Genetics and Cancer Risk
Join subject matter experts from Roswell Park Comprehensive Cancer Center for an interactive for a previously recorded educational event: “Genetics and Cancer Risk." This event aims to educate healthcare providers on the importance of genetic testing for mitigating and understanding the cancer risks of their patients. Our experts will discuss Roswell Park’s new Clinical Genomics Program, the first of its kind in the nation, and its focus on diagnosing and caring for patients whose genetics or family history increases their risk of cancer.
Moderator
Assistant Professor of Oncology
Chair of Perioperative Quality Committee
Director, Gynecologic Oncology Fellowship Program
Department of Gynecologic Oncology
Experts
Professor of Oncology
Chief, Clinical Genomics
Departments of Medicine and Cancer Prevention & Control
Senior Genetic Counselor
Clinical Genomics Counseling Service
Hello everyone, and thank you for joining. I'm Dr. Katie Major, gynecologic oncologist here at Roswell Park Comprehensive Cancer Center in Buffalo, New York. It gives me great pleasure to welcome you all to tonight's event entitled Genetics and Cancer Risk. I'm looking forward to serving as your moderator this evening for what we hope will prove to be a valuable and informative session. Tonight we'll hear from both Dr. Ken O'Nell, Chief of Clinical Genomics, and Molly Hutton, Roswell Park senior Genetic counselor. Immediately following their talks, we will host a live question and discussion period where the experts will answer audience submitted questions based on the presentations you've just seen. You are encouraged to submit your questions at any time throughout the night, as they'll be collected and reviewed as they are received. As always, we at Roswell Park appreciate. Participation in educational series of this kind, as we utilize them as a means of connecting with our peers both in the community and in other institutions statewide. It is our hope that you will find this program informative, and we ask that you please provide your feedback when prompted. Again, thank you for joining us tonight as we welcome Dr. O'Nell. Good afternoon. My name is Ken O'Nell. I'm the chief of clinical genomics at the Roswell Park Cancer Center. Thank you very much for joining us today for this, what I hope will be very exciting and informative webinar. What I'd like to do is start by talking about clinical cancer genetics and cancer risk. What is it and why is it important? When a patient is diagnosed with cancer, they have two questions. The first question is, will I be OK? The second question is, will my kids be OK? When they ask about whether their kids will be OK, what they're really asking about, even if they don't know it, is about genetics. So what are genes? Well, differences in our gene sequences explain the wonderful diversity and variability that is us as humanity. Similarities in our gene sequences explain traits that are shared within families, such as the red hair that is the trademark of the Weasley family. Sometimes, however, differences or variants in our gene sequences hold the key to wellness and illness in our families. Here's Angelina Jolie. She in 2013 wrote an op ed piece in The New York Times in which she described the fact that running in her family was breast cancer and ovarian cancer. Her mother died of breast cancer. And it turned out that she herself was predisposed to breast cancer and so as a result she chose to have a prophylactic bilateral mastectomy to remove her risk of breast cancer. Her goal was in contrast to her mom, who was never able to hug her grandchildren. Her hope was that she herself would be able to hug not just one grandchild child but all her grandchildren. Um, and so we see that genetics can be important, but what exactly do I mean by genetics? What's a gene? Well, let's go back to school. So, uh, genes are the instructions for how our cells work. There's a total of 22,000 genes. Genes are themselves made up of DNA. There's pieces of A, C, T, and G that we all learned about many times in school and in medical school. Um, our genes are exactly the same from the moment that we're conceived until we pass away. And so what that means is that if our genes are the same, our DNA is the same. Now, if we look at any two people, however, even though each of them has exactly the same gene set, the exactly the same DNA sequence in every cell of their body, when you compare between the two of them, there are going to be differences between the two of them, and those differences are called variants. And each of us actually has somewhere between 10 million and 30 million of these variants, so that's a lot of variation that is littered throughout our genome. Now we have two copies of every gene, one that we inherit from our mom, the other that we inherit from our dad. And so you can imagine that if our mom has a variant, as in this example here on the slide, uh, then. We have a 50/50 chance of inheriting that variant because of course a person's mom will have two copies of every gene, one with the variant, one without, and she would pass that one copy with the variant off to her offspring, OK? So variants can be common. Variants can be rare, right? It turns out that most of the variants that are associated with an increased risk for cancer because they are because they are deleterious to a population are in fact very rare. They occur less than 0.025% of the time within a specific population. Now where do variants come from? If they're inherited from our parents, they're actually largely reflections of ancestry where families come from. So here in this slide, variants across a range of different populations were determined and then compared and what you can see in the upper left hand corner, the red uh uh uh dots, um, our population, the red. Letters, uh, there are populations of individuals who are of African ancestry, and you see their variation clusters together. If you look in the upper right hand corner on the other hand, what you see in the orange are individuals of East Asian ancestry, and once again you can see that different populations have variants that cluster together. And then finally down at the bottom of the screen, the green represents individuals of Northern European ancestry and again variation within those populations clustered together. So variants reflect where our families come from. Within a family, however, variants are inherited. We mentioned that everyone has two copies of every gene, um, one that we inherit from our mom, one the other that we inherit from our dad. Now this slide over here is what's called a pedigree, and it's a visual snapshot, a representation of a family. The way that pedigrees work are that squares are boys, circles are girls, vertical connectors are biological siblings, horizontal connectors are biological parents. slashes represent family members that have passed away, and then in this case, the filled in circles are individuals who have a specific trait. You can imagine in terms of inheritance, if we look at the person at the bottom of the filled-in circle at the bottom of the slide, um, female, she has two parents, uh, and she has a trait, right? Uh, if we look at her parents, um, her father has two copies of every gene. Her mother has 2 copies of every gene. Each of them will give to her one of their 2 copies. So she'll have a 50/50 chance of inheriting a predisposition to a trait from her mom or from her dad. OK, that makes sense. We'll go into that a little bit later, uh, much in in greater detail. Um, now when we think about the contribution of variances to human disease, we can think of it as a continuum. Here on the x axis is the frequency or the commonness of variants, and on the y axis is how important a specific variant is towards a specific trait. If we look at the green box on the lower right hand side, we think about common variants, so variants that are present in a population at over say 1% of that population. Well, if a variant is common, it can't have a great effect, right, on a trait because it's too common. If it results in disease, then everyone who is the variant would have, would have the disease and it would be deleted from a population over generations. So variants that can have significant effect on disease risk have to by definition be rare, right? And we see them at the upper left hand side of the screen, uh, my left hand side. Um, in the red box, and these are variants that if you have them, you're highly likely you're predisposed to develop a specific trait. So this is an important conceptual framework to thinking about the role of human variation and human disease. Now what is genetic testing? My colleague Molly Hutton will go into greater detail regarding this topic. It turns out that of the 22,000 genes that are in each of our genomes, only between 40 and 100 have been identified that are important for defending against the development of cancer. You can imagine that if one of these genes has a variant that disrupts the function of that gene that acts as an off switch for that gene, then the risk of an individuals developing cancer will be increased. Genetic testing um actually takes some subset of those 40 to 100 genes, sequences each one of them. And asks whether or not there are rare variants in any of those diseases, any of those genes that acts as a genetic off switch, OK, that's all genetic testing is, um. Importantly, as we saw from the example before, if an individual has an off switch in a gene that is associated with an increased risk for cancer, then 50% of that person's first degree relatives, parents, siblings, children are at high risk of also sharing that, that off switch, that genetic off switch, and therefore being at increased risk for cancer. Now there are two things that have actually made it possible for us in the modern era to perform genetic testing to scale and in an affordable manner. The first are breakthroughs in the technology of DNA sequencing. This is a comparison of the cost of DNA sequencing as compared to Moore's law. Moore was the founder of Intel who in the 1960s made an empirical observation that every two years, the power of computing doubled while the cost of computing decreased in half. If we take that line and start it. The cost of the sequencing of the original human genome and we sort of trend that out to the modern era, we would expect now that the cost of a genome would be still well over $100,000. Thanks to breakthroughs in technology, we're now at the era of a $1000 genome and actually it's possible to sequence the human genome for about $100 using specific. Uh, technologies. So, technology has really enabled the broad application of genetics in uh the, the interrogation of human wellness and human illness. The other landmark that's really made it easy and possible to do genetic testing is a result of a landmark Supreme Court case, the Association of Molecular Pathology versus Myriad Genetics. Myriad had attempted to patent some genes in the, in the human genome that are associated with an increased risk for cancer. By virtue of their patent, they had a monopoly on genetic testing. In 2013, the Supreme Court decided that in fact genes which are our shared patrimony are in fact not patentable. What that Supreme Court decision did was that it opened the door for other companies to enter the field and um participate in genetic testing. And you can imagine the result was as more companies entered the fray, service improved, cost went down, the ease of testing increased, and the work that we historically have thought of as being required for a person to have a genetic test was mitigated and in many cases eliminated. So in fact, competition in this case did exactly what it was supposed to do. Now I'd like to pause for a few minutes and introduce to you my colleague Molly Hutton, who is a senior genetic counselor here at Roswell Park, a very close and dear colleague of mine. She will be speaking to you about genetic testing and who should have genetic testing. Hi, I'm Molly Hutton, senior genetic counselor at Roswell Park. Um, I'm happy to be speaking with you today a little bit about family history collection and the genetic testing process. Um, and so one of the big questions often is how to identify candidates for genetic testing. So we're going to kind of look at some of the characteristics that might be, um, good red flags to help identify patients who would be a good candidate, how to collect the necessary information to really discern that, and then we'll talk about the genetic testing, um, process, what's involved, um, to be able to help facilitate genetic testing or appropriately refer a patient for genetic testing. So typically families or individuals who are suggestive of an inherited risk for cancer have some key characteristics within their personal or family medical history that we would be looking for. And so that may be that there's either multiple people who've been affected with cancer, there may be the same type of cancer coming up over and over or different cancers that could be related to each other showing up in a family. We often are looking at age of diagnosis, you know, cancer is an aging process, so it's not as unusual to see people diagnosed in their 60s or 70s. We're looking for earlier onset, 30s, 40s, generally anything under the age of 50 would certainly be a bit of a red flag, um. And then certain ancestral groups, you know, certain conditions are more common in certain ethnic groups. When it comes to cancer, we often are looking for Eastern European Ashkenazi Jewish ancestry as being an indicator of a potential higher risk for a genetic or inherited condition. And then any rare types of tumors may also be suggestive of genetic risk. And so again, really important to kind of uh collect that information from your patients on not only their personal but their family history to really assess for any of these characteristics. You know, I think it's important to realize that just because there's a lot of cancer in a family doesn't always mean that there's a hereditary risk or a need for genetic testing, so we often are looking for patterns of things and at the same time having a limited family history of cancer does not necessarily rule out the need for genetic testing either. You know, we often use criteria to really help discern the need for testing or not, the appropriateness for testing. But we certainly know that the criteria is not fail-safe. And so we know that the criteria is not the end all be all, and certainly there will be families who have hereditary risk who don't meet the existing criteria today. As we're thinking about genetic testing, who should we be doing this testing for? We often think that the best person to test in a family is the individual who's already had a cancer diagnosis, which sometimes is contrary to what many would think. I've already had cancer. Why do I need to have testing? But what we know is that if there's a genetic risk for cancer, most likely we're going to find it in the individual who's already had that cancer diagnosis. So that's going to be the most informative way of testing a family. But we need to keep in mind that those individuals are not always available or willing or interested to pursue genetic testing, and so certainly testing close relatives to those individuals is also an appropriate consideration. So we often, you know, use the NCCN criteria. The National Comprehensive Cancer Network has guidelines for genetic testing embedded within them, and these are usually a good starting point, not only to help identify patients appropriate for testing. But this often is what is used by the insurance companies or the payers as to whether they would cover the cost of testing. And so this is a good resource to rely on to help not only identify patients but help identify patients who are likely to have insurance coverage for genetic testing. Beyond that, another good resource um is an article that was published. It's about 10 years old now, so it is a little bit older, but it still serves its purpose in that um beyond the most Typical cancer diagnoses and, and kind of considerations for genetic testing. This breaks down things even further, a little more of the rare diagnoses or rare situations to really help, again, guide people towards when genetic testing might be an appropriate consideration. So obviously we've talked about the criteria that would be appropriate to be able to really determine whether a family meets that criteria. We have to collect that family history. And so what is involved typically with collecting a family history, we want to make sure we're collecting at least 2 to 3 generations of family history, so we can't limit it just to siblings and parents. We need to extend further. We need to make sure as we're collecting that family history. That we're looking at both, you know, maternal and paternal sides of the family and that we're documenting, you know, where these relatives um lie because family history spread across both maternal and paternal is not additive. We need to look at them in their own singular silo. And again, we need to always ask about ancestry because certain ancestral groups may, um, just based on ancestry indicate a need for genetic testing. When we're documenting family history, the cancer history obviously is what we're really focused on here when we're thinking about genetic testing for cancer. And so we want to document the specific type of cancer whenever possible, um, the age of onset, and again, which side of the family that family member is is from. It's important whenever possible to really kind of ascertain the confidence that somebody has in the diagnosis that they're reporting and really try to determine is this a new primary versus a metastatic site. Obviously the important pieces to us really are about the new primaries and the more accurate the information we have, the more accurate our assessment's going to be as to the likelihood of there being a genetic risk. And I think the biggest piece is to know that we have to update family history regularly. Family history is always changing. There may be new diagnoses from one year to the next, and there may be an individual who's not suggestive of genetic risk that a year later, based on changes in their family history, that could certainly have changed the assessment. You also want to be careful as you're collecting family history to not limit the questions or the, the family history information you are collecting to uh a specific clinic site, you know, we don't wanna ask only about prostate cancer family history when we're working in neurology, um, or only asking about. or uterine cancers from a gynecology office. We know that these cancer risks, um, are not limited to a single disease site when there's an inherited risk. It's often going to involve multiple organs and therefore, the presentation in a family history could be spread across multiple body parts. So there's a couple different ways, you know, that people can go about collecting family history. One would be simply to use a family history questionnaire that either can be sent to patients in advance of being seen in the office or it could be completed while they're in the waiting room. Something as simple as just kind of walking them through each of the relatives and, you know, their 1st, 2nd, 3rd generations of the family and asking specifically about possible cancer diagnoses and age of diagnosis. Alternatively, there are online resources as well, um, you know, a pedigree is is essentially a family tree in genetic speak and so there are um free online resources that can be used again could be sent to patients ahead of time to ask for them to provide this information to the office. And then also the, um, surgeon General's office put out a, a family history, um, collection tool many years ago that is still available, um, that is another resource that could be used to help with the family history collection process. So now that we've talked about how to identify patients appropriate for genetic testing, the next question becomes what now, you know, ideally any patient who's going to pursue genetic testing would have some form of genetic counseling ahead of time prior to testing, ideally with a formally trained genetics provider. We know that that's not realistic. however, you know, there, there's not enough providers readily available. Patients may not be willing to, you know, go to another location, have another appointment. And so there's a lot of new service delivery models being, you know, considered, and, and one of them is what we call a point of care or a point of service model where the patients within their home clinic, whether that's their primary care provider, their GYN, whatever it may be that those offices may start offering genetic testing to people directly with the assistance and support of the genetic providers in their community. And specifically, that would be to, you know, refer the more complex cases or the results that are not quite as clear to meet with a genetics provider after the testing's already been completed. And so we are a resource here to help with that. You know, I think some of the common myths that cause health care providers to avoid genetic testing is the idea that it's expensive, it's not covered by insurance. This is just something that patients aren't going to be able to get done. I think it's really important to realize that in fact, most insurance companies cover genetic testing when people meet appropriate criteria and are appropriate candidates for the testing themselves. This even includes Medicaid and Medicare. Uh, the genetic testing laboratories often are gonna to interface directly with the insurance to, um, do the billing and, and confirm coverage and benefits. So it's not something that the healthcare providers have to take on firsthand. And additionally, a lot of the genetic testing laboratories offer reduced prices and financial assistance for patients, whether they don't have full insurance coverage or they're paying out of pocket completely. Testing often can be done at a fraction of the cost that most people think. Another important piece a lot of people are concerned about discrimination is, you know, having a genetic test result that says I'm higher risk for cancer going to somehow impact my insurability. And so I think another important myth to to bust is to know that that's not the case. There's actually laws that exist on a federal level that have been in place for quite some time that help to protect a genetic test result or the genetic information from an individual. Essentially these laws indicate that, you know, you cannot lose your health insurance, you cannot be denied employment based on a genetic test result. And so the idea that genetic testing is expensive, it's time consuming, it's complex. Um, actually, once you kind of figure out a few of the logistics and have some support in how to do the process or the workflow, actually comes to find that it's not so difficult after all. So you know what are the steps to doing genetic testing? We've already talked about first and foremost is identifying who's appropriate for it. Once we've identified, you know, an appropriate patient for the testing, the other thing we have to do is know where are we doing that testing. There's a handful of laboratories in the country that do this testing. They all have pros and cons to them, but generally speaking, they are offering a good service, and so you need to interface with those laboratories and with their lab reps to identify what might be best for your practice. You also have to identify what testing you're gonna be doing, um, you know, more is not always better and at the same time we don't want to do too little of testing that we might be missing anything, whereas historically genetic testing was often done in a single gene process as more and more genes have been discovered that are contributing to cancer risk in families, we nowadays do often multi-gen panel testing where we're gonna look at a lot of different genes all at one time. This is certainly a more efficient approach. And what we've learned is that a small percentage of families and patients may have more than one genetic risk factor, and the only way we would know that is by having done more expanded testing for them. So it's important to have a discussion with the patients prior to testing, to explain to them the value of the testing, you know, what is going to be done, what information might we learn from the testing, what are we going to do with that information? There are resources available to help with that as well, and in fact we have a patient education video that we use in the clinics here at Roswell that just in brief kind of gives that bare bones overview so that patients have a better understanding of what to expect and what they might be pursuing if they decide to move ahead with testing. Another important piece to the genetic testing process is written informed consent, and so New York state law does require that this be on file for any patient pursuing genetic testing. A lot of the laboratories have a generic consent form that can be used and so you can certainly create your own or on the other hand, look to the laboratory that is your choice to see if they can help with that. Essentially informed consent is important to make sure that it's including a description of what testing is being done and the purpose of that testing, the possible results that could be derived from testing, and finally a plan for disclosure of those results. Once you've gone through those steps, obviously you need to collect um the sample from the patient, the blood sample, sometimes testing can be done on a saliva sample. There's a test requisition form that the laboratory would help you with, and then ultimately a plan for disclosure. Genetic test results will usually come back about 3 to 4 weeks after a sample's been collected and submitted. And so then a plan as to how those results are going to be discussed with the patient is important. I think the next step to know is that, you know, what are the possible results. A lot of people expect genetic testing to either be, you know, yes or no, positive or negative. We found something or we didn't. Unfortunately, it's not always that clear. Um, certainly we have those situations, and in fact, most people who pursue genetic testing are negative, meaning that there were no mutations identified. Doesn't mean they don't have a risk for cancer, but it does mean we've ruled out to the best of our ability whether that they have any type of inherited or increased risk for cancer. A lot of times in those situations, the recommendation will be that they're going to be screened and followed based on their personal and family history still, which may still indicate a need for increased screening. I think obviously the other end of things is, you know, a positive result we found something indicating an increased risk for cancer in these situations there may be very specific recommendations for medical care and and changes to medical management, which certainly Doctor Onell is going to um discuss in more detail here. What I want to touch on is the, the third possibility, which is this middle of the road here. Um, sometimes we will get a result that is called a variant of unknown significance. Um, these variations essentially mean that there is something different about the gene than what was expected. But we know that all of us have variations in our genes. They don't always affect our health. And so just because something has shown up different doesn't mean that it's actually posing a risk or disrupting the function of that gene. At this time, the recommendations are is that medical care should not be based on a variant of unknown significance. What we know is that most of these variations after further research end up being reclassified as benign. And so in the presence of a variant, the recommendation is that the patient continue to be followed based on their personal and family history and not based on that genetic finding. So some key takeaways, you know, as you think about the consideration of genetic testing for your patient population, like I said, very important to have a conversation with the patient, to explain to them why testing might be worth considering, what that information might mean for them and their families, and how that can be used to their benefit to be more proactive about their medical care. Important to make sure you're obtaining informed consent and a signed documentation of. If you're going to help facilitate genetic testing for a patient, I think it's important to know, you know, where you might send patients for a conversation. You know, if you're going to do your own testing, make sure that you have resources available to you for those more complex patients, for those results that are a little more complicated. Certainly genetic resources exist, you know, here in western New York and otherwise that can certainly support you with that. Like we said, a negative. does not mean that we've ruled out all possible risk. It's important to make sure patients understand that as well. Negative results never the get out of jail free card. It does not mean that there's not higher risk that they need to be screened for still. We just talked about the consideration of having a variant of unknown significance come up on testing, and I think it's important to remember that a variant means we just don't have an answer. Those variants should not be used. To make decisions about medical management but rather should kind of be tucked away until more definitive information might become available down the road. And then again, it's really important to keep reviewing all of this, you know, we talked about that the family history can change over time. I think it's important to remember that genetic testing changes over time as well. Technology advancements. There may be things that we can test for down the road that aren't available currently. And so even in patients who've already had testing, it doesn't mean they're not a candidate for more testing down the road. So like I said, we are certainly a resource here at Roswell Park. Our clinical genomics service has both genetic counselors as well as physicians and advanced practice providers who can help assist patients with having genetic testing, interpreting and understanding their test results, as well as managing their risk. And so certainly we're a resource for all. Doctor Oll's going to talk a little bit more about the medicine side of the service and how for patients who are identified to have hereditary risk, what the next steps might look like for them. Thanks very much, Molly. That was fantastic. Again, I'm Ken O'Nell and uh uh now let's continue with our discussion of of genomic medicine cancer risk. So as Molly described, genetic testing is is a critical part of the entire cancer risk endeavor. What I'd like to do now is just take a moment to show you how we do, how we use it in practice. Now you may recall this pedigree we looked at it earlier, although now what You can see is that the trait that we were discussing is actually the occurrence of cancer within specific family members. Now this is an actual family that we cared for. Um, what happened was that there was a young woman aged 38 who was diagnosed with breast cancer. She was offered and had genetic testing performed, and it turned out that she was positive for an inherited predisposition to breast cancer and ovarian cancer. Um, we know that she has inherited this trait from one of her two parents, as we discussed previously. However, we don't know which one. the next person in our family who was tested was her father's sister, her aunt, who had been diagnosed with breast cancer at age 42. And it turns out that her aunt was also positive for the same inherited predisposition to breast cancer. Now, if we think about it, If our patient is positive for a predisposition, her aunt is positive for the very same predisposition, what that must mean is that our patient has inherited that predisposition from her father. Even without testing, we know that this must be the case, right? In fact, we tested him and of course he was positive, OK. Now, we then turned to the two adult children of uh our, our patient's aunt who had been diagnosed with breast cancer at age 42, her daughter and her son. And we offered testing to each one of them, and what we found is that in this case her daughter was negative, had not inherited the genetic predisposition to breast cancer and ovarian cancer, but that her son had inherited that predisposition. So as you can imagine, a positive result is important because it identifies people who are at increased risk for cancer, but importantly, a negative result is also important. It doesn't mean that, uh, our, our aunt's daughter is never going to be diagnosed with cancer. It means that she's not at risk. For cancer, but importantly, what it also means is that since she has no inherited predisposition to pass along, none of her future children can possibly inherit a predisposition from her, right? So a positive and a negative result can have significant meaning for individuals and for families. But genetic testing is just the first step, so we test a person, we find that they have an inherited predisposition to cancer. What do we do now? Well, in fact, clinical cancer genetics is genetic medicine, it's not just genetic testing. It turns out that thanks to knowledge, thanks to investigation, thanks to clinical research that has been performed here at Roswell and elsewhere, genetic testing has transitioned from having limited clinical applications to having profound medical consequences. It's important for patients diagnosed with cancer because in some situations it helps guide their therapy. It's important, as we've seen, for individuals and families without cancer but at high risk for cancer because it helps us determine how to best keep these individuals and families. safe. So specifically for uh individuals who have been diagnosed with cancer, understanding predisposition helps us to find precision cancer therapies for these patients that improve outcomes. Some examples are listed here on the slide. Um, it's also important because it helps us anticipate future risks for other cancers as well. For individuals or families that have not been diagnosed with cancer. Understanding their predisposition helps us prepare with them and oversee with them surveillance right across multiple cancer types for which they might be at risk, um, you know, so it's also important. Uh, for cancer prevention, for example, individuals who are at increased risk for breast cancer or ovarian cancer may choose to actually, if their ovaries are the tissue that's at highest risk for cancer, they may choose to have a risk reducing surgery and remove completely that tissue from risk, thereby, uh, getting rid of their increased risk. For families that are thinking about having children, knowledge of predispositions can be used to guide family planning. In fact, there's something called PGTM or pre-implantation genetic testing of mutations that can be used for an individual who has an inherited predisposition to cancer to ensure that their future offspring doesn't have that predisposition. What would happen is, uh, let's say there's a woman who's at increased risk for cancer. Her eggs would be harvested, they would be fertilized in the laboratory, uh, with her partner's sperm, um, and, you know, embryos would be created. The embryos would be grown to 6 cells or 8 cells, and then one cell would be tested for the uh for the genetic predisposition, the pathogenic variant that the mother carries since all cells of every individual have exactly the same DNA. Sequence gene sequence, if that embryo does not have that variant, then the baby that results from that embryo will also not have that variant, and it's a guarantee. So in fact, it's it's like Star Trek, you know, these tools that we have now can just change the trajectories of our families. Um, of course, also understanding risk in in an individual can help us with what's called cascade testing or genetic testing of family members to help them learn of, understand, and face their risk, um. So what is important to realize is that pre-test genetic counseling in many cases is now being supplanted by post-test genetic medicine. This is where we actually get to help our families and so thinking about heritable cancer predisposition, it's really changed from learning of a person's risk to actually taking action. And uh it's moved to the realm of prevention and wellness, and that's the modern era of, of, of cancer risk. So, as an example of what we can do for individuals who might be at an increased risk for cancer, let's think about BRCA2. There are sets of cancers for which individuals who have a pathogenic variant and off switch in BRCA2 are at risk. They include breast cancer, ovarian cancer, and endometrial cancer for women. We can offer them surveillance or risk. surgery to actually remove the risk, surveillance for breast cancer would be alternating a breast MRI and a mammogram each once a year, alternating by every 6 months for ovarian cancer because we're just not that good at um uh ovarian cancer surveillance, we really would offer her um risk reducing surgery. What's called the bilateral salpingo oophorectomy between the ages of 40 and 45. After she's finished having children and uh at the same time as we would uh perform the bilateral. Salpingo oophorectomy, um, we would propose that she have, uh, her uterus removed to remove, uh, any excess endometrial cancer risk, OK? For men. Uh, men are at increased risk for prostate cancer if they have a BRCA2 pathogenic variant. So what we would do is a digital exam and a PSA starting at age 40. For women and men, there's an increased risk for pancreatic cancer, um, and, uh, for that extra risk as compared to the general. Population we would again do surveillance. We would do what's called an MRCP, which is an MRI of the pancreas, once a year, alternating every 6 months with an endoscopic ultrasound, which is endoscopy, uh, down into the small intestine and then into the pancreas to visualize the parts of the. And the thing that's amazing is that this pancreatic cancer surveillance has been shown to work and to be highly effective at detecting pancreatic cancer at an early stage and what is most important to definitively improve outcome in what is thought to be a uniformly fatal disease. Um, there is potentially an increased risk of melanoma as well in individuals who have a BRCA2 pathogenic variant, and as we would for every human being on planet Earth, we would recommend that they see a dermatologist for an annual skin check looking for skin cancer. So as you can see just from this very simple example, surveillance after genetic testing is complex. It has lots of parts and lots of different specialties, and that is definitely a problem for many of our patients, and it's something that we need to think about as we offer them genetic medicine. Before we actually talk about that, however, what I wanna do is just run through some numbers, OK? So, who gets cancer, OK? So it turns out that in the general population, 1 in 2 men and 1 in 3 women will be diagnosed with cancer over the course of their lives. Turns out that somewhere between 7% and 10% of all cases of cancer, um, are the result of inherited predispositions, OK? So that's quite a percent, right? But it's not 7 to 10% distributed uniformly. Some cancers are more likely to have a genetic etiology and some cancers are less likely to have a genetic etiology. Uh, liver cancer, hepatocellular carcinoma, for example, is highly unlikely to be the result of an inherited predisposition. Um, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, endometrial cancer are much more likely to be the result, uh, of, of an inherited predisposition. A factor that may have meaning both for treatment of these patients and of course for their family members as well. Other cancers such as sarcomas and pheochromocytomas and paragangliomas, the contribution of genetics or the individuals who have inherited predispositions is even higher than that 10 to 20% that we see for these other cancers that we've just enumerated. Importantly, I really want to point out that cancer risk isn't just something to think about in people who are diagnosed with cancer. If we think about the general population and we think about risk factors for breast cancer, it turns out that somewhere between. 15 and 20% of all women on planet Earth, 1 out of 5 women on planet Earth, uh, meet what are called high risk criteria for breast cancer and as a result, uh, qualify for a genetic evaluation and genetic testing. And an annual breast MRI alternating with their annual mammogram. Both of these are standard of care. Both of these are covered by insurance, no questions asked. So it's important to think about not cancer risk, not just for patients that are seen by. Oncologists or oncologic surgeons, but for patients that are seen in the general community as well, um, because, uh, they may need a significant proportion of them may actually need uh uh cancer risk evaluations, OK, and interventions to keep them safe. Uh, now if we think about patients here at Roswell, let's run the numbers. We see here roughly 10,000 patients newly diagnosed with cancer each year based upon criteria and professional society guidelines, about half of them, or 5000 should be offered genetic testing. OK. Of that 5000, roughly 20% or 1000 will be positive for some sort of inherited predisposition. Now let's think about their families. Each person with a positive result is going to have say 4 1st degree relatives in the Buffalo area parents, siblings, and children, OK? All of them will need genetic evaluations, half of them will be positive for an inherited predisposition. And need to be followed. So if we just think about these numbers, 1 year's worth of new patients seen here at Roswell, that's 9000 patients each year who require a cancer risk evaluation, 3000 patients each year who require ongoing cancer surveillance and cancer risk care based upon an inherited predisposition. Then of course, we've already, uh, we have to think about as well, the 15 to 20% of all women and many other members of the community who require evaluations and surveillance as well. So the need therefore is integrative care and queer coordination. How do we do this? How do we help all of these families? Well, there has to be systemwide and community-wide access to genetic testing, and then equally important, testing has to be coupled to a medical safety net for patients who have already who have undergone genetic testing and need to be cared for. Given the various specialties that are involved in care. There's a requirement for ongoing multidisciplinary medical surveillance across the multiple specialties that are involved, and then of course we have to help family members, right? We have to help make this accessible not just to patients at Roswell but to patients in the community as well, OK. And so that's what we've done here at Roswell. We've actually formed the first of its kind, a clinical genomics medicine service that's dedicated to caring for patients and families that are at high risk for cancer because of their genetics or family history. It doesn't exist anywhere in the country. And so we formed this new department. It has two parts, a counseling service that's led by Molly. Uh, um, that is to help people who have not had genetic testing, get genetic testing. And then for those who test positive, they they they are referred to the medicine service where we oversee and manage their ongoing medical care to keep them safe in collaboration with their oncologist, with their surgeon, or with their primary care provider, OK? This is, I think, a primary care adjacent program that is uh uh that feeds back and forth with an individual's regular physician. So our mission statement is that what we're creating is a cancer wellness medical specialty home for patients and families at high risk because of their genetics or family history. We link genetic testing with ongoing medical care and we coordinate in an ongoing manner our patients' multidisciplinary service needs and partnerships with their providers and with the many cancer experts here at Roswell Park. Conceptually, this is what it looks like. So clinical genomics is the medical specialty home we oversee and coordinate care and then we have a variety of high risk clinics that are run by domain experts who are part of our department. Um, who understand and are familiar with genetic predispositions in their area of expertise. We in the clinical genomics medicine service coordinate for all of our patients, their ongoing needs across these different Um, um, high risk clinics. Importantly, prevention and wellness is not just about, um, a high risk clinic, it's about prevention and wellness, and so there are other components of care that are important for us, so reproductive medicine. Endocrine and metabolic health, diet and nutrition, smoking cessation, and of course mental health, right? And these are all woven into the, the network of care, the network of wellness, uh, that we provide our patients. So, uh, again, it's a medical home dedicated to prevention and wellness. If we think about it in Buffalo terms, we are the Josh Allen. Of the cancer risk team, we quarterback care for our patients and families to ensure that they stay safe. And again, we're the first of our kind. Nobody else is doing this, so there's a unique opportunity for Buffalo and Western New York patients to take advantage of a really innovative and important program that can change lives and change families. Um, uh, our goal is to be patient and family centered in this medical home, but we collaborate with our colleagues, right? We are a consult service just like every other consult service. We have, uh, a multi-specialty care team. Facilitate testing, um, we care for in partnership with uh uh community doctors, patients that we see and we facilitate communication. We make sure that all members of a patient's care team, uh, talk to each other and of course we're more than just surveillance, right? We're a source of medical truth, one place to turn to for our patients and their families about cancer risk and how to think about it and how it fits into their lives and their families' lives. Um, importantly, we facilitate testing for patients here seen at Roswell. They don't need to be seen by our genetic counselors. We've enabled here just as part of routine care, our providers in the various specialties to order as part of their routine. initial workup of patients, genetic testing for all patients who are seen at Roswell. And so it's an important component of how we think about care and how we integrate all aspects of cutting edge therapy into defining precision medicine care for patients who are seen here at Roswell. Um, our scope is prevention and wellness again, I, this is the theme that comes up over and over. We're a collaborative program to serve our patients, their families, and their communities in partnership with their primary care providers and with Roswell experts. Um, we have empowered our colleagues here at Roswell who are caring for patients. Diagnosed with cancer to perform point of care testing to ensure that every patient who needs a genetic evaluation as part of their precision cancer care here at Roswell Park gets that. Um, we in the medicine service provide longitudinal medical follow-up for all patients with heritable cancer predispositions. Or high risk family histories and our major job is to coordinate care and help patients navigate the myriad components of the medical system. We review and we interpret the surveillance results, we facilitate subspecialty follow up, we facilitate communication. Uh, among all members of the care team, and we, you know, take advantage of complement with, and synergize with the existing well wellness programs that are here at Roswell. We also, uh, complement and work in partnership with an individual's primary care provider if they're referred from the community. Uh, the point is that this is a collaborative enterprise to keep people out of the hospital and out of Roswell, OK. Um, and of course we oversee cascade testing for family members as well to make sure that what we learn from one patient can help all members of their family, OK? So who should be seen by the counseling service, who needs a genetic evaluation? Molly has already touched on this, but I would summarize it as anyone who would benefit from a genetic evaluation and or genetic testing for cancer risk. Anyone with a family history of cancer, anyone meeting criteria or diagnosed with certain cancers that are very highly genetic, such as the pheochromocytomas and paragangliomas that we mentioned earlier. Anyone who's been diagnosed with breast cancer, ovarian cancer, pancreatic cancer, colon cancer, endometrial cancer, or uh high risk prostate cancer, especially if they have an Ashkenazi Jewish ancestry. Um, of course, if, if individuals with these cancers can't be tested, then their close family members can be and should be as well. Then of course there's the whole population health component. We've already touched upon the up to 20% of all women meet high risk criteria for breast cancer and should be offered genetic testing. It actually turns out that among individuals with Ashkenazi Jewish ancestry, 1 in 40, 2.5%, have an inherited risk for cancer, 2.5%. That's a public health crisis, and I would argue that all Ashkenazi Jews should consider genetic testing because of that. So who should be seen by the medicine service? Well, anyone who has a positive result or a variant of uncertain results irrespective of where the testing was performed, any patient with a negative result who has a family history, right, uh, any patient with a positive family history irrespective of their genetic testing result. So our job is to care for patients after they've had testing longitudinally and make sure that they stay safe. Um, our team is multidisciplinary. We have doctors, we of course have genetic counselors. We have APPs, navigators, or high risk specialists. There are a variety of associated specialties and of course social work to ensure that we can actually do what we promised to do for our patients and their families, um. Key takeaway points, right? So clinical cancer genetics is not just about genetic testing, it is about genetic medicine, care coordination, and providing a medical home for patients and families. Half of all patients diagnosed with cancer should have genetic testing because it matters for their treatment. Thanks to the new technologies, comprehensive and inexpensive genetic testing is easy and accessible. Providers can perform point of care testing or refer to us for uh for evaluation and testing because prevention and surveillance involves managing patients across many specialties for life. The Clinical Genomics Medicine Service serves as a medical liaison between expert subspecialists and primary care. Uh, we also of course facilitate care for family members. So this is the landscape scape everywhere of cancer risk care right now. It's ad hoc. It's catch as catch can. It's if someone thinks about it. Where we're headed and where Roswell Park Comprehensive Cancer Center is leading the way is moving to the worlds of precision risk assessment, disease prevention, and therapy. I want to come back to where we started thinking about Angelina Jolie. At the end of the day, knowledge is power. This is about taking action, keeping yourself and your family safe, and of course for you, uh, my colleagues, your patients. With that, I'll end. Thank you very much. OK, thank you everyone so much for joining us this evening. Um, again, I'm Doctor Katie Major, one of the DN oncologists here at Roswell Park, and thank you so much to Doctor Ken O'Neill and Molly Hutton here for um these amazing presentations and um. We were going to go ahead and jump into some questions that have come up from the presentation, um, so feel free to keep sending those our way. Um, we'll jump right in in a minute and of course, um, uh, please feel free to add anything additional. So, um, starting with one question we had here, if a patient has had previous genetic testing, how do we know if or when they should be tested again? Molly, maybe you want to take that one. So that's a great question. Um, you know, I think historically testing was really done single gene testing. So depending on how long ago it was, it may have been very limited, and now that we're doing multi gene panel testing as kind of the standard of care, um, anyone who has had very limited testing, that alone should be a good indicator. But even when panel testing first started, it was on a very small basis, and so we may have only been looking at 5 or 6 genes in a panel, whereas now we may be looking at 50 to 70 genes. You know, I always say I think a good rule of thumb is that if anyone was tested before 2015, it's probably a good indicator that they should revisit it, but you know, there's going to be a lot of different parameters to be looking at, but that's a good starting point, I think. And I just wanna add that the identification of one pathogenic variant in the gene. Doesn't mean that our work is done. If we look at data from all of the major testing labs and from panels that have been performed by the major testing labs, what we've learned is that 3 to 5% of the general population actually has more than one pathogenic variant, and that proportion can even be higher in specific populations like Ashkenazi Jews where there are common founder variants. OK, well, I, I think following up on that question, you know, you um detailed in your presentation, uh, some groups that have higher rates of specific genetic mutations that can predisposed to cancers. You know, are there, are there any groups that, um, That would very much benefit from genetic testing or, you know, are there any barriers you sort of identify uh within any groups to to getting genetic testing? Um, I think that genetic testing is a personal decision, and I really think that, uh, generalizing is not a good idea because it's such a personal decision. Um, globally, I think that genetic testing is important for everyone, um, because knowledge is power, and if there's an inherited predisposition that someone carries, it really doesn't care whether you know about it or not, right? So you might as well know about it because then you can do something. In terms of thinking about different groups and genetic testing. Um, what we know is that if, uh, uh, an individual of European ancestry has genetic testing, um, there are fewer what are called the fewer variants of uncertain significance that are identified. Um, and that's because more individuals of European ancestry have been genetically characterized than individuals of other ancestries. So, uh, when thinking about the results of testing as opposed to who should be tested, um, we as clinicians uh know to expect more uncertainty in our results, uh, from individuals who are non-European ancestry. And it's really just a function of we just need to sequence more people of diverse ancestries and backgrounds. I think the one other thing I would mention, you know, not that there's necessarily a group who's resistant to testing, but I think globally there's a lot of misunderstandings about genetic testing. And so I think the myths and those misunderstandings maybe keep people from choosing to pursue testing. And so we are always encouraging people to have the conversation, you know, go have a meet with a genetic counselor or talk to your doctor about the option of testing. It doesn't mean you have to do the testing. But it might be that the reason you are hesitant or resistant is based on misinformation and so really wanting to just make sure people are at least having the conversation. Great, um, and so speaking about conversations around genetic testing, um, the question from the audience, if a patient has a genetic predisposition to if a patient with a genetic predisposition to cancer has adult grandchildren, should they encourage them to get genetic testing? Molly, you can take that one, Well, so let me clarify that the person has a genetic predisposition, so we know there's an identified genetic risk in this family, so perfect. So you know, kind of like Dr. O'Neill said, right, knowledge is power. We absolutely want to see these families, you know, passing that on to those next generations and really having that. Conversation to at least let their relatives know that genetic testing might be something they want to consider. It is an individual choice. It's not something everyone's going to choose to want to have that knowledge for, um, but we want them to have that choice. So we encourage everyone to share their test result with their relatives, let them know that testing is an option for them. Um, generally, these inherited risks for cancer are adult onset risks, and so, right, we, we're not worried about the little people, the children, the teenagers, but as they reach adulthood, these are conversations we would encourage families to have with, with those adults. With regard to that question, was it asking if someone has a known predisposition should their adult grandchildren? What about the children, right? Right? And so that's an important consideration because if a person has an inherited predisposition, then that person's child would have a fifty-fifty chance of inheriting that predisposition. If that person does inherit the predisposition, then that person's child or the original person's grandchild would also have a 50/50 chance of inheriting the predisposition. On the other hand, if the original person's child did not inherit the predisposition. Then that person's child would have nothing to pass along to their grandchildren, so. Building on what Molly is saying, it, it just really depends upon the chain of inheritance. Uh, in terms of determining what the grandchild would do, right, but certainly, you know, we always point out to go, although it makes sense, right, let's hit the child first because if they don't have it, we don't need to worry about the grandchild, but there may be reasons why, you know, that person is resistant, that person's not available, and so we would never, right, and so we would, we would say, you know, certainly we don't. Limit testing to that grandchild, that next generation, because the one before them weren't tested because there may be situations where that's just not possible. Right. OK, great. Um This I think is a, is a very meaningful question. Um, your group is focused on cancer. What if another inheritable trait is identified? Huntington's, for example. Who handles those patients? Are there resources in the region? So the answer is definitely yes, there are resources. We work very closely with our colleagues at UB um led by Laurie Sadler, who is a wonderful colleague, a wonderful geneticist, um, but it's important to. You understand that when we do genetic testing or genetic evaluations for our patients, we really do focus on cancer predispositions. Certainly there are some conditions like ataxia telangectasia that have non-cancer associated. Uh, components and so we do manage those patients in collaboration with other specialists, both at Roswell and at UB, um, or other centers actually nationally, but, um, we specifically don't do non-cancer conditions. Our mission is really cancer related inherited predispositions. So, I'll ask a follow-up question, um. You know, sort of related to this idea of broad genetic testing. I think a very, you know, common phenomenon now is these direct to consumer, um, gene tests, right? And often they're related to ancestry and genealogy, um, but there is a component that can be looked at that is, you know, these types of genetic, um, changes and can span the spectrum, right, from cancer disposition to predisposition to others, um. What would you say, I guess this is a two-fold question, what would you say to, you know, uh, providers who are in the primary care setting, right, if the patient asks them about whether or not they should do that type of testing, you know, in that setting. And then, When they get a result. Um, you know, often these, these, uh, companies will offer genetic testing, you know, should they come and see somebody beyond that. Do you want me to try this? Sure, it absolutely definitively they need to see someone um. Who's doing a medical grade test now and it's important to remember that a lot of these companies actually don't do genetic sequencing. What they do are genotyping using microarrays, and that's why most of the time they actually don't give results that are medically meaningful, right? Um, because it's not the the purpose of what they're doing. Um, so, But even the ones that do in very limited ways uh uh look for and give results that are potentially medically meaningful, it really needs to be confirmed by a practitioner in a CLAA certified laboratory in an environment that is medical grade, because otherwise they're just not actionable and Um, to sort of add to that, there was a very interesting experiment performed by the Medical Journal of Record, The New York Times, um, in which there was a reporter who sent his sample to 3 different genetic testing labs and just looked at the results, and they differed one from the other by 50%. It's just Crazy, so I'm very nervous about believing anything from these direct to consumer laboratories. Well, and I think to take the other side also is I think often patients will come in and say I've had this done. It was negative. I've already been tested, and I think it's, you know, one thing to go, Hey, we don't want to trust the result when there's a result, but I think we also need to be very cautious of we've not ruled everything out by any means because these tests are never testing for everything. And even way back when these first rolled out thinking about the BRCA genes, which most people are somewhat familiar with was that A lot of people believed they were being tested for the BRCA genes and in its initial format these direct to consumer tests were only looking for the three founder mutations that were common to the Ashkenazi. And so if you weren't Jewish, then this probably wasn't even starting to touch on. And those were the only medical grade. Tasks that were offered by 23andMe at that time. And so a lot of people that I've met with patients who believed they had already been tested and ruled out and when we talked in more detail they went, Oh gosh, no, I didn't even get close to really being tested for this yet. Yeah. OK, um, another question, what recommendations do you have for someone who is adopted or does not have access to their family history? So that's, that's a really great question, and we see a lot of patients in that situation, more and more so. um, you know, genetic testing used to always really be based on a family history. What was your personal and family history is testing really indicated. Because we know that a lot of cancers are not genetic, and so a lot of times genetic testing may not necessarily be beneficial, but we meet with a lot of people who go, I don't know my family history, and in those cases it's kind of a black box and so we absolutely will offer genetic testing to anyone. Limitation unfortunately is that a lot of times insurance coverage hinges on whether there is a family history and so in the absence of somebody knowing that, you know, somebody who is adopted, oftentimes what our discussion will be is that absolutely we can do testing, however it likely is going to be an out of pocket expense. The good news is that most of these commercial testing laboratories today offer significantly reduced rates for people who don't have insurance coverage who are paying out of pocket. A lot of times these tests can be done for $250 or less, and so we encourage people to consider it still. And the companies have financial assistance programs. Right. Um, all right. Well, thank you so much everyone for joining us. I think that will, um, uh, conclude our Q&A session. Thank you so much to our experts here and all your insights and um. Have a great evening.
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