Breast cancer in Australia: Breast cancer genetics
It was a revelation that resonated around the globe.
In the time since Jolie's announcement, breast cancer genes BRCA1 and BRCA2 have become celebrity alleles of the human genome, but what exactly are they? And how do they influence whether or not someone will develop breast cancer?
In this second instalment of a two part special on breast cancer in Australia, Joel Werner investigates the role being played by genetics research in the diagnosis and treatment of breast cancer.
Angelina Jolie: I feel great, I feel wonderful, and I'm very, very grateful for all the support, it's meant a lot to me. I've been very happy just to see the discussion about women's health expanded and that means the world to me, and after losing my mom to these issues I'm very grateful for it, and I've been very moved by the kind support from people, really very grateful for it.
Joel Werner: Hi, and welcome to the Health Report. I'm Joel Werner. And that was Angelina Jolie. It's been almost a month since she announced via a New York Times op-ed that she'd chosen to have a preventative double mastectomy, a decision reached after learning she carried a mutation on the BRCA1, or Braca-one gene. It was a revelation that resonated around the globe.
Clara Gaff: I thought it was very courageous of her to make public what for many people is a very private decision, and to let people know what was possible and to encourage people in similar situations to her to find out what their situation is and make their own choices.
Joel Werner: Associate Professor Clara Gaff is a genetic counsellor. She's also manager of genomic medicine at the Walter and Eliza Hall Institute for Medical Research. While Clara's reaction to Jolie's Times article epitomised that of many, her colleague Professor Geoff Lindeman wasn't quite so absolute in his praise.
Geoff Lindeman: I think it was somewhat of a mixed blessing. It's always good to have appropriate publicity in this area so that people can be aware, but similarly I think many women must have felt that they had the sword of Damocles hanging over their heads, and that's not necessarily the case for the vast majority of women and even for women who have mutations in the BRCA1 or 2 genes.
Joel Werner: Today on the Health Report it's part two in our special on breast cancer in Australia, and this week we're examining the role genetics plays in the diagnosis and treatment of the disease.
Over the past month, BRCA1 and 2 have been the most heavily publicised genes in the world; celebrity alleles of the human genome. But have you stopped to ask yourself what they actually are? Or how they influence the development of cancer?
Geoff Lindeman is head of the familial cancer centre at Melbourne Hospital, and joint head of breast cancer research at the Walter and Eliza Hall Institute.
Geoff Lindeman: So these were genes that were discovered in the mid-1990s that were identified through women who had a very high risk of breast or ovarian cancer running in their families. The discovery of these genes really helped us to understand their role in helping keep cancer in check. They are basically suppressor genes which help repair DNA in our genome that has become damaged. And for reasons that we still don't fully understand, breast and ovarian cancer are quite prominent amongst the things that can go wrong when there is a fault in these genes.
Joel Werner: And that's the thing, it's when you have mutations in these genes that things go wrong.
Geoff Lindeman: That's right. So every one of us has two copies of the BRCA1 and the BRCA2 gene, they are genes that we inherit from our mums and dads, and occasionally one of those copies will be faulty that they've inherited from either their mother or father. And under those circumstances that can potentially increase the risk, particularly if you are a woman of course, for breast and ovarian cancer. But having a faulty gene is by no means a guarantee that somebody will get cancer, it just means that their risk is increased, and in a sense they should be managed and look after themselves appropriately.
Joel Werner: And that's an important point. Even if you have a mutation on one of these genes it doesn't guarantee that you'll get breast cancer. Indeed, not all breast cancers are caused by mutations on BRCA1 or 2.
Geoff Lindeman: We think at the moment about 20% to 30% of hereditary breast cancers would be accounted for by the BRCA1 and 2 genes. They are what we would call highly penetrant genes, meaning that the lifetime risk is quite high if a faulty gene is inherited. But we believe that there are quite a substantial number of other genes out there, probably each incrementally contributing to small amounts of breast cancer risk in our community, but of course as a group accounting for a substantial proportion of hereditary breast cancer.
Unfortunately there aren't really very solid numbers for the Australian context in terms of risk, but these would be an appropriate ballpark risk that are often discussed with patients in terms of their risk for developing breast cancer if they carry a mutation.
Joel Werner: If Angelina's New York Times op-ed has got you thinking about your own breast cancer risk, chances are you're not alone. In the fortnight after Kylie Minogue announced she had breast cancer, bookings for cancer screening increased by 40%. I was curious as to whether Angelina's article had a similar effect.
Clara Gaff: I've been told that the familial cancer services that specialise in this area have been contacted by a lot of people following on from that story, and that also many of those women have been people that have got a family history in the same way that Angelina Jolie does.
Joel Werner: So if women are concerned about breast cancer, what would you recommend they do?
Clara Gaff: I guess the first thing is to really understand what their risk is. So in most women the risk comes from a number of factors, and family history plays a part but it's certainly not the only factor. So one way of getting a risk assessment initially is to go online on the Cancer Australia site. They have a breast cancer risk calculator that will also give information about what those risk factors are.
For people that have some family history that they are concerned about, then talking to a general practitioner or ringing Cancer Council Helpline to find out to what extent the family history might play a role in their breast cancer risk and whether they are in a high risk situation like Angelina Jolie.
There are different levels of risk, so I guess the first thing is the chance that there is a mutation in the family, and then the other part of it is the chance that a person who carries a BRCA1 or BRCA2 mutation will develop breast cancer. So it's clear in Angelina Jolie's case that she said she had an 87% risk. In the clinics here we wouldn't normally be that precise. The calculations are done on the basis of studies of families that have these mutations and they look at how many people in those families develop breast or ovarian cancer and then base their risk estimates on that. So usually we are talking in a range and the range is between 50% and 80% chance of developing breast cancer. That might be influenced to an extent by how strong the family history is.
Joel Werner: It's one thing to attribute a number to a risk of developing breast or ovarian cancer, but the decisions that you make on the back of that number are often life-changing decisions. How do you counsel someone to bridge that gap?
Clara Gaff: It's really their own personal situation, and people's perceptions of risk are very different, and the amount of uncertainty or risk they can tolerate is very different. I thought that was really very evident in people's comments about Angelina Jolie's choice to have surgery. Some people couldn't understand why she would do that without a 100% risk, whereas other people did understand that, and that reflects different people's perceptions of risk and the consequences of the options that people have available to them.
So risk might be a number, but what that number means to people is very different. A woman who has a family history of breast cancer where most of the women or all of the women in the family have survived and done fine would have a very different perception of breast cancer potentially to a woman whose close relatives have died of breast cancer.
Geoff Lindeman: I mentioned previously that some women feel that they might have the sword of Damocles hanging over their head and I think this is one of the issues that has arisen with this recent publicity. I'd hate women to have the feeling that they need to rush out and make a decision today. That's because the risk can vary for women at different stages in their life if they are a [faulty] gene carrier. So really it's understanding the risk over the next year or the next decade or for the whole of their life that needs to really be considered in terms of selecting the appropriate strategies to manage risk.
For many women who carry a BRCA1 or 2 gene [mutation] that really means engaging with specialists in the area who can help oversee their management. So, for example, for breast cancer risk one would want to be seeing I think a breast specialist with expertise in this area who could supervise the appropriate scans from about the age of 30 as well as clinical checks for ovarian cancer risk, seeing a gynaecologist with expertise, and thinking about having tubes and ovaries removed at an appropriate age is also an important consideration. I think what I'm saying is that there are different stages in a person's life where they need to think about specific aspects of managing their risk.
Clara Gaff: The key is that it's counselling not advice. So in each step along this process before somebody has a genetic test, when they have breast or ovarian cancer, before they have a predictive genetic test, if they are in Angelina Jolie's case, and afterwards as well, it's really helping that person understand their situation from that sort of medical and scientific perspective, but very much exploring what their own expectations are and the decisions that they might make to ensure that they have really fully thought about the possibilities. People might make assumptions and some women will assume that they will carry the gene, others will assume that they won't, and if they get a result that is different to that they might be unprepared for it. So the counselling is really preparation for test results, and then the exploration of those people's own circumstances and values.
For some women, like Angelina Jolie, a genetic test for breast cancer risk is a pre-emptive step based on a known family history. But for other women, the genetic test comes after a cancer diagnosis.
You might remember Dr Heidi Hilton from last week's Health Report. Heidi's a breast cancer researcher at the Westmead Millennium Institute for Medical Research.
Four years ago, Heidi was set to move to London to start a postdoctoral fellowship. But those plans changed when during a regular medical check-up her GP felt a lump in her breast.
When we left Heidi last week, she just had a lumpectomy.
Heidi Hilton: And then I went back to the doctor because they do pathology on what they take out, and all the margins weren't completely clear. So there was still a bit of cancer left in the side. So they knew that they would probably have to go back and either take a little bit more out or do a mastectomy. Because I was so young they thought maybe it could be genetic.
Clara Gaff: The first step really is to do an assessment of the family and to look at the likelihood that the family may have a breast cancer mutation causing their family history. I should say as well, we talk about breast cancer genes but they can also cause ovarian cancer, so we look for patterns of breast and ovarian cancer in the family.
Heidi Hilton: So they asked me whether I'd had any family members that had had breast cancer and I said no, but I had a grandmother who had died of ovarian cancer when she was 76. And then when this was all happening I was speaking to my parents and we knew that my grandmother's sister had died young, she was 46 we thought the time, but no one really knew how. So we actually dug up her death certificate and it turned out she had died of ovarian cancer as well but we didn't know. So when I told my doctors that and the fact that I was diagnosed myself at such a young age, that alone was enough criteria to fulfil me being able to get the test, which would be funded by Medicare.
Clara Gaff: The first step is to test an affected family member, that is somebody who has had breast or ovarian cancer. We need to give ourselves the best chance of finding a mutation in that family and there are many, many different mutations that can cause breast or ovarian cancer. So there's a family history assessment done, and if people are considered likely to have a mutation in the family there is pre-test counselling where the testing is discussed and the potential implications for the person being tested and their other family members.
Geoff Lindeman: In a familial cancer centre in Australia, patients would receive genetic counselling with respect to what the presence of a finding might be, if a mutation were to be found or weren't to be found, and importantly all of the potential downstream issues that might be faced once genetic testing occurs.
Genetic testing itself simply requires a blood test where a blood sample is given and the white cells in the blood are collected and DNA is extracted, and it's this DNA which is then used to be tested in specialised laboratories. What normally happens is that the relevant components of BRCA1 and 2 are tested, and another test is also carried out to look for deletions or big chunks of DNA that have either been gained or lost in the BRCA1 or 2 genes.
When we think about testing, these are quite complex genes and we're really looking for a very simple spelling mistake in a very long alphabet soup of DNA, and so what we really need to do is to go to an individual where possible in the family who is the most likely person to carry the gene change. That often means testing somebody who themselves has been affected by breast cancer, if they are prepared to consider testing after counselling, and then if a mutation is found then we can go back and test family members for that specific gene change.
Clara Gaff: People where a mutation is known in the family are in a different situation, so if the causative mutation in the family has been identified, then relatives of the person can have a test to see if they've inherited it or not, and in that case their chances of inheriting it are based on how closely related they are to the person who has been found to have the mutation. And that test, it's not a full screen of all of the mutations, it's more just targeted at that particular mutation and that's a much more informative test, is if the person has the mutation it's saying yes, they are also at higher risk like other family members, and if they are found not to have the mutation it's very clear cut, they haven't inherited the high risk that's in their family, so they are at average population risk.
Geoff Lindeman: So if a mutation is found in the BRCA1 or 2 gene through genetic testing, then we specifically look at that changed to determine whether or not it looks like a card-carrying mutation, something we call a pathogenic mutation, which would increase the risk of breast or ovarian cancer. Because we are all necessarily different, human beings, I mean we all have huge numbers of gene variations that make us the individuals we are, it's not surprising that sometimes we find different types of spelling in the BRCA1 or 2 DNA. And so one of the other things that has to be thought about here is whether or not these changes are part of our normal tapestry of being different or whether they are disease-causing.
So these sequence changes are known as sequence variants. Most of these end up being benign. Some of these might end up being pathogenic, and this is an area of very active research internationally to try to further characterise and to be sure that a gene change one finds is truly pathogenic or just an innocent variant.
Clara Gaff: So there are two possible results. One is that a mutation is found in the family. So that means that the history of breast cancer or ovarian cancer in the family has been caused by genetics and other family members are also at increased risk and might have inherited that mutation.
The other possibility is that there is no mutation found, and in that case that's what we call uninformative. There are several reasons why that might have happened. One is that there is no genetic mutation in the family, so there's nothing to find. The other is that there might be some genetic tendency but it's not due to breast cancer genes BRCA1 or BRCA2, and because it's only those two genes being tested nothing has been found.
Or the other possibility is that there is a mutation in the breast cancer 1 or 2 genes but that there are technical limitations to the test and it might be that the mutation in that family can't be found. In some cases we might find change but we are not certain if it's cancer causing or not. So in the results there can be quite a lot of uncertainty still.
Heidi Hilton: So I had the genetic test and it turned out that I did have a BRCA2 mutation. So this was through my father's side, so it's not like I had mothers and sisters and aunts and grandmothers all with breast cancer. The family history was there but we just didn't really know about it.
So because of that, that made me decide to have the mastectomy, and I thought, well, I may as well just have both. If you're going to reconstruct one breast I think it would be easier to do both and then I don't have to worry about this ever coming back. So I chose to have a double mastectomy and reconstruction.
I went through a private hospital because I wanted the immediate reconstruction. So what they do is normally if you have a mastectomy and you want a reconstruction just through the public hospital you can have to wait a long time in between, but I decided to spend the money and get it all done at the same time. So I had both my surgeon who had done the first…the partial mastectomy, and a plastic surgeon who…they work closely together, and they were both great, they were both extremely helpful and supportive of my decision.
So the surgery itself took quite a few hours I think, the removal of the breast tissue and then putting in what they call tissue expanders. So these tissue expanders are injected with saline gradually over the next couple of months. But that surgery itself, I was in hospital for five nights, and yes, it was quite uncomfortable, it felt very tight around the chest, it was painful, I couldn't move my arms properly for a while.
But yes, once I was home I took a couple of weeks just to rest and get my movement back, and the tissue expanders started getting bigger, you can inject them to the size of your own personal preference. And then once that was finished they then switched the tissue expanders for permanent silicon implants, and once that was done it all felt a lot more comfortable.
Joel Werner: How long after first diagnosis was finally getting the silicon implants?
Heidi Hilton: That was pretty much exactly a year that it all took.
Joel Werner: Right. What a year!
Heidi Hilton: Yes. And also in between that I had started hormone therapy which was taking a daily tablet of tamoxifen and also a monthly injection called Zoladex. Because my particular tumour was hormone responsive, that was to stop my body responding to oestrogen.
Geoff Lindeman: At the moment we think about breast cancer as being quite a heterogeneous disease. And if we look at the genetic level we know there are something like five or six what we call molecular subtypes, and these are characterised by a set of genes which are switched on and off and therefore account for the way that the tumour looks in terms of its microscopic appearance and potentially the way that it behaves. So one particular subtype, the triple negative breast cancer, is a phenotype that one can see in patients with BRCA1 mutations. On the other hand, patients with BRCA2 mutations are more likely to get a different subtype of breast cancer which express the female hormone receptor oestrogen. So these are oestrogen receptor positive tumours.
Joel Werner: And those differences in tumours feed into the treatment choice.
Geoff Lindeman: Very much so. There are major decision points that clinicians make in terms of treating breast cancer, and oestrogen receptor is one key, because if a tumour is found to express the oestrogen receptor then one would think about endocrine therapy as at least part of their treatment because anti-hormones will help switch off tumour growth.
Tumours that contain the oestrogen receptor can act, if you like, as a docking site for oestrogen that is either produced locally in the tumour or systemically by the patient. And oestrogen acts as a growth promoter for those tumours, so switching off this pathway can be very helpful for the treatment of such cancers.
For triple negative cancers where oestrogen receptor is not present in the tumour of course that doesn't form part of the potential therapy. So for these sorts of patients chemotherapy often forms a part of the therapy.
Joel Werner: Genetic research isn't just at the forefront of breast cancer diagnosis, it's revolutionising the way we treat the disease.
Geoff Lindeman: Our group is very interested in understanding the normal process of breast development with a view that things go awry when breast cancer happens. So really we view breast cancer as pretty much being a caricature of normal development going wrong where cells that should stop growing continue to grow or in a way change their fate in an unexpected fashion, all due to genetic mishaps.
So over the last few years we've been trying to understand stem cells and the hierarchy of cells which make up the epithelium, that's the cells which line the breast ducts and which in a mature breast are important for producing milk. A few years ago we were able to identify the stem cell using mouse models and then subsequently we were able to do that in human breast tissue.
One of the very exciting findings I think was that patients with BRCA1 mutations seem to have a fault in the daughters of stem cells, the progenitor cells. These cells are very highly proliferating cells in the breast, and you can imagine that if these cells go awry due to a faulty BRCA1 gene, the DNA repair can't happen efficiently in these cells and that can ultimately give rise to breast cancer.
By understanding the cell types in the breast which give rise to cancer we in a sense have a roadmap of genes that we can look at to try to develop novel therapies to either treat or prevent breast cancer.
Joel Werner: Can you take us through some of the novel therapies that may be arising from the work you are doing?
Geoff Lindeman: Well, one of the molecules that we've discovered that appears to regulate stem cell function is a molecule called RANK ligand. There is an inhibitor of this available in the clinic for another purpose and we are very interested in knowing whether or not this inhibitor would help switch off stem cells and therefore potentially act as something that could shut down aberrant cell growth in the breast tissue. It's still very early days but that's one of the avenues that we are pursuing.
Recently Bhupinder Pal in our group identified an important process which is the intersection between the environment and DNA which is an area known as epigenetics. It was discovered that female hormones like progesterone can very profoundly modify molecules that decorate DNA which in turn tell DNA whether to switch on or switch off genes. So this in a sense has linked the environment or hormones to how they can switch on breast cancer predisposing genes. And it will take time, but in the longer term it will certainly be important to know whether it is possible to interfere with breast cancer predisposing signalling pathways like this. So I think increasingly what we're going to see is a very personalised approach to cancer therapy, not only for breast cancer but for many other types of cancer that really is beginning to play out now.
Joel Werner: Before we go, let's catch up with Dr Heidi Hilton to hear how she is doing now.
Heidi Hilton: At the end of last year I had stopped taking tamoxifen, I'd been on it for 3.5 to 4 years, so I did decide to come off it slightly early. I knew the risks and my doctor was happy for me to come off it early, just because I wanted to get my body back to normal so that I would be ready to have children at some point, because I'm 33 now.
And then in February this year I found a small little lump myself. I felt it myself, it was small. I knew that the chances of the cancer coming back was very small, but they always tell you that when they remove all the breast tissue they can't guarantee that it will all be gone. So it was a bit of a panicked moment when I felt the lump, but having had all my doctors already in place I was rushed through, we had the core biopsy done nearly immediately. It turned out that it was cancer, it was the same type as the one before but it was very small, and they took it out pretty much a week later.
They did the pathology on it and it was the same type, which has a good prognosis. They recommended going back on to some more hormone therapy, and I am about to start radiotherapy, which is going to be five weeks every day, 20 minutes of radiation. And then that's the treatment for this time. So basically I'm treating it as a wake-up call to just keep on top of it but know that I can catch it early if it ever comes back again.
It was disappointing because I kind of felt like that year in 2009 was a bad year, it was extremely unfortunate with the timing and all, but then since then everything had gone back completely to normal, I had been married, we did lots of travelling, everything was great. So I kind of always thought of it as just that one bad time when I was 29. But for it to come back, yes, as I said, it's a reminder that it's a condition that I will have to deal with for the rest of my life. But hopefully, yes, it's just a chronic illness.