Welcome back to an introduction to breast cancer. I'm Dr. Anaise Chagpar. Remember back when we talked about cancer? We said that this was an abnormal proliferation of cells. Cells that were growing with an accelerator pedal and no brake pedal, and we said that the risk factors were really many. The primary ones were being a woman and getting older. Certainly your family history increases your risk, and we talked a little bit at that time about genetics. That some genetic abnormalities could predispose you to getting breast cancer. Today we're going to take a deeper dive into genetics. Let's get started. So the first question is how much of breast cancer really is hereditary? That is to say caused by a genetic mutation. You may be surprised to learn that it's really pretty small only about 5 to 10%. The vast majority of people who present with breast cancer don't even have a family history, but these 5 to 10% of people matter, because sometimes we can figure out what that genetic mutation is before they get breast cancer, and we can use some of the risk reducing strategies that we talked about to reduce that risk. So let's look at which genes may predispose to developing breast cancer. We talk a lot about BRCA one and two. This was the breast cancer one and two genes that all of us know about. The same one that Angelina Jolie for example had a mutation in, but there are actually many genes that can predispose you to getting breast cancer if those genes are mutated. Let's look at this graph. You can see here in the upper left genes that have a high relative risk. That is to say when they're mutated the risk of developing breast cancer is high, but these genes are very rare. This is the cluster that has BRCA one and two, but other genes also exist within this cluster. Things like P53, P10, CDH1, STK11. A lot of these you may not have heard about yet, but we're going to change that and talk a little bit more about them as we go along. Then there are what I call the moderate penetrance genes. Those genes in the middle, things like ATM, PALB two, Check two. These genes have a lower relative risk, so they do increase your risk of developing breast cancer, but not quite as much as BRCA one and two for example, but they're a little bit more common. Then on the far right you have the genes that are low penetrence. They're pretty common and we can find these mutations, but the risk that they infer for a patient in terms of breast cancer is pretty low. So let's look at these in a bit more detail, and we always start with BRCA one and two. These are the ones we know the most about. They're high penetrence genes And they're carried in an autosomal dominant fashion. That is to say with every gene you get half your genes from your mother, half your genes from your father, and in autosomal dominant patterns you are going to pass on one set of those genes to your progeny. For BRCA one and two remember that their risk is quite high. So when we compare to the general population the risk of developing breast cancer by various ages, or even other cancers is quite high. Let's take a look. So for breast cancer in the general population the chances of you getting breast cancer by the age of 40 is about half a percent, but if you carry a BRCA one or two gene mutation it's about 10 to 20%. Similarly in terms of breast cancer your risk of developing breast cancer by the age of 70 in the general population is 8%, but if you carry a BRCA one or two gene mutation it could be as high as 85%. So now you can understand why some people would opt for risk reducing measures. To reduce that 85%. Now it's important to remember that breast cancer doesn't just occur in women. Indeed about 1% of all breast cancer in the general population occurs in men, but for BRCA two mutation carriers That number is much higher about 8%. And so when men get breast cancer you really want to start thinking about do they carry a BRCA two gene mutation? Because remember even if you are a man you can pass that genetic mutation on to your children whether they're boys or girls. BRCA one and two can also increase your risk of ovarian cancer. In the general population it's pretty rare to get ovarian cancer. Less than 2%, but in BRCA one and two mutation carriers that's up to 40%, and it also increases men's preponderance of getting prostate cancer. In the general population it's about 7 to 15%, but for BRCA one and two gene mutation carriers it's 40%. Similarly for pancreatic cancer. Pretty rare for the general population less than 1%, but for BRCA one and two mutation carriers It's fourfold that. So it's important to keep in mind that a mutation in BRCA one or two does increase the risk not only for breast cancer, but for a whole variety of cancers that are in that same cluster. So things like ovarian cancer, prostate cancer, pancreatic cancer. Now when we talk about genes and mutations you have to think well how do I know if I have a genetic mutation, and what can I do about it? Well the first step is always to see a genetic councilor, and I separate genetic counseling from genetic testing. It's not simply to take a saliva test or a blood test and send it off to a lab It's really important that you have that counseling aspect. Why? Because it's important that we talk about the right patient, the right test, and the right interpretation. As we go along today you're going to find that we talk about a number of potential genes all of which could be mutated. So how do you know if you're testing for the right gene, and we'll talk about the interpretation, which isn't always as simple as a positive genetic mutation or a negative genetic one. It could be variance of unknown significance, which is the equivalent of getting a report that has a big question mark on it. How to interpret what that question mark means is also the purview of a genetic counselor. So, let's suppose you have a family history and you're worried about having a BRCA one or two gene mutation. Maybe you look at your family history and you say, my goodness. There are many people in my family who have had breast or ovarian cancer. Should I be tested? Well, the first thing to remember is you might not be the right person to be tested. Oftentimes it's better to test the person who has the cancer, and then test you to see if you have the same mutation. I often use the analogy of a book. Let's suppose you have a very thick book and I tell you that we suspect that there may be a spelling mistake somewhere in this book, but we don't know. Now there's another copy that I know if any book has a mistake, that book would. Let's say it had a faulty production line. If we can look through that book and identify that the mistake is on page 57, paragraph three, second line, third word in. Then if I give you a new copy of the book and say, it came from the same production line you might go straight to page 57, third paragraph, second line, third word in and see if the same mistake exists. So who should at least be referred for genetic testing if you suspect a BRCA 1 or 2 gene mutation? Here are some criteria that are put out by the NCCN. The NCCN is the National Comprehensive Cancer Network. This is a group of major cancer centers all over the United States that have put their heads together to really come up with some guidelines of who should be tested and whom this is warranted? So if you have a known mutation in your family, it may behoove you to get genetic testing as well. If you have a breast cancer and you were diagnosed very young say less than 45, there is an increased likelihood that you carry a genetic mutation or if you've had bilateral breast cancer. So cancer in both breasts, particularly if the first was diagnosed less than the age of 50. Triple negative breast cancer is another one. Remember back to when we talked about the types of breast cancer and we talked about different receptors. Estrogen receptor, progesterone receptor and her too. Well for patients who have a breast cancer in which all three of those receptors are negative, that's called triple negative breast cancer. And if you're diagnosed with triple negative breast cancer under the age of 60, you're also at increased risk of carrying a BRCA 1 or 2 gene mutation. Ashkenazi Jewish people at any age should be tested, why? Because we know that in this particular population of eastern European Jews, there are three particular low side or spots on the BRCA 1 and 2 genes which can often be mutated increasing their risk to developing breast cancer. Anybody who has ovarian cancer should be thinking about BRCA 1 or 2 gene mutation testing. Remember back to the previous slide when we said, ovarian cancer in the general population is pretty rare. But the risk is significantly increased in people who carry a BRC 1 or 2 gene mutation. Similarly, for men who develop breast cancer. And you always want to be thinking about what are the other cancers come in that cluster. So breast, ovarian, pancreatic, prostate. When you start seeing a family history or a pedigree where all of those cancers cluster together, you want to start scratching you head and saying, is this a family that could potentially carry a BRCA 1 or 2 gene mutation? But remember that it's not just BRCA 1 and 2 that increases your predisposition to developing breast cancer. There are other genes that can be mutated as well that also increase your risk. Let's take a look at some other cancer genetic syndromes that also increase your risk of developing breast cancer. Things like Li-Fraumeni Syndrome. This is a syndrome that's characterized by a mutation in another gene called P53. And this increases your risk of developing breast cancer such that the risk is about 50 to 80% by the age of 45. Now, Li-Fraumeni syndrome, is a syndrome. So it's associated with other cancers as well. Patients who have a mutation in P53 are at increase risk of developing sarcoma's, acute leukemia's, lymphoma's, adrenocortical cancers, so cancers of the adrenal glands or brain tumors. So again when you see that cluster, you want to start thinking about a potential P53 mutation. There's another syndrome called Cowden syndrome. This is characterize by a mistake or a mutation in a gene called P10. Now in this particular mutation, we often find benign lesions as well. So remember, not all cancer syndromes are just about cancer, we can often find benign things as well. So hamartomas, which are completely benign lesions. Uterine cancers, these patients often have thyroid disease. It may be benign or malignant, and they then to have macrocephaly. So when you see a genetic counselor, one of the things that they'll do when they're worried about Cowden syndrome, is measure your head. Now, these patients are at increased risk of developing breast cancer, such that it's associated with about a 20 to 50% lifetime risk. Some genetic syndromes are associated with gastric cancer, so CDH1 is a syndrome that has breast and gastric cancers associated with it. This is related to a mistake or a mutation in CDH1. This is also called the ecad herein gene. Remember when we talked about lobular cancers. We talked about them being sneaky. They follow a single file pattern. They tend not to clump like ductal cancers. Well the reason for that is that lobular cancers don't express e-cadherin which is an adhesion molecule that keeps cells together. So it's not surprising that patients who have mistaken CDH1 which is this e-cadherin gene tend to get diffuse gastric cancers. Cancers of the stomach that tend to be more widespread. And have an increase risk of breast cancer but their breast cancers are more likely to be lobular. That sneaky single file discoherent breast cancer, with about a 39% lifetime risk. The last syndrome I want to talk about is Peutz-Jeghers. Peutz-Jeghers is associated with a genetic abnormality in a gene called STK11. And similar to Cowden Syndrome, it's really associated with many benign changes. So things like hyperpigmentation of the oral mucosa. Often times when you asked patients to open their mouth you'll see these dark spots inside their mouth. And they can often get a GI polyps although these polyps are generally benign as well. But Peutz–Jeghers syndrome is associated with an increase risk of breast cancer with the 32% risk by the age of 60. Now all of those are autosomal dominant transmission they tend to be high penetrant genes those genes that were in the upper left of the graph that we looked at. What about moderate penatrence genes? Genes that may be mutated a little bit more frequently, but don't increase the risk of developing breast cancer quite as high as those. Well there are a few that fall into this category. Things like PALB2. PALB2 was recently discovered as a partner or localizer of BRCA2. It tends to hang out in that same loci, that same spot on that gene, and it's associated with a two-fold increase of developing breast cancer. Similarly, a mistake or a mutation in something called ATM, or the ataxia telangiectasia mutation, try saying that three times fast, is associated also with a two-fold increased risk of developing breast cancer. Other mutations like that of CHEK2, have a 20 to 40% lifetime risk of breast cancer. So these are now mutations that we can discover, as we're doing more and more panel testing. In 2013, there was a Supreme Court decision that was really important for breast cancer genetics, and in fact genetics in general. Myriad Genetics was a company that held the patent for a BRCA1 and 2 gene mutations. So all genetic testing prior to that time had to be done through Myriad Genetics. Well, in 2013 the Supreme Court overturned that decision. They decided that no company was allowed to hold a patent to a gene, that a gene was actually a naturally occurring thing. And so that opened the flood gates for many laboratories to actually do test to look at many different genetic mutations. And so now we can have tests that look at these genes as well as a number of other genes to find mutations. This is what we call panel testing. So, do we do panel testing on everybody? Just some people? Do we still test for particular mutations or do we do these large panels on everyone? Well, stay tuned because we're going to interview a guest who's going to help to answer that question. But the short answer is, not really. There are advantages and disadvantages to each technique. Panel testing, for example, has a number of advantages. Certainly from a time and cost efficiency standpoint, we can look at many genes all at once, and so for patients and their families who are at high risk, we can look at a variety of mutations all in one shot to see whether they carry any mutations. On the flip side, that also means that we're going to find a lot of mutations that we didn't expect, and maybe some mutations in genes that we don't have a lot of experience with. And so we may get those variants of unknown significance, the big question mark on many reports. Sometimes the genetic mutations that we may find, we may not have enough clinical information as to what they mean and it may not accurately reflect what the patients came in with to begin with. So when we look at these pie charts, looking at BRCA1 and 2 testing versus panel testing, we can see that the number of times we come up with no mutation actually goes down. So we're finding more mutations that can explain why patients get breast cancer, but the number of variance of unknown significance actually goes up. So the question mark that says I'm not really sure how this impacts your breast cancer risk, will also be increased. I'm really excited about the interview that we're going to be doing today. I hope you'll stay tuned and join me for that. We're going to be talking to Erin Hofstatter. She's a breast medical oncologist and the co-director of Cancer Genetics here at Yale. We'll talk to her about a whole bunch of things. Does she do panel testing, or does she do single gene testing? Who needs to be tested and why? How has Angelina Jolie's story and increased public awareness really impacted her practice? How did the Supreme Court decision impact things? And what are the legal and ethical ramifications of increased genetic testing for patients and their families? How does this affect insurance, for example? I hope you'll stay tuned. it should be really interesting. Until next time, I'm Dr. Anees Chagpar.
