Dana-Farber’s Young-Onset Colorectal Cancer Center's Gut Instincts quarterly webinar series continued on Thursday, June 9, 2022 with an educational workshop on Best Practices for Genetic Testing. Topics include assessing for inherited cancer risk, genetic testing and counseling, management for patients with inherited risk and a patient's perspective. This webinar is for healthcare professionals, patients, and supporters.
Hello everyone and welcome to this next installment of gut instincts, which is a quarterly webinar series that the young onset colorectal cancer center here at Dana Farber puts on to educate the health care community about issues relevant to our young patients with colorectal cancer. I am Kimi and I am the director of the young onset Colorectal cancer center here and I'm really pleased to be moderating this session today. I think that you will all find it very educational. I actually learned a lot as I was going through the slides myself. So, um I am really eager to to hear what you all think and to answer all of your questions afterwards. We will have each of the speakers introduce themselves and then each of them will talk for about 10 minutes and we should have ample time at the end for a question and answer session. Please use the Q and a function to type in your questions as you think of them and we will address them at the end. So without further ado, I'd like the speakers to each just give a brief introduction as to their name and their role here at Dana Farber. So we'll start with dr jorgensen. Hi, my name is Matt, you're going, I'm a Gi oncologist here at Dana Farber. So and I see and treat people with a variety of GI cancers. I also work in our genetics group um as the director of our lynch syndrome center where I oversee the work up and the treatment and management of people with, with lynch syndrome and other forms of inherited Gi cancer risk. Thank you and welcome. Hi, I'm a new Chittenden. I'm a genetic counselor, a senior genetic counselor and lead genetic counselor for the Lynch Syndrome Center at Dana Farber. And I have been working in cancer genetics for more than 20 years. Hi and I'm Ramona limb. I am a gastroenterologist at the Brigham um in women's Hospital as well as um working in cancer genetics in our dana Farber lynch syndrome center. Um and I have a special interest in our endoscopic management as well as many of our patients with hereditary cancer syndromes, including lynch syndrome and other polyp oc syndromes. Hi everyone. I'm rich Barbarino. I'm going to be representing the voice of the patient as it relates to colorectal cancer and genetic um genetic disposition. I'm a computer engineer. So I'm going to come from a layman's point of view. Thank you all so much for being here and without further ado matt, why don't we get started? Great. So um so I'm gonna start with just some, a bit of an overview on some concepts related to assessing for inherited cancer risk. Um And then a new will get into I think some of the more nitty gritty about details of genetic counseling and genetic testing and um And Ramona will talk some about some of the management piece is relevant for our patients with inherited cancer risk. So next slide, these are just my financial disclosures. Next so brief outline, I'll start off talking a little bit about multi gene panel testing for inherited cans a risk um which is still a relatively new phenomenon as far as how we how we actually work out people who are seeing us for for potential genetic testing. Just give after that some basics on hereditary colorectal cancer and then hopefully if you kind of take home points about who to test and how to test. So next slide. So I contrast on the notion of syndrome specific genetic testing with multi gene panel testing, syndrome specific genetic testing is how we've done genetic evaluation really for for the most the majority of the time that genetic testing has been a thing. Um you know and that refers to the phenomenon in which individuals who meet specific criteria for a specific syndrome get genetic testing really for that syndrome. For example in the old days we would do lynch syndrome genetic testing for people who had a colorectal cancer that was mismatch repair deficient and RMS high high. We would do genetic testing for the A. P. C. And H. Jeans if somebody had multiple colon adenomas. Um but as I'm sure people are familiar with in the recent years there's this phenomenon now of multi gene panel testing which utilizes next generation germline sequencing where really you can perform germline testing of dozens and really even hundreds of genes in parallel. Um there's a number of different commercial labs that offer this testing. Um depending on the lab, there could be organ specific panels where you can order a colorectal cancer panel or breast cancer panel and increasingly a lot of the labs are offering pan cancer panels kind of the test everything approach. Um, a lot of new genes are constantly being added to these panels and for better and maybe for worse, the more you look, the more you find. So next slide. Um, so a couple of pieces that I want to point out though, genetic testing rarely gives a black and white yes or no answer to the question of does this person have inherited cancer risk? You know, a quote unquote positive test, the finding of a pathogenic or likely pathogenic germline variant or mutation doesn't guarantee the development of cancer. Um, and oftentimes the magnitude, the spectrum of cancer risk associated with a given gene might be uncertain, especially as more and more genes are added to these panels. Oftentimes their genes we don't understand very well. Sometimes we're finding mutations in genes that have nothing to do with why we sent this person in for testing in the first place, especially with these larger panels on the flip side, negative results don't necessarily mean that there's no cancer risk. Sometimes we're testing somebody who clearly has a high risk family history, we find nothing that doesn't mean that they're off the hook from increased screening and increased risk. Maybe we tested the wrong genes, maybe we tested the wrong person in a family that that does have inherited risk or maybe it's risk that we just don't fully understand yet and where there might still be the need for high risk screening even with unrevealing genetic results. And then I think the most prominent example of this is variants of uncertain significance of what we call the U. S. S. Next slide. So I won't go through this in too much detail because I know I knew was going to cover it. But these essentially represent germline genetic variants where the effect on the gene function and therefore the effect on cancer risk is unknown. These are hugely common. We find them in at least 30% of people getting multi gene panel testing maybe more like 40% with some of the larger panels. Um and I know I knew we'll talk a little bit about just how we think about the classification and reclassification of these. But it's important to kind of dig a little bit deeply on some of these. Especially if there's concern that it might actually account for the family history and to look at how different labs might classify an individual variant. At the same time though, I would say that there is significant concern about over treating patients based on these uninformative results. Next slide. This is just from from the lay press from a handful of years ago. Um you know where essentially a case of somebody who underwent risk reducing surgery, mastectomy hysterectomy simply because somebody didn't really know the difference between a variant of uncertain significance and a true harmful pathogenic variant. So the interpretation here really is is key and that's where we rely a lot on our genetic counseling colleagues in cases that are a bit ambiguous. Next. So some basics about lynch syndrome which is far and away. The most common form of inherited gi cancer risk that we see, particularly when we're talking about young onset colorectal cancer. Um in the old days we used to call this H. N. P. C. C. Although the term has fallen out of favor simply because of some I think misperceptions of the term non polyp Asus and the fact that it only really focuses on the colorectal cancer aspect. Um Some people call this the meritorious syndrome when we see the dermatologic manifestations, it's not as almost dominant cancer predisposition syndrome. It's it's actually really common. Um We think it accounts for about 3% of all colorectal cancers and 2% of all. And the material cancers and some high quality data have estimated that the population that the prevalence in the general population Maybe as high as one in 279, which means that there's more than a million people in the us. By these estimates that have Lynch syndrome, the overwhelming majority of whom are undiagnosed next. So lynch syndrome is defined nowadays by the presence of a pathogenic germline variant or so called mutation in one of the D. N. A. Miss Metro pair jeans, M. L. H. One M. S. H two, M. S. H six or PMS two or the UPC um gene. Um And when you're testing for lynch syndrome and people with colorectal and endometrial cancer More most commonly will find mutations in H one or H two. If you're looking at the general population though, PMS two is actually far and away, the most common in the general population, it's got a very low penetrates though the risk of cancer with PMS two is actually reasonably low. Um And so an overwhelming, overwhelmingly large fraction of people with PMS two related lynch syndrome are undiagnosed simply because they don't have obvious family histories next. So lynch syndrome associated colorectal cancers, these classically arrives in the proximal colon and the sycamore, the ascending colon, but they can be seen anywhere in the large intestine. Um Their histology is usually pretty ugly. You expect to see often poorly differentiated high grade histology, sometimes medullary features signet ring cell histology histology. In spite of the ugly histology though, they tend to have better prognosis stage for stage than their sporadic counterparts. Um These have classically been described as having a quote unquote like reaction with tumor infiltrating lymphocytes which probably has a tip off to why these cancers respond so well to immune checkpoint inhibitors that these are very just immunogen IQ cancers in the first place, these cancers are thought to arise from your run of the mill traditional adenomas. Although they probably go through the process of carcinogen icis quite a bit more quickly than their sporadic counterparts. There's also some intriguing data nowadays that some lynch associated colorectal cancers might skip the adenoma precursor face entirely. Um you know, which has led to some concerns about um you know whether there might be just a ceiling to the benefit of of colonoscopies. And these people, these cancers almost universally display mismatch repair deficiency by I. H. C. Um and high level micro satellite instability. They virtually never have be wrapped mutations which you do commonly see in sporadic forms of MSC, high colorectal cancer. And there's a significant risk for synchronous and arm attack Cronus colorectal cancer. Next so people are probably pretty familiar with this. There's a number of ways to test a tumor specimen itself to look for evidence of micro satellite and stability, therefore is a tip off for lynch syndrome. You can do pcR based M. S. I. Testing, you can do immunization chemistry to stain for the DNA mismatch repair proteins which is probably the most common way in which this is done across the country and really across the world. Um Usually with that you expect the expression of the mismatch repair proteins or the absence of that expression to be paired M. L. H one N PMS to dim arise. And so if you have a germline mutation in Ml H one, you don't express M. L. H. One but PMS two can't bind to an absent Ml H one and therefore both of them are actually absent when you go staining. Whereas M. S. H 20 and M. S. H six wood stain intact in that situation and vice versa. So usually you will lose expression of two proteins with a single germline mutation In the old days. We would triage the use of this tumor testing. We would test people if they were diagnosed at a young age, but otherwise we weren't testing all comers. But over the past 10-15 years it's really been clear that we need to be doing this tumor testing in all colorectal and all endometrial cancers if we want to be finding lynch syndrome really regardless of age, regardless of family history. Um, and as a way to identify people with lynch syndrome. And so nowadays for anybody who has a tumor that's mismatch repair deficient. And RMS I high um we recommend germline testing unless there's an obvious sporadic explanation for that mismatch repair deficient status. Next, it's important to point out to on on a bit of a tangent here that really we should be thinking about germline testing for anybody found to have an M. S. I. Hi mismatch repair deficient tumor even if it's a tumor type, not classically associated with lynch syndrome, This is a publication from our colleagues at Memorial Sloan Kettering a few years ago where they did this testing with Germline testing on really all comers with all cancers and they found lynch syndrome in M. S. I. High cancers in cancer types that we don't think of as being lynched associated. So adrenal cancer, prostate cancer, germ cell cancers, sarcomas, mesothelioma is melanomas, they were rare. The overwhelming majority of people had M. S. M. S. Stable tumors. They didn't have lynch syndrome. But you would find a handful of these from time to time. So when we're doing this type of testing, even if it's just to look for benefits from immunotherapy nowadays um we really should be thinking about limp center. If the if the results come back abnormal and send somebody for genetic testing next, I would also point out that tumor testing is not the only way to identify people with lynch syndrome. Our group has published the prem model. Um you can find it. It's a free online tool just google prem P. R. E. M. M. It's a quick tool. It takes about a minute to complete somebody's premise score and you put in some very basic variables um the individuals age their sex, whether they've had a personal history of lynch associated cancers and their family history of lynch associated cancers and it spits out a number of predicted probability of having lynch syndrome. National guidelines nowadays recommend genetic testing for lynch syndrome for anybody found out a prem five score of 2.5% or higher. This is really easy to do. And it's a very effective way, especially if somebody doesn't have a tumor that you can actually test. But they have a concerning family history. This is a really easy and effective way to find lynch syndrome. Next So multi gene panel testing to identify Lynch syndrome or to identify inherited cancer. Overall, this is a study we put out a handful of years ago looking at over 1000 people with colorectal cancer seen at Dana Farber where we did multi gene panel testing with what would nowadays be considered a relatively small panel 25 genes on all comers. When you did this panel testing, we found almost 10% had a pathogenic germline mutation, 3%. Head lynch syndrome. Kind of fitting with what we expected from historical data. They almost all the lynch syndrome patients had M. S. I. High tumors, but there were another 7% who had other forms of inherited cancer risk. The majority of whom didn't have obvious clinical features. And some of these were genes that we don't even think about as being colorectal cancer linked B R. C. A one and two pel B to tP 53 a smattering of others. So the question becomes, how do you actually identify people who have these non lynch syndrome forms of inherited cancer risk next slide. So Prem five actually turns out is actually halfway decent at doing this. We put out a subsequent study showing that in people who had colorectal and endometrial cancer. Prem five was very good at finding lynch syndrome, but it's also pretty good at finding people with other forms of inherited cancer risk to. Um So that's really led to a recommendation nowadays that anybody with a prem five score of 2.5% or higher really should get a panel, not just testing for lynch syndrome or in the process of trying to develop a new version of prem. That's really going to look across the wider spectrum of cancer predisposition syndromes that will really be designed more so for multi gene panel testing. But in the meantime, Prem five actually works pretty well for that. Next switching gears for for a second, just to talk about the polyp Asus syndromes. Most people are familiar with Classic type F. A. P. In med school, we see the textbook of the picture from the colonoscopy where somebody has literally hundreds if not thousands of adenomas. It's pretty striking. Um Classic type F. A. P. Is almost always caused by germline. A pc mutation typically manifest pretty early in life in the second or third decade with high risks of manifestations outside the colon as well, including destroyed tumors most commonly in the abdomen funded gland polyps of the stomach adenomas and cancers of the duodenum and the ambulance and thyroid hyperplasia. You can also have attenuated forms of F. A. P. What we call it. Attenuated F. Ap some but not all of whom have journal in a pc mutations. These usually this usually manifests dozens of adenoma sometimes are pretty subtle um pretty subtle phenotype and you you much less frequently see the extra colonic manifestations. Next, a closely related syndrome is mute, Yh associated polyp posts or M. A. P. This is one of the few syndromes relevant to colorectal cancer that's autism. A recessive where it requires biologic inheritance of muhd mutations. There's a pretty wide spectrum of polyp burden and colon cancer risk that you can see here. It's usually more in the realm of what we expect with. Attenuated F. A. P. In fact, when you look at cancer patients, colorectal cancer patients with M. Ap actually a large fraction of fewer than 10 autonomous at the time that they develop cancer. So even if there's a low polyp burden, it's not necessarily indicative of low colorectal cancer risk, interestingly, M ap colorectal cancers frequently have a specific KRS mutation KRS G 12 C which is relevant because that's one of the KRS mutations that actually nowadays do have good effective targeted therapy for But also point out that monolithic mute wage mutations are exceedingly common when you test all comers. This is probably one of the most common incidental findings, but probably about 2% of the general population has a single mute wage mutation at least. People of European ancestry having a single monolithic single mute wage mutation does not cause M. A. P. And it's really debatable whether it causes anything. Some studies have suggested maybe a very mildly increased lifetime risk of colorectal cancer. But some studies have really said that there's no meaningful risk whatsoever really. The main implication of finding a single monolithic meditation is making sure you're not missing a biologic carrier somewhere else in the family. And so that's an important piece of the counseling. Next. And so which colorectal cancer patients should get Germline testing which I would say should be with a multi gene panel. I would say all individuals diagnosed at age 50 or younger anybody with a mismatch repair deficient and or MSC high cancer unless that's really conclusively explained by somatic causes such as the presence of a beer f mutation. I would say anybody with a prime five score of 2.5% or higher anybody with 10 or more lifetime adenomas and click next. And really I think the question is should we just be testing everybody? In fact coincidentally the N. C. C. N. Guidelines for colorectal cancer genetic testing. We're just updated today where nowadays they're starting today there's a recommendation in there to consider Germline genetic testing for all people diagnosed with colorectal cancer, even those who are over age 50 who don't have any of these risk factors. I would say it's controversial but it is now at least in the guidelines to consider that next. Um And I would just highlight that just last week, myself and my colleague heather Hampel from City of Hope put out a perspective piece. Just looking at the pros and cons of really testing all commerce with gi cancers. So if it's a question you're interested in um give it a read. It was a fun piece to put together but I think there's upsides and there's downsides really to doing this. So we need to think through it pretty carefully click next and then this is just a graphical breakdown in the middle there you can see the colorectal cancer studies um the color, the different colors really just kind of represent the spectrum of the different genes and syndromes. You expect to see if you test all comers whether it's colorectal cancer or other types of Gi cancers. Um so with that I think I'll hand it over to a new to talk about genetic testing. Hi everyone. Um So I have no disclosures next slide. Thank you. So I wanted to speak a little bit about genetic counseling for inherited cancer risk. And dr Glenn has brought up several issues that I'm going to be talking in more depth about. But you know, as you may or may not know, genetic counseling involves the assessment of personal and family history of cancer and then helping patients consider genetic testing and its risk benefits and limitations. Not everyone has access to or needs to meet with the genetic counselor. And in fact at Dana Farber, we have a process that we call our rapid access genetic testing process where oncology patients can have genetic testing done the same day by watching a short video meeting with one of our genetic testing coordinators. And then if they're comfortable with the information going forward with genetic testing, next slide please. So when we think about the risks, benefits and limitations, you know, starting out with the risk, we know that there are psychosocial issues surrounding genetic testing that go beyond the diagnosis of cancer itself, patients may learn about additional cancer risks when they're in the middle of their treatment or trying to make treatment decisions. They may learn about risk to family members and this may cause strain in their relationships with family members are also feelings of guilt because they are worried about having passed on something we try to emphasize with patients that we don't have control over gene mutations that we inherit and pass on. But it sometimes it can be difficult for patients to kind of reconcile that. And then of course, inconclusive or uncertain results, as Dr jurgen had pointed out in a family where there's a strong family history of cancer. If you have a negative test result, That can be confusing and sometimes disappointing and then the issue of variants of uncertain significance is uh large with us because we do know that up to 40% of people will get an uncertain result. And that can again cause some frustration for patients. And then the most common question that we get here in the States about about testing is about costs and insurance issues. Next slide please. So we know that the benefits of testing include the idea that this could be useful for cancer treatment options for patients. It could also explain their diagnosis because patients often wonder why they developed cancer and it can help them be proactive about additional cancer risk or give information to family members so that they can be proactive for their own risk. It may also reduce anxiety and worry for some patients knowing that they have a hereditary cancer syndrome. Can give them a plan for what to do next and how to be screened and followed next time. And the limitations of testing. As again, Dr Glenn had pointed out, testing is not 100% sensitive. There's no single technology that is perfect in detecting mutations in these genes. NGS is very good but it's still not perfect. It can't detect these rare and tronic deep and chronic variants um effects from other genes that are far away from the gene that you're looking at. And we know that genetic testing improves over time. So what you're looking at is really a snapshot for the day but it's not necessarily what's going to be the be all end all of testing and then the variants of uncertain significance that we get may not be reclassified in a timely manner or at all. I've definitely had patients that I've met with over 20 years ago who've had variants that have still not been reclassified. And as after you're going have pointed out as well, there are really no absolutes and cancer risk. Even if you have a hereditary cancer predisposition syndrome, there's not 100% risk to get a cancer or uh, second cancer. And conversely, cancer risk is present for all of us even with negative results. So we have to use the family history and personal history as a guide next slide. So going through some of the more common questions when we talk about risk benefits and limitations, cost of testing is probably the number one question that we get Here in the states may, most of the major labs have reduced the cost of testing to about $250. So that is doable for most patients. There are still some patients for whom that's not going to be doable. And most of the labs do have financial need guidelines and programs that can be used in that situation. However, the cost to insurance is about, You know, $1500-$6,000. So it's a big difference in the cost and I think some of the things that we address with patients is that sometimes, you know, patients will say to us, my insurance company will cover this. The problem is they may have a coinsurance or there may be additional costs even if insurance covers it. And it may turn out to be that the self paid prices less than having it go through their insurance. And we're finding more and more that insurance coverage for multi gene panels is limited. They're trying to ask us to justify every gene on the panel which is not practical for us. Um, so it's something that definitely we probably need to be better advocates for in terms of trying to make sure that insurers do cover this type of testing. Next slide please. And then discrimination. And I would say privacy concerns as well. We know that the affordable Care Act protects cancer patients with access to health insurance and Gina, which is the genetic information. Nondiscrimination Act protects unaffected patients from discrimination in health insurance and employment. These two links below are give you more information about this Gina act. And then there's also a state database of legislation. So different states have enacted legislation to try to address things like life insurance, long term care, long term disability in massachusetts, there is a state law addressing discrimination for these types of insurances, but unfortunately because it is a state law, it doesn't have the same weight as a federal law would, So we don't know how good the state law will be at actually protecting people against those types of discrimination. Next slide please. And in terms of limitation, I just wanted to point out here is a published pedigree, uh, that's two siblings who had greater than 20 adenomas and one also had a germ cell tumor at the age of 12. This family was negative for a multi gene panel next slide please. But in fact they turned out to have an autism, a recessive condition called envy D for multi tumor predisposition syndrome. And this is a very new gene. It's been linked with colorectal polyp Asus with AML and with you feel melanoma. So it just goes to show that, you know, again, what we test today may not be what we test tomorrow and especially those families that do have strong histories of polyps or cancer. We have to be, you know, vigilant. And just make sure that those patients are coming back in to get updated testing as new genes are found next slide please. So, if a patient comes in has gone through this information is ready for testing again, As Dr Glenn had pointed out, we tend to do multi gene panels minimally with all the colorectal cancer genes that we have. But we do recommend doing a broader hereditary cancer panel because as you saw in the data before, there are many patients who have mutations and other genes that we wouldn't have classically thought to be associated with colorectal cancer and especially with DNA repair genes. This has seen very often. Next slide please. So why do panel testing when there is you know, a known mutation in the family. So this is an example of a family that we saw a little bit changes that have been made to the family tree. But In this family you can see the patient is 34. She has a brother who's 38, Their mother had ovarian cancer at 63, a maternal around with endometrial cancer at 50 and a maternal uncle with colon cancer at 40 and grandmother with colon cancer at 75. So quite a striking family history of cancer very much looks like lynch syndrome and in fact the family had an M. S. H. Two mutation and both she and her brother tested negative for that mutation when the testing was first offered. Next slide please. Unfortunately her brother developed colon cancer at 32 was found to have a PMS two mutation. And so this turned out to be from her father's side of the family. So I think one of the important things that we counsel patients about is that there is millennial risk, which is why we try to take a complete family history. But even in that sense that family history changes over time and second mutations are not that uncommon. So in our Experience 1-2% of patients will be found to have a second mutation in the family. Not all of them are high risk mutations but they are relatively common. When we do look next slide please. So this is as dr Glenn had said sort of the most straightforward situation. You suspect that someone has lynch syndrome. They do the genetic testing. They come back with a pathogenic or likely pathogenic mutation in a lynch syndrome gene and I wish that this was what we found most of the time. But it's actually usually more complicated than that. But this would be a kind of a more straightforward test because we wouldn't know what to do in this situation. Next slide please. The second type of test result that we see is a positive result for an incidental or secondary finding. And so in this situation you can see that the patient was found to have an A. T. M. Mutation A. T. M. Has not really been associated with colorectal cancers. There's been a few reports suggesting that A. T. M. Might increase the risk for colorectal cancer but Largely we don't change management based on having an 80 mutation. So we would in this case a team is a moderate risk breast cancer gene. It's also associated with an increased risk for um uh pancreatic cancer, slightly increased risk for ovarian cancer. And um some possibly prostate cancer as well. So we would you know make sure that the patients are being followed based on the A. T. M. Gene. But we also use the personal family history as a guide for any colon cancer risk as well. Next slide please. And then negative result, which is still the most common test result that we give out. We still have to use personal and family history to guide follow up on the long term next time please. So as you can see here, you have a patient on the left who was diagnosed with colon cancer at 45, mother had colon cancer at 55 and maternal grandfather had colon cancer at 59. A negative test result. And how you follow this family is going to be very different than the patient who has colon cancer at 45 and no other family history. So long term follow up, it's going to be very different for these two patients. Next slide please. And then the last and probably dreaded variant of uncertain or unknown significance in this situation. This patient has an M. L. H. One mutation. So if there's a family, I'm sorry, Emily, H one variant of uncertain significance. So we want to really try to do our due diligence on this and make sure that there isn't a concern about this particular variant. But if we determine that this is a true variant of uncertain significance, then we would essentially still use personal and family history to guide care for this family next slide please. So what do we do with variants of uncertain significance? The first thing we do is we look at the N C. B. I. Database on variants and that's very easy to check for. So what we try to do is check for conflicting interpretations from reputable labs in Klin Bar to see if there are labs that are classifying these variants of uncertain significance as pathogenic or likely pathogenic. We tend to review all the variants and make sure that there isn't a conflicting interpretation. Um but as time goes on, you know, the lab will also issue amended reports with reclassifications of these variants of uncertain significance. So it's important to tell the patient to try to maintain their contact information with you. If you want to try to make sure that you can send those amended reports over time. And then as unfortunately, we know that patients will pass away and we have to have a plan for those patients to try to make sure that we can get the information to their family members as well. And then sometimes additional follow up is helpful for variants of uncertain significance. If you have a variant of uncertain significance in the splicing region, an RNA analysis might help to clarify the variant and help to reclassify it or additional family member testing can sometimes help to for high risk hereditary genes. If you find that the US on the side of the family that doesn't have the cancer risk. This might be helpful in another point for the testing lab to be able to reclassify next slide please. And so just to think about, you know what we do for follow up in families. The first thing I wanted to mention was partner testing. So if a patient is found to have a lynch syndrome gene, let's just say an M. S. H. Six mutation. We always recommend partner testing if they are of childbearing age because we want to make sure that their partner doesn't have a mutation in the same gene. If By chance the partner does have a mutation in the same gene, then their Children would have a 25% risk of having constitutional mismatch repair deficiency, which is different from Lynch syndrome. It's a rare childhood cancer tumor syndrome That you can see very early onset cancers and tumors, hematology malignancies, they can present like they might have neurofibromatosis type one. And even for other DNA repair genes that are often recessive conditions associated with them like the A. T. M. Gene. If if someone is found to have an A. T. M mutation, if their partner also has an A. T. M. Mutation. And and they have a child together. Again, the Children would have a 25% chance of having a taxi tell inject asia, which is a rare severe progressive neurological disease. So we always try to recommend that if not the patient at least family members who are of childbearing age, consider partner testing And then for reproductive planning purposes because of that 5050 risk for passing on the gene mutation to future Children for these dominant conditions that we know about. If someone is interested in using the information they may want to consider options like preimplantation, genetic testing, which is a combination of IVF and testing embryos for the mutation and then implanting only those embryos that did not have the mutation. And we're always looking for ways to try to increase cascade testing in the family. Um so we try to use family letters where we have the patients send out the letter themselves, but with the information that we've provided and we also try to provide resources for them to find places to test at. You can go to the National Society of genetic counselors website and there are also direct to consumer options which are Very cost effective if there's a known mutation, sometimes the cost can be as low as $50 to get the testing done. Next slide please. So, I'd just like to finish up by kind of pointing out that when we talk to patients about, you know, having a gene mutation that increases their risk for cancer, the genetic test result is very important, but it's not the be all end all in terms of trying to determine cancer risk. As dr garland had pointed out, you know, we don't know exactly what that patient's risk of cancer will be having that gene mutation, but there can be modifying factors including modifier genes. Um there could be environmental factors which patients may or may not have control over and then hopefully lifestyle and behavior factors that they do have some control over. So we want them to try to feel empowered in dealing with cancer risk as well. So I'd like to stop there and turn it over to dr lin. Thanks a new and today I'll be talking about best practices and surveillance for hereditary colorectal cancer and young onset um colon cancer is next slide. I have no disclosures. It's and we will be talking about surveillance guidelines um in our hereditary cancer syndromes that that matt and a new have both touched upon. In in their talks, we'll talk about how there are specific peri operative postoperative considerations for these syndromes as well as some of the extra intestinal manifestations that we take into account in management next slide. And the reason why we want to recognize hereditary colorectal cancer is it may really alter one surgical approach at the time of their diagnosis. Um there may be an increased risk of attack. Cronus colorectal cancers, as well as extra colonic tumors, as well as the increased risk of cancer to family members. Next slide and as matt had alluded to, we talked about how lynch syndrome typically more subtle in in the sense that we um present with a non polyp Asus phenotype. So we don't expect to see many, many polyps that's supposed to our polyp oSA syndromes where with the attenuated F. A. P. Um and even math, which tends to fall into that attenuated or Allah gopal IPO sis range of polyp burden and then the classic F. A. P. That we all know and recognize and it's very obvious because it's sort of what we were accustomed to learning about halitosis as in medical school next slide and it changes quite a bit because the cancer surveillance after diagnosis is quite different. Our standard surveillance after colorectal cancer and reception maybe to do a colonoscopy at one year Repeating it sooner. If the baseline colonoscopy at the time of the diagnosis was incomplete. From for example, an obstructing tumor than a colonoscopy should be repeated in 3-6 months and thereafter if these are negative. The intervals suggest that we can increase the surveillance intervals to three years and five years thereafter for our standard surveillance. But that's very different with our hereditary colorectal cancers because after that first year we continue to follow closely in terms of endoscopic surveillance depending on if they've had A partial collect a me or even a more extensive risk reducing surgery with lower G. I surveillance. Typically in the 1-2 year interval per guidelines of that specific syndrome. Next slide please. And so matt touched upon the fact that you know, lynch syndrome, autism or dominant with um anything that we would want to think about in terms of individuals that are presenting with young onset um colorectal cancer. But with the idea that there are many other um extra colonic tumors particularly endometrial and other G. I. Tract cancers um gynecological cancers um that an individual with lynch syndrome may be predisposed to. And it will be important because some of these individuals certainly have a new family history for us to suspect this. Um But others may be the first individual in their family um to to have a lynch diagnosis and therefore that may help us really make management decisions quite differently up front at the time that they're diagnosed. Next slide please. So part of the reason why it's critical to ascertain um And and consider pursuing genetic testing early at the time of diagnosis may be that there may be a question of whether or not um approaching it with a standard approach of a segmental resection, like a right hemi collect a me or a sigmoid. Ectomy would be advisable versus a risk reducing collect a me because of the risk of future cancers. Um I think that there's always going to be individual considerations as well depending on individuals in terms of reproductive risk as well as their even baseline bowel habits. Um And and whether or not someone has diarrhea versus constipation, they sway them one way or the other. Um Or or if they've had a prior history of radiation for an endometrial cancer. Those are all um considerations when going into surgery for the for a new diagnosis and certainly um if appropriate. Um can commentate timing along with a risk reducing hysterectomy with or without uh oh for ectomy at the time of their cancer diagnosis may make sense. Um So it's certainly important to have a conversation up front about whether or not that's timing as appropriate after um Colorectal cancer or even after a diagnosis of lynch without a cancer diagnosis, we know that it's important that we recognize that right sided lesions can predominate and that the typical adenomas can look quite atypical as well, can be flat, subtle and even depressed um and highlighting the importance of regular follow up with the intensive surveillance because of the fact that there is that accelerated adenoma carcinoma sequence. Um It really highlights the importance of us doing a really good high quality colonoscopy examination including repeating the examination with a better prep. Um If there's anything suboptimal about the visualization and very rarely um you know risk reducing, collect a me can can sometimes be be considered as a management option even without a diagnosis of cancer. Next slide please. And so our um surveillance guidelines um include colonoscopy every 1 to 2 years beginning age 20 to 25 most recent updated and CCN guidelines had even added starting a little bit later um at age 30 for PMS too. Um And we happen to be one of the programs that really advocates speaking at an annual schedule. Um For the colonoscopy upper endoscopy is performed every 3 to 5 years um With a baseline assessment for other modifiable risk factor of h. Pylori infection which can be treated um in terms of a gastric cancer risk or looking to see if they have intestinal medical asia at the time. And looking to see if any type of endoscopic surveillance and ongoing biopsies would be useful during the during the evaluations. Um And then discussing the possibility of other screenings including endometrial and ovarian cancer screening. The discussion of prophylactic um th. B. S. So um as well as dermatologic evaluations, there are other extra intestinal um risks such as pancreas um urinary tract and even small bowel cancers that can separately be screened for. Um but but are not universally recommended for all individuals with lynch syndrome depending on the specific gene mutation. As well as family history considerations. Next slide please in F. A. P. This this is exactly um you know as matt had mentioned, you know a polyp assis individual where it's very classic, you know, hundreds of thousands carpeting the colon um with where the penetrates is near complete and in these individuals without colonoscopy or without Without collecting me. Um the estimated lifetime risk of colorectal cancer is 100% in classic. Um and therefore most individuals at some point will require um a risk producing, collect a me and hopefully it's before they have cancer. Um And we ascertained that information from family history and genetic testing. But there are some individuals a significant proportion who are de novo mutation carriers and are sometimes the first individual in the family to be affected and can present with rectal bleeding or an obstructing cancer and then discover that they have a um and obstructing plus polyp. Oh sis so much more to think about in terms of of management specifically for that individual and then for their family members. Next slide please. And certainly we can see that there can be genotype phenotype correlations with um classic F. A. P. And the milder attenuated forms um Where the gene mutations tend to be located in the three prime and fried five prime meant of the of the gene. Next slide please. And some of the things that we continue to deal with in terms of risks is that it's not just a colonic colonic polyp assis risk is that there's a significant upper gi track risk of particularly duodenal and AMp Hillary adenomas and carcinomas that may be difficult to manage and is a much bigger surgery potentially if we can't endoscopic we manage these because individuals that have um significant duodenal polyp Asus for example have a pretty extensive surgery that is equivalent to an individual that has pancreatic cancer. If they if they can't be endoscopic lee managed because these individuals could have the need for a whipple um which which would would remove the duodenum. Um And the and the ambulatory adenoma or cancer certainly the more pronounced the polyp. Oh sis is in the duodenum the higher the risk. And we sort of score that according to Spiegelman um score which is an endoscopic risk assessment. Um We also can see funded gland polyps that can carpet the stomach and they can actually be very numerous. And fortunately the risk of gastric cancer arising from gastric funded gland polyps is more rare in this syndrome. Next slide. And many of the extra extra intestinal other manifestations in F. A. P. Um can be benign um Such as congenital hypertrophy of the retinal pigment, epithelium, extra teeth, epidermal cysts. Um But some brain tumors um as well as thyroid cancer and and Desmarais tumors can can lead to significant morbidity in this syndrome. Next slide. So some of the management options that we think about with F. A. P. From a surgical perspective may include removing the entire colon with colon and rectum removed and an end Elias, to me, not necessarily what anyone would ideally prefer to have. Um In terms of lifestyle. Um after after this type of surgery. So practical ectomy with the creation of an illegal pouch or j pouch is commonly. Um The type of connection can can also be another option. And then third option may also include for individuals where the disease burden or polyp burden in the rectum is not very large. Doing a total collect a me along with an ilia rectal anastomosis um may actually preserve the rectum. And in both of these instances of the pouch and the ilia rectal anastomosis. There's still a significant risk of polyps in the rectum or filial pouch in the future. And that still requires endoscopic surveillance. So the cancer risk is not gone after the the the the initial surgery and collected me is is is is undergone next slide. So pre operatively it's typically, as we mentioned, total collect a me with ilya rectal or anal anastomosis. Um I think that you know typically we wouldn't pursue something like a segmental. A partial collect A ME unless someone presented with an obstructive cancer and needed to deal with that first Before thinking about risk reduction. Um It may be important to consider if there's significant upper Gi tract polyp assis at the time probably wouldn't worry about it as much if it was a cancer surgery that we were undergoing from a from a colorectal standpoint. But if this was more for risk reduction, that may be something very appropriate to time. Because that that that may be actually be significantly worse. Um In this case risk producing collect A me is quite common. Um But as I mentioned, lower and upper G. I tract surveillance is still warranted post op next slide and typically um we we may start colon cancer screening For individuals at age 10-15 with colonoscopy and then pouch endoscopy or flexible sigmoidoscopy after. Um Upper and endoscopic surveillance depends on the burden of polyps in the duodenum or stomach. Um And consideration for thyroid cancer screening and inter abdominal desk lloyds. Excellent. And with attenuated F. A. P. When these are due to um a a pathogenic variant. Um in a pc we can still see a significant lifetime risk of colorectal cancer, but at later ages. And the screening um tends to tend to be a little bit later. We also know that the extra colonic risk can be similar to F. A. P. But but again less common. Next slide considerations would also be similar to F. A. P. In the sense that we would consider segmental versus partial collect a me as appropriate for a cancer diagnosis versus a more extensive surgery to address not only the cancer but the future cancer risk due to polyp Asus burden. Um And then the same type of considerations for upper gi tract halitosis whether or not um risk producing collectively could be considered and ongoing surveillance from the upper and lower G. I tract thereafter. Next slide and these are quite similar. Um But but we we started a little bit later for individuals who have had a family history with attenuated power process. Next slide with associated polyp oh sis. Um This also tends to present with a more attenuated polyp assis phenotype. Um And we have extra colonic manifestations that can sometimes mirror and be quite similar to the attenuated F. A. P risk And colonoscopies are beginning at age 20-25-30. Next slide We repeat them every 1-2 years again depending on polyp burden. And follow up surveillance with pooja's copy or flexible sigmoidoscopy if they've had to collect a me um and similar recommendations for upper endoscopy and thyroid cancer screening to be considered um with individuals that that that carry a biologic mute. Yh next slide and even other considerations that are helpful to to consider when we have individuals who are undergoing surgery for addressing cancer or risk reduction. It's important to ensure that that there that the surgery's still still allow them to have access uh to endoscopic evaluation for other cancers. I think one of the more common things that we often see is that there are more people that are undergoing bariatric surgery electively. Um and therefore those individuals can often be counseled to to consider a more um limited sleeve gastrectomy over something like ruined y gastric bypass where you would leave a large portion of an excavated stomach or duodenum, difficult to access endoscopic li for for ongoing surveillance. Thank you. I'll turn that over to Rich. Now appreciate it. Thanks dr lim. I have no slides. I'm just gonna tell you all my story and a little bit of the perspective of how I thought about the relevance of genetic testing and how it affected my family and my Children and how we process that while While going through this adventure. So flash back to 2018, I was 43 years old, some pain in my abdomen, I just thought it was cramps uh lead to getting it checked out a physical and M. R. I. Um as it turns out I had um colon cancer and small bowel cancer as well, which led to a small bowel recision which led to a collector me at the time, six days in the hospital. I'm proud to say I only missed six days worth of work. I'm not sure I should be proud of that. But and then, you know, following that six months of chemotherapy, you know, poured installed all of that. So as I was my first month of chemotherapy, I was introduced to dr Kirkland and the thought of testing based upon, you know, how I presented and we, you know, we learned about the prim and learned about another things that it would be a good idea to get tested from for lynch syndrome. While obviously I was uneducated, did not know what it was and now I'm more than educated in it. Clearly not as much as this panel, but at the time was trying to seek to understand what it was, process that and then understand what it would do. I think if you can imagine a patient navigating not only the medical ecosystem to advocate for themselves with the financial component from a health insurance perspective, um especially when, you know, the younger onset portion of this, you know, with the younger family with a career, you know, at that same point for myself being the sole provider for my household, how to navigate those things and then being, you know, presented with, well, we think this may be genetic and it may affect your kids that, you know, causes some consternation. Right? Um, so for us, uh, sitting down with the genetic counselors and having them lay out and explain what the test was, what they were trying to seek to understand what ultimately the benefits may be, right, notifying and seeing, you know, once I understand that I have this and then figuring out what the appropriate time. But to test my Children, clearly I did not understand or was aware of this when my Children were born, uh now figuring out a path forward, right? Understanding what I have and then how that might affect surveillance and then how um, you know, that may benefit all of us going forward. The one thing I may seem trite to the folks on this call that that do this for a living. This is new territory for most patients, right? Most younger patients, I've never spent a day in the hospital until this happened. So processing information when you're going through an emotionally tense time and quite frankly, not only tense for myself, tens for my wife tense for for my mother um is difficult, right? Meaning I don't think the cpus in my brain were working as they should, but using time and reflection and you know, speaking to the genetic counselors allowed me to process it at the rate that I could at the time didn't take me long. But I think when you're fueled on emotions, especially when it affects your loved ones, guilt sneaks in. I gave this to my Children. Now I'm depressed about that even though I know I didn't know and was completely innocent there and it's still, I was wracked with guilt. I still didn't know what my outcome would be at the time. Right in the middle of chemotherapy As I got more um times there under my belt will put it. I started feeling much more confident. I tolerated chemotherapy very well. As I said, I didn't miss any work. I coached soccer, I did a number of things that, you know, relatively normal. I would say 95% normal but the emotional component of it, it was something that I wasn't prepared to deal with. I never had to deal with something like this before in my life. Um, so that threw me off kilter a little bit to process the information that was coming my way. The other thing that I found um is google is helpful and not helpful when you're trying to navigate the world of information. You need a guide. If you're in virgin territory. You know, I can answer questions on nuclear engineering computer, that's my space. But when you start venturing out into areas that are unknown, it becomes scary. So anchoring back on, you know, dr dr Patel dr Iran and all of these fabulous and the genetic counselors as well. Um anchoring back on them and then allowing the information that they give you to serve as your learning and almost think of it as a learning plan, right? Going to learn about this genetic test that we're doing. Uh that does provide exposition provides background and then it provides extension where I'm going to leave that alone and allow them to tell me what that means. So, you know, I had to filter out the noise, focus on what was in front of me. Use the experts that were available to me as well and then allowed time, right, go home, think about it, process it, sit on it for a while and then make a decision. You know, one of the things doctor told me early on was, you know, my wife's proclivity was we should just get the kids tested right now and I didn't agree with it at the time. But argument at that point in time was not my best tactic. The best tactic was to go home, sit on it for a little bit, think about it and you know why, you know, why does that make sense if we're not concerned about them until 18 or 21 or a little bit down the line doing it when they're six and um 10 doesn't make much sense at this point. So knowing what other people have done, having options and then allowing for time to process that, especially when you're going through something emotional for me. I was never emotional about myself. I was emotional about how it affect other people and when you do this level of genetic testing. And the one other concern that I have, and I think a new touched on it earlier was the laws and the regulations. Right. If I get this genetic testing, will I be discriminated against when I go to get health insurance or will my Children be discriminated against because they may or may not have this particular central. Now, of course there are state protections and there are legislation federally, I think that are moving forward. But that's scary as well. Just given the discriminatory practices that happened in our economy and, and especially in health care and on the insurance side of things that's completely foreign. Right? So, we're looking for in this case data farm in the genetics testing group. Uh, other councils, Excuse me, to educate us on, should we be concerned about that? And is that a concern for our kids? And do we worry about that discrimination? We happen to live in a fairly progressive state from that perspective. But, you know, my Children may not always live in massachusetts. So there's a lot of things to process at the same time and processing it during an emotional time, made it a little bit more difficult. But, You know, the end of my story really is about, we did do the genetic testing, we did find out about it. Um, you know, I was able to tolerate chemotherapy fairly well and now we're sitting here in 2022 and I am in the surveillance program and knowing that that surveillance program has been tailored based on the information has come back. Not only gives me peace of mind because my white peace of mind, but also we know that when the time comes a couple of years down the line, we'll have my Children tested and God forbid if they do have the same Issue, if you have Lynch syndrome, then we will get them in a surveillance program and the advances in modern technology over the next 20 years or 30 years. Um, to me, it's just going to be exponential. So, you know, there is hope there and there is um, peace of mind at least from a patient's perspective to know that, okay, we've got the outcome we wanted in the surveillance program that uh, is best aligned to my particulars and also will be best aligned to my Children, particularly going forward. So, you know, the one word I would have, you know, patients for all of the oncologists on the line, I think patients understanding the processing of your patience and understanding the processing of their loved ones, but then optionality as well at the end of the day will benefit them so they can take it away and come back because these decisions don't need to be made within a minute or an hour. They can be made over a number of days. So I appreciate you giving me this forum and I want to thank dr jurgen especially for inviting me and thank you all. Thank you so much. You know, I you know, for sharing that story. I think you beautifully summarized not only the medical and health impact of this diagnosis on you and your family, but just all the other human aspects of of what this does and how you have to process it. So thank you. Um thank you to all the other panelists too, which is extremely informative and educational. So I know we're a little bit past the hour but you know maybe we have just a few extra minutes for those who want to stay on for one question for each Panelist and this will be recorded and placed on our website. For those of you who do have to drop off, you can always come back and watch it later. So maybe I'll start with you Rich since you just finished sharing your story. Um, you know, clearly it's important to know about family history and um the types of surveillance that then have to be done to try to prevent cancer in both you and your other family members. But some of these conversations are difficult to have. Do you have advice for other patients out there on how to bring up sometimes these subjects and talking about some symptoms that are maybe not comfortable to talk about, um, in finding out your family history. That's an excellent question. Uh, family history sometimes can be known or can be completely unknown, right? Or, or it's known, but no one is saying and you have to dig into it a little bit. I found it to be tougher with my mother if I have to be honest. I think, um, Older generation, you know, baby boomer generation that I want to paint her that way. But born in 1940, um, was a difficult conversation because they just did not talk about those things. Um, but once, I I, you know, I sat her down and, and, and, and I leveled with her and I said, mom, this is important because it will help me when I came from that perspective, I still can't get it to stop talking at this point. The stories just started to flow out about uncles and aunts and, and, and my grandmother who went through colon cancer in the early 19 seventies, I wasn't born until 1974 so clearly did not know this or remember this, but I had not heard this story previously. So while it was known to certain people in the family, it wasn't known to folks who, you know, came along a little bit later and you know, perhaps seventies and the eighties. So it was really sitting my mother down and explaining how it could help me. And I know it's uncomfortable mom, and I know you don't like talking about this, but I need you to help me. And you know, I think that's the that's the tack that I would almost guarantee that any mother couldn't refuse. That's a great approach. Thank you. Um And maybe a new, I'll go to you next because Rich brought this up as well. You know, so many of our patients present at a young age and do have young Children, how do you go about thinking about when to do germline genetic testing on Children? Yeah, that's that's a great question. Um It's really variable depending on what the syndrome is, what the gene is. Um You know, even within lynch syndrome, we have genes that have sort of different presentations, different risks. Um So usually with Some of the genes, we recommend starting at a pretty young age. So as dr Lin was talking about with FAP, you may be testing Children when they're 10 for this, or sometimes even younger if you're talking about trying to do happen to glass dome a screening in them, but typically we recommend starting if it's not that classic F ap we recommend starting later when they are adults. Um and people often ask us to when we when how should we talk to our kids about this. When should we start talking about this? And I think um it's important what we've heard from a lot of Children who have gone through this and as they become adults is that it's important to have like an open dialogue with them. Obviously you're not going to share something with a really young child about cancer risk, but you know, they may have questions about why you go to the doctor and it might be a time to kind of open that window to to talk about, you know, very rudimentary things and then as they get older, start talking more about what this might mean for them as well. And so, um I think it's just important to try to to frame it and show that you're there to answer questions for them? That's great, thank you. And then maybe I'll go to Ramona next. Um You very, you know, nicely outlined the surveillance recommendations for the various syndromes to look for various cancers. And, you know, we're lucky here that we have the lynch syndrome here, the lynch syndrome center here at Dana Farber to help oversee that. But many places, um other cancer centers and community centers don't necessarily have this in place. How well are these guidelines being followed in the community and are are you working on efforts along with other colleagues in the genetics division here too better disseminate what the best recommendations are for cancer surveillance. Yes, Thank you, kimmy. Um I think if anything it can be overwhelming. Um you know, certainly there are, we're lucky to have lots of great um you know, practitioners throughout our state um you know our our gastroenterologists, oncology colleagues, um you know, where where there are lots of individuals where the guidelines are are strictly being adhered, but it can be challenging to keep up with those guidelines and therefore yes, I think um we we've been trying to help, you know, trying to help disseminate information by having webinars such as this um and and other and other outreach um where we have uh provider conferences and our patient conferences as well annually. Um that can help that can help. And and we also um certainly help to um evaluate individuals to help their local providers um as as a putting together lynch syndrome care plants. That's great. And it's so important. Um And then the last question is for matt, um you know, you mentioned that not every carrier for example, for lynch syndrome will go on to develop cancer. And then they only go on to develop certain types of cancers if they do develop a cancer diagnosis. What research is going on to help better personalize um surveillance strategies and also better understand who is at risk of what particular cancer. It's a great question. And I think we're really just scratching the surface of it. Um we know that across the five different lynch syndrome genes, there's pretty drastically different risks. Gene to Gene to Gene. Um, and that's something we've really only appreciated in the past few years. You know, just a few years ago, it was kind of one size fits all. You had lynch syndrome. We kind of didn't look at which gene all that closely was just everybody got screened for everything. And I think nowadays we can be a lot more sophisticated about looking at things like the specific gene, like somebody's sex, like their family history, and starting to tailor some of these screening and surveillance programs based on risk factors that we know about. But there's still a lot, we don't know. Um, I'm sure things like diet, lifestyle exercise play in, but it's probably well above and beyond that too. And so there's a lot that we're doing in the lynch syndrome center here and that other researchers are doing really around the world to look at things like the microbiome in the stool in the colon, and how that factors into risk diet, lifestyle and exercise, other genetic factors, immune factors. Um, and I think there's a whole lot more to come that will help us better understand an individual person's own lynch syndrome risk profile. Um, so it's a really exciting time, but, but we've got a long ways to go to, to to get there. Thank you. So, I think that brings us to the end of our webinar. Thank you again to all the panelists, for your expertise and your time, and especially rich for sharing your story. And uh, again, this is being recorded. So if anyone wants to come back and watch again, this will be posted on our website soon. Thank you all so much for attending.
