How Does Breast Cancer Metastasise?

That’s the area that I’ve spent most of my career looking at – the processes by which some cancers do metastasise and some don’t.

I’m interested in biological processes that help cancer cells to escape, and interested in some processes which are ‘borrowed’ from embryonic activities when our bodies are very small, multi-cellular things which are starting to organise, or when mammary glands are formed, and ducts are expanding. Some of those processes do help cells move from one place to another and they can be purloined by the cancer through genomic rerouting to help the cancer cells spread.

So it’s pretty much accepted that, primarily, cancer cells spread through the blood vessels and the lymphatics. There can be some local extensions where the cells move through the tissues. It’s a real decathlon for cancer cells to spread and studies have shown that only a real minority of cancer cells can actually survive it.

They have to be able to escape from the initial collective, they have to survive as individual cells, in the blood vessel they’re subjected to enormous stresses they wouldn’t normally feel, they have to get out of the blood vessel at the target organ and survive and grow there – so they’re selected to be very hardy, if you like.

Often they get to the target organ and they lie dormant. This is a real problem, particularly in breast cancer and particularly in hormone receptor positive, ER-positive breast cancer, there’s examples when those cancer cells may not be evident for a long period of time, and then they’ll flare up maybe 10, 12 or 15 years later. It’s unusual, but it does happen?

Why Is Metastatic Breast Cancer Difficult To Treat?

It’s not 100% clear but the contributing factors are thought to be that in most cases, not all, they’ve already been exposed to therapeutic drugs and so they’ve already had an opportunity to acquire some resistance to that.

There’s likely to have been additional genetic events that have occurred during the course of their disease and over the period of time while they’re regrowing, that have made them more resistant to therapies. Finally, we don’t necessarily have the same opportunities to de-bulk the metastases – it’s not so easy to remove them surgically before treating them, so they’re bigger and bulkier in most cases than we might be treating in the primary site. So it’s harder to treat.

The observation is that they’re very tough to treat. We can get some palliative benefits, we can treat with a number of things, but in most cases eventually we run out of things to treat them with.

We’re very keen on understanding the processes better so we can be more targeted and strategic about it – this is why we’re looking at those embryonic processes, for example, that help them get to the target organ. Those processes also seem to be related to the ability to lie dormant in a stem-like state, and also a link to therapy resistance. If we can understand how that’s regulated and reverse it, we may have better effects in treating breast cancer when it has spread.

What Are Some Of The Areas Of Research Into Metastatic Breast Cancer?

There’s a number of things we’re looking at, a lot of them relate to therapy resistance and getting better efficacy of our agents or identifying molecular processes that the cells have used in that journey to get there and have their effect. So comparing metastatic tissue to primary tissue.

We also look at cells in the bloodstream. We call it a window of opportunity or a liquid biopsy, it’s an integration site to some extent. It’s proving very difficult because there are a very small number of cells, but there’s been great success with looking for circulating tumour DNA as well as circulating tumour cells, so we could get access to material which is in the bloodstream but it’s come from the metastases.

It’s great because it may have come from several different metastases of different sizes – very difficult to sample each – but this integration site can give us that access. There’s a lot of work being done in this area that may identify causative, driving factors that we could then target. So it’s very exciting.

The easiest thing for us to determine is the genetic changes that may have occurred in the metastatic cells. This is proving very helpful in some other cancer types where specific and targetable activating mutations occur.

Unfortunately, it’s not quite so focused in breast cancer. There’s a large number of mutational causes so it’s difficult to know what we could specifically target. But there is some and HER2 amplification is an example. Indeed, HER2 amplification is under study in three separate trials at the moment because it seems that cancer cells can actually switch that on in the bloodstream and in the metastatic site, even if their primary was negative.

So it’s possible that some women who weren’t initially HER2 amplified and Herceptin-responsive may be Herceptin-responsive in the disseminated site. So that’s just one example that’s being actively explored.

But we know that there’s a lot of other genomic loci that associate with breast cancer, we know that there’s half a dozen or so relatively high-penetrance mutations that occur and some of those have therapeutic partners if you like. So if we could see what they were, we may be able to use a therapy and select a therapy that’s targeting the cells that have ended up elsewhere in the body.

No Evidence Of Stress Increasing Risk Of Breast Cancer In Women Already At Higher Risk

A new study by Australian researchers including Breast Cancer Trials’ Professor Phyllis Butow AM and Professor Kelly-Anne Phillips is reassuring for the many women who worry that stress in their lives puts them at risk of breast cancer. This study found that stress does not increase the chance of developing breast cancer, in women who are already at higher than average risk of developing breast cancer.

Study Details

The study, conducted through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, included women with a family history of breast cancer, or a known gene mutation (such as BRCA1/2), who were asked about stress in their lives over a 15 year period. The likelihood of developing breast cancer was the same in women who were more stressed, compared with women who were less stressed.

Of 3595 consecutive women invited to participate, 3054 (85.0%) consented. Of these, 2739 (89.7%) from 990 families (range 1-16 per family) completed at least 1 assessment point. During the study, 103 women were diagnosed with BCa. No stressor or psychosocial variable or interaction between them was significantly associated with BCa in unadjusted or adjusted models (total acute stressors HR = 1.03 [0.99-1.08], P = .19; total chronic stressors HR = 1.0 [0.90-1.11], P = .98). This study did not demonstrate an association between acute and chronic stressors, social support, optimism, antiemotionality or anger control, and BCa risk. Women should focus on proven methods of BCa risk reduction.

This is helpful information for women at increased risk, and the results are similar to previous high-quality studies that have not shown any consistent link between stress and breast cancer in the general population.

Study link: https://www.ncbi.nlm.nih.gov/pubmed/29677398

Why Less Can Be More

The last 40 years have seen breast cancer treatment come a long way. It’s quite likely that our mothers and grandmothers were treated with the Halsted – or radical – Mastectomy which involved the removal of the entire breast, the skin and underlying muscle, as well as the lymph glands.

Professor Bruce Mann’s clinical trials research is looking for ways to safely de-escalate treatment for breast cancer patients.

“I think patients are probably unaware of the whole ethical background that clinical trials are designed with. Patient safety is very much top of mind.

“Most trials that have happened in medical oncology with drugs have been about so-called ‘standard treatment’, or the current best treatment vs the current treatment plus something else.

“A patient will say, ‘I want the best’, and in medical oncology we can present what is currently known to be the best available treatment. We know it’s imperfect so a clinical trial will compare a new idea, a new treatment, that we believe may be better than the current best treatment. That becomes the clinical trial.

“Clinical trials in breast cancer surgery have been quite different to that. A lot of the research has been about doing less surgery rather than current standard treatment – so-called ‘de-escalation trials’.

Picture: Dr William S Halsted pictured in 1902. Halsted is considered a pioneer of the radical mastectomy, blood transfusions, and sterile operating rooms and techniques. Johns Hopkins Medicine.

“Then there was total mastectomy vs breast conservation surgery – not removing the whole breast but taking the tumour out and giving the patient radiation. Again, this showed no difference, so the breast conserving treatment became standard.

“With the lymph nodes, the standard was to remove them all. It was thought this was essential, but the new procedure of sentinel node biopsy showed that just identifying the key lymph node and leaving the others if the key lymph node is not involved showed that was just as safe. That’s another example of de-escalation. “

Examples of De-Escalation Clinical Trials

A number of Breast Cancer Trials current clinical trials are investigating safe de-escalation including EXPERT, POSNOC and PROSPECT.

“My experience is that patients undoubtedly want to be cured – that’s their number one concern. But their second concern is can they be cured with less treatment? If so, that’s even better. So there is an appetite for de-escalation trials.

“Clinical trials have been through the ethics process and been judged independently to be safe. It could be that one of these trials will show that we have de-escalated as far as we can and that by reducing the extent of treatment there may be more recurrences. That would be an outcome.”

“My experience is, however, that most patients are very receptive to the idea of de-escalation. Some people still won’t feel comfortable to participate, but most people are.”

“We haven’t yet got to the stage of ‘no surgery’, of leaving the cancer there and just using drugs. That may be the case in some types of breast cancer in the future.”

How Far Breast Surgery Has Come

“Clinical trials have clearly shown that breast conservation surgery, ie avoiding mastectomy, is safe. When I mention that, the immediate reaction of a lot of patients and couples is, “No, no – take it (the whole breast) off!” The assumption is that somehow more treatment is better; if it doesn’t hurt it can’t be good – but it’s simply not true. We know that breast conservation is at least as safe as mastectomy. Once someone understands that, the reaction for most people is that are very happy to avoid a treatment if they can safely do so, and that’s one of the roles of rigorous clinical trials of de-escalation – to provide the evidence that people can safely avoid a treatment.”

“It’s hard because when it’s a trial where the proposition to the patient is that we believe this less intense treatment will give just as good a cancer outcome as the current standard treatment with reduced side effects, some people say, “OK, but I’ll just have the standard treatment thanks”. That’s OK, but some people will agree to take part in the clinical trial.”

“Sometimes what happens is that people reflect that the only reason we’re not doing the Halsted radical mastectomy is that generations of patients have taken part in successive de-escalation studies that have brought us to here and if we are to identify the minimal effective treatment, we do need to do more de-escalation studies.”

“Indeed the Edwin Smith Papyrus, an ancient Egyptian medical text, contains the earliest medical writings in existence. There is one which clearly talks about breast cancer and, to para-phrase it, the ancient medico says, “This is a condition that I treat with the fire-stick” – presumably an ancient form of cautery to stop bleeding – but later on also says, “This is a condition that can’t be treated”.

“We’ve come a very long way.”

The Risks And Benefits Of HRT

There’s been a lot of controversy about hormone replacement therapy and breast cancer. It is complicated.

There are a lot of reasons to expect that hormone replacement therapy slightly increases the risk of a woman developing breast cancer, so it’s probably a bit much to say that HRT causes cancer, but we could say that HRT might be a partial cause of some cancers.

So the way we would translate that into the real world is that we’d say, “If you’re going through menopause and you’re having a lot of very troublesome menopausal symptoms, hot flushes and things like that, and that’s really interfering with your life, then it’s not unreasonable to be on some hormone replacement therapy, but the aim should be to be on the lowest possible dose that helps you, and to be on it for as little time as possible or to try to wean off it after a year or two.”

I think the blanket idea that you should never have HRT because it will be a disaster is going too far. However, studies have made us change our view. 20 or 30 years ago, some people had the view that all post-menopausal women should be on HRT because there would be a lot of health benefits from that, and the studies that have been done have shown that’s not the case.

It does likely slightly increase your risk of breast cancer, but it can also have an impact on other things like heart attacks and strokes.

In your fifties when you’re going through menopause, and you’ve got a lot of hassles and symptoms associated with that, that’s a perfectly reasonable thing to do, but you don’t really want to be on HRT for 10 or 15 years.

Lastly, I’d add that if you’ve had breast cancer, you probably do not want to be on HRT even if you’ve got really bad hot flushes, but that’s something that you definitely need to talk to an oncologist about, don’t make that decision on your own.

Although we focus a lot of thought about how to find the cancer, the operation, and sometimes for those who need it the chemotherapy which is unpleasant, an important part of breast cancer treatment is the hormone-blocking treatments like tamoxifen and the other drugs called aromatase inhibitors. They’re very effective but to be most effective you need to be on them for many years. I see a lot of that because, luckily, those women stay well and alive for decades and most of them never die of breast cancer at all, so I see a lot of them in the clinics.

Potential Side Effects Of Hormone Replacement Therapy

These drugs are very effective but they potentially cause quite a lot of side effects, so one of the things that I think a lot about and spend a lot of time trying to help is those gynaecological/menopausal side effects – hot flushes, vaginal discomfort, problems with sex – which are partly related to those tablets that we still want you to take because they’re the thing that’s stopping the breast cancer from coming back, or they may be related to the fact that you had some chemotherapy that brought on the menopause.

Discussing Hormone Replacement Therapy With Your Doctor

I think that’s something which, as doctors in the past, we probably haven’t done that well. Probably particularly male doctors, I suspect, that have been too scared to ask about some of those side effects. I’ve certainly noticed in my practice that I ask about that a lot more and spend more time trying to work out how to make that better.

When I was in my mid to late thirties, and I was first practicing as a specialist, I was probably pretty nervous about asking about sexual activity or vaginal discomfort. I guess with increasing oncology experience and life experience, I’m much more comfortable about that. I think, although you’d have to ask the women that I’ve spoken to, that when you feel more comfortable about it you generate a certain calmness and confidence so that the woman is not too fussed about you asking about it, in fact, is quite grateful that you’ve asked about it because no-one else has.

I find that’s an important part of my job to educate the younger doctors that are working with me and tell them about that and explain to them how important that is because chemotherapy is not nice, but at least it’s all over in six months, whereas you might be on these pills for many years. I should emphasise that many people don’t have side effects at all, but those that do – as doctors we do them a disservice if we don’t ask them about these things and at least see what we can do to help them.

For more information, visit the NSW Cancer Council link: https://www.cancercouncil.com.au/754/cancer-information/cancer-research-cancer-type/latest-research/cancer-council-new-south-wales-combined-hormone-replacement-therapy-and-cancerfact-sheet/

Who Should Have Genetic Testing?

The question of who should have genetic testing is a very important one and it’s important to note that most women should not have genetic testing.

The vast majority of breast cancers are not because you’ve inherited a particular mutation from your mother or father, but because of lots of environmental issues – some of which we know about and some we don’t.

So for those women who have a genetic mutation in their family, they’re the ones that we want to particularly target. These are the women who’ve either had breast cancer themselves at a very young age, say under the age of 40, but particularly those women who have a lot of breast cancer in the family. Breast cancer is, unfortunately, quite a common disease.

So all of us, if we look hard enough, can probably find some breast cancer in our family, but what rings the alarm bells is if you’ve got a number of fairly close relatives – sisters, mothers, aunts – who have had breast cancer, particularly in their younger years – not when they’re 75 but perhaps when they’re 40 or 50. They’re the women who potentially might have genetic testing.

The reason we have to be a bit careful about this is because the whole genetic aspect of cancers is incredibly complicated. If you do genetic testing in everyone, you’ll find a whole bunch of abnormalities, or variations, because we’re all human beings and we’re all different and we won’t actually know whether some of those might be disease-causing changes or not. So we’ll cause a lot of panic and probably not a lot of good.

Whereas, if you’ve got breast cancer at a very young age, or you’ve got a number of relatives who have had breast cancer at a very young age, then there are specific tests we can do that might identify a mutation that you want to know about because there might be something you can do about it.

So, the first point is that we shouldn’t be running off and testing every single woman who is either at risk of breast cancer or has breast cancer – we should be targeted about it, and just look at younger women or women with a lot of breast cancer in the family.

The second point is that this sort of genetic testing should be done in collaboration with genetic counselling because you need to talk to qualified professionals before you have the test. They can explain to you what the pros and cons are.

For example, it’s possible that having a genetic test might have some implications for things like life insurance, so you need to discuss that before you do the test. Secondly, once you’ve got the result from the test these genetic tests are not like some of the tests that we do that give you a definite yes or a definite no. You either have a heart attack or you don’t, for example. Or you have cancer or it’s not cancer.

What Happens If A Genetic Mutation Is Found?

These tests are very complicated and they require some interpretation. If you’re going to have genetic testing, you need to talk to the experts about it first, and you need to have arrangements, which they will do for you, so that when the test result comes up, you talk to them about it and they can explain to you whether they think this, in fact, a serious finding or perhaps not such a serious finding.

It’s always difficult, if a mutation is found, that we identify is for example a mutation in the genes BRCA1 or BRCA2 that we know most about, where we can say, “Unfortunately we’ve found this mutation and this means that you do have a very high risk of developing breast cancer”, or in some cases ovarian cancer. It’s true that presents you with some difficult problems but it’s generally probably better to know than not to know.

So the first thing is there are some things you can do yourself, you might be enrolled in a program where you get extra MRI scans, for example, that can be funded to look very carefully for breast cancer. You might decide that if you’ve finished having children and the doctors say that ovarian cancer is part of the problem that you could have your ovaries taken out because that’s a relatively minor operation and is likely to fix that side of the problem. More radically, you might decide to actually have breast surgery to have breasts removed and to have reconstruction, but that’s obviously not for everyone.

The difficult situation is when a woman does have a very strong family history, there are a lot of relatives who have had breast cancer at a very young age, and you do the testing and you don’t find a mutation, because although we can’t prove it it’s likely there’s a mutation in something, it’s just that we can’t find it. Then you have a difficult situation and that’s something you should talk to the experts about, whether that means that you should do some of those potentially radical surgical options or extra tests or whatever. That’s obviously something we’re working hard to get better at.

Given the pace of advancing technology, we will get better and better at identifying those mutations, always remembering that around 95% of all breast cancer does not involve inherited mutations that we can identify. It’s those women who are getting cancer at a young age, or who have family members at a young age who are at risk of this.