Breast cancer genes

Dr Elizabeth Farrell: I would like to introduce Associate Professor Adrienne Sexton. She’s a genetic counsellor with interest in neurogenetics and cancer genetics. She’s a graduate of Melbourne University and has done her PhD in molecular biology. Adrian is widely published, more than 40 publications, and she works at Epworth Healthcare in genetic counselling as part of the Cancer Services Clinical Institute there. Thank you, Adrian.

Dr Adrienne Sexton: So today I am going to cover briefly about breast cancer genes, not just BRCA1 and 2, but the more recently discovered genes and what we’re learning about those, and what those mean for families. I’ll then talk about endometrial ovarian and bowel cancer genes and how to recognise a family history where those might be relevant. And I do want to mention at the end of the talk about polygenic risk, which is the next advance that will be happening in clinical practise in genetics in the very near future, or currently.

So right now, and I should say that I’m talking about inherited genes rather than tumour specific gene changes, so that’s a whole other field, genetics of the tumours themselves. So in clinical genetics, in terms of hereditary genes, we often think about the high-risk variants like BRCA1 and BRCA2. We think about new genes that are being discovered, and those are constantly getting added to the gene panels that we test for. But first we’re checking what level of evidence do we have for those, and can we actually provide advice that’s evidence-based to people before those are added to tests? And we also are thinking about common variants in all of our background, 20,000 genes, and that’s called polygenic risk.

So only about 5% of breast cancer cases are due to an inherited gene, and the other 95%, there’s no clear single major gene. At the moment, we do test routinely for about 8 genes. Some gene panels add a lot more genes than that, but the evidence for some of those other genes is a bit more, under further investigation. So we’ve got 8 genes that we would definitely test for, and those are mostly relevant for adults and adult onset cancer risk, not for children. They can be syndromic, so with other health symptoms and signs of the condition, or non-syndromic. And they’re all dominantly inherited for breast cancer. And that means that you only need one copy with a problem to have an increased cancer risk. And we’ve all got two copies of all of these genes, one from mum and one from dad. And I should say that the genes can be equally inherited from men or women.

The new technology means that we can test lots of genes at the one time. We can test many thousands of genes, but then it’s a question of what do you do with the results in those genes, and a lot of uncertain findings. So at the moment in cancer genetics, we mainly restrict that to the genes where we have clear evidence for next steps if there’s a problem in one of those genes.

So you probably all know about BRCA1 and BRCA2, and some of the other genes I’ve just listed here, and I’ll talk a bit more about those. PALB2 is a gene that’s quite similar to BRCA2, although the ovarian cancer risk is lower. It’s still a risk of about 5% compared to 1% for the general population, so it is increased, and people would think about having preventative surgery, but it’s not as clear a recommendation as for BRCA1 and BRCA2. The CDH1 gene has a very high risk over a lifetime of breast cancer, of lobular pathology, and it does have a risk of stomach cancer, which is also very high. But it is a very rare gene and we usually would not find problems in that gene unless there’s a clear family history of gastric cancer, of diffuse gastric cancer, and lobular breast cancer.

Li-Fraumeni syndrome, caused by the TP53 gene, causes a very high risk of many cancer types at very young age. So this is sometimes an explanation for when somebody’s had breast cancer under the age of 30 and when there’s a family history including sarcoma or other rare cancer types. And this one’s really important to find because people need lots of different types of screening and checkups for that. And this is the only one that is usually relevant for children. So I will talk about ATM and CHEK2 as very common, but moderately increased breast cancer risk genes. And those are becoming better known now, in that lots of people have a problem in those genes but wouldn’t be aware unless they had this sort of test.

Just to show you what the curves for the risk over a lifetime look like, we’ve got the age along the bottom there up to age 80. You can see that BRCA1 and BRCA2 are still the highest risk genes on this list. We haven’t included the very rare ones, TP53 and the gastric and lobular breast cancer gene there. But the moderate risk genes, which, sorry, I don’t think, my pointer doesn’t work on the screen, but you can see that CHEK2 and ATM have a lower risk of breast cancer, although still a lot higher than average.

Just interrupt me with any, if you do have a question as we go. So usually we would gather a really detailed 3-generation family tree, if possible. And this is a quite striking one because there is breast cancer under the age of 40, there’s bilateral breast cancer, there’s male breast cancer, and there’s ovarian cancer. So this would have a very high chance of finding a BRCA gene problem.

In the genetics clinics, we would take the family history information, together with any pathology details about the breast cancer, and other factors such as breast density, and do a thorough risk assessment, which gives these type of predictions, which I don’t expect you to be able to see the details of, but it can tell us a few things. One is, what’s the chance of finding a gene problem if the person chooses to go ahead with testing? And sometimes that helps people decide whether that’s important to them to go ahead or not, knowing the chance is often really low. We also can predict what their risk of breast cancer is, and ovarian cancer, using this type of algorithm. In this case this is the CanRisk algorithm. And that can be useful for guiding screening decisions and prevention decisions.

And it can be used also for if people have questions, ‘What is my daughter’s risk?’ So some of the chances, percentages, for finding a gene problem I’ve just included here to show you. If you just take all breast cancers, the probability of a genetic cause is low, 5% or so. And if the breast cancer is at young age, so under 40, that’s increasing to above 10%, usually. If it’s triple-negative type of breast cancer, the chances are high, so 10 to 15%. And that depends also on the age at diagnosis. For men with breast cancer, that chance is usually above 10%. And we do think about a few other things like a history of sarcoma, or if the person has bilateral lobular breast cancer, then it is worth thinking about that rare gene that’s also linked with risk of stomach cancer.

So just a refresher on some of the cancer risks associated with the genes. BRCA1 and 2, we, at the moment, the current data suggests that that risk to age 80 is about 70%, but most of that chance is increasing from 40 onwards. And PALB2 is about 55%, but can vary, and I’ll talk about that a bit more in a minute. So that is compared with the population risk of about 12%. There are some risks of other cancers, including an increased risk of pancreatic cancer, which is smaller and not properly quantified, but perhaps increased. And also for male breast cancer, especially with BRCA2.

So with BRCA1 and 2, the guidelines, which I think other speakers will talk more about, options for risk reduction, and that does include considering medication and a high level of screening versus preventative breast surgery. And it does include the recommendation to have the ovaries and tubes removed as a prevention from about age 40.

With other genes though, that is not so clear, and it can vary a lot depending on the exact spot in the gene. So CHEK2 for example, it’s very common, one in every 75 people have a problem in this gene, but the cancer risks are not as high as for BRCA1 and 2, for example. In the range of about 15 to 40%. 40% is obviously still high at that end of the spectrum, but that is for people with a particular family history and for specific DNA variants in that gene.

So this is when the risk assessment, based on all those different factors, including the family history, the age that the person is, and the exact spot in the gene, becomes really important. I put this here, not for you to read all that, but just to know that there’s a lot of options that people have, and it does depend a bit which category they’re in and how they feel about what prevention and surveillance to do, and what their specialist advises.

This is similar for the ATM gene, although the breast cancer risks usually range from moderate to high for this gene. Again, it’s quite common, one in every 250 people have a problem in this gene. It doesn’t mean that they will get cancer, but their chance of breast cancer is known to be higher. The chance of pancreatic cancer is a little increased for this gene as well. But when we’re talking about increased pancreatic risk, it’s usually still low because the population risk is low. So again, for this gene, because there’s a lot of variation in the risk for any one person with the same problem in the same gene, it does depend on lots of other factors including family history, breast density, and the specific variant in the gene.

Talking now briefly about polygenic risk, that is more complex combinations of additive, small genetic factors in our background 20,000 genes. So research has shown that variants throughout the genome can add together in some people and some families to explain why there might be more breast cancer than in other families. So maybe they’ve had testing for the major genes, nothing found, but they’ve still got a strong history, and we know maybe there’s some genetic factors behind this risk. And up til now we haven’t really been able to test for that. But the tests for the polygenic risk in the setting of breast cancer are currently moving from the research setting to the clinical setting, and they’re much better validated than they have been. But they do take very, very large studies, because each factor adds only a small amount to the overall picture, so they have to have sample sizes of more than a hundred thousand people.

So we can use this in different ways. We can use it as we’ve been talking about for genes like ATM or CHEK2, or even BRCA where we know that there’s a spectrum still of one person’s risk of breast cancer compared to another. And the polygenic risk information can add another level of information and accuracy to their predicted risk and their decisions that they make based on that. We can use it in the population, in theory, although obviously there’s lots of cost effectiveness and other aspects to consider, but it can separate out who needs less screening or more screening, and from what age.

Just to show you what that looks like, it gives us outputs that we based on that combination of particular markers with additive effects, some people will be in the highest bracket for risk of breast cancer, and some might be in the lowest, and most people will be somewhere in the middle. It can do that for lifetime risk, but also on the right, I’ve just put an example showing if their specialist, for example, or a doctor wanted to know, what’s the risk for this person in the next 10 years, how urgently do they need to make decisions about preventative surgery or other prevention?

And looking at that in a different way, just showing the graph at the top there is the different major genes and how any person with that gene, their risk can vary within that bell curve. And so adding in the polygenic risk score, it’s really shown to be helpful in making that more accurate.

We’ll switch just quickly to talk about genes for endometrial, ovarian and bowel cancer, the main ones being the genes for Lynch syndrome. This is a condition which one in 300 people in the population have, but again, they may not be aware of. And some other genes I’ve just listed quickly there, newly discovered genes POLE and POLD have an endometrial cancer risk, not as high as for Lynch syndrome, and also risk of bowel polyps, but those are relatively rare. And the same with RAD51C and D. There has been some studies over time showing maybe those genes are linked with an increased risk of breast cancer as well as ovarian cancer, but that’s a small increase in breast cancer risk, and larger studies haven’t really been able to show that that’s very significant.

Lynch syndrome is mainly linked with a high risk, up to 50% over a lifetime for men and women, of bowel cancer and endometrial cancer, the two main cancers. But it also has an increased risk of ovarian cancer. And some of these other cancer types, but to a lesser extent. So it does depend on which of the four genes for Lynch syndrome that somebody has as to what their exact cancer risks are. And that varies depending which gene it is, some have lower risks. The screening for this would start from age 25 with colonoscopies. So it really makes a big difference to the healthcare of families if they know about this. The prevention guideline for endometrial cancer, depending on the gene, is to consider preventative hysterectomy from the 40s.

So as I mentioned, some tests are covered by Medicare, and that is increasing all the time, which has been really good for patients. If people don’t meet criteria but they want to pay for their own test, most of these cancer gene panels are about $450. They take about three months for results as well. And they’re just done by a blood test. In the public system, they do have strict criteria, so they’ve got to meet high risk criteria for the referral to be accepted. But you can refer to the private clinics, and if people have got concerns about family history, which many people, as you know, do have worries, ‘It’s in my family, am I at high risk? What does it mean for my children?’ And it’s good if they can have an opportunity to ask about that and have more detailed conversation about it and risk assessment.

So these are just some of the criteria that would be likely to make a family more higher chance of having a genetic cause for cancer in the family. In terms of bowel cancer, it’s a similar idea, in that if a person’s had a young age at diagnosis, under 50, with bowel cancer or if there’s bowel and endometrial cancer in the same family, or multiple relatives with those cancer types, then that’s becoming a lot more likely. Now it’s pretty standard that people with bowel or endometrial cancer under the age of 50, or even 60, will have had the immunohistochemistry test. And that looks for the markers for this genetic condition for Lynch syndrome. So if the markers are absent, then that means that the chance of a genetic cause is high, and they’d be referred. Other cancer types linked with it, which is sometimes in the family histories, includes cancer of the ovaries or the ureter small intestine and stomach cancer.

So the genetic counselling for panel tests, it does involve thinking about how the person has experienced cancer, for themself or their family, what emotions and concerns are linked with that, because otherwise the information is not as meaningful to them. So genetic counsellors have a lot of training in counselling theory and models and strategies for being able to address the psychological and familial aspects of thinking about genetics.

The informed consent is important, and we do raise the possibility of uncertain findings in the genes, because some people are concerned about that possibility that there might be something in their DNA, but we don’t know what it is. We can’t then test other people in the family, and we don’t know what it means for their health or what screening that they should do. A lot of the time those uncertain DNA variants turn out to be just harmless variants from one person to the next, but the lab will report it if we don’t have enough evidence to be sure at the time that the test is done. Insurance issues are pretty minimal in Australia. It does not affect health insurance, they can’t ask about genetic testing in any way, and for life and income insurance, they can only ask if it’s quite a large policy.

So just to sum up, the most common genes, the most relevant genes, are still BRCA1 and 2. The most common genes are probably ATM and CHEK2 with that moderately increased breast cancer risk, but still really important for people to know about in their family. And Lynch syndrome is the most common cause of inherited endometrial and bowel cancer. Screening for these genetic conditions usually starts at a young age, for BRCA1 and 2 from 25 to 30, for Lynch syndrome, again, from 25 to 30. For ATM and CHEK2, depending on the risk assessment, that might be breast screening from 40. And for CHEK2, I should mention for that gene, it’s not one where we’d normally recommend that they needed to have a preventative mastectomy.

So the goal of the cancer clinics in genetics is to do the risk assessment and provide advice and counselling to provide support for thinking about this, which often raises lots of emotions. It’s linked with experiences of grief and other fears for people’s relatives, and sometimes conflict about how people see genetics. Maybe one person in a family really wants to know and another doesn’t. So we try to help people work through how to talk with their family about it as well. And the family history is really important, as well as the pathology records. There’s been a lot of advances in genetic health care, including access to testing, the price of the test has really come down, and the accuracy and thoroughness of what we can do with one test has really improved in the last few years.

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