Kim Thiboldeaux 00:08
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. We have two great guests joining us today. Dr. Alpa Patel is the Senior Vice President of Population Science at the American Cancer Society, where she oversees a team of approximately 50 research and study operations staff who use their research expertise in epidemiology and behavioral science to increase the understanding about the causes of cancer and how to improve outcomes after a cancer diagnosis. Her team’s work is conducted within the American Cancer Society’s large longitudinal studies, known as the Cancer Prevention Studies, that follow hundreds of thousands of participants over several decades. Dr. Patel earned a PhD in epidemiology at the Keck School of Medicine at USC and holds an MPH in epidemiology from Emory University and a BS in zoology and animal biology from the University of Florida. Dr. Tina Clarke is Epidemiology Vice President and Distinguished Scientist at GRAIL. She joined GRAIL in 2016 and remains among its most tenured scientists. Before coming to GRAIL she worked at the Cancer Prevention Institute of California, part of the Stanford Cancer Institute, running multiple NIH funded research projects, including the Bay Area Cancer Registry. She has authored over 178 scientific publications describing the epidemiology of breast cancer, melanoma, lymphoma and other cancers and has an h-index of 77. She’s a Colorado native and received a bachelor of science degree in biology from Duke University, a master’s degree in public health from Tulane University, and a doctorate in epidemiology from the University of California, Berkeley. Woo! Impressive, ladies. Thank you so much for joining us, both of you.

Dr. Patel 02:05
Thank you for having us.

Dr. Clarke 2:06
We’re so excited to talk about this.

Kim Thiboldeaux 02:08
Great, awesome. Let’s jump in. Today we’re going to explore cancer risk – how we measure it, how we approach it now versus in the past, and what else we may need to be considering when it comes to our own risk of cancer and what actions we can take to prevent it or detect it earlier. Dr. Tina Clarke, I’m going to start with you. To set the scene, could you tell us about the absolute risk of cancer? Well, first of all, what is absolute risk of cancer?

Dr. Clarke 02:34
Yeah, absolutely. Let me let me dive into absolute risk, because it’s such an important concept. And Alpa and I are both epidemiologists. We’ve been working together for many years on this on this essential scientific activity of quantifying the risk of cancer. So people want to know, like, how likely am I to get cancer? What are those actual statistics and probabilities? And we do a ton of very special research that we’ll tell you about in the next, the next few minutes about how scientists determine risk of cancer. But absolute risk of cancer is really just a probability. It’s saying, what is the probability that somebody is diagnosed with cancer in a certain timeframe? And so we look at, you know, what is your probability of being diagnosed with cancer this year? You can also, you know, pull the time out and say, what’s the probability that you get diagnosed with cancer in five years, or in 10 years? And it’s very important statistics for helping people understand their own risk, how to manage their healthcare. So obviously, one of the most important actions we can take to reduce our own risk of dying of cancer is to get screened. And so understanding what age does that risk really get to a point where cancer screening becomes important is central to cancer screening, and that’s why Alpa and I work so hard on it.

But really, absolute risk is this actual statistic that we can calculate from observing cancer patterns in large populations over time to be able to tell people, here’s the probability that you develop cancer over you know, in a certain time period, that’s an absolute risk. We want to distinguish that from what you might hear about a lot in the in the media or just talking to your friends and family about cancer risk factors. Cancer risk factors are things that we think increase your risk of cancer. And smoking is the most important, we’re going to talk about that some more too. Smoking is a classic risk factor for developing cancer. When we talk about risk factors, we usually talk about them in terms of a different type of measure, a different type of risk, that’s relative risk. So a relative risk is when we say your risk is 20% higher than someone who has the same characteristics as you – the same age and sex and race maybe. And that’s a relative risk. So when you’re reading the newspaper, and you’re hearing about things that might raise your risk of cancer, so smoking, obesity, you know, sometimes we talk about environmental exposures, they might elevate your risk 10% higher than someone who’s otherwise just like you. That’s a relative risk. That’s really, really different from an absolute risk. You can have a very low absolute risk of something happening to you. But if something increases over time, a classic example is we’ve heard a lot about increases in early-onset colorectal cancer lately. The American Cancer Society just changed their recommendations for people to get screened for colorectal cancer from age 50, to age 45, because of relative changes in the risk of cancer in people who are that age, but that is a percentage change. That is not the same thing as what is the absolute risk, what is the risk of something happening to you over time? So that’s the difference, Kim, between absolute risk and relative risk. And it’s really confusing and hard for people when they get all this information thrown at them through the internet or on Twitter or what have you to distinguish between those two things. But Alpa and I really want to dig in today on this idea of absolute risk and how you can use it to manage your own health, your own health care.

Kim Thiboldeaux 06:24
Sure. So can you just take one more minute, Dr. Clarke to talk about – so you talked about some of the risks for cancer today. Right? You talked about smoking, you talked to you about obesity. Are there other things that folks should be aware of, you know, what are the main factors for risk today?

Dr. Clarke 06:38
Yeah, let me dig into that a little bit. So the most important risk factor, and nobody’s gonna like this very much. The most important risk factor that we’ve studied extensively as in terms of how it changes your own cancer risk is age. It’s not glamorous. It’s something that we all do. But really, every year that you age increases your risk. And I’m going to tell you what those absolute risks are just so you have a sense of what that range is, but relative change we see. I mean, imagine, you can’t see me on this podcast, but I’m taking my hand and like making a rocket ship to the moon on a graph. Like every year you age, raises your risk of cancer pretty dramatically. It raises it about 9% when you’re younger, and about 4% when you’re older. So it’s, every year you age, is the most important risk factor for cancer. So let me give you a sense of what is that absolute number and how it changes over your age. At age 30, the probability that you develop cancer, on average, in the next year is very, very low. It’s 0.08%. So that’s basically saying eight in 1000, people are going to develop cancer – very low. However, when you get up to your older ages, up at age 80, that number is 2%. Two in a hundred. So it has changed very dramatically as you age. And I think that obviously comports with most people’s experience of friends and family developing cancer when they’re older. The biology behind this is that we think that as you age, your DNA gets mutated just due to you know, things that happen in your daily life with things you’re exposed to, just natural DNA gets mutated as you get older, and your DNA accumulates those mutations in such a way that might cause cancer, might change the cell growth patterns in such a way to cause cancer. So again, this is not very glamorous, but age is your number one most important risk factor. And the change over your lifespan is quite dramatic. It goes, again, from a very, very low, you know, very few people in 1000s when you’re when you’re young. And when you get into your 70s and 80s, we’re talking a very material proportion. It’s now the number one cause of death in many populations in the US. So, sure, is it’s a serious threat. And as you get older, it gets more and more. Yeah.

Kim Thiboldeaux 09:00
So my answer to that is boo. [Laughs] That’s what I want to say. But I know we’re going to talk about things we can do to reduce our risk today. So I think that’s also important that we can be educated and empowered. Dr. Patel, let me bring you into the conversation. How have we historically looked at cancer risk, and, you know, what’s sort of the status quo and I know we’re making some changes and making some progress.

Dr. Patel 09:24
So you know, we’ve historically looked at it very much from the perspective of one cancer at a time and in fact, with technology, you know, even if you take something like breast cancer, whereas before you thought about breast cancer all being the same thing. Now we actually cut and splice it into different what we call molecular subtypes of breast cancer. So that the majority of research actually focuses on one cancer type at a time. And sometimes even like I said, looking more finely within that one type. That is really important from what we call an etiologic perspective, and what I mean by that is what is actually driving that cancer in that specific part of the body to develop. So when you think about sex hormones like estrogen and how they feed a lot of breast cancers, right, that’s how we learn about what is actually causing a specific type of cancer to develop. But what we don’t look at as much is the overall risk of all cancers. So Tina just talked about, you know, the absolute risk and how it changes as we age. But there, you know, there’s a lot that we need to understand about how different, how any cancer develops, you know. I mean, I’ll be honest, I would prefer not to get any type of cancer, versus, you know, it’s not like I am trying just to prevent one type of cancer. I want to prevent getting any type of cancer. And so that’s a different question, right? It’s not as much biologically driven, but it’s more, how do we actually prevent as much of the total burden of cancer in the population as is possible? And that’s something that is a little less well studied. Because we’re so curious about what is causing cancer to develop biologically, that we’re not as much stepping back and looking at the whole.

Kim Thiboldeaux 11:30
So let’s break that down a little bit. Dr. Patel, let’s talk about the risk of developing one of the cancers that has a screening tool, right. We know, breast colorectal, cervical, prostate, sometimes lung. How does that compare to the risk of developing a cancer that we’re not currently screening for?

Dr. Patel 11:49
So when we think about it from the ultimate endpoint of, you know, death from a cancer, about two thirds of all cancer related deaths actually come from cancers for which we don’t currently have a screening test. So –

Kim Thiboldeaux 12:06
Wait, say that, say that again. Because I think that’s a really important statistic, say that again.

Dr. Patel 12:12
Of course, so about two thirds of all cancer deaths are due to cancers for which we don’t have a current screening test. That is both good and bad news. Obviously, it means we have a lot of work to do to think about the cancers from which people are dying from. But it actually supports the notion of both prevention and early detection. Because for those cancers that we can detect earlier, we can intervene earlier, we can treat them hopefully better. And we can prevent that death from that cancer from happening, right. So that’s really what we’re interested in doing. But when we look at those cancers, that we have screening tests for, only about 15% of all the cancers diagnosed are actually being diagnosed with these different guideline based screening tactics. So there’s a lot of cancer out there, that we don’t have, you know, a screening paradigm for right now that we really need to focus on.

Kim Thiboldeaux 13:23
Really interesting statistics, and I think eye opening. Dr. Clarke, you recently co-authored a paper titled “Rethinking Risk Assessment in the Era of Multi-Cancer Early Detection.” So number one, just very quickly, for our listeners, if you can explain what is multi-cancer, early detection, and then number two, what did you learn, what’s the summary of this paper?

Dr. Clarke 13:47
Yeah, so Alpa and I recently wrote this paper together. And it’s open source, and it’s up online so people can look it up. And maybe we can add the link to this podcast so people can look it up. But we wrote a paper to, to really flag that now that we have ways of screening people simultaneously for multiple cancer types. Remember, in the past, we’ve been able to screen you one cancer type at a time. We can do breast cancer, separately from colon cancer, separately from cervical cancer, etc. Now we have these new technologies that allow us to simultaneously screen for multiple cancers. This helps us really think about risk differently, right, like we might have, Alpa just explained that previously, we told you, these are all your risk factors for breast cancer only. And we did that because we wanted to understand how to give women mammography, according to their risk of breast cancer. But now we want to think about risk in a different way, which is actually the way Alpa just described, the way we all kind of think about it as patients, which is like, hey, I’m sitting here. I know I’m at risk of all the cancers because all human beings are at measurable risk of all the cancers. I don’t really, I don’t really want to pick or choose which I just want to know what is my absolute risk of all the cancer. So we wrote a paper, we leveraged some really amazing resources that Alpa is in charge of at the American Cancer Society. These are cohorts of patients, sorry, of volunteers. They’re just people that are amazing that come to American Cancer Society events, you know, community runs and walks and things. And they answer tons of questions about their medical history and their exposures to things and their risk factors. And the American Cancer Society really is one of the world leaders in compiling these studies, which are called cohorts, to understand what are the risk factors for cancer. So these cohorts Alpa and her team have used extensively over decades to look at things like smoking and cancer risk, what are other cancers that are related with smoking, all of that work was used many decades ago to drive public health policy around smoking cessation. These are incredibly valuable cohorts. But nobody had ever, and I’m excited to hear Alpa kind of comment on this too, nobody had ever used these cohorts to just track what were the most important risk factors for developing any type of cancer at a time. So just again, grouping all the cancers together, what is the risk there? And again, the reason this is important now is that people now have the option to learn about multi-cancer early detection, what are these new technologies that allow me to screen simultaneously for multiple cancer types? So we’re trying to really rethink the idea of cancer risk in a way that is, we actually think comports naturally with how people think about cancer, which is – I don’t get to pick if I get it. I don’t want to get any of them. Why are we doing this one at a time. Let’s look at them all together. So I wrote a paper, we published it in the journal Cancer last year. It’s got reams and reams of absolute risk estimates in the tables that you can really look at. And what the bottom line of what we learned is that there are two risk factors that really help us understand the spectrum of risk in these cohorts, and one was single year of age. We told you why that’s important. The second was really smoking. Smoking could really be divided into – are you a current smoker? Which means that you know, if you’re an adult you’ve been smoking for many years. Did you quit in the last 10 years? Are you someone who quit smoking, but you quit relatively recently? Those people are at much higher risk of cancer than people that never smoked, or who quit many years ago. So we looked very carefully at all the risk factors that you’ve heard about – obesity and physical activity. And I mean, literally, we looked at like 20 or 30, different diet and other risk factors. And we found that there really were two that like, really, really drive the most difference in risk. And those are single year of age and smoking. And we wrote up that we think these are what doctors and patients and people can use for really separating people into groups of what their risk is.

Kim Thiboldeaux 18:01
Right? Really helpful. Dr. Clarke. Dr. Patel, jump in, let’s talk a little bit more about this article that you that you guys published, but also how can we use absolute risk to really understand the benefit of enhanced screening. For example, this multi-cancer early detection screening that we’re talking about this, blood test that is an early detector of many, many cancers, and not just the five that we’re currently screening for.

Dr. Patel 18:25
Yeah, so I think, you know, just to build on what Tina just talked about, I think it’s really important to think about, again, you know, not to reiterate the same boring fact that age is unfortunately, the single most important risk factor for cancer. But when you think about absolute risk, you know, a big question is, well, you know, is every 50 year old the same? And, you know, how do we appropriately drive these kinds of screening tests and test for early detection of cancer? You don’t want to have your risks outweigh the benefits of a test. So you don’t want to test a ton of people in whom you’re very, very unlikely to find a cancer or a positive finding. And you know, that requires workup and so on. So you want to make sure that your tests are really being, you know, being used at the population level where they’re going to have, for lack of better words, the most bang for their buck. But when you fold in other risk factors, like smoking in particular, as you’re thinking about the risk of developing any type of cancer, just to give you one kind of data point to think about – if you are a, if you are a woman, for instance, who is around the age of 55, who’s never smoked, and we’re just looking at smoking and age, compared to a woman who’s 10 years younger, but does currently smoke, your risk is actually a little bit higher, if you’re a 45 year old woman who had who is currently smoking compared to a 55 year old woman who isn’t smoking. Now that’s of course risk at the population level, that’s not the individual’s risk. But it’s important to think about absolute risk, right, the absolute five year risk of developing any type of cancer is greater for someone who currently smokes, but is younger than someone who is slightly older, but has never smoked. So when we think about really these types of study results, and where and how they can be helpful with enhanced screening is, you know, okay, well, you know, how do I make that decision with information other than just age, in terms of when to get screened? And so I think that’s really, what was, it’s so interesting to see through our publication last year was how you can actually start to distinguish between different patterns of risk based on factors in addition to age.

Kim Thiboldeaux 21:12
Interesting, Dr. Patel, and one of the things I’m trying to understand, as you’re explaining, so how does this approach that you’re describing, this issue of overall this overall risk lens, right? How does it impact sort of the future of the possibility of population scale screening, right? We all know, I can go and get my mammogram, I can go and get my colonoscopy, based on my age, right, all of those things, right. But if we’re looking at these new cancer screening tools that are that are coming up, where do we need to go to say, okay, I can go to my doctor every year and kind of get this test from a scientific standpoint.

Dr. Patel 21:48
I think from a scientific standpoint, it’s exactly what motivated us to publish the paper that we did last year, right, is when you think about the decades of data that tell us which women will benefit most from getting a mammogram starting at what age, you know, that is how those kinds of evidence based guidelines are built. You know, right now, when you think about most general population guidelines, they are built on age only, again, because not to rehash the same point. But age is the most important risk factor for –

Kim Thiboldeaux 22:23
You guys are killing me with that statistic. I thought we’re gonna be friends, but – [laughs]

Dr. Patel 22:31
The alternative, the alternative is a worst thought.

Kim Thiboldeaux 22:33
I agree. I agree.

Dr. Patel 22:35
I’d rather age.

Kim Thiboldeaux 22:37
Yeah.

Dr. Patel 22:36
But, you know, when we think about, for instance, lung cancer screening, right, that is actually both a risk factor and age-related screening test. So it’s based on the total number of years that you’ve smoked, and your age. And so I think when we think about population level screening, we know that age is going to be important, but part of the research really is how can we make sure that anyone who is at an elevated absolute risk of cancer at different ages, who should go and get this test? And that’s really the research that needs to, that needs to be built now, just like we have historically, for single cancer screenings. We need to do that for multi-cancer screenings as well.

Kim Thiboldeaux 23:27
Okay, Dr. Clarke, we’re getting to the end of the conversation here. I could talk to you guys for days. So hopefully, you’ll come back because there’s so much more that we want to cover. We might need to do a part two on this. But I just want to get back to this idea that, so we have this blood test, this multi-cancer early detection test, that is a, you know, early detector of 50 different cancers, right. That’s what the science is showing now, in that, you know, in that ballpark. And you gave us some statistics at the top of the show that we’re only screening for a few. We’re only detecting a fairly small percentage of cancers with our current screenings that are, you know, that are out there. So just Dr. Clarke, as we close, talk a little bit more about those rare cancers, right? We’re never, Dr. Patel, you said we’re never going to be to a point where we have a screening for all 50 of those cancers, right. It’s just not going to happen. Talk about, Dr. Clarke, these rare cancers, and how do they factor into this perspective in this discussion on cancer risk and the importance of these new tools that are coming forward?

Dr. Clarke 24:21
Yeah, so again, you don’t get to pick if you or your loved one gets cancer and you don’t get to pick which type you get. And many cancers, a substantial part of the cancer burden is caused by cancers that are very uncommon. It’s the accumulation of these uncommon cancers. And if we look at these cancers, one by one, they’re so uncommon that they’re very difficult to enroll people into clinical trials for treatments, and they will sadly, never have a dedicated screening program because it’s just too difficult. It’s not cost effective to be looking for such an uncommon cancer type. So one of the most exciting things about multi-cancer early detection is because it screens simultaneously for a common cancer signal that is shed, this DNA methylation signal that is shed by many, many cancers, it actually gives us a way to screen for those uncommon cancer types that together cumulatively are a part of the burden. So um, so those cancers, those uncommon cancers are bundled into this measure that Alpa and I have been working on, which is talking and thinking about risk of developing any cancer type at a time. And we’re, that makes us happy because we think that really, you know, provides hope and representation to the many cancer patients who are diagnosed with very rare cancer types for which there will never sadly be dedicated screening options.

Kim Thiboldeaux 25:52
Really, really helpful and interesting to hear and understand. I want to thank both of you for joining for the podcast today. Dr. Patel. Dr. Clarke you both have been terrific in helping us understand some of these fairly complex concepts. We do hope you’ll come back because there’s so much more I’d like to ask you and I think a lot that other folks would like to hear and learn from you as well. We’ll all become sort of, you know, armchair epidemiologists, the more we hear from you and the more we learn about risk and learn about the great research that you both are doing. This is the Cancer SIGNAL presented by GRAIL. I’m Kim Thiboldeaux. Please rate our podcast, or leave a review and subscribe to learn more about the impact of early cancer detection on future episodes.

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.

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