[MUSIC] Today, I want to talk about the way in which family history of cancer can effect the way we treat patients who come to us without cancer, but want to know if they're at increased risk or not. We'll talk about breast cancer today, and in the next module we'll talk a little bit about colon cancer. So, the case for today is a 37 year old woman who is seen for counseling. And the reason she comes for counseling is because her mother died at age 56 of ovarian cancer. Her mother's sister has advanced breast cancer at the time the patient is seen. Her mother's mother died of cancer we don't know what sub-type at age 45 and that grandmother's mother died at age 53, also of ovarian cancer. So this patient comes because they have a very strong family history both of ovarian cancer as well as a history of breast cancer. Now, the patient is Angelina Jolie. And, I know this history because I read it on the internet. When we look at patients who have cancer, some small proportion of them will give a very strong family history, as in this case. And of those with a very strong family history, there's a much smaller segment, perhaps 5%, perhaps 10%, in whom we can discover genetic variants that place them at increased risk for cancer. There's another 10 to 15% who will give a very strong family history of cancer. You have to suspect there's something genetic going on, but we don't at this point have the ability to identify the genes. And then for most cancers, the disease appears to arise sporadically. There's not a strong family history and we don't know the role of common or rare genetic variance in those kinds of families yet. As a matter of principle, the way in which we think this happens is that cells as they divide through the course of a lifetime, often when they replicate their DNA molecules don't do an absolutely perfect job. They occasionally will acquire a mutation. So you see the two chromosomes on the left, they've replicated and they've created a little mutation, a little red spot. Now the body has mechanisms to correct those mutations, DNA repair mechanisms. And so, most of the time, those abnormalities are repaired, and we don't accumulate mutations at a high rate over a lifetime. But occasionally, we will end up with a mutation in a gene, and that may or may not cause a problem. But over time, you get multiple mutations. And as that happens, the cell may develop the ability to start to replicate itself autonomously in a cancer-like fashion, develop a tumor. The way in which we think this happens, often, is mutations in DNA repair genes themselves may be a problem, and mutations in genes whose job in life is to suppress cancer, tumor suppressor genes, may acquire mutations and therefore lose function. So that's the way we think cancer may arise over a lifetime. The problem is that some people start life with a mutation in their germ line. So they start life with a mutation, and then over the course of a lifetime may develop other mutations. And it's the combination of what they're born with plus what they acquire and accumulate over a lifetime that results in the cancer. The reason I have the arrows drawn the way I do is that most of the mutations you acquire with each cell replication get repaired. So we don't accumulate them, but a small number do. And of course there are many things that cause mutations. Some of them are just random. And some of them are things like carcinogens, so tobacco smoke, for example, is the most commonly recognized form of an external chemical that can induce these kinds of DNA mutations that ultimately lead to cancer. So in the case of Angelina Jolie, the two most likely genes in which she harbors a mutation are genes called BRCA1 and BRCA2. They are involved in the DNA repair mechanism in ways that are not completely understood. So, if you take a person like Angelina Jolie, who has only breast cancer in her family. Well, let's talk about Angelina Jolie who has breast and ovarian cancer. 80% of the time, she will have a BRCA1 mutation, another 15% of the time, she'll have a BRCA2 mutation. And then there's a small number of other mutations that I'm not going to talk about that could also cause this familial susceptibility. Take patients who have only breast cancer in the family, and not breast and ovarian cancer. Then the likelihood is that she has BRCA1 or BRCA2, or one of these other syndromes, as shown on the pie chart on the top. So, faced with a patient who comes to us with the question, I have a family member who has cancer, should I get genetic testing? So, the specific question in terms of taking care of this particular patient is, does she have enough of a family history that genetic testing is something that we should do. One, some people argue that everybody should have genetic testing anytime they want. The problems are that genetic testing is expensive. The consequences of genetic testing can get expensive. Some of the times, the genetic testing results in results that we don't understand completely and it just confuses the patient. But in settings where there's a high likelihood that there's a genetic contributor to cancer susceptibility and we would do something about it. That's when genetic testing is most likely to be useful clinically. So in a patient we ask, are there more than two breast cancer primaries on the same side of the family, or breast cancer and some other cancer? And the other cancers are ovarian, pancreatic, and a number of others which I'll talk about. Is there a family member with ovarian cancer, period? Is this a family in which somebody is known to have a BRCA1 mutation? If you have a family in which somebody has a BRCA1 mutation, then genetic testing for that mutation is a very reasonable thing to do. And then there are two other groups that are at particularly high risk. One is Ashkenazi Jews have a 1 in 30 chance of carrying a BRCA1 mutation that predisposes to breast cancer. There are three mutations that are prevalent in the Ashkenazi population, so it's pretty simple to test for those three variants in Ashkenazi Jewish women. And then breast cancer arising in a man should really raise red flags that that may be a genetic syndrome as well, often BRCA1 or BRCA2. As high as 40 or 50% of men with breast cancer may have mutations in those genes. That, of course, is important for them, as well as family members who happen to share their genetic material. So, when we are faced with somebody who's doing genetic testing, we have to always ask, what will we do with the results if we get them? So, if they turn out to be positive or negative. So, if a person like Angelina Jolie were to get tested and have a mutation discovered in BRCA1 or BRCA2 that has been previously associated with cancer risk, we would say they are at increased risk for getting cancer. And then we'll talk in a little bit of what we would do about that. But that principle applies to genetic testing of all types, for cancer, for cardiomyopathy, for arrhythmia susceptibility. If you find the mutation that has previously been associated, that makes increased risk. But sometimes, that's not the situation. Now, what we would like to do, in Angelina Jolie's family and every other family, is actually test somebody who has cancer. Test somebody in whom we think there's a genetic contributor to cancer already established. We would test that person, if we found a BRCA1 or BRCA2 mutation, for example, then we could test every other member of the family and ask the question, do they share that mutation? If they don't share that mutation, then they should be treated like any other person who comes to you and says am I at risk for cancer? And the answer is that you are at no more increased risk for cancer than anyone else. Another scenario is a patient who comes to you like Angelina Jolie, who says, nobody in my family has previously been tested. I have a very strong family history. And, what should I do? So, you do the testing, and it turns out they have no mutation that you can identify. The family history smells like something that would place her at increased risk, but you can't find the mutation. So, the answer there is you continue to watch them, you may do surveillance examinations such as a mammogram more often. But you can't declare them as having increased risk at this point. And then, the biggest problem with contemporary genetic testing, in my view, or a big problem, is that sometimes you get patients who have the testing, who don't have a family member who has cancer yet, or you don't have an indexed family member. And the testing results and the detection of a variant that's never been seen before in a gene like BRCA1 or BRCA2. In that setting, you can't say that the genetic variant is likely to increase the risk. You also can't say the genetic variant can simply be completely written off. So those are also patients where there's a heightened surveillance and a heightened sensitivity to the possibility of cancer, but you can't declare that patient as having very high risk of cancer susceptibility. So what happens to people who have BRCA1 mutations? Well, it turns out that patients who have BRCA1 mutations have a very high likelihood of developing breast or ovarian cancer by the time they reach age 70. You can see the likelihood reaches up to 90% in these studies. And the risk starts at age 40 or less for these young women. So remember, Angelina Jolie was 37 at the time she encountered the medical system for this particular problem. Just as a point of reference, the population frequency of breast cancer is around 2% at age 50 and around 7% at age 70. So, these are really dramatic increases in the cancer risk. The other thing to say about patients who have breast cancer and who have a BRCA1 or BRCA2 mutation is that they're at very high risk for having a second cancer develop in the contralateral breast. So those patients need particular surveillance as well. So what do you do with a person like Angelina Jolie who tests positive for a mutation that's previously been associated with cancer. We assume that's what happened to her. So there are really three options and they are very personal. This is an example of personalized medicine where the patient is the personalizer, and the patient decides what they want to have done. Increased surveillance, that means more frequent mammograms and in fact more frequent gynecological examinations, is one option that many women opt for. A second option is prophylactic mastectomy and prophylactic salpingo-oophorectomy. And that's another option that many women opt for. And then there is some thought that some medications that have cancer suppressing capabilities like Tamoxifen may be useful in women who choose to go that route. And that's again, a very personal choice, and that's a decision that the woman has to make along with her physician and her family. So the real bottom line is who should get special attention for looking for cancer susceptibility genes. Angelina Jolie's family history is really very, very striking. And so it was very reasonable for her to go and ask the question, should I get genetic testing? There's a lot of controversy around the particular kind of genetic testing she had because there's a controversy about the fact that it's very expensive. And a controversy around the fact that it's licensed by one company who are fighting in the courts with whether they can have exclusivity over that or not. And that's not an area of personalized medicine I choose to discuss in detail here. But faced with a patient, the kinds of clues that give one pause to think, maybe this person should be seen by a family cancer specialist. Who will think about not only BRCA1 and BRCA2, but other genes, less common genes, that can also have mutations that predispose to cancer. Breast cancer at age less than 50, Ashkenazi Jewish women, especially with a history of breast or ovarian cancer. More than one ovarian cancer in the family, breast or ovarian cancer in the family. A man with breast cancer should open that family up for further genetic evaluation. Pancreatic cancer, it also arises from BRCA1 and BRCA2 mutations and more than one pancreatic cancer in the family should lead to an evaluation. Colorectal cancer at age less than 50 and many colon polyps, I'll talk about that in the next module. Some pheochromocytomas are familial and then medullary cancer of the thyroid is another typical cancer that often runs in families and should prompt a referral to a family cancer specialist. [MUSIC]
