Understanding Genetics, Family History and Breast Cancer RiskRebecca Sutphen, MD

February 23, 2008

SUE FRIEDMAN, DVM: Good afternoon, everyone. This is the workshop on “Understanding Genetics, Family History and Breast Cancer Risk.” My name is Sue Friedman, and I’m the executive director of the organization FORCE, Facing Our Risk of Cancer Empowered, and we deal with hereditary breast and ovarian cancer. There is some literature in the back about FORCE if you’re interested [http://www.facingourrisk.org]. But on behalf of the Young Survival Coalition, Living Beyond Breast Cancer and [Susan G.] Komen for the Cure, I’d like to welcome you to this workshop. You can get more information and resources on their web sites. The Living Beyond Breast Cancer web site is wwww.lbbc.org. Young Survival Coalition web site is www.youngsurvival.org, and the Komen web site is www.komen.org.

Our speaker today is Dr. Rebecca Sutphen, and she’s an associate professor in the Department of Interdisciplinary Oncology and Pediatrics at the University of South Florida College of Medicine. She’s the director of the Clinical Genetics Program at the H. Lee Moffitt Cancer Center and Research Institute and the director of the Family Cancer Genetics Network Registry, which is a national registry for hereditary cancer. The focus of her research is clinical cancer genetic epidemiology, specifically heritable cancer risk, factors that modify cancer risk and development of strategies to reduce risk and improve early cancer detection.

She also focuses on population-based ovarian cancer studies and the development of an ovarian cancer biomarker test for early detection and accurate diagnosis and effective treatment. Dr. Sutphen is a member of the National Comprehensive Cancer Network panel on genetics and familial cancer screening, which sets the standard of care guidelines for management of individuals with hereditary risk. She’s also a great speaker, so please welcome her. (Applause)

REBECCA SUTPHEN, MD: Thank you. What I’m going to do is try to start off the talk by making sure that everybody is on the same page, and so for those of you that may know a lot about hereditary breast cancer I’m going to ask your pardon right up at the front, because I’m going to spend some time at the beginning just making sure that we don’t leave anybody behind. So let me start out by saying how much of breast cancer do we think is hereditary. I would say this is sort of a moving target, actually, partly because the way that we use that word “hereditary” is kind of changing. And partly because, as time goes by, we know more and more about the hereditary component of breast cancer. So let me start by saying this is sort of a typical slide that you would see in a talk like this, and then I’ll make a few comments about it.

So here it’s showing that about five to ten percent of breast cancer is strictly hereditary. I would say that means that an individual in this little piece of the pie really got their breast cancer because of a major hereditary predisposition to get breast cancer. They had a better chance to get breast cancer than not to get breast cancer, maybe even higher than that. Then here you see in this wedge that certainly there are many women who have a family history of breast cancer, and the more familial, the more people in the family with breast cancer and the more factors that add up to suggest that it’s hereditary the more those may also be genetic, but maybe not such a major

predisposition. Maybe something more you’d describe as a tendency. So that individual did have a genetic basis that moved them in the direction of getting breast cancer. That may not have been the one or overriding factor.

Actually, I think that as we find more and more genes that can put people at risk for cancer, whether breast cancer or other cancers, what we’re learning is that actually up to about 50 percent of all cancers have some hereditary component, so some susceptibility or tendency to cancer. Now, let me put that in context, because, again, I want to make sure we’re understanding. If I understand about half of heart disease has some hereditary component, nobody would shake their head to that, right? Or if I said about half of type 2 diabetes may have some hereditary component. So actually it’s turning out that cancer is probably not very different than that, but an individual’s risk for cancer could be something that’s a little bit higher than the average person’s, or it could be substantially higher. I’m going to focus mostly on talking about people who have substantially higher risk for cancer from birth because of an inherited mutation.

So before we do that, though, I want to talk about cancer. Again, I apologize. I know, I’m speaking to many people here who have a lot of knowledge about cancer. So I don’t mean to oversimplify that, but from a genetic standpoint I think it’s helpful for us to recognize that really is it a process of genetics that leads to cancer. This is a malignant cell. It doesn’t look anything like a normal-appearing cell. Cells that are cancer have uncontrolled cell division. They’re able to grow very quickly. They can outgrow normal cells. They look irregularly shaped. They don’t function normally. They can lose their communication with neighboring cells. They can even lose it in such a way that they can move away from the tissue of origin, can separate and even metastasize throughout the body. So these are very, very abnormal cells.

Here in this picture you see there are some stars in the nucleus of the cell, and that is indicating the genetic process behind cancer, which I’m going to go on to talk about. So again this is just a sort of cartoon that displays this, but I think it gives a good representation of the genetic process. Again, if we’re talking about saying that most people who get cancer don’t get it because of genetics, right, so for most people, most people would start out in the left hand column. That is, in the nucleus of their cells they have their DNA and their genes. But they don’t have any mutations. So they’re born without mutations. Then at some point in life, let’s say in a breast cell, there is some damage to one of the genes.

And the DNA gets some kind of damage overtime for all kinds of reasons. In fact, we even introduce DNA damage over time because we make new cells. And every time we make new cells we copy our DNA, and we can make mistakes and introduce those. So for all of us, we are actually accumulating genetic mutations as time goes by throughout our lives. Part of the reason cancer is largely -- and again I’m considering the audience -- but largely a condition that we don’t expect in childhood and we do expect at the end of life is because it is part of the normal process of accumulating damage to our DNA as we go through the world. So in most people who don’t have a hereditary predisposition, at some point there is this first mutation, whatever the cause.

But the important thing is if a cell in my breast has a mutation in it, then when it reproduces itself it will make another cell with that same mutation. The cell is blind to what’s there and where it

came from. It just says whatever is there, I’m copying it. So that cell sets up a little population of cells in the tissue that is predisposed to cancer. It’s not cancer yet. At some point in time, though, within that little group of abnormal cells, one of those cells may, again, undergo some type of damage such that now there are two genetic mutations.

And if these genetic mutations are such that they occur in genes that allow the cells to grow more or to act in abnormal ways that are similar to cancer cells, then these cells already have some advantages, in a way, in terms of growth. So they’re growing faster than they’re supposed to. And they get more and more abnormal, and you can kind of see how over time, then, one accumulates what we think the requirement is for about four or more mutations until a cell within that original group of abnormal cells now is sufficiently abnormal that it is really malignant. And of course when it copies itself it’s copying faster than it’s supposed to, and it’s copying all of those mutations, all four of those mutations.

So this is the process of cancer development. Cancer is a genetic process, a process of accumulating genetic damage. But not everybody starts out with a problem. So before I move on to talking about the hereditary type of cancer, then, I want to make sure that we know when we talk about genes and DNA. So in a simplistic way -- again, you may know a lot about this -- but in our cells we have our DNA. It’s present in all of our cells. It’s the same in all of our cells. And it’s in these packages called chromosomes that are sort of these rod-shaped structures. But the bottom line is when you unwind a chromosome it’s really this long, wound-up helical strand of DNA that has this bar code, here shown as four different colors. Sometimes you hear about the four letters of DNA: A, C, G and T. Here it’s shown as four colors.

In any case, a gene is simply the section of the DNA that it takes to be the recipe for a protein, whatever that protein is. Some genes are small; some genes are big. Some proteins are small; some proteins are big. And we just define the gene by the length of DNA it takes to be the recipe for a protein. So it makes sense, then, that if you have a quote “normal recipe,” normal gene, then you make a normal protein. And in your cells you’ll be making that protein, and it will be doing its thing, and everything will be normal.

Now, imagine, though, if you had a mutation in a gene. Then when you go to use that recipe to make the protein, you’re not going to be able to make the protein in the usual way. So you will make an abnormal protein, or maybe you won’t have the protein, because the recipe is so abnormal, it just can’t even begin to make the protein. When this happens, this is where we’re talking about a mutation. The result of a mutation is the protein that it’s supposed to make isn’t made normally, and, therefore, it affects the way that cell can perform.

Now I’m going to focus on inherited mutations from this point on. So when we talk about an inherited mutation, here you see this mutation in the egg. But let me say that equality here, it could be in the sperm or the egg. We get 50 percent of our genes from our mom, 50 percent from our dad. We have two copies of all our genes, and it can come from Mom or from Dad. So inherited tendency to cancer can be from either parent. Then it’s present in the first cell of the human being. This is the most important point, because if it’s inherited from a parent, it’s present in the first cell, therefore, just like I said, whenever you copy a cell, whatever is there will get

copied. This individual, then, has a mutation literally in every cell of their body. That same specific gene is mutated in every cell of the body.

So if I go back to this picture, then we’re talking about a person who actually starts out life in this column, in all the cells of the body. They don’t start out life in this column. Every single cell already has a first mutation. So I think here we can start to see what would we expect then to see that’s different in this individual from someone who starts off life in the left-hand column. First of all, we would say this person has more of a chance of getting cancer. Every cell already has that first mutation. Secondly, since every cell has that mutation, this person is likely to have more than one cancer develop. It’s one thing if I start out here and just one cell somewhere gets a mutation, and then I might get a cancer there, but every other cell doesn’t have the mutation. But if I start out life with a mutation in every cell, then it makes sense that I might get more than one tumor.

Then it also makes sense that this person might get cancer at an earlier age in life than the average person, because they started out day one with that mutation, rather than maybe the first mutation occurred when they were in their 20s. So cancers that occur at a younger age can be a sign of potential hereditary mutations. Then you could also imagine that a person might get cancer in more than one tissue of the body, not just more than one cancer but more than one tissue of the body. So these are some of the features that I think it makes sense from this process that you might see in an individual who has a hereditary reason for their cancer.

WOMAN: I don’t know if this is cancer, but if you’re talking about somebody starting life with the first mutation, has already mutated, how do you know if they enter life with that first mutation and that’s not their normal, what is normal for them? How can you determine that?

REBECCA SUTPHEN, MD: I will answer that. I’m not just about to get to it, but I will answer it as we go through. At the end, if I haven’t, then let me get back to it. But I am going to talk about the mutation exactly, what is it specifically and how would we know it is a mutation. Now, if I move on from this point, I’m showing you this picture of the chromosomes to emphasize one important point. Here, again, I talked about the chromosome packages. So when we talk about BRCA1 and BRCA2, which I’m going to spend some time talking about, the BRCA1 gene happens to be located on the one we call number 17. These are just really ordered mostly by their size. And BRCA2 happens to be on chromosome 13. That really is fairly irrelevant.

But the point I wanted to make is when I’m talking about an inherited mutation, I’m talking about a person who has a mutation on one copy of their gene, not both copies. So they’ve inherited it from one parent, but not both parents. Let me just go back for one second here to say the other thing you don’t see is you don’t see a person with an inherited mutation being born with cancer. You don’t have cancer when you’re one year old, even if you have an inherited mutation. Why is that? Looking back at the process, it’s because you only have one mutation. You don’t have four mutations. It still takes time for mutations to occur.

Let me also say: Could it be that a person could start out life with this in every cell of their body and never get cancer, they would live long enough or in some ways, whatever the factors might be, and they might even have some areas of the body where they have two mutations or three

mutations, but they never end up getting all of the way to a fourth mutation in any cell of their body, so they never end up with a cancer? Yes, it is. So having a hereditary mutation is not 100 percent you will get cancer. It’s just a very high risk.

So on this slide, when I say that you have it on only one copy, what that mean is imagine this is me and I have a mutated copy of the BRCA1 gene, but I also have a normal copy. So I got one mutation from one of my parents. Then when I go to pass on my genes to my children, I’m going to pass on half. They’re going to get the other half from their dad. And so it’s a flip of a coin. Every egg I make, I’m going to put in either this copy or that copy. When we make an egg, we just pick one or the other of every pair. Dad does the same thing, and then that combination is what the child gets. So a person who has a hereditary BRCA mutation -- and most of the genes that cause inherited cancer -- has a 50/50 chance with each of their children to pass on that risk, an important reason many people want to know whether they have an inherited mutation.

Now, you could ask me, if this individual is born with a mutation in every cell of their body, then are they going to get cancer in every tissue of their body. The answer is no, because different genes have different functions in different tissues. We know that we have our eye color gene in our leg muscle. It’s doing nothing down there. If it were mutated, it wouldn’t cause me any problem in my leg muscle. So wherever that gene has an important function in the body, then there can be a risk for cancer. This is why we certain patterns where we might see breast and ovarian cancer, for example, but we don’t see other cancers in other tissues of the body. I don’t mean that exclusively, and I’ll make a comment about the pattern in the genes I’m going to discuss.

So what kinds of genes are these? And this looks very scientific, but don’t get concerned. Basically, imagine that our body has a system that tells the cells when to reproduce. If that weren’t true, then every day I might be making new skin cells, and pretty soon I’d just be flooded with more rolls that I already have. Or let’s say that my skin is sloughing off every day, and I’m not making new skin, I’d run out of skin eventually. So there is a system that tells every tissue of the body: Make a new cell when it’s needed. Don’t make a new cell when it’s not needed. The genes that tell the cell to make a new cell are called oncogenes, and the genes that tell the cell not to make a cell when it’s not needed are called tumor suppressor genes. We have these genes that function in all of the tissues of our body to keep that system under control.

So you can see how if I had a mutation in a gene that tells the cell to reproduce, and if this mutation was letting that cell reproduce whenever it wanted to, then that could lead to a tumor developing. By the same token, if this is the breaks on that process, and I have a mutation on the breaks, and so there is no way to tell the cells not to reproduce, then they’ll just go ahead and reproduce. That would lead to tumor development. So in general, when we talk about inherited mutations that put a person at risk for cancer, they’re called either oncogenes or tumor suppressor genes, as a general category. Am I making sense so far?

WOMAN: Yes.

REBECCA SUTPHEN, MD: Now, here it says hereditary breast and ovarian cancer, because, as I said, certain genes have certain functions. It turns out that two big genes involved in

hereditary breast cancer also predispose to a risk for ovarian cancer. Those genes are called BRCA1 and BRCA2. There are a few other genes that can cause a risk for both breast and ovarian cancer, but there aren’t very many, frankly, and there probably aren’t going to be very many, even as we identify more genes. So this pie chart here is showing us when you’re talking about hereditary breast and ovarian cancer. I’m making that clear, I hope. Not just hereditary breast cancer, because more genes are involved. But when you see hereditary breast and ovarian cancer in the same family, or you may not see ovarian cancer, but there is a risk for it, then we’re talking about these two genes. I’m going to spend some time talking about those, but I’m also going to mention other genes involved in breast cancer.

So we said that tumor suppressors are one category of genes that can be mutated. BRCA1 happens to be one of those, and it has an important function in breast and ovary. I’m showing this picture down below of the gene itself, which is basically, to me, saying it’s a big gene. Down below it’s showing all of the different kinds of mutations and their locations. Basically it’s saying it’s a big gene, and mutations can happen anywhere in this gene. So one of the points here is that part of the reason, although don’t get me started on the reason why the price for testing is so high. But part of the reason is that it is a big gene, and one would have to generally look at every single letter in the gene to look for a mutation, because they could be anywhere. The cost of testing for BRCA1 and 2 is about $3100 at the moment. Now, what are the risks associated with BRCA mutations? Yes?

WOMAN: If you are given a break on the expense, the insurance, will specifically look for that gene.

REBECCA SUTPHEN, MD: Right, yes. And let me go back and say that now, though I believe I will say it further on. But I think it’s an important point. So the first person tested in a family, we don’t know where to look. So we just do the testing. I’m going to say a few more points on this, too. But so we just do the whole gene, basically. But let’s say I find a mutation on that test. Then my question for the rest of the family is did you inherit that same risk or not. So I don’t need to look through the whole gene on the second person in the family. I already know the gene mutation is that one right there, then we just test for that specific mutation. So it’s only the first person in the family tested. When we find a mutation, others can be tested. The current price for single-site testing of a known mutation is $385.

So what are the risks that are associated with having a BRCA1 mutation? Recent numbers suggest that in some families the percentage may be slightly lower, but suffice to say, the risk is at least 50 percent by age 50, and it’s at least 65 percent in a lifetime. This says 50 to 85 percent, and there certainly are many families where that is true. You also see often there are early ages of diagnosis. Again, if we go back in our minds to that picture, that first mutation being there from day one, it makes sense why you would get there sooner. Then there is also a risk for a second cancer for the same reason we talked about. That mutation is in every cell, so there is about a 50 percent chance that if a woman gets breast cancer due to BRCA1 she would get another breast cancer if she takes no action to prevent it.

For ovarian cancer there is a risk of up to 45 percent. Again, it’s a range of 15 to 45 percent, so some women may have a lower risk than that, but this is the range. Then we see families, lots of

families now, where there are excess of prostate cancer and colon cancer and actually other cancers as well that are suggesting that there may be some other cancers associated with BRCA1 mutations. The data isn’t as clear on those, and the risk, in some cases, for prostate cancer, for example, are not so big that they’re anything like what we’re talking about here for breast and ovarian cancer. The lifetime risk for ovarian cancer is 1.6 percent. So if your risk is 15 to 45 percent, it’s multiple times higher than the average person. As you well know, this is multiple times higher than the average person for breast cancer, so the big, big risks are for these.

Now, what does a family history look like? This is a classic family, so I would like to say before we talk about this that many people don’t have a family history like this, and it doesn’t mean they don’t have a BRCA mutation. But I think for the sake of discussion, this is helping us to put it into a frame of reference. What would a family history look like? The circles are the women; the squares are the men. Go figure. Then these lines are indicating that a person has the gene mutation but has not had cancer. Then the orange circles are showing us where a person has had cancer.

So, first of all, you see three generations of people with cancer here. You also see lots of breast cancer and the pattern of breast and ovarian cancer in the same family, a very strong indicator that a BRCA mutation is involved. You see premenopausal breast cancer happening. You also see the pattern of inheritance is actually, it turns out, about 50/50 for each person who has the mutation to pass it down to their children. So actually here is a woman who lived to 92, and she has not had breast or ovarian cancer. So we talked about you can live your whole life and never get cancer. It’s less likely than you will get cancer. But then she has passed it down to her son, and we know that because his daughter got breast cancer at 36. So men and women can both inherit it, and they can both pass it down. I think those are the main features that I wanted to point out here; enough said.

BRCA2 has a lot of similarity with BRCA1, and I’ll tell you a bit about why, but there are some differences as well. It’s also a tumor suppressor gene. I showed you it was located on chromosome 13. It doesn’t really matter. It has an important function in breast and ovary tissue. Again, it’s a big gene, and there are mutations all over the place. Most people who are tested for BRCA are tested for both BRCA1 and 2, all the way across both genes until we find the mutation in the family; then we target the testing. The risks are similar for breast cancer. They’re a little bit lower but still very high compared to the average risk for ovarian cancer. There is some risk for male breast cancer, so I want to say six percent, which we all know is less than any average woman walking on the street. So I don’t want to make light of it, but it’s not the hugest issue. And men have very flat chests, so palpating for something is a very different thing.

With BRCA2, we do know there is an increased risk for melanoma, for prostate, for laryngeal cancer and pancreatic cancer and probably other cancers as well. These specifically we do know. So again we take it into account when we’re looking at the family history. If there is pancreatic cancer, for example, in some males in the family that’s something that needs to be considered when we’re evaluating whether this is likely to be hereditary.

I wanted to make a comment here about testing in the Jewish population. If I just grabbed the average non-Jewish, Caucasian person off the street it’s about a 1-in-500 or so chance that they

would have a BRCA mutation. But if I grabbed the average Jewish person it would be a 1-in-40 chance that they have a BRCA mutation. So these mutations are much more common among Jewish individuals, and Jewish heritage is one of those factors to consider in suggesting it may be hereditary. Why is that? I could say cystic fibrosis is much more common in Caucasian Americans; sickle cell disease is much more common in African Americans. You can pick any group and you can say there are certain gene mutations that are more common, and that’s all because for centuries most people married within their own ethnic group. That’s why those genes, whatever they were, stayed within groups.

So the same thing here. This is why you see this among Jewish people more commonly. But the other side of that coin is that when we test a Jewish individual we actually test for these three specific mutations. The reason is because there is about a 95-plus percent chance that if you’re Jewish and you have a BRCA mutation it’s going to be one of these three, because you inherited from your parent who inherited it from their parent, and it’s the same three mutations that have been there for hundreds of years.

I’m just going to say a few words about genetic counseling. I think genetic counseling is very important. It’s an important discussion to understand what you’re doing when you get genetic testing. It has ramifications for you, for your family members. It’s important to get support about that, education, information, resources, and a clarification of what the options are and really supportive information. Whatever it right for you is the right answer. Then if there’s going to be a test, what is the appropriate test? Help with getting insurance coverage of the testing. Discussion about what’s it going to mean if you have a mutation, what choices might you make. Then information about insurance discrimination, laws in your state, which vary from state to state. I’m just going to make a broad statement here, and I will address questions about this topic if you want me to at the end. But let me say that although there’s quite a fear about genetic discrimination it essentially is not really a very real problem. I’ll just say that blanket statement, although I’m happy to talk about it.

Genetic testing itself is a blood test. It’s a test only for known mutations in known genes. Certainly we can’t test genes that haven’t even been identified yet. Then it helps people make decisions about their risk management but also about treatment, and I’m going to talk a little bit about that. Sometimes I have people say to me “If I have breast cancer then what does it really matter what caused it?” I think as time goes by, the more and more we know about the different causes underlying any individual tumor, the more likely that treatment can be targeted directly to that individual and their tumor and may be more effective. And there is some evidence for that now in BRCA carriers. It helps your family members understand their risk.

Certainly I think any person who gets cancer says, “Why?” And “What is the risk to my loved ones?” and, “Is there anything I can do to give information to them that might arm them against cancer?” Certainly genetics can help to do that. If a mutation is identified in the family, other family members can get a yes or no answer: I have this risk or I do not. Then it’s a rapidly evolving area, so it is helpful to know what gene tests are out there, who is it appropriate for, what new information can you give me. Talking to a genetics expert is usually the best way to do that, because physicians are, of course, very knowledgeable about cancer, but it’s a rapidly

moving field, and most of them don’t have the background or the ability to keep up with those changes and to take the time that it requires to sit down and talk with you about those issues.

What would you do with a family where you find that there is a BRCA mutation? I’m going to put this broadly here. We just said it becomes possible for other adults in the family to get tested and find out if they have this risk. People use increased surveillance, sometimes make lifestyle changes, may take some drugs to reduce the risk for cancer or may even undergo prophylactic surgery. I’m going to touch on some of the points here without going through the whole gamut of all of the possibilities, but one of the comments I want to make is how about in people who have had breast cancer.

Here is a study looking at would tamoxifen benefit in terms of women who had a previous history of breast cancer and wanted to see if they would reduce their risk for getting breast cancer in their opposite breast. As we talked about, with BRCA mutation there is about a 50 percent chance you would get another breast cancer at some point without some intervention. So you see there was a beneficial effect of tamoxifen. So tamoxifen can reduce the risk for a subsequent breast cancer in addition to being given to women who are known to be carriers of BRCA mutations before they ever get breast cancer, if they know that. So that’s one option.

The drug raloxifene is also an option, and I could speak more to that. I decided not to, but I certainly answer questions if you have some about that. Then some people choose to have prophylactic mastectomies in order to prevent a future breast cancer, whether they’ve had breast cancer or haven’t yet had breast cancer. What you see here, this is just data from one study, but the data holds up over time. A hundred thirty-nine women with no history of cancer, tested positive for a BRCA mutation, BRCA1 or 2, followed for three years. Seventy-six of them underwent a prophylactic mastectomy. Sixty-three underwent surveillance.

The surveillance in this group of women is every six months. No cases developed in the women who had had prophylactic mastectomies, and eight cases developed in the surveillance group. So I think the point here is certainly anybody considering surgery, that’s a major issue, and no one would ever say this is a blanket recommendation. But because the risk for breast cancer is so high, some women feel that this is an appropriate choice for them. The current data suggests that the risk for a BRCA carrier to get breast cancer is about 1.7 percent per year. So you’re talking about much more significant risk than the average person, and that’s why this choice becomes one of the options.

What about ovarian cancer risk? Wow, do we wish we had better techniques for that. I’m sure you know that we don’t get any screening for ovarian cancer. People don’t, in general. Three-quarters of women who are diagnosed with ovarian cancer do not have curable disease, and we should have some early detection tests. That is actually a focus of my research. But what we do when we know a person has a BRCA mutation is put them on the surveillance that we do have, although it isn’t great. Usually in our clinic it’s every six months, starting at 25 to 35 years of age we do a transvaginal ultrasound with color Doppler imaging and a CA.125 blood test. Together those two modalities, if you do that every six months, they have a 70 percent chance, if the woman gets ovarian cancer, that it is detectable at a curable stage. There is a 30 percent chance

that an early-stage cancer would get missed by those techniques, and that’s why we’re not very happy with those options.

Some women take oral contraceptives, obviously for lots of reasons. It’s just important to point out that really for women in the general population, women who have had breast cancer, women who have BRCA mutations, pretty much taking oral contraceptives for four years or more reduces the risk for ovarian cancer by about half. That’s pretty much across all folks. So if we know that a young woman has a BRCA mutation, during the time that she’s not trying to get pregnant, we would recommend oral contraceptives, if she can take those without other contraindications.

Then we do discuss, especially with women who are at the time of menopause and beyond, we discuss having the ovaries removed. A big part of that reason is because there is a risk for ovarian cancer. There’s no good screening. If they get ovarian cancer, it’s not likely to be curable. So your ovaries are not doing a whole lot for you from menopause on. There is really not much to consider, frankly, for women who are menopausal. But for women who are premenopausal, of course, this is not a no-brainer.

We recommendation consider of prophylactic oophorectomy at age 35 or after completion of childbearing. Now, beginning at age 35 or after completion of childbearing. I can tell you that most experts in this field really tell women that you’re pretty safe up until 40. Most of the ovarian cancer that occurs does not occur prior to 40 years of age. And also because right now the last sentence here says, “More effective screening is on the horizon.” I really think that is very true. We’re within a few years of having some kind of a screening. When we have effective screening for ovarian cancer, we certainly won’t be recommending just every woman when you’re done having your children have your ovaries removed. That’s not the ideal case. It’s just the best we can do for now. Because it induces menopause, of course. And this is a big issue.

I’m going to touch a little bit now on the issue of is there any treatment specifically for breast cancer in women who are known to have a BRCA mutation. Yes, there is. It’s a therapy that specifically targets tumors that lack a working copy of the BRCA gene, which are women who have BRCA1 or 2 mutations. Currently it’s in phase II clinical trials for women only with stage IV breast cancer and a BRCA1 or 2 gene mutation. There are also trials in ovarian cancer in the same group of individuals. Yes?

WOMAN: I’m actually in the trial, and I am considered just IIIC. I had a local recurrence and a supraclavicular lymph node. And they put me on the trial.

REBECCA SUTPHEN, MD: That’s good information to know. Thank you for sharing that. You may know that sometimes there are eligibility criteria for trials, and I myself find there will be like here is this study, and then we read the criteria and you don’t really fit it. But then if your physician follows through and tries to help or you even follow through and try to see, in my particular case, is there a way, sometimes depending on what the circumstances are, there may be broadening of the criteria. I want to be careful in saying that, but it is true that, depending on what the situation is, there may be indication for doing it, even if you don’t strictly meet the criteria.

The most important thing, I think, is it’s not for early-stage breast cancer. I’m going to say a little bit more about you have to have had a prior therapy, and you have to have been at least 28 days off that therapy and have failed that therapy, essentially, in order to be eligible for the trial. So obviously when you’re talking about phase II trials, what we’re trying to do here is say can we give this to people and can we see any positive effect of this, and can we get a better idea about how the dosing should be and things like that. Once that happens, if the results are good, then it will get broadened to more people. More people even potentially with earlier stage disease. And the criteria won’t be as tight, so this won’t be the end of the road for this drug, hopefully. These drugs will move forward. So far the news looks good. It’s very early at this point.

So I’m going to say a few words about this. Sue warned me it’s a little bit “sciencey,” but oh well. So we talked about tumor suppressor genes. All I want to show you on this picture is here’s BRCA1; here’s BRCA2. And this is a pathway that involves how all of the proteins involved in how you repair certain breaks in your DNA. So when you get DNA damage, there is actually a system that’s supposed to go in there and fix that. And sometimes it does that, and it’s not foolproof, like everything else. But I just wanted you to see that BRCA1 and BRCA2 are actually in the same pathway in many ways, but they’re widely separated in the pathway. They’re not close neighbors. So you would expect from this to see some similarities and some differences between them.

The most important thing I wanted to say is one of the main functions of these two genes is we all get DNA damage, and BRCA1 and BRCA2, when they’re normal, are supposed to be involved in repairing that damage so that cells don’t go on to reproduce and create more abnormal cells. You can imagine then if a person doesn’t have working copies of BRCA1 or 2 they’re not able to properly repair DNA damage, and then those cells are going to go on and reproduce themselves and create more problems. So this PARP inhibitor trial, this drug that we’re talking about ... and again, this is a busy cartoon here. But let me just walk you through it, because this is really not all that complex.

So when we have DNA damage, it’s like you’ve got this break in the strands of DNA. If you have a working PARP, which you’re supposed to -- you’re born with it -- then the PARP goes in there, and it basically kind of stabilizes this little patch. And it sends up a flag, essentially, a sort of flag saying, hey, DNA damage over here. You DNA repair proteins come on over here and fix this. Then that’s what happens. It gets fixed, and the DNA is repaired. Then that cell will go on and reproduce without sending on that mutation. So this is a normal process that occur.

So the PARP inhibitors are taking advantage of the fact that people who have a BRCA mutation in lots of their cells, they have these breaks. BRCA1 isn’t working. It’s not repairing DNA properly. Lots of their DNA has these gaps and breaks in it. What it’s doing is saying let’s inhibit the PARP. Let’s make the PARP so it cannot go in there and fix damage. If we block that from happening, then this cell will actually kill itself off.

Cells, when they’re treated with a PARP inhibitor, instead of fixing DNA damage ... cancer cells now, so think of it that way. This cell was already on its way to becoming cancerous, or is it cancerous in the case of the PARP inhibitor clinical trials. We think this can also be used for

prevention. Basically there is DNA damage all around, and it could get fixed by your PARP, but if we inhibit your PARP, it will be so widespread, the DNA damage, that this cell will just say, I need to kill myself. And cells do that. There is a system in the body called apoptosis; you may have even heard of it, where the cell just says, okay, I’ve had it, and I’m going to kill myself. Right on. I hope yourselves are killing themselves right now. (Laughter) There is not a whole lot of toxicity involved with PARP inhibitors, because if your cells don’t have DNA damage, then they’re not going to kill themselves out. So it doesn’t really do anything. It only does it to the cells where there is DNA damage. That’s why it’s hopefully a good drug. So far, so good.

I was going to mention here that if you happen to know anyone who has ovarian cancer late stage, it’s also available for BRCA carriers there. Dr. Tutt in London is the PI on that. There is more information about the PARP inhibitor trials in the back, in case you want information about it, and where to go, where can you go for more information. Now, I want to say a few words here, because sometimes I’ve found people tend to know something about BRCA1 or 2 and then it’s like, okay, is that it. Are those all of the genes that cause breast cancer? The answer is, no, they aren’t. What if a person gets the BRCA test, a person who either was very young and/or has a pretty strong family history of breast cancer, may even have ovarian cancer in the family, and the BRCA test is done and it doesn’t show anything. What does that mean?

First of all, there is a slight chance of a missed BRCA mutation. When I say a slight chance, maybe two to five percent. Why is that? There is actually an additional type of testing that is not part of the $3100 usual BRCA sequencing test, which is actually a very good test and finds about 95 percent of mutations. But if I have a family that comes in, and people are really young getting breast cancer, and there are lots of people with breast cancer in the family, and I feel like, there is a very good chance here that it is a BRCA mutation. We did this test, and it doesn’t show anything. We will push on to what’s called BART testing.

So there is another layer of testing of the BRCA genes that isn’t part of the standard test that’s ordered. I would point this out also for people who are tested before 2006, it wasn’t available at that point in time. So people who got a BRCA result in the past, let’s say, in 2000, and it was normal, if there’s strong enough realization to believe there may be a BRCA mutation in your family, it may be worth pursuing the BART testing. Then the second thing is, there could be another gene involved. IF it’s a different gene causing the breast cancer, then testing BRCA1 and 2 is of course going to be normal. That’s not the problem.

So I’m going to talk about at least one other gene I think is fairly important in causing other breast cancer, but there are also other genes we haven’t identified yet. You may have heard that in the year 2007 we started to begin to identify other genes that do cause risk for breast cancer. We don’t know enough about those genes at this moment to actually do tests on individual people, but eventually, I would say within five years, we will have probably a panel of genes. So when a person comes in and says, “I’m young,” or “I had a family history,” and “I want to know why I got this,” and “Do you know it’s genetic?” we’ll have a whole bunch of genes that we can test. And many women, maybe 80 percent of those who have a genetic reason, will be able to get the answer. Right now if I only have three genes I can test, and there are 30 genes that cause breast cancer risk, I’m only going to be able to give an answer to about 10 percent of the people.

The other reason, of course, is that it’s not a main genetic cause. I just want to say of course not everybody who gets breast cancer has a genetic cause. I don’t mean to give you that impression at all. I think at least half of people who get breast cancer probably don’t have a hereditary cause. But if you have the young age or family history then that’s where we shouldn’t just drop it because the BRCA test is normal. So I’m going to talk about this one other gene called p10, because I think it’s important, and I think there are signs of it that people aren’t aware of and then miss it, even in genetics clinics, frankly. So p10 causes an increased risk for breast cancer, about 25 to 50 percent lifetime risk. This is not as high as BRCA1 or 2, but it’s high. It causes an increased risk for uterine cancer, endometrial cancer, of about five to ten percent. And it causes an increased risk for thyroid cancer of about 10 percent.

So obviously if you knew you had this gene; you got breast cancer, and you found out you had this gene, then we would monitor you for these other issues. But it also causes problems that are really quite common, thyroid problems like hypothyroidism or hyperthyroidism or having a goiter. It causes uterine fibroids. Now, of course, fibroids, lots of women have fibroids. But this gene causes that in association with cancer risk. And it causes fibrocystic breast disease. Again, many women have fibrocystic breast disease, and many women who get breast cancer have fibrocystic breast disease.

It doesn’t automatically mean you have a p10 mutation just because you have those two things, but a pattern of these things, including skin tags and lipomas ... lipomas are benign, fatty tumors. Most people who have them say it’s kind of like a doughy ball under your skin. It can be anywhere on the body, and they’re benign. They don’t cause you any problem. But they’re fatty tumors. Any of those things in you or in your family in the setting of breast cancer, and especially, again, young onset of breast cancer, because you started out life with that mutation, those are the things that would make me think of considering a p10 mutation. This is a gene that can be tested for. So I’m going to stop there, and I would be happy to answer questions, as much as I can, on any topic. (Applause)

WOMAN: I have a question if there are genes that we should be looking at or testing for if we go in for genetic counseling that are colon cancer/breast cancer genes. I know my brother had colon cancer at 25, and I had breast cancer at 28, and I’m not the only person I know who has that kind of relationship. If you are BRCA negative, are there other genes you should be asking for that are colon cancer related?

REBECCA SUTPHEN, MD: I’m glad you asked that question. There is a paper in a journal this month that is debating that issue. I can tell you, I’ve been the director of the genetics program at Moffitt since it started in 1996, so I’ve seen thousands and thousands of families. I can tell you that based on the experience, there are families that have colon cancer in the family and have breast cancer in the family. I’m going to tell you a little bit about two different genes that can be considered. When you said that your brother had colon cancer at 25, 25 for colon cancer is very unusual, obviously. So that suggests a major predisposition gene. There is a group of genes called hereditary non-polyposis colorectal cancer. They’re also called mismatch repair genes. That’s a little bit easier. And those genes account for about five percent of all colon cancers, but they certainly can cause cancer at a young age.

Now, in the original and up-to-date description of having mismatch repair problem, it doesn’t include breast cancer in the list of cancers that one can have. The list includes colon cancer, other GI cancers like stomach cancer, duodenal cancer, small intestine cancer, rectal cancer, anything in the GI system. It also includes pancreatic cancer; it includes gall bladder cancer, sometimes thyroid cancer and sometimes brain tumors. That doesn’t mean a family doesn’t have those gene mutations if they don’t have those other cancers. Colon cancer is the predominant cancer in those families.

But I can tell you from experience that a lot of those families do have breast cancer in the family and even young onset breast cancer. Of course lots of families have breast cancer in the family, and if it happens in your 83-year-old great aunt then you may not raise an eyebrow. But if it’s happening in a young woman, then you say could that be part of their hereditary pattern. So there is actually a debate in the literature right now about don’t we seem to see a pattern on breast cancer associated with those mismatch repair genes. What that’s telling me is even the experts think that may be true.

The second thing I would mention is there another gene called CHEK2. CHEK2 is a gene that we know can cause breast and colon cancer in families, but it doesn’t typically cause breast or colon cancer at such a young age as you’re telling me, and it usually only gives people about double the risk of getting a breast or colon cancer. So seeing a strong pattern in a family, two first-degree relatives as you and your brother, and being so young, it doesn’t sound much like CHEK2.

But that is another gene that can cause breast and colon cancer. So I think a good point is if you’ve very young and you have cancer, and/or you have family members who have cancers, it makes sense to go talk to a genetic specialist, because the average person, even a great doctor, is not going to know what other genes to consider. Although I’m giving you a lecture today and I’m trying to include sort of focused information, we certainly do go into detail into your entire family pattern of cancer and look at all of the possibilities and discuss them.

WOMAN: If you do test positive on the BRCA and you have breast cancer and you have a hysterectomy, what are the chances of getting ovarian cancer after the hysterectomy?

REBECCA SUTPHEN, MD: I didn’t focus on that on the slide I showed, but I did include it in the prophylactic oophorectomy slide. I won’t even go back to it. With BRCA mutations there is a risk for ovarian cancer. I just want to say that, because, as you know, having your ovaries removed, it can be done in different ways. Some people have just their ovaries removed laparoscopically. Some people have a hysterectomy, either an abdominal hysterectomy or a vaginal hysterectomy, where they take out the uterus and the ovaries and the tubes. BRCA is associated with ovarian cancer and fallopian tube cancer. It is not associated with uterine cancer. So that’s why it’s okay for some people who say, I’m just going to get it done through my belly button and get my ovaries and tubes, but not my uterus. It’s an individual decision there.

If a person has a BRCA mutation and they have their ovaries removed, there is less than a two percent lifetime chance that they would get ovarian cancer after having their ovaries removed. The reason is because we all have a pelvic lining that is composed of the same type of cells as

our ovaries, and that pelvic lining cannot be removed. So those cells cannot be removed. And it’s kind of like saying if you have a mastectomy but you can’t remove every last cell, could you still get a cancer in there. So it’s a small risk, and prophylactic oophorectomy is considered not eliminating the risk for ovarian cancer but almost.

WOMAN: I actually have two questions. One of them is: When you go in for genetic testing, what do they consider strong family history? At what level in the family tree does it have to exist?

REBECCA SUTPHEN, MD: That’s another good reason for genetic counseling, and I’m happy to talk to you individually if you’re interested, but basically it’s looking at how many people in the family have had cancer. But on the other hand, what if I’m talking to a person who’s adopted or a person who it’s coming from her dad’s side of the family, so of course her dad didn’t get ovarian cancer. And her dad has got three brothers, and they all had boys. So depending on the family history, you can’t just make a cut or dry you need this many people at this age and you have to have this and that and the other. The clues would include premenopausal breast cancer, that’s under 50 years of age, a person having bilateral breast cancer that’s not spread from the primary, a person having breast and ovarian cancer or a family having both breast and ovarian cancer. That would include even if it’s your cousins.

The important thing to look at when you’re looking at your family history is if you’re talking about inherited risk, it’s only going to be coming from one side of the family or another. So don’t take a couple of relatives on dad’s side had breast and then a couple on mom’s side had breast and add that up to four people. It’s one side of the family or the other, but then if you see these clues: young age, bilateral disease, more than one primary breast or ovarian cancer, multiple relatives with breast or ovarian cancer, multiple generations of cancer, having Jewish heritage, having any males in the family with breast cancer ... all of those things suggest that you should at least talk to a genetic counseling.

The National Comprehensive Cancer Network’s on recommendations for genetic counseling basically say that it’s appropriate for any woman who had breast cancer premenopausally to go for genetic counseling and certainly any women 40 and under should go for genetic counseling. Just get a thorough evaluation of your family history and make sure that an expert doesn’t feel that this is a hereditary susceptibility. Then I’ll just say one more thing about that. I think the way we’re doing things today is going to be very different than the way we do it five years from now, because five years from now I think the majority of people who get cancer are going to get some kind of genetic test to see was there something that underlies you getting the cancer in the first place in addition to what does your tumor tell us genetically about how to treat that. So it’s going to be more focused, more directed, more personalized and more people will get answers.

WOMAN: Also is there a gene that looks at risk of uterine and cervical as well?

REBECCA SUTPHEN, MD: Cervical cancer is largely due to the human papilloma virus, which is transmitted from sexual intercourse with males who don’t show any symptoms of it, so that’s why it’s fairly widespread. This is why the new vaccine came out, and people are just going to start getting vaccinated against it. Cervical cancer does not have a strong hereditary

component. Endometrial and uterine are the same. Uterine cancer can be due to a p10 mutation, and it can be associated with breast cancer in families. Uterine cancer can also be associated with the colon cancer genes that I mentioned, the HNPCC mismatch repair genes. So if there is colon cancer and uterine cancer in the family, that can suggest that group of genes. There are other genes as well. Those are two majors.

WOMAN: I have a family history of polycystic ovaries and endometriosis in myself, my sisters, my cousins, my aunts, my mother, and now I have breast cancer. And I understand there is a connection between breast cancer and ovarian cancer. The polycystic ovaries, is that a genetic thing that might affect ovarian cancer or lead to that? Is that something that we need to watch a little closer?

REBECCA SUTPHEN, MD: At this moment in time it doesn’t seem that it is a strict genetic inherited factor that would be predisposing you to cancer if you have polycystic ovarian syndrome. However, let me just say that we are starting now to understand a lot about the metabolic nature of some breast cancers having to do with ... it’s kind of like you would say well ... and I don’t mean to say that people who have polycystic ovaries have a high-fat diet. But why would a high-fat diet cause breast cancer? Does that make any sense?

But if it’s related to insulin metabolism, and insulin metabolism is related to overall body metabolism, and metabolism is related to polycystic ovarian syndrome, you can start to see ... and when you start looking at the genes and the proteins that are involved in all of that process, we’re starting to see that those things may, in fact, give you some susceptibility to breast cancer. So it’s a little different. I guess what I’m saying is maybe there are some genes that cause a person to have polycystic ovarian syndrome, and those genes in themselves wouldn’t give a person a high risk for cancer. But they set up a metabolic situation in their body that then might give them a higher risk for developing cancer. So we’re learning more about that right now.

WOMAN: My geneticist recently shared with me that she had seen some evidence from a recent conference that there has been laboratory or research proof that in BRCA1 they have shown that selenium has acted as a PARP inhibitor. Do you know anything about that or have you seen it?

REBECCA SUTPHEN, MD: I am pretty familiar with a lot of research that goes on and include nutrient-based research that goes on, and especially related to BRCA. I would say that sometimes we get a little information. There isn’t good information at this moment in time saying that selenium acts as a PARP inhibitor or that if you have a BRCA mutation it’s a good idea to take selenium, although I can tell you that Dr. Steven Narod, who is a world-renowned expert on the subject of BRCA -- and we collaborate a lot with his group -- he personally believes that it is helpful. He actually kind of promotes things that a lot of other clinical people, scientists and the National Comprehensive Cancer Network, don’t feel comfortable saying, “This is a good idea.”

Let me just make a statement there. I have a great deal of respect for Dr. Narod, so I’m not saying at all that he’s wrong. But I sit on the panel of the National Comprehensive Cancer Network guidelines panel, and let me just say a word about how that works. I encourage you to go on their web site, because it’s got information about every aspect of cancer. So anything that

you can think of, there are guidelines in there. They’re available on the public web site. It’s really written for healthcare professionals, but you can go on there and read all you want. It’s nccn.org. Essentially, all of the NCI centers ... so like Moffitt is the only one in the State of Florida, and then there are NCI centers all over the place: Memorial Sloan-Kettering, Dana-Farber, MD Anderson, blah blah. Basically for every aspect of cancer, they made this decision, hey, you know what, we should be funding all of the experts to sit down together every six months and say, “What are you recommending?”

Then it’s not up to whatever doctor you happen to go to and what he happened to know and happened to read and happened to find out. Some experts actually sit down every six months. The thing I love about this ... so I’m on that panel, and I’m trying to remember how many people. But it’s basically 39 comprehensive cancer network ... it’s the head of genetics at every one, and then there is the head of whatever at every center. They all sit down together. It forces you, first of all, to sit down and talk about these things. So there is open discussion about it. The other thing is, it’s not a group of people who are saying, oh, let’s wait, there’s not enough research; there’s not enough literature. No.

They’re saying, look, I’m talking to people every single day, and these are the questions they’re asking, so let’s give them the best answer we can. But let’s all put our heads together and come up with the best answer. Then they publish those guidelines. So that’s a great way to do things. That’s a very humanistic way to do things, in my opinion, very different from medical literature, the way things get handled, and a lot of policy statements. “Finally we’re going to say we should offer MRI.” Well, guess what? MRI was here for a while. And the NCCN panel, I am happy to say, had recommended use of MRI long before this new ASCO recommendation came out. So it’s just a different approach, and I think, a very good approach.

I’m going to make one comment about selenium so that you don’t think Dr. Narod, the world expert, is the best voice. Most other people in the field who are experts do not think that taking selenium is a good idea right now. There have been a number of studies that showed that you actually can increase the risk for cancer by taking selenium. So I think in this particular case, until the data is in and a group like NCCN can come out and say, “This is a reasonable thing to consider,” I would recommend against it.

WOMAN: I was diagnosed with breast cancer at age 48. My sister was diagnosed at 43. We were ER positive. We had the BRCA1 and 2 testing done, and it was negative. I had a grandmother on my dad’s side that had postmenopausal breast cancer many, many year ago. My sister and I both had a sister that had leukemia when I was two. She passed away. She was three or four. And just last week my mother was diagnosed with breast cancer. I don’t have the results back for her for her ER test yet.

REBECCA SUTPHEN, MD: How old is your mother?

WOMAN: She is 69. Two questions. Is there any evidence of leukemia having anything to do with breast cancer? Also, my niece is 19. I’m worried about her, of course. She’s very worried. Should she ever consider taking oral contraceptives?

REBECCA SUTPHEN, MD: First of all, I would say there is still a possibility that there is a BRCA mutation in your family that wasn’t detected, but that probably isn’t my number one suggestion as to whether there is a mutation in your family. I think it’s worth considering whether there could be a p10 mutation in your family. That’s a lot of breast cancer, a lot of young-onset breast cancer. You do see that with p10 mutations. Let me just say on these issues about p10 -- I’m going to move to the next slide -- when I talk to people all of the time, what’s the chance you’re going to know if your cousin had fibrocystic breast disease or fibroids?

We don’t know that information. I’m lucky if I know that about my sister. So unless you know the questions to ask ... and this is why I brought this topic up, because these are relatively common things, but they’re not things that you would necessarily know unless you asked the question. So I would go and explore this possibility in your family history and find out if this is something that ought to be pursued. Because even without some of those other things it would be worth considering it in your family. I can give you some information about how to get in touch with those folks.

The other thing is that when you have a family history of breast cancer only and there’s no ovarian cancer in the family then most likely you do not have a high risk for ovarian cancer, most likely. I can’t say it’s impossible, but it’s not likely to be a high risk. That’s because when we’ve studied families where there is breast and ovarian cancer, the majority of those families, as I showed you, those families have BRCA1 and 2 mutations. So unlike breast cancer families, where if you just study families that have a lot of breast cancer, there is a fair percentage that have BRCA1 and 2 mutations, but there are a lot of families where there’s a lot of breast cancer and they don’t have BRCA1 and 2 mutations. What that’s telling us is there are other genes that cause hereditary breast cancer. Oh, yes, there are. But we haven’t found them yet. But they don’t cause ovarian cancer, generally speaking.

In general, would I recommend oral contraceptives for a 19-year-old? If she has other reasons to take them, and she doesn’t have any other contraindications to taking them, then, as I said, oral contraceptives reduce your risk for ovarian cancer by about half, and so there can be lots of good reasons to take them. Relatively speaking, for lots of women, they’re not difficult to take. So I wouldn’t recommend against it.

WOMAN: And the leukemia?

REBECCA SUTPHEN, MD: Leukemia, yeah, sorry. Yes, leukemia is on the list of things that may be associated with BRCA, especially 1 mutations. It’s not a known association. There are other genes that are associated with both breast cancer and leukemia, although your family doesn’t really sound like it. If you would see me afterwards I’ll talk a little bit about it with you. I try to be careful what I say, just to make sure that it’s somewhat in context. But I would be happy to talk with you.

WOMAN: I don’t have a genetic question per se; I have a financial question. Given that insurance companies do not want to pay for geneticists but the majority of us are under 40 and need genetic testing, what are our avenues to get that paid for?

REBECCA SUTPHEN, MD: So the National Comprehensive Cancer Network guidelines say that if a person has breast cancer under 40, it is recommended that they see a genetics professional. If your insurance company doesn’t pay for that, you need somebody to fight for you to get that covered. If you have average insurance -- I see every insurance just about that there is -- they should pay for that consultation. So if you’re not getting that done, then keep on going,

WOMAN: What was that network?

REBECCA SUTPHEN, MD: The National Comprehensive Cancer Network, the nccn.org. This is where you say, look, the standard of care is if I am 40 and under when I have breast cancer, I get a consultation with the genetics professional. That is the standard of care. I fight with the insurance companies all of the time. I bet you do, too, huh?

It’s an individual thing about insurance companies. As lots of you in this room already know, it’s not because they don’t know what’s going on. I have to say, there are some good insurance companies. Let me just make a pitch; I’m going to say a word about Aetna. Aetna is very proactive when it comes to genetics. They are the ones that have really taken the bull by the horns and said, “We have guidelines, and we’ll follow them. If it’s an NCCN guideline, it will get covered.” Let’s say that there is a young woman, and her mother had breast cancer and is no longer living, and she wants to know if she’s got a hereditary risk for breast cancer.

They’ll actually say, okay, well, is there anybody else in your family who’s living who has had breast cancer that could be testing. We’ll pay for them. Even if they don’t have Aetna insurance, we’ll pay for them to get tested so we can get the answer in your family. That’s outstanding. I don’t mean to say they’re great about everything, because I don’t mean to say that at all, but I think this proactive approach ... and start using the information, the knowledge that we have available to us, because it makes a difference for people.

SUE FRIEDMAN, DVM: I want to interject a small plug about FORCE, because do we have resources on the web site.

REBECCA SUTPHEN, MD: Can I just interrupt you, Sue? I’ll make my own plug about FORCE. So if you don’t know anything about FORCE, FORCE is an outstanding organization. It is dedicated to hereditary breast and ovarian cancer. It is full of information. The web site is www.facingourrisk.org. It’s hard for me to ever find a person who finds out they have a BRCA mutation who doesn’t know about FORCE or find out about FORCE. I love the name, too, “FORCE.” We are a force, and we’re interested in knowing, being empowered, taking action, sharing information. Go on the message boards on FORCE. Right now I have chills on my arms, because I can’t go on the message board without just being overwhelmed by what people share there.

So if you have any possibility of having hereditary cancer, breast or ovarian cancer, in your family, or you’re even thinking you might, please go on that web site. There is not anything that I could tell you that isn’t covered on that web site. It’s www.facingourrisk.org. Please just go on that web site. Any question you can come up with, the answer is on that web site, in plain

language. It’s been reviewed by medical experts. It’s just an outstanding organization. I can’t say enough good about it. Peer support, toll-free helpline. You find you’ve got some unusual situation, and they’ll find somebody who’s got the same situation living in Podunk, New Mexico, and get on the phone for you.

WOMAN: Is there any link between triple negative and BRCA1 cancers?

REBECCA SUTPHEN, MD: There is.

WOMAN: Yeah, so triple negative is one of the things that we see in BRCA1 families. When you have a triple-negative breast tumor it doesn’t mean you have a BRCA1 mutation, but if you have a family history and you have triple negatives in your family, then it’s more likely it could be a BRCA1. I think a good thing about that, because sometimes you feel like it’s not the best thing to have, but a good thing about that is we are really learning a lot about BRCA1 cancers and triple-negative cancers. I think there is real hope on the horizon here in the short run for dealing with these very aggressive kinds of tumors.

BRCA1 tumors are largely triple negative.

WOMAN: I’ve heard the tumor whatever gene, p53, and then I think it’s Li-Fraumeni syndrome.

REBECCA SUTPHEN, MD: Li-Fraumeni.

WOMAN: Yes, that’s the one. What are those?

REBECCA SUTPHEN, MD: Actually, this is the comment that I was going to make. So I always hesitate to talk about Li-Fraumeni syndrome, and I’ll tell you why. I’m sure every single one of you know what I’m talking about: You can go on the Internet and read the most awful, horrible outcome of your particular situation that ever mankind could write on there. Then you start talking to other people and you go, wait a minute, that isn’t the whole story. There is a whole lot more hope here than I knew, and there are more people that have had this situation. I’m not really getting a balance view of that. So historically Li-Fraumeni syndrome, most of the time when genes were first found, they were found because there was some really bizarre situation, and then somebody could study that in some family that had this really bizarre situation, and a gene might get found.

But then the next thing it say, okay, well, let’s say, in that family ... so the typical Li-Fraumeni, classic Li-Fraumeni, if you read about it, is very scary. It says that by the time you’re 40 years old more than 50 percent of people in Li-Fraumeni families will have gotten cancer. By the time you’re 60 years old, something like 95 percent of people will have gotten cancer. And you can basically get cancer almost anywhere in your whole body, including leukemias and young-onset breast cancers. But what happened is then we started saying, we don’t have answers for some of these other families that have breast cancer. I wonder if they could have a p53 Li-Fraumeni mutation in their family.

Then you study and you say, okay, yeah, but now when I look at their family history, most people had maybe one cancer. Lots of people survive. Some people didn’t get cancer. People didn’t get cancer in every organ in their body. So you start to see that even though you found the gene in this really bizarre, way-out-there kind of awful risk situation, actually other mutations in the same gene can cause not so significant levels of risk. So if you have young-onset breast cancer in your family and you have leukemia in your family, I would, as a geneticist, be thinking maybe you have a p53 mutation. But I would want to talk with you about that so that you don’t go on the Internet and read about Li-Fraumeni syndrome and think you’re going to die tomorrow, because that is not the spectrum of what we see today about Li-Fraumeni.

WOMAN: You had mentioned about breast cancer and insulin, and I was diagnosed with breast cancer at 36. I’m the only one in my family that has breast cancer. I lost my pancreas due to nesidioblastosis disease. I’m just curious, because I know that with the pancreas it plays a role with the insulin. Can you touch on that a little bit? Because breast cancer doesn’t run in the family.

REBECCA SUTPHEN, MD: Did you have the pancreas problems prior to having the breast cancer diagnosis?

WOMAN: Yes. I had a total pancreatectomy.

REBECCA SUTPHEN, MD: So I just want to get the frame of reference for what you’re saying. So your pancreas is what produces your insulin, and then people who get type 1 diabetes in their juvenile years ... now you have a different reason why you had the pancreas problem, and I understand what you’re talking about, but I’m just saying as a general comment to everybody that type 1 diabetes, you can have problems producing insulin, so you end up getting diabetes. Then other people who get type 2 diabetes, the kind that’s associated with older age and having obesity and things like that as we get older, that’s really not because your pancreas wasn’t making insulin. It’s because you taxed the system by taking in a lot of calories and sugar, and insulin had to be produced again and again and again and again and again and again and finally kind of wore out your pancreas. That’s sort of the bottom line of it.

Now, that doesn’t mean that everybody who has type 2 diabetes had awful habits. People have genetic susceptibility to lack of response to insulin and other things, so I don’t mean to paint a picture that it was all due to your own doing. But it kind of explains why it’s very much related to body metabolism, and what we see is that insulin is a growth factor, so when you produce a lot of insulin and when you have fat, or your pancreas is acting abnormally, and let’s say, it’s producing insulin in an abnormal way, that’s like sending out a growth signal. It seems that breast cells are particularly responsive to those growth signals. So having a pancreatic problem, I’m not saying that it’s related to your breast cancer developing, and there’s an equal chance, if not better, that it isn’t related to that. But could it be that something with your insulin signaling was very abnormal and you were producing this weird growth pattern factor and as a result you ended up getting breast cancer? There could be some link between those, yes. Does that help you?

WOMAN: Yes.

REBECCA SUTPHEN, MD: It’s a complicated topic.

WOMAN: With the BRCA testing, would that sort of ...

REBECCA SUTPHEN, MD: Help clarify things?

WOMAN: Help you clarify it?

REBECCA SUTPHEN, MD: If you’re 36 and you had breast cancer, then considering BRCA testing is a reasonable thing to do. If you had a BRCA mutation, then it would suggest that that was the primary cause of your breast cancer, but whether the pancreas problem and the insulin problem promoted the process and made it even earlier, that’s still possible. So, yes, I would say you’re a good candidate to go for BRCA.

WOMAN: I know you had mentioned about the testing for someone. Are you saying that once someone is tested and you find that gene that the other sibling doesn’t need to be tested?

REBECCA SUTPHEN, MD: So the question is if you’ve 36 years old and you have breast cancer, and you go get tested for BRCA, if we find a mutation, then everybody else in your family can get that same mutation tested for, for $385, and then get a yes or no answer; they have this risk or they don’t; they can pass on the risk or not. However, if you’re tested and no BRCA mutation is found, then it makes no sense for your sibling to go get tested, because if we didn’t find it in you, we’re not going to find it in them. It’s something else.

WOMAN: Now would that also pertain to the child? Like if I had the [inaudible].

REBECCA SUTPHEN, MD: Yes, would that pertain to a child? If you have a BRCA test, and it’s negative, there is no point of testing your child, because the only thing ...

WOMAN: I meant if I do have it ...

REBECCA SUTPHEN, MD: If you do have a BRCA mutation ...

WOMAN: Then they would only have to test for that one mutation in my daughter.

REBECCA SUTPHEN, MD: If you do have a BRCA mutation then there is a 50/50 chance with each of your children to pass it on, and they can be tested just for the specific mutation found in you and get a clear yes or no answer, but that should not be done prior to 25 years of age. I would make a comment about that. I’m going to say why. Any adult 18 and over in the United States can get a gene test, but if a woman comes in my office and she’s 19, I’m thinking, “Oh, why am I going to have this conversation with a 19-year-old?” First of all, she’s not going to get breast cancer at her age. Twenty-five is a very conservative age for us to begin doing screening, and we do. Mammograms and breast MRIs starting at 25. But please don’t come in my office at 22 and find out you have a BRCA mutation, and then I say, okay, now we’re going

to wait until you’re 25 and then we’re going to start you on a screening program. Can you imagine? No. So 25 is a good age to start that. Yes?

WOMAN: At 42 I was diagnosed with a primary breast cancer, ER-receptor positive, and also a secondary in my other breast, so bilateral breast cancer. After mastectomy and whatnot, actually my surgeon recommended I get the genetic testing. I didn’t see a geneticist, we just sent it in and my insurance covered it 100 percent. But also right after that, I went, even though it was a little early, and I said, I want to do a colonoscopy. And they found a large polyp that was precancer. My BRCA1 and 2 came back negative. Should I just be done with the genetic stuff or should I be looking further at some of this?

REBECCA SUTPHEN, MD: I would be looking further.

WOMAN: I do have some of all that stuff for the p10, and that’s in my family.

REBECCA SUTPHEN, MD: Yes. I think you should come and talk to a genetics expert. I don’t mean to downplay that physicians sometimes order BRCA testing in their office, but you don’t typically get a good evaluation of your family history and a good discussion of what the possibilities are. Then if the test comes back normal, it’s kind of like, “Okay, we’re done now. Wait a minute. We really need to take a close look.” That’s why it’s worth going for an evaluation.

Insurance covers the cost of meeting with a genetics expert. I’m going to make a comment here: Sometimes people say to me, “Well, I’m not in an area where there is a genetics expert.” It’s easy to go if you’re aware there is a big center like in Tampa, for example. But I’m just going to make one comment that there is starting to be availability for genetic counseling that is available by telephone, and I have a big conflict of interest with a company called Informed Medical Decisions [http://www.informeddna.com]. I’m on the board of that company.

But Aetna has just accepted them as a national provider for genetic counseling by phone. So basically you call a 1-800 number, schedule an appointment, and you can talk to a genetic counselor on the phone and get the same level of service. So I think you’re going to see more and more of that happening. That’s a good thing, because to me it’s about access. It shouldn’t be that I live three hours away and I have to take another day off work just to go talk to somebody who’s an expert. It should be available to people. So I hope that we’ll see that as a trend.

WOMAN: What’s the name of the company?

REBECCA SUTPHEN, MD: It’s called Informed Medical Decisions. I have a huge conflict of interest there. I don’t usually mention it, for that reason.

WOMAN: I was diagnosed at 35, 10 years out. But my mother was diagnosed with ductal carcinoma 18 months prior to me, having lobular carcinoma. But when I asked about genetic testing 10 years ago in 1998 I was recommended not to have it because there could be some insurance things with my sisters and things.

REBECCA SUTPHEN, MD: I’ll make a comment about insurance. First, let me say, what they told you 10 years ago, it’s outdated now. At that time people didn’t even think DCIS was associated with BRCA mutations. That isn’t true. Now the National Comprehensive Cancer Network says DCIS should be considered just the same as invasive cancer when it comes to evaluating the family history for BRCA mutations. So DCIS in the family is just as significant, and the age, as if the person had invasive cancer. I forgot what else I was going to say.

WOMAN: Insurance.

REBECCA SUTPHEN, MD: Oh, insurance. Insurance discrimination, that was it. So I tell people this. Let’s say she comes in my office. She’s 33 years old and she has breast cancer, and she wants to know if she’s got a BRCA mutation. Let’s say it sounds to me like it could be, and if it is, she wants to know. So I say, here’s the issue: In the State of Florida at least, we helped to get a legislation passed that says the health insurance company cannot ask for your genetic test results and they cannot use your genetic test results for any insurance purpose. If they try to do that, there will be a lawsuit. So there is good protection about your health insurance.

However, what if when you’re 50, and you’re at the age where everybody says, okay, now we need to look at our life insurance, our long-term disability, our long-term care and all of this other stuff. And when you’re 50, it’s been 17 years since you had breast cancer. The insurance company doesn’t even care. They won’t even care about that. But they might say, well, hey, we see you had a genetic test when you were 33 years old. So we don’t want to give you a life insurance policy or a long-term care policy or disability, which you otherwise would be able to get. So is this going to cause you some problem down the road with other kinds of insurance, not health insurance? Here is the way most people present that equation to me.

So I’m not saying this is the answer for everybody at all, but just so I can tell you. They say, look, probably I don’t have a BRCA mutation. It’s the rare individual that I’m saying it’s a greater than 50 percent chance you have a BRCA mutation. Usually it’s 40 percent or maybe 20 percent. It’s worth finding out, and if you do then it’s 100 percent. But most people are going to end up getting a normal test result, out of all of the people who get tested. So if you get a normal test result, then that hasn’t done you any harm.

You go get a policy, they say you had a genetic test. You go, yeah, I did, and here are the results, and they’re normal. If only if you have a mutation that it could cause you issues. Another benefit of going to a genetic center like ours is that we keep your records entirely confidential. We won’t release your results to anybody except you, not even to the physician, for that very reason, that it tends to get copied in the medical record, and we don’t think that’s a good idea.

But most people say if I have a BRCA mutation then that is information I want to know right now, because I will make changes, and I can spread information to my loved ones that will be more valuable to me than the potential problem I might have some day about some life insurance policy down the road. That’s the way most people balance that. In general when it comes to health insurance, in the State of Florida ... now, laws vary from state to state, and Sue is a big proponent of getting GINA passed, and let’s move on and get beyond this and let people get

information and empower themselves. But until then, at least in the State of Florida, health insurance you have good protection in place. Yes?

SUE FRIEDMAN, DVM: I think one or maybe two more questions.

WOMAN: I just had a question about the age thing. I have a strong family history of breast cancer, and I was diagnosed at 29. My doctor recommended that my daughter be tested 10 years younger than I, which would put her at age 19, and even to start having mammograms then.

REBECCA SUTPHEN, MD: You’re making a good point. So first, I’m thinking, did your doctor suggest you get a BRCA test?

WOMAN: Yes.

REBECCA SUTPHEN, MD: Okay, so if you get a BRCA test, and then you find out you have a mutation, then we say, okay, there’s a 50/50 chance this could be passed down to your daughter. Since you were only 29 when you had breast cancer, we have to ask ourselves, “Hey, is 25 an okay age for us to start doing screening on your daughter? Do we feel comfortable with that?” So I, and others, and the national panel all say 25 years is when we start, or 10 years younger than the youngest age of diagnosis in the family. So you’re making a very good point. The recommendation is 25 and beyond, but the exception is if you’re that young, and it’s 10 years younger than the youngest age of diagnosis, we actually will start doing testing on people who are younger. So good for him is what I would say about him.

WOMAN: Do you mean BRCA testing?

REBECCA SUTPHEN, MD: Yes.

WOMAN: Or screening tests?

REBECCA SUTPHEN, MD: I’m talking about both. So in a family where you know there is a mutation, it makes sense to go ahead and find out. Because if your daughter didn’t inherit the mutation then we don’t need to do anything for her. But if she did, we would be willing to start screening as young as 10 years younger, even if she’s 19 years old. And it’s not because we think she’s got cancer. It’s just because why are we going to sit around waiting.

WOMAN: If someone tests BRCA positive and they have an identical twin ...

REBECCA SUTPHEN, MD: Then the identical twin has the mutation.

WOMAN: I was pretty sure, but it’s been a while.

REBECCA SUTPHEN, MD: Only identical, though. If she’s not identical then she only has a 50/50 just like any other sister.

SUE FRIEDMAN, DVM: One more question, and this will be the last one.

WOMAN: It’s really quick. So if family history is enough to get insurance help, is it also the same for ethnicity, specifically Jewish?

REBECCA SUTPHEN, MD: Can you repeat it?

WOMAN: Sure. If family history is enough to get insurance help then is it the same for if you were Jewish?

REBECCA SUTPHEN, MD: So if you have breast cancer and you’re Jewish, then most likely you can get a genetic consultation covered by your insurance.

WOMAN: What if you’re just Jewish?

REBECCA SUTPHEN, MD: If you’re just Jewish then it’s a 1-in-40 chance that you would have a mutation even if you don’t have cancer. And some people do pursue genetic testing who are Jewish for that reason. Because you only have to test for three mutations, the cost of that testing is $460. So your insurance may or may not cover the cost of it. Some people get it done anyway even if their insurance doesn’t cover it. I can count on one hand the number of people who paid for the full sequencing, $3100, in my whole career. But $460 may be worth it in some cases.

WOMAN: Add one. My cousin did.

REBECCA SUTPHEN, MD: Add one.

WOMAN: Thank you.

REBECCA SUTPHEN, MD: Thank you all very much. (Applause)

SUE FRIEDMAN, DVM: On behalf of Living Beyond Breast Cancer, Komen for the Cure and the Young Survival Coalition, thanks for coming.

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