Breast cancer risk reduction

Dr Elizabeth Farrell: Jane O’Brien is a breast surgeon who specialises in breast cancer surgery, risk reduction surgery in high-risk women and men. She’s trained as a surgeon specialising in breast surgery, with fellowships in Melbourne and Edinburgh. She worked for eight years in the UK, and on return worked at Peter McCallum and also Breast Screen. She now practises at St. Vincent’s in East Melbourne. Jane is going to talk to us today about the evidence for risk reduction surgery versus conservative management. Thank you, Jane.

Dr Jane O’Brien: For these women who have one of the high penetrance genes, so, associated with a very elevated lifetime risk, many of them, particularly if they come from a family with a close relative with breast cancer, have a sense of inevitability that they’re going to experience a cancer, and so their levels of anxiety are high from the first consultation. For the vast majority of women, though, who choose bilateral risk reduction mastectomy as their chosen form of risk management, the survival benefit is not necessarily their major motivation. They’re hoping to avoid the lifelong anxiety of screening, the recalls from screening, having to face a cancer diagnosis still after all of that screening, and then having to go through, potentially particularly with the BRCA1 carriers, chemotherapy, perhaps more aggressive or invasive auxiliary surgery, and then moving on to breast cancer surveillance rather than just screening.

Liz and Grace were pretty specific about what they wanted me to talk about, and they specifically asked for the current evidence for all of these risk management strategies. I included all of that in the documentation that I sent in because there’s nothing more boring than sitting, watching forest plots and so forth. But all of the data that I’ll quote is published and is available in those specific papers that I’ve listed. So first of all, what’s the evidence for risk-reducing surgery as opposed to any other management of a high-risk individual? And what is the evidence for more versus less surgery in high-risk patients who develop breast cancer, or women who develop breast cancer and are subsequently identified as being high risk? As is often the case these days, they may not be tested until the time of diagnosis and then identified as being high risk.

Most of the currently offered interventions, specifically with surgery, things that are offered rather than recommended, because there are other options, and in terms of decision or regret, certainly feeling pressured into it or feeling that the health professional has strongly recommended one option over another tends to be associated with a low level of satisfaction after surgery. The measure of the intervention efficacy really depends on what you’re aiming for. The perception of the risk-benefit ratio will vary between individuals and often between the individual and the health professional. And, really, the trick is often working out what each individual patient, and yourself, think in their circumstance is the benefit-risk ratio, and that may differ enormously from what the health professional sees it and the patient themselves.

First of all, in terms of defining risk for the purposes of ordering genetic testing, eligibility for Medicare-rebatable screening MRI, the two commonly used categories are the one used by Cancer Australia, which is the multiple of time, lifetime risk. So a average risk is less than one and a half times lifetime risk of population. And then the other way of doing it is with an absolute lifetime risk, which the eviQ use based on the UK NICE criteria.
It is important when you are looking at risk reduction strategies that you are very specific about defining the risk reduction terms. How you frame it really influences how the patient will interpret the information, whether you frame it in a negative way or a positive way. And, as we know from COVID, the average population, probably most people, are pretty statistically enumerate, and how you describe the risk reduction can be very persuasive.

So for example, the first Pfizer paper on the vaccine, they quoted no absolute risk reductions, it was only a relative risk reduction, and the absolute risk reduction when you actually went down to the figures was 0.84%, whereas the only figure that appeared in the public domain at that stage was the 95% efficacy. And that sort of thing is particularly misleading to patients, in that they assume if you say 95% efficacy, that means 95% chance you won’t get it. Whereas obviously 95% is a 95% risk reduction, and that depends entirely on what their baseline risk is.

So assuming, therefore, any given intervention for argument’s sake, i.e. surgery, you may expect to get a 95% risk reduction. Whether or not that intervention is felt to be worthwhile depends on the patient’s baseline risk. So a 95% risk reduction if you are at population risk, so about a 12% lifetime risk, only gives you an 11.5% absolute risk reduction. Whereas if you are at a high risk, as in a BRCA carrier, and your lifetime risk is roughly 70%, that’s a much higher absolute risk reduction, 67%.

The key, really, then is to identify patients who are likely to get more benefit and less risk. So looking at the risk from the surgical risk reduction point of view, you’re looking at patients who are fit for surgery, and, particularly if they’re entertaining immediate reconstruction, are suitable for reconstruction. And then in terms of benefit, as I said, you are looking at selecting people who you’ve identified as being at elevated risk.

The risk benefit ratio will change over time, and that has a lot to do with the selection of the timing of surgery, and how far patients want to push the envelope is also important. Some patients may want a low risk, low benefit intervention because they want to do something that’s more than nothing, but they don’t want to go to the whole hog and have surgery. And so that is an important discussion as to the relative benefits you may get from the various interventions.
It is a multidisciplinary involvement, particularly initially following risk assessment with the genetics team. The bulk of the surveillance at present does tend to fall to the breast surgeon, which I think, given the Medicare criteria for screening MRI, is becoming rapidly unsustainable because of the fact that the numbers of women now who are eligible to age 60, and I’ll come back to the criteria in a sec, but that does largely fall to the surgeon, as does lifelong surveillance, whether or not women pursue surgery. So the process for the high-risk individual is, obviously, first of all, risk assessment, and then the risk management really falls into two categories, high risk or enhanced screening, and any risk reduction strategy. So taking the high-risk screening, clinical breast examination I’ll come back to, and then some form of breast imaging. With respect to risk reduction, lifestyle modification, as in the general population, risk-reducing medications, and then risk-reducing surgery. And I’m going to, first of all, go through the breast cancer treatment differences between high risk and population risk individuals.

So the most appropriate risk management strategy may vary throughout someone’s life. And so whilst someone may declare from the outset that they’re planning to pursue risk reduction surgery, depending on which genetic mutation they carry, they may elect to delay the surgical intervention until their early thirties or maybe mid-thirties, and so other strategies are obviously going to be important at the beginning. So each individual patient may work through a series of strategies prior to coming to surgery, if they come to surgery at all.

Just to summarise my take on the current evidence for each strategy, there’s little or no evidence for clinical breast examination in women who are undergoing high-risk MRI screening. It’s pretty well a waste of time. Obviously it is done as the patient attends to access the request to have the MRI. The majority of cancers that are picked up clinically are picked up by the patient, and there are a significant number, unfortunately, of interval cancers still. With breast imaging, ideally it would include MRI if the patient’s able to have MRI, and there is evidence for MRI as opposed to mammography and ultrasound. Lifestyle modification, exercise and weight control appear to confer the same relative risk reduction in high-risk patients as in the general population. The natural thought is, ‘Oh, it’s a drop in the ocean if you are at 80% lifetime risk’, but it is still worth reinforcing to patients the lifestyle modification. There’s less evidence for exogenous hormones and alcohol, really, there’s not a lot of evidence either way with those, and so I don’t think you can be prescriptive either way with that.

Risk-reducing medications, which I’ll come to again about the popularity or lack thereof, there is a significant risk reduction, however, I think patients do tend to polarise into one camp or the other. And therefore oftentimes with risk-reducing medication, it will be primarily an option taken by women who are planning perhaps to have surgery in a few years’ time. Risk-reducing surgery obviously effectively reduces the risk of developing breast cancer. In the current, the more modern series, probably between 95% and 100%, although normally you would quote maybe a 90, 95% risk reduction. It has been more difficult because of the lack, obviously, of randomised trials to establish survival data. There are modelling studies that have shown definite survival advantages, and cohort and observational studies which have shown a survival advantage. But it has been difficult to prove, as has the benefit of MRI screening.

The treatment of breast cancer in the high-risk individual, basically, if a patient is suitable for breast conserving surgery, there’s no contraindication to the breast being conserved for the treatment of the index cancer. However, patients who are high risk, particularly certain mutations, have a very high risk of developing a second primary breast cancer throughout their life, whether that be in the ipsilateral conserved breast or in the contralateral breast. So whilst breast conserving surgery is appropriate for the cancer itself, it may not be, in the bigger picture, the most appropriate option for the patient. This is just a busy slide of the ASCO guidelines, but virtually every step of the way for the high-risk individuals these days, there are international guidelines. And so things have become easier in terms of advising patients because of the presence of guidelines, and the guidelines are all either consensus-based or some of them are pretty heavily evidence-based.

So for the patient who presents, who is known to be a mutation carrier and is suitable for breast conservation, breast conservation is an appropriate option to discuss. However, for the high penetrance genes, it is appropriate also to discuss the fact that they may wish to entertain bilateral mastectomy, or even a staged option. Unilateral mastectomy, possibly, because, particularly if they’re having intermediate reconstruction, doesn’t hold a lot of advantages, and you may burn bridges with respect to, particularly if it’s tissue flap reconstruction. So I think if a patient is suitable for breast conservation, they either have breast conservation or a bilateral mastectomy, there’s really not any particular advantage to them in having a unilateral mastectomy.

Depending on how long your local genetic service takes to get the genetic test back, the result back, staged surgery is an option for women who are suitable for breast conserving surgery who are not known to be gene carriers. So if you’ve got a patient who presents, who’s got a family history perhaps, and presents at a relatively young age with a triple negative cancer, which we know are overrepresented in the BRCA1 gene carriers, you may suggest to them, ‘Well, your tumour is triple negative, there is going to be a recommendation for either neoadjuvant or adjuvant chemotherapy.’ You either give the chemotherapy in the neoadjuvant setting and wait for the genetic result, or give, if they’ve got a very small triple negative cancer, you may in fact operate first, and the genetic test result will come back while they’re having their chemotherapy, and then the final decision can be made as to whether they’d proceed with bilateral mastectomy or lumpectomy followed by radiotherapy.

Patients who are not suitable for breast conserving surgery either have a unilateral or bilateral mastectomy plus or minus reconstruction. And as I said, there’s really not a lot probably to recommend unilateral mastectomy in that setting. I mean, these women are at extremely elevated increased risk, particularly the younger women. BRCA1 and 2 mutations particularly are associated with a very high risk of ipsilateral and contralateral second primaries. And that paper there, which is the one that’s very often quoted to patients, there are tables in that paper from 2017 which let you work out, together with family history, what the patient’s risk over time is likely to be with respect to development of ovarian cancer, the development of second primary. And the level of risk of ipsilateral or contralateral second primaries depends very heavily on the type of the mutation and very much so on the age at the first breast cancer diagnosis, and also family history, to be fair. So the family history is still important, even in the setting where we’ve got proven mutation.

Although, like in sporadic breast cancer, the risk of local recurrence after breast conservation and radiotherapy is higher if the breast’s conserved compared to mastectomy, that does not appear to translate in high-risk patients into a survival disadvantage, and it is conjectured with some of the mutation carriers that, particularly those who may have high-risk initial index cancers, that many of the cancers that are included as second primaries in some of these studies, included as recurrences, may be second primaries, they’re early second primaries rather than recurrences.

The issue as to what to do with patients with moderate risk genes is a little bit more difficult, and the patient will often make that decision themselves. If they’re found to have a moderate penetrance gene and they’re having a unilateral mastectomy, it is probably not unreasonable for them to have a bilateral mastectomy. There’s no evidence of increased toxicity or contralateral breast cancer in mutation carriers undergoing radiotherapy post breast conservation. There was some concern raised regarding ATM carriers, and I think that’s pretty well been dispelled. However, with TP53 mutations, radiation is probably best avoided in all shapes and forms, and therefore mastectomy would certainly be the preferred surgical option.

The following factors I’ve listed there are predictive of a higher risk of contralateral breast cancer over time. Age at diagnosis, which, as I said, is the highest risk factor. Family history. The other thing that needs to be taken into account is obviously the overall prognosis of the patient, whether that be from their breast cancer or a competing cancer such as ovarian. And in terms of the risk management of women who are found to have a BRCA mutation by virtue of an ovarian cancer diagnosis, you want to be fairly conservative in terms of your risk reduction strategies. I.e. I think most people would suggest waiting probably five years, and depends on comorbidities and life expectancy, and the ability of the patient to undergo screening, particularly MRI screening.

The issue about survival benefit with contralateral prophylactic mastectomy, quite similar to that with risk-reduction mastectomy, it has been difficult to show a survival advantage, but nonetheless, there are studies that do show a survival advantage. And again, it’s mainly in women who are diagnosed with cancer at a young age, and there has been a survival advantage shown in those younger women.
It is important to provide patients, when you’re talking about contralateral prophylactic mastectomy, particularly when it’s done in a delayed fashion, with an absolute risk of estimate for their risk of getting another cancer in the other breast.

And those figures there again, come from that paper that I quoted. At 25, someone diagnosed at 25, the risk for a contralateral breast cancer is 68%, I think it says there, versus 20% at 50 years. So the age is extremely important.

So coming back to how you frame the strategy to start with when you first see a high-risk patient, it really depends on the endpoint. I think patients, and you wouldn’t think it needed to be reinforced, but it does, that screening doesn’t reduce any cancers. None, zero. And I think sometimes patients are dismayed if they have, are diagnosed with a cancer during screening, ‘But I was doing everything I could.’ Well, no you weren’t, really, because we’re talking about early diagnosis, we’re not talking about prevention. That’s not to say it’s not effective, and it’s not worthwhile, but you need to be fairly clear about what you’re going to achieve with each of these strategies.

So in terms of benefit, if you are looking at reducing the risk of breast cancer, risk-reducing mastectomy is, surprise, surprise, by far the most effective, but unfortunately also obviously the most radical. If you are talking about reducing deaths from breast cancer, there’s not really actually all that much in it, potentially. And maybe part of that is due to the fact of better early detection methods with MRI screening, better treatment for hereditary breast cancers, et cetera. But there isn’t an awful lot in it on paper. So an unaffected individual, what is their chance of dying from breast cancer if they adopt each of those strategies, and there’s no survival difference really, probably, not a significant one.

So it’s not like a dramatic, that women, in terms of presenting them information about what is the most likely to reduce your death from breast cancer, overall, there’s not a lot of evidence to suggest a huge difference, and there’s no evidence for a survival advantage with the risk-reducing medication. And so I guess that does raise the question, ‘Is preventing a breast cancer better than curing it?’ Well, that depends I guess how you look at it. Mary Claire King, who isolated the BRCA gene, makes that comment, ‘Every breast or ovarian cancer patient with a BRCA or BRCA2 mutation detected after diagnosis is a missed opportunity to prevent a cancer.’ And the other way of looking at that is, every breast or ovarian cancer diagnosed in a known BRCA carrier represents a failure of risk management, really.

So quickly going through the risk management options, as I said, there are guidelines now pretty well for every step of the process from various countries in Australia. There are the eviQ guidelines, the NCCN guidelines from the States. There are nice guidelines in the UK and ESMO guidelines from the Europeans. For risk-reducing mastectomy, the American Society of Surgical Oncology published guidelines. And for contralateral prophylactic mastectomy guidelines, every time you pick up a journal there’s a new guideline.

They’ve largely been driven by the panic in surgical circles about the epidemic, which appears to have sort of waned, of women requesting bilateral mastectomy who are at population risk and have a breast cancer diagnosis that’s perhaps suitable for conservation. So a lot of these CPM guidelines don’t directly, the motivation for their establishment wasn’t necessarily for high-risk patients, although they all include high-risk patients. And then lastly, the probably most comprehensive treatment guidelines for high-risk individuals are the ASCO guidelines, and they’re extremely comprehensive and go through every evidence base.

So although, ideally, the patients have undergone some form of formal risk assessment prior to seeing, well, I guess the surgeon who is going to ultimately, in a lot of cases, be responsible for surveillance, the surgeon does need to clarify with the patient what they understand about their risk and therefore does need to know a little bit themselves about the risk assessment. And there are now available quite a few tools that you can just use at the desktop to work out lifetime risk, 10-year risk, et cetera. And they’re not just appropriate to reinforce to the patient what their risks are, but importantly to show the patient what their risks are over time. So, okay, your lifetime risk may be 70%, but your risk over the next 10 years is only 0.7%, and therefore doing a radical risk-reducing procedure at your age when you don’t have a partner, you’re wanting pregnancies, et cetera, there is no rush.

So the various risk calculators include all of those factors that I’ve put there, most of which also include breast density. And the calculators are also useful for clinicians in that several of them will give you an estimate of the presence of a gene. And that’s useful with respect to a patient who’s got a new diagnosis, for example, whether they’re eligible for genetic testing, and also for the high-risk patients who don’t have a proven gene mutation, do they cross the threshold to make them eligible for high-risk screening MRI?

Just to quickly go through iPrevent, Kelly Phillips gave me some bit of help with this talk, and I’ll come back to her risk-reducing clinic. But iPrevent isn’t necessarily the easiest one to use, and it depends on the individual patient, but for the purposes of just demonstrating the sort of information you can get from these programmes to give the patient, I’ve just picked out a random and put in a 25-year-old unaffected BRCA carrier. So you can give them lifetime risk compared to the general population. You can give them a graph, which, as I said, is useful for demonstrating to them, ‘Your risk may be exponential over your remaining lifetime, but actually over the next 5 years, 10 years, even 15 years, is really quite manageable and therefore there is absolutely no rush in you coming to a decision tomorrow.’

The programmes will look at risk interventions, the expected benefit. They’re all done through a formula for the benefit, I think it’s 90% for risk reduction surgery and maybe 38% or something for, 40% for the risk-reducing medications. And so they’re useful to go through with patients primarily to give them a framework as to the time of their risk. And they will go through recommendations at the end regarding lifestyle factors, et cetera, and screening, which basically is if you fall into category of being at high risk and you are relatively young, MRI screening will be recommended. And once the risks have been estimated, then, depending on the magnitude of the risk, having a discussion of the possible effectiveness of interventions, and the individual’s preferences, risk tolerance, et cetera, you then go on to form a strategy.

Now all high-risk patients should ideally have high-risk screening, and the screening recommendations internationally are fairly similar with minor modifications. Really the only difference is some guidelines recommend staggering the screening 6-monthly, others will do MRI one 6-month and mammogram the other 6-months. And that’s kind of personal preference really. I don’t think there’s a huge difference in the two. So these are just the various guidelines, and as I said, they are, with respect to screening, all pretty similar.

The Medicare eligibility for high-risk screening, when it was first introduced, was largely family-history-based. In November 2022 it was amended quite significantly. It increased the age cut-off to 60 years, and it also changed the criteria from largely family-history-based to include all women diagnosed breast cancer under the age of 50, and also risk criteria. So if you have a remaining lifetime risk of 30% or more, or a 10-year risk of 5% or more, that renders you eligible. And that has sort of crossed the problem of women who come from small families or not many women who may be high risk and weren’t previously able to fulfil the eligibility criteria.

This is just to point out, this is a information sheet published in JAMA, just to point out, no wonder patients are confused. They describe screening as a risk-reducing strategy. Well, it’s not a risk-reducing strategy, it’s screening. It’s early detection. And I think it’s no wonder patients get confused, if what appears in information they’re given isn’t correct. So, assuming that patients are attending for screening, and the results in a lot of the studies of screening are obviously better than in real life, with respect to compliance and the perennial problem of what to do around pregnancies and breastfeeding, which is, it’s always tragic when a patient’s diagnosed with a high-risk cancer during, when they’re breastfeeding. So risk-reducing medications, and this is slides courtesy of, again, of Kelly. Look, there are guidelines through COSA about the various medications available. Even the zealots can’t get patients to want to take them, though. It is very difficult, patients do not want to take them.

Kelly has just started, at Peter McCallum, a telehealth service for high-risk women to discuss risk-reducing medications, and it takes the form of a single consultation, a discussion about the medication, et cetera, et cetera. And it is really good for patients who are perhaps high risk but may not necessarily fall into that high-penetrance gene high risk. So a patient who may have a pathological risk factor like ADH or LCIS. It is an ideal way to have someone talk to them about the medication who may be more persuasive than you are as a surgeon. And they’re the criteria for referral down the bottom there, and the referrals are just through Peter Mac.

So the patient’s decision making, it really varies, what motivates patients to make the decision one way or the other, to go down screening only path or the risk-reducing surgery. The patients who make a decision to go down the screening path are often deniers, and so their compliance is probably lower. The patients who are, the women who are planning to have a timed surgical intervention at a specific age do tend to turn up more regularly for screening. And everyone says fear is not a great help with decision making, but it’s kind of, really, except for the, ‘I want to take control of the situation’, which is one school of thought, pretty much the other side of the coin is, ‘Which do you fear more, surgery or getting breast cancer?’ I mean, I think that often in the end is the decision-making that the patients face. Do they want to have an operation? Well, no, they don’t, but equally they don’t want to get breast cancer.

So just quickly going through the risk-reducing surgery, why, for whom, if, when, what and where. Why, obviously, because it does reduce your risk of breast cancer dramatically by 90% at least, and it is pretty clear from the published theories
that it is effective in reducing the risk of breast cancer and is probably associated with a survival advantage. Who would you consider for risk-reducing, bilateral risk-reducing mastectomy I’m talking about now, so the patient who hasn’t got cancer, well, high penetrance gene carriers in the absence of any associated poor prognostic tumour, basically. And most of the guidelines suggest restricting, offering risk reduction mastectomy to those women who are at very high risk. There are increasing numbers of women with the moderate penetrance genes who are, after a period of time, electing to proceed, but they obviously need to be aware of the fact that their absolute risk benefit is lower because their lifetime risk is lower.

So who would we consider? Well, any of the high-penetrance gene, so BRCA1, 2, PALB2, and any of the others that Adrian mentioned, the less common ones. Prior thoracic radiation, mantle radiotherapy for Hodgkin’s prior to the age of 30. Some of the histological risk factors, although it is uncommon that women with the histological risk factors alone, in the absence of another issue like difficult surveillance or multiple biopsies, et cetera, the contralateral prophylactic mastectomy in women with cancer, and less and less as time goes on, the compelling family history. As I said at the beginning, risk reduction mastectomy is offered rather than recommended, and women opt for the surgery hopefully of their own volition. There’s no real single threshold above or below which you would proceed, although as, I guess, a general ballpark, most people would not be jumping into a bilateral risk reduction mastectomy in someone with a lower than 30% risk. I think that would probably be the lower end.

It should not be offered to the following circumstances. Individuals in whom you’re unable to make a risk. The occasional patient who you think is, it’s a fictitious family history, and it’s quite difficult to chase that up, because there are a lot of excuses about the various things. Patients who’ve had blood taken for genetic testing. And there is also the issue of the patient who, well in days gone by, I guess, where we would proceed on the basis of a compelling family history. These days with the availability of self-funded genetic testing, that’s less common. Most people would encourage patients to have a genetic test. I guess you have to have a thought beforehand, how the result is going to be dealt with. Would you take away the offer of risk reduction surgery if the genetic test is negative or doesn’t show a mutation. The patient’s being pushed into surgery.

And the final one is, which is more common than you think, is patients who are completely unrealistic about what they’re able to achieve. And you show the standard photographs of, this is an average result, this is a poor result, this is a good result. They look at the good result and they just are horrified, and you think, well, there’s not going to be any pleasing this woman. She’s not going to be happy with whatever. And it bears no relationship, in my experience, to what the breasts look like to start with, in that you might be thinking, ‘Oh, we can make you look probably better. We can elevate this dah, dah, dah’, and no, that looks terrible. And you think, okay, well there you go.

So I guess one of the things is, if patients proceed, it’s stating the obvious, that’s what we see with the pedigree, but to the patient, that’s what they see. They see their family, they see the people, the close relatives who’ve died of breast cancer, and probably the single biggest predictor still of proceeding with risk-reducing surgery is a close female relative who’s died of breast cancer, particularly if it’s a mother or sister, and at a young age. The uptake of risk-reducing mastectomy has increased over time, but probably not as towards as higher level as you would think. Even in documented high-risk patients, probably only around 20% in all Australia. It does vary culturally and according to the sort of funding of health systems, but it is not particularly high. This local paper from 2013, I mean, it has probably gone up but bit since then, 21%.

Risk-reducing medications, even less popular, as I said. And then all I was going to touch on there was the motivating factors that we know are associated with a higher chance of the patient going down the surgical path. So risk perception, anxiety, family history. And then once you’ve made the decision to proceed with surgery, in a nutshell, the level of risk reduction is the same irrespective of what mastectomy you do, whether you do a simple mastectomy with no reconstruction, whether you do a skin-sparing mastectomy, or whether you do a nipple-sparing mastectomy. These days, with all three techniques, the level of risk reduction is not ostensibly different. And with nipple-sparing mastectomy, the initial reservation when it was first reintroduced for risk reduction purposes was that there would be significant residual breast tissue behind the nipple. And that really hasn’t panned out. The majority of case series that have looked at women developing primary breast cancer in residual breast tissue is actually in the axillary tail.

Now, whether that’s because the surgeon hasn’t recognised the tongue of tissue up into the axilla, or whether they’ve attempted to do the operation through an inframammary incision that’s too far, but that does tend to be where patients will develop a new primary breast cancer. And I mean they’re not common, but they do, I haven’t had one, and I mean there are now, though, large case report series of them occurring. And you have to explain to the patient that it isn’t a 100% risk reduction and that, in order not to devascularise the skin flaps, there will be, inevitably, some residual breast tissue cells.

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