostate cancer in men in the intended use population for MCED, that’s men between 50 and 79, the incidence of prostate cancer in that population is very high, and so it’s important that we understand how an MCED test used at a population level will perform with respect to prostate cancer. 

And I want to make clear that the study we published was not a head to head comparison of PSA testing versus MCED testing. That’s not what we’re trying to get at here. What we did is we looked at two studies, our case control CCGA study, which was 15,000 people with and without cancer, and the PATHFINDER study that I mentioned earlier, to see how MCED testing performed in detecting prostate cancers. And we found two important things. One is that this particular MCED test does not detect low grade prostate cancer, and really important, use of this MCED test in men at risk for all the other cancers that they potentially can get is not going to subject them to over treatment for cancers that don’t need to be treated. The flip side of the coin is that the cancers, the prostate cancers that were detected were generally of high grade and of higher stage. And so we know that if you have an MCED test that’s that has a Cancer Signal Detected and predicts that you have prostate cancer that should not be ignored, that’s something that should be referred to urologist for an MRI and a prostate biopsy.

Susanna  15:35
So Dr. Klein GRAIL’s data at the International Society for Pharmacoeconomics and Research, also known as ISPOR, was a bit different, focusing on the emotional and economic impacts of cancer screening. Tell us about what you learned from that research. How do cancer screenings have an emotional or behavioral impact?

Dr. Klein  16:00
Yeah, this study, we in this study, we looked at what the perceived value of having an MCED test that reported negative no, what we call no Cancer Signal Detected. How did people react to that, and how did it make them feel? That’s really important, because MCED is intended to be used in addition to standard of care screenings, not to replace them. And we want to be careful that people understand what a no Cancer Signal Detection means, and to not dissuade them from continued to being screened for cancer. It’s important to understand that if you have a negative colonoscopy or a negative mammography or a negative MCED test, that doesn’t absolutely guarantee that you’re cancer free at the moment that you have those tests, but it also doesn’t change what your potential risk is for developing a cancer in the future. So we wanted to again, understand what a no Cancer Signal Detected meant. Most participants in this survey anticipated that if they had an MCED test and got a negative test result back, that they would feel positively about that. Most reported that they would maintain or improve their current health behavior. So those are lifestyle things, like not smoking and, you know, not being overweight and exercising and that sort of thing. And about a quarter of them reported that this would help them maintain or improve financial and family, family planning sorts of things to understand that. We also looked at whether or not they would in being reassured that there’s a negative signal there, if that would impact lifestyle changes. And a pretty significant portion of the population of this survey, again, said that, yes, if I know I don’t have cancer now and I’m educated on what I can do to prevent cancer, again, losing weight, not smoking, eating healthily, exercising, all of those things, that they would be inclined to do those sorts of things. So to summarize the data, we saw really positive effects in the way people would think about their health if they had an MCED test that was negative.

Susanna  18:21
So Dr Klein, GRAIL’s poster at the National Comprehensive Cancer Network looked at a similar topic, evaluating how cancer affects employment and productivity. How can cancer screening help reduce these burdens?

Dr. Klein  18:37
Yeah, again, another very important question and one that’s relevant not only to individuals and families who are affected by cancer, but to employers. So if you have an employee who’s diagnosed with a cancer that translates into loss of productive time and loss of productive economic time, with all the associated costs and the challenges of recruiting replacements, temporary or permanent replacements when necessary, and caring about the employees and getting them back. And what we saw here was that a cancer diagnosis and treatment impacts all of the things that you would think it does, your ability to function day to day, how you feel, fatigue, side effects from treatment, perhaps inability to support your family depending upon your employment circumstances, but we look specifically at whether or not those impacts were better if you were diagnosed with an early stage cancer as opposed to a late stage cancer, because one of the important goals of MCED testing is to shift the diagnosis of cancers to earlier stages, because we know that they’re easier to treat, and the technology helps us do that. And in fact, the study that we presented supported that hypothesis. Individuals reported across a number of different measures about how they felt, how they were able to function, whether they were able to work, whether their ability to concentrate at work was affected and so forth, was far better if you were diagnosed with an early stage than a late stage cancer. And in other work that we have presented and published, we’ve also found that individuals who are diagnosed at early stage disease miss far less work than individuals who are diagnosed at late stage disease. So this is another important observation about the potential benefits at a societal level to MCED testing.

Susanna  20:30
So npj Precision Oncology is one of the premier scientific journals in the world, and a recent publication in npj Precision Oncology from you and a few colleagues highlighted the utility of the Galleri testing for three individuals who were caught at early stages of biologically significant cancers. Can you talk a little bit about what were the learnings from these case studies?

Dr. Klein  21:01
Sure, these are three real world examples of how Galleri can perform and diagnose cancers in individuals who were asymptomatic, who with one exception, did not have any risk factors other than being over age 50, and how they were diagnosed with early stage cancers. The first was a 67 year old woman who had no symptoms, who, I think, got her Galleri test as an employer, an employer benefit, and she had a Cancer Signal Detected that predicted that she had what we call a Müllerian origin tumor, either of the uterus or the ovary, and so she went on to have a diagnostic evaluation. And let me sort of take a pause here to emphasize that MCED, blood-based testing is a screening test. It’s not a diagnostic test. So if you have a positive MCED test, just as if you have a positive mammogram, you need to have a diagnostic evaluation. In the case of mammogram, you need to have a biopsy. In the case of an MCED test, you do a diagnostic evaluation that’s based on the predicted origin of the cancer. So she had a pelvic ultrasound to start with, and had a large mass in the pelvis. It wasn’t clear whether it was coming from the uterus or ovary. She had a CT scan that suggested it was an ovarian cancer, and she went on to have surgery, and she was diagnosed, again, completely asymptomatic and no risk factors other than her age, with an early stage ovarian cancer, and she got what we call adjuvant chemotherapy, according to guidelines, afterwards, and she’s free of cancer now at almost two years. And it’s highly unlikely, because we know this from ovarian cancer, the population level, that this cancer wouldn’t have been detected unless, until it became symptomatic, at which time it would most likely have been higher stage. 

Similar story for the second patient, a 55 year old woman, again, no risk factors and no symptoms. Had a Cancer Signal Detected that predicted as the most likely place kidney cancer, and she had a very easy diagnostic workup. She had a CT scan of her kidneys, which showed about a four and a half centimeter mass in her right kidney, and she had the appropriate surgery for that, which was a removal of the tumor and saving of the rest of the kidney. And she had a high grade kidney cancer, which is one that definitely needs to be treated, or needed to be treated, and again, is not one that is likely to have been diagnosed unless she presented with symptoms, or unless she had a CT scan for some other completely unrelated reason, not what we call an incidental cancer, and she’s free of disease at about 13 months afterwards. 

And the last case was a 75 year old man who did have some risk factors. He had a blood-based cancer called chronic lymphocytic leukemia, although he’d had it for 17 years and didn’t need treatment. We know that CLL patients are at higher risk for other cancers, and he had a Cancer Signal Detected that suggested a what we call a head head and neck cancer. And he went ahead and had a PET scan that showed a hot spot in his the area where his tonsil was, and went to see an otolaryngologist who palpated or felt a lymph node in the man’s neck. Biopsy did prove to be a squamous cell carcinoma, an HPV associated squamous carcinoma, also stage one, also treated and free of disease about 14 months later. So these are three great examples from the real world of how MCED testing can identify cancers at an early stage.

Susanna  24:49
It’s extraordinary. MCED testing is really changing the face of cancer. Thank you so much for joining us today. Dr Klein, it was a pleasure to talk with you.

Dr. Klein  24:59
Likewise, and thanks for having me.

Susanna  25:01
This is The Cancer SIGNAL presented by GRAIL, and I’m your host, Susanna Quinn. Remember to subscribe, and we look forward to having you listen in next month. 

Voiceover  25:12
Based on a clinical study of people ages 50 to 79 around 1% are expected to receive a Cancer Signal Detected result, which includes predicted cancer signal origins. After diagnostic evaluation, around 40% of people are expected to have a confirmed cancer diagnosis.

The Galleri test is prescription only. The Galleri test is recommended for use in adults with an elevated risk for cancer, such as those age 50 or older. It is not recommended for individuals who are pregnant, 21 years or younger, or undergoing active cancer treatment. Galleri should be used in addition to routine cancer screening. Galleri does not detect a signal for all cancers. False positive and false negative results do occur.

For more information, including Important Safety Information, please visit Galleri.com.

Important Safety Information
The Galleri test is recommended for use in adults with an elevated risk for cancer, such as 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 (CAP). The Galleri test was developed, and its performance characteristics were determined by GRAIL. The Galleri test has not been cleared or approved by the 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.