breastBTK_Episode4
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[00:00:00] Welcome back to Behind the Knife and The Breast Specialty podcast series. Today, we're talking about breast cancer risk reduction. This is an important topic because breast cancer is common, but risk is not the same thing for every patient. For example, a 32-year-old with a BRCA1 mutation, a 48-year-old with atypical ductal hyperplasia, or a 60-year-old with no family history of breast cancer all have very different risk profiles and very different prevention options.

So in today's episode, we're going to break down the following objectives. First, what do we mean by breast cancer risk? What factors are modifiable versus non-modifiable? How do we assess risk in clinic? What can we do to reduce risk for our patients? We'll cover high-risk screening, lifestyle interventions, endocrine risk-reducing medications, management of high-risk breast lesions, and risk-reducing surgery, including prophylactic mastectomy for the highest risk individuals, such as those with genetic [00:01:00] predisposition syndromes.

Joining me today are two of our breast surgical oncologists, Dr. Pilewski and Dr. Downes-Scannar, who spend a lot of time counseling patients about exactly these decisions. So welcome back.

Thanks so much, Rashmi, for having us. Great to be back, and this is a topic that is definitely near and dear to my heart

Thanks for having us.

I'm looking forward to joining Dr. Paluski, who is an expert in this area, and it's also an area where surgeons play a major role, not just in the operating room, but also in helping patients to understand their risk and choose amongst the different prevention options.

Perfect. Let's start at the beginning.

When we say someone has high risk for breast cancer, what do we actually mean?

We just need to put this in the context of what is average risk of breast cancer, and then how do we define individuals who exceed that? So when we talk about risk, this is the probability that an individual will develop breast cancer over a [00:02:00] defined period of time, and this is typically defined as five-year risk, 10-year risk, or lifetime risk.

And putting this in context, we know that average risk for breast cancer for a woman in the United States is one in eight, which equates to a 12.5% lifetime risk. And in the United States, if someone has a lifetime risk that exceeds 20%, we consider that to be high risk.

This brings the question of what causes high risk in individuals.

There are a variety of factors which we will discuss in the next segment, including modifiable and non-modifiable factors. One thing to remember is that a factor that doubles risk sounds terrifying, but if the baseline risk is very low, the absolute increase may still be pretty small. So another thing I wanna take the time to define is the concept of risk reduction.

When we say risk reduction, we cannot eliminate risk altogether, but we are aiming to [00:03:00] decrease the overall risk of breast cancer from developing

Right, that's a key point. So what we're often trying to do is help someone who is at high risk get closer to the average risk of breast cancer, and we can reduce risk, sometimes substantially.

And so our goal is to reduce the risk of developing breast cancer as much as possible while balancing the side effects, harms, patient values, and quality of life.

So let's organize the risk factors and start with the modifiable ones, ones we and our patients can both target for change.

Thanks. Yeah, so obviously modifiable risk factors are those that we may have control over.

Um, and one that is very common right now is obesity. And there is robust data looking at post-menopausal obesity as a risk factor for, in particular, estrogen receptor-positive breast cancer. And so right now we know that obesity is defined as a BMI of greater than [00:04:00] 30, and this is likely related to both an increase in peripheral estrogen because of a conversion in adipose tissue, as well as insulin resistance and inflammatory changes related to obesity as this link to breast cancer risk.

As Dr. Paluski mentioned, the BMI greater than 30 is the threshold for obesity, and most recent data from 2019 is from the World Cancer Research Fund that released a meta-analysis of over 20 studies that showed that the impact of obesity is particularly related to an increase in hormone receptor-positive breast cancer.

As Dr. Paluski mentioned, this is specifically in post-menopausal women. Currently, we don't have enough data to suggest that pre-menopausal obesity has a significant correlation with breast cancer risk.

In addition to obesity, a- Second, often thought of as related, but independent risk factor is physical inactivity.

We [00:05:00] have, again, robust data suggesting that regular physical activity is associated with lower breast cancer risk. And this is a really interesting area of ongoing investigation right now to define what the appropriate dose of exercise is that is actually associated with a reduction in cancer risk.

And the American Cancer Society currently recommends at least five hours of moderate physical activity per week.

But if you actually look at the individual studies, most report that you need seven to nine hours of moderate physical activity per week, which translates to more than an hour a day of brisk walking, for example. And this reduces your overall risk at most by three percent for individuals that have an average risk of breast cancer.

Right. And so another lifestyle factor that we often talk about in terms of breast cancer risk is alcohol consumption. What we've seen in the literature is that individuals who drink more than one drink per day on average have a modest increase in [00:06:00] risk. And aside from the lifestyle factors, we also think about hormonal exposure, and that may be related to timing of pregnancies, but also things like menopausal hormone therapy.

There are a number of studies that show that combination estrogen and progesterone therapy increase overall breast cancer risk. The data is less robust for estrogen-only therapy, where we have more mixed results. This is a complicated and nuanced decision for individuals that should review this with their physician to understand the balance of risk versus benefit for hormone therapy.

Lastly, I just want to briefly mention the potential benefit of breastfeeding. All the things we've talked about so far increase breast cancer risk, but breastfeeding is actually protective in terms of long-term cancer risk.

And I'll just add very quickly that with regards to alcohol use, because that's often tested on exams and trainees often encounter smoking and alcohol use with respect to increased overall risk [00:07:00] across cancer types, the data for alcohol use is best reviewed in a twenty-fifteen meta-analysis that specifically looks at breast cancer risk and alcohol consumption.

And alcohol use of greater than thirty grams a day, which is roughly two to three standard drinks, is actually associated with an increased risk of developing both estrogen receptor-positive and negative breast cancers. Um, and that's across numerous studies. So that was an instrumental piece of data that came out in twenty-fifteen.

Thanks,

Rashmi. And then lastly, I just wanna touch on tobacco use. Obviously, robust data for lots of cancers with smoking exposure. The data is there, a bit less well-defined for breast cancer, but overall, tobacco is bad for your health for many reasons, and we should continue to counsel patients they should-

So if I'm counseling a patient, our takeaway would be the lifestyle headline is to, you know, continue to try to maintain a healthy weight, be physically [00:08:00] active as much as possible, greater than an hour a day is excellent.

Breastfeed if possible and desired, and be thoughtful about hormone therapy.

And importantly, we don't want to frame this as blame. Many risk factors are outside of a patient's control, and though lifestyle changes can help, they're really only one piece of risk reduction. There are also many non-modifiable risk factors to be aware of, and we'll touch on some of the biggest, most important.

So first, sex assigned at birth. Most breast cancer overwhelmingly happens in women. And age is a risk factor as well. Most cancers occur in women over 50 And then two related issues are genetic predisposition and family history. So there are people who inherit pathogenic variants in certain genes like the BRCA1 and 2 genes and others, which can [00:09:00] significantly increase their risk of developing breast cancer.

And then there are people who don't have an identifiable pathogenic variant in a gene but who have a strong family history of breast cancer. For example, a first-degree relative with breast cancer, particularly if that person is premenopausal at diagnosis or has bilateral breast cancer. Those are suggestive of increased risk or are known to increase the risk of that individual developing breast cancer.

Then certain factors related to the breast itself. So people who have a history of high-risk benign breast lesions like atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ are at higher risk of developing breast cancer. And those with dense breasts are both at increased risk to get breast cancer and also have sort of the double whammy of having reduced sensitivity with mammographic screening.

Next [00:10:00] is prior chest radiation, especially mantle radiation for lymphoma given during adolescence or childhood, which is often not used anymore. But, um, we'll still see patients in their thirties and forties who, who underwent this type of treatment, and they can have a very elevated lifetime risk, often approaching that of those patients with pathogenic gene mutations.

And then reproductive and hormonal history also influence risk breast cancer. So early menarche, late menopause, nulliparity, and older age at first birth increase risk, not necessarily modifiable in that once you've met a patient, often these can't be changed, but they're really an important part of risk estimation.

And that's a perfect transition to risk estimation and assessment. So if a patient comes to clinic and says, "You know, my mom had breast cancer, am I at high risk for developing breast cancer?" For the residents, this is a common [00:11:00] clinical question you will encounter in the surgical oncology clinics. What's the first step?

It's always a structured history, and make sure that you obtain, in addition to age, menstrual and reproductive history, prior history of breast biopsies and pathology, personal histories of cancer, family history of breast cancer and other related cancers on maternal and paternal sides. The related cancers that pop up in these syndromes include ovarian, pancreatic, metastatic prostate any incidence of male breast cancer is notable, sarcoma, brain tumors, thyroid cancer, or diffuse gastric cancer And ages of diagnosis in relatives that have been affected, and as Dr.

Danskanor mentioned, any prior chest radiation. These details help us decide whether the patient needs formal risk modeling, genetic counseling, any type of enhanced surveillance, or risk-reducing interventions. And then we come to the question of after we gather all of this history and data, how do we choose the right risk model to [00:12:00] put that data into?

Right. So sometimes a complicated question, but there are a number of models that have been developed in different populations. So understanding the risk profile of your patient helps us identify the appropriate model to utilize. Some of the most commonly used models are number one, the Gail model.

This is a tool that estimates five-year and lifetime risk for invasive breast cancer and includes an individual's age, reproductive factors, number of biopsies, presence of atypia on pathology, and first-degree relatives. It is easy to identify. You can Google search this and pull up the Gail model. But it does have limitations.

It does not fully account for extensive family history, paternal family history. It doesn't include age of onset of cancer within relatives, and it's often thought to be not representative of a diverse patient population and background, [00:13:00] and does not take into consideration genetic risk. Other studies have also shown that it can underestimate risk among those with high-risk breast lesions, and so typically we don't rely on risk calculators for individuals who have increased risk based on pathologic features.

And I just wanna chime in for a second and say that as we were preparing for this episode, I actually got an outside question about this on our Q bank, where we were specifically asked to comment on the pros and cons of using the Gail model. Um, in this particular question, the question stem told us about a sixty-two-year-old female who presented for assessment of breast cancer risk.

She had a history of DCIS, and the clinician was considering using the Gail model to estimate her five-year risk. And the question posed was, "What aspect of the history will cause the model to underestimate her true risk?" And the answer was her DCIS history, which is exactly what Dr. Paluski was talking about, that the model will underestimate risk among those with high-risk breast [00:14:00] lesions.

Yeah, and important to know that we don't use these models for individuals who have a history of personal breast cancer. The secondly, I would say probably most commonly used model is the Tyrer-Cuzick or IBIS model. This is a model that was developed based on a cohort of individuals with strong family history, and it incorporates a much more detailed family tree.

It takes into account personal factors such as reproductive history, benign breast disease, and breast density, and estimates lifetime risk. This is often used to identify individuals who are eligible for supplemental screening with MRI, and can be quite accurate for those with a strong family history, but has also been shown to overestimate risk with those who have a history, again, of high-risk lesions with atypical hyperplasia or LCIS.

And then a third model I wanna comment on is the Breast Cancer Surveillance Consortium model that also includes age, race, and ethnicity, family [00:15:00] history, breast density, and biopsy history, which can be another useful tool when estimating risk and has been shown to have less variation with the incorporation of high-risk lesions.

A common threshold for many of these models is twenty percent or greater lifetime risk, which we discussed earlier, which often qualifies a patient for an annual breast MRI in addition to mammography. What is the threshold for chemo prevention?

Sure. So for chemo prevention, which is medication to reduce the risk of breast cancer, many guidelines consider patients with an elevated five-year risk or those with a history of atypical hyperplasia and LCIS.

Historically, a Gail model five-year risk of one point seven percent or higher has been used by the US Prevention Services Task Force, though some recommendations use higher thresholds depending on age and risk-benefit balance. Women most likely to benefit from chemo prevention are actually the high-risk cohort under the age of [00:16:00] fifty.

And when should we consider referring for genetic counseling or testing?

Patients should be referred for genetic counseling or testing when personal or family history suggests hereditary cancer risk. So this would be breast cancer diagnosed at a young age, triple-negative breast cancer, particularly under age forty, but now really anyone with this type of cancer gets referred due to how it may have implications for treatment.

Ovarian cancer at any age, male breast cancer, multiple relatives with breast, ovarian, pancreas, or metastatic prostate cancer, a known familial pathogenic variant, bilateral breast cancers, and certain syndromic cancers like sarcoma with early breast cancer suggestive of a TP53 mutation

Yeah, I mean, the list is long for factors that we're looking for to identify individuals who would benefit from genetic [00:17:00] counseling and screening. And I think one point to highlight here is that risk assessment is not a one-time event. It is something that individuals should have formally with their primary care physician, but it's something that is a process and needs to be updated across someone's lifetime as things change, like a new cancer diagnosis in a family member, when breast imaging becomes available with density, or when biopsies occur and pathology is available.

And I wanna take the time to clarify one more other point, that screening is often discussed alongside prevention, but as we know from our prior episodes too, screening does not actually reduce incidence, and that's an important distinction.

That's right. Screening is very important, right? We want to identify early breast cancers, but this is early detection, not prevention.

So when we think about average-risk individuals, those who do not have the list of high-risk features [00:18:00] that we've talked about, screening here entails mammography. That is the kind of staple for breast cancer screening, annual mammography starting at age 40. But when we think about those who are at increased risk, we often think about supplemental imaging.

Often, this is the addition of an annual breast MRI, in particular for individuals who have a lifetime risk of greater than 20% based on family history, those with a known genetic predisposition, or prior history of chest wall radiation. We also think about the age of when we would start screening, and that is dependent on an individual's risk profile.

So for many high-risk women, our screening is alternating mammogram and MRI every six months. And we also think about other screening modalities. Cases, this may be supplemental ultrasound based on having dense breast tissue, um, or using something called contrast enhanced spectral mammography, or CESM, and [00:19:00] this may be included for individuals at moderate risk or when MRI is not a suitable option.

And Dr. Danskin, you had mentioned how patients, um, with the higher breast density, the mammographic sensitivity actually declines. So could you comment a little bit more on your strategies for helping patients with denser breasts?

Right. So we mentioned that not only do patients with dense breasts have a higher risk of developing cancer, but mammography sensitivity is reduced w- when breast density is increased.

So they often benefit from individualized discussions about supplemental imaging, which sometimes can be ultrasound or potentially even MRI.

So as a takeaway, surveillance can be thought of as risk management. It is not risk reduction

Exactly, Rashmi. I completely agree.

So now to the central question, and the most exciting part of this topic: Can we decrease breast cancer risk?

Yes, absolutely, [00:20:00] and there are sort of five major buckets that they fall into. So the first is lifestyle modification. The second is risk-reducing medications, which are sometimes called chemo prevention. The third is risk-reducing surgery. The fourth is how we manage high-risk lesions, and the fifth is clinical trials and emerging prevention approaches

Great.

Let's talk about the lifestyle modifications, especially since we spent a lot of time discussing obesity as a risk factor for breast cancer, and weight management and bariatric surgery have really been impacted by the GLP-1 agonist. We sort of see ads for these medications everywhere. What's new is that GLP-1 agonists are now giving many patients a more effective medical option for weight loss.

The literature is very new, and the recent studies are beginning to ask whether GLP-1 medications could actually influence cancer risk, including breast cancer risk. Some of these studies build on earlier [00:21:00] data from bariatric surgery, where it was noted that substantial and sustained weight loss in certain individuals was associated with lower rates of obesity-related cancers.

So now, newer observational studies are looking at whether medication-induced weight loss may actually have similar downstream effects.

Yeah, I think this is a really exciting area, Rashmi. When we talk about lifestyle modifications for individuals who are interested in making changes that may impact their risk, when we counsel patients on obesity, this opens the door to more options.

We know that weight loss can be challenging and often is not sustained, and so bariatric surgery and medical weight management may be excellent options to both manage weight and cardiovascular and metabolic syndromes, but now also potentially obesity-related cancer. I do think that the data specific to GLP-1s is new.

It's emerging, but there are a lot of studies that are [00:22:00] ongoing, and I think that it's really pointing us in the right direction that this may be a great option because if we look at the kind of map both in the United States and worldwide, the proportion of adults who are obese and may benefit from these interventions is significant.

We know that that's more than half of adults in the United States who may reduce cancer risk with these interventions.

Dr. Paluski has a couple of commentaries out on this, one with Dr. Howard from University of Michigan as well, who's a bariatric surgeon, and that's a very interesting commentary on GLP-1s and weight loss in, um, cancer risk reduction.

So please take a look at that. Now let's do a deep dive on the chemoprevention or the risk-reducing medications. Dr. Downes-Garcia, could you help us understand these tools a little bit more?

These medications can really reduce the risk of estrogen receptor-positive breast cancer in appropriately selected patients, and they kind of fall into [00:23:00] two major categories.

The first is selective estrogen receptor modulators, or SERMs. That's tamoxifen and raloxifene. And the second is aromatase inhibitors, or

AIs, most commonly anastrozole and exemestane So tamoxifen, which is one of the SERMs, can be used, used in both pre and post-menopausal women and reduces the risk of ER-positive breast cancer, including in women with high-risk lesions like atypical ductal hyperplasia, atypical lobular hyperplasia, and LCIS.

And typically, this is given at a dose of 20 milligrams daily for five years, which is also very similar to the dose used for the treatment of estrogen-positive breast cancer.

The major side effects of these SERMs include hot flashes, night sweats, vaginal symptoms, mood changes, and menstrual changes. More serious but less common risks also include venous thromboembolisms, and in post-menopausal women, the risk of [00:24:00] endometrial cancer.

And so there's also growing interest in trying to understand, is a lower dose of tamoxifen daily also going to give you the same benefit? So Dr. Paluski, can you discuss the TAM One study that looks at low-dose tamoxifen dosing for prevention?

Absolutely. So as you mentioned, the kind of nidus for this is trying to understand if there are other effective options for medical risk reduction that don't carry the same side effect profile that would be more appealing, uh, to high-risk women.

And so the TAM zero one trial, it came out of Italy, was a randomized control trial that enrolled women both pre and post-menopausal who had breast intraepithelial neoplasm. So that is DCIS, LCIS, or atypia, so these high-risk lesions. And women were randomized to five milligrams, so much lower than the standard twenty-milligram dose versus [00:25:00] placebo over a three-year course, so lower dose in a shorter timeframe.

And overall, we saw a fifty percent risk reduction with this strategy, so very exciting. And the kind of icing on the cake is that there were far fewer side effects reported in the TAM one trial. No significant difference in endometrial cancer or thromboembolic events, and the only significant difference was a slight difference in hot flashes for patients on low-dose tamoxifen, so appeared to be quite well-tolerated.

The caveat here is that the subset analysis of this trial showed that the majority of the benefit appeared to be in post-menopausal women, and we did not see that same benefit in pre-menopausal women. And so this is still an area that we are studying to try and identify how we can personalize the lowest dose of tamoxifen that is effective for each individual based on changes that we see currently in a trial of mammographic [00:26:00] density.

Other options, as we heard from Dr. Donskenner, are raloxifene. So this is an option for post-menopausal women, um, also been shown to be effective in reducing incidence of estrogen receptor-positive breast cancer, and also has favorable effects on bone density. And so for some patients, this is killing two birds with one stone in terms of the benefits there.

And compared to tamoxifen, it has a lower risk of endometrial cancer and thromboembolic risk. But when we kind of think about pros and cons in a head-to-head trial, the STAR trial, we did see that tamoxifen was slightly superior to raloxifene in terms of breast cancer development. But for many patients, raloxifene is better tolerated and also has the added benefit of bone protection.

And so we counsel patients on, on both sides of that spectrum. The other class of medications, as we heard about, are aromatase inhibitors, again, specific for post-menopausal women. These are drugs like [00:27:00] anastrozole or exemestane, which again reduce estrogen receptor-positive breast cancer by greater than fifty percent in high-risk women who take these medications.

They are not used routinely in premenopausal women because they work by blocking conversion of estrogen in the adipose tissue in the periphery. And in premenopausal women, there is still production of estrogen from the ovaries. And so these drugs alone without ovarian suppression would not be effective and would not be a standard for primary prevention.

And when we think about downsides of aro-aromatase inhibitors, the most common side effects that we hear about are athr-arthralgias definitely the most significant side effect, just muscle joint aches and pains. Some patients also experience hot flashes, um, and importantly can have bone loss. And so bone density assessment and management is critical for patients on these medications.

So when you have these patients come to clinic, how do you decide who should be offered [00:28:00] these risk-reducing medications, chemoprevention or endocrine prevention as we've just covered?

Yeah, so in general, we want to identify patients at high risk of developing estrogen positive breast cancer, and those that are 35 and older, and those would be people who have a history of atypical ductal hyperplasia, or LCIS, or an elevated five-year risk by one of the validated models we discussed earlier, an elevated lifetime risk by one of these models, or a strong family history when genetic testing is negative.

But the real key is in shared decision-making. So it's important to know that the benefit is going to be greatest when the baseline risk is higher, and that the harms vary depending on age, menopausal, menopausal status, clotting risk, whether or not the patient still has their uterus, the patient's bone density, and their preferences.

So as always, in [00:29:00] most of our discussions, everything is measured, right? It's not everyone should take tamoxifen. It's always for the right patient, this particular strategy can cut your positive breast cancer risk significantly, but we need to personalize the decision and the patient selection.

That's exactly right, and actually, as a result of the ten-year follow-up of the TAMO-1 trial, ASCO guidelines now recommend providers discuss risk-reducing medications for certain populations.

And those ten-year results show that tamoxifen five milligrams once daily for even three years reduces the development of invasive breast cancer among patients with high-risk lesions who were in that study without long-term adverse events

Let's talk about high-risk breast lesions. These are particularly informative for the trainees because this is a common surgical question.

For example, a patient has a core needle biopsy that shows ADH, which is [00:30:00] atypical ductal hyperplasia, or atypical lobular hyperplasia, or lobular carcinoma in situ. How do surgeons think about each of these with respect to risk?

Yeah, that's a good question, and actually, I think I may have even stolen this from Dr.

Paluski one time. But the way that I frame this for patients is that there's actually two questions when someone has one of these lesions. One is, "What does this do for your risk of developing breast cancer?" But another important and separate question is, "Do we need to take this lesion out because we are worried that when we take it out, we may find a more serious diagnosis like DCIS or invasive cancer?"

So the first lesion we can talk about is atypical ductal hyperplasia, also known as ADH. So this lesion is both a marker of risk, but also the answer to that second question, "Is there a risk of upgrade?" Is yes for this lesion. So in about 20% of patients [00:31:00] diagnosed with ADH on a core needle biopsy, that can be associated with DCIS or invasive cancer on surgical excision, which is generally why it is recommended to excise.

However, some very carefully selected low-risk cases could be considered for surveillance, but this is, uh, variable depending on the institution. Long-term, ADH confers an elevated risk of breast cancer, and so separate from the issue of excision, these patients need to be counseled about enhanced surveillance and risk-reducing endocrine therapy.

The other lesions to talk about fall into this broad category of lobular neoplasia. There's ALH and classical LCIS, and these are considered risk factors for the development of breast cancer actually in either breast, not just the breast where the lesion is diagnosed. If imaging and pathology are concordant and there are no concerning features, there's no need to excise [00:32:00] these lesions because the overall upgrade risk is low.

However, if there is discordance, a mass lesion, or for some reason a concern for a more aggressive variant, which I think we will probably also talk about during this podcast, then excision is recommended. So there are non-classical types of lobular neoplasia like pleomorphic or florid type LCIS, where the upgrade rates are actually quite high, in excess of 20%.

Uh, this is different than the classical type where upgrade is probably about 1%.

Yeah, I just wanna highlight that in the prospective trial that assessed the safety for observation for patients with lobular neoplasia that defined this very low upgrade rate of around one percent, patients with non-classic type LCIS were not included there, and so surgical excision remains the standard for pleomorphic or florid type LCIS.

So when [00:33:00] we look at these non-classic LCIS lesions, pleomorphic and florid, they look and behave more like potentially DCIS, um, or in situ neoplastic lesions, and have a higher propensity to progress into an invasive carcinoma. And so we treat them more aggressively, um, starting with surgical excision with attention to the margins.

So negative margins here are important.

So now let's talk about the most invasive of the interventions, which is the risk-reducing surgery. So when you think about who is being offered prophylactic mastectomy, Dr. Paluski, can you talk about, uh, factors that you think of when you're considering patients for this procedure?

Yeah, absolutely. So, I mean, we typically think about risk-reducing surgery for individuals at the highest risk for developing breast cancer. And so most commonly, that is related to those with pathogenic [00:34:00] variants in high penetrance breast cancer genes such as BRCA1 or BRCA2, and PALB2 for select patients, TP53, PTEN, CDH1, STK11.

It's quite a long list. It's growing, um, but the most common that we encounter are BRCA1 and two, P53, and CDH1 in my practice. And that is not a black-and-white decision. We know that individuals with high-risk genetic variants are often interested in thinking about risk-reducing surgery, but it may also be appropriate for patients who've had negative genetic testing but have very strong family histories where their estimated lifetime risk is still exceedingly high.

Those with prior chest wall radiation where their lifetime risk of breast cancer if they received radiation at a young age actually mirrors that of an individual with a BRCA1 pathogenic variant or, you know, [00:35:00] other extreme risk profiles in select situations.

So one question that comes up is, how much does this risk-reducing bilateral mastectomy actually reduce risk by?

Yeah, the data shows that doing risk-reducing mastectomies in high-risk women reduces risk by about ninety to ninety-five percent, and there are a handful of studies where this comes from. One example is the PRO study that compared bilateral risk-reducing mastectomies in women with a BRCA1 or two pathogenic variant and compared subsequent breast cancer development among those who underwent surgery versus no surgical intervention, just ongoing observation, and found that significant, uh, risk reduction with the addition of mastectomies.

Importantly, we know that we will never reduce risk by a hundred percent. Mastectomies are very effective at reducing the vast majority of breast tissue that's there, but we know that it doesn't remove a hundred percent of breast [00:36:00] tissue underneath the skin and subcutaneous fat.

So Dr. Downskanner, can you talk to us about key counseling points that you cover when you're consenting patients and talking them through this procedure?

Sure. Well, I think the most important thing is what Dr. Peluski just talked about, that we can expect quite a large risk reduction, not 100%, but really effective risk reduction. But that there is always a small amount of residual risk given that we cannot remove every bit of microscopic breast tissue.

Beyond that, we wanna talk about what could it look like if the patients actually go through with surgery. So what are the potential complications of the surgery? What are the options for re- reconstruction? What are the types of surgeries that are available to them? Is the patient a candidate for nipple-sparing versus a skin-sparing mastectomy?

It's important that patients understand that even with a nipple-sparing mastectomy, where cosmetically the nipple may [00:37:00] look normal, we expect sensation loss and that is typically permanent. We mention the impact that this could have on their body image and their sexuality. It's also important for them to understand that they may need multiple operations to complete their reconstruction if they choose to have it.

So they should also understand how much time they'll need to recover, how much time away from work and their normal life activities, and then what are the alternatives to this? Could they pursue enhanced surveillance, plus/minus lifestyle modification, plus/minus chemo prevention as an alternative?

When we think about risk-reducing surgery, another surgical intervention that's considered is also salpingo-oophorectomy.

Could you, Dr. Notoskin, talk a bit about bilateral salpingo-oophorectomy as a prevention strategy?

Yeah, this is a great question. I think a lot of patients come in thinking that because they've had breast cancer, they're at risk for ovarian [00:38:00] cancer, and I think maybe there's just a little confusion out there.

So people who have a BRCA1 and BRCA2 mutation are at risk for both types of cancer because of the gene mutation that they have. And so bilateral salpingo-oophorectomy is an important intervention and prevention strategy for these patients. Typically, for BRCA1 carriers, this is recommended after childbearing, around age 35 to 40, and maybe a little bit later for those with BRCA2, around 40 to 45, because ovarian cancer risk tends to occur later than those with the BRCA1 mutation.

And the surgery really reduces the risk of ovarian, fallopian tube, and primary peritoneal cancer, and improves mortality in BRCA mutation carriers. Its effect on breast cancer risk is slightly more nuanced, but because of reducing that exposure to estrogen, it's most notable that among premenopausal women with a BRCA2 mutation, those who undergo bilateral [00:39:00] salpingo-oophorectomy and are put into early menopause, they will have some risk reduction from the operation.

However, the primary reason to perform the operation is to reduce the risk of ovarian cancer.

This process requires careful counseling because premature menopause also has real consequences.

Right. So the symptoms of menopause, which include vasomotor symptoms, sexual dysfunction loss of bone density, impact on cardiovascular health, cognition, of course, fertility.

And then it's also important to talk about in patients who are unaffected by cancer but undergoing risk-reducing surgeries, is there any possibility of actually hormone replacement therapy if they've undergone both risk-reducing breast surgery and bilateral salpingo-oophorectomy.

I mean, I think it's worth mentioning there's so much misinformation about avoidance of hormone replacement therapy in these young women, and I would say that I don't even think they need to have undergone their prophylactic mastectomy.

But if you've [00:40:00] had a BSO and you are still premenopausal, that the data supports a short course of hormone therapy.

Let's make this a little bit more practical for our listeners. So if a patient comes to clinic worried about breast cancer risk, can both of you give us your framework for approaching this type of patient?

Yeah, sure. So I think the first thing to do is identify the risk factors, which you should do with any patient when you're taking a personal and family history, which should include a review of their breast density and any previous breast biopsies and what those results were. And then choose an appropriate validated model to assess the patient's risk.

If you are concerned that there is potential for hereditary breast ovarian cancer syndrome, you'll want to refer them for genetic counseling. And then once you quantify the risk using an appropriate model, then you can sort of put them in a category of average risk, intermediate, or high lifetime risk, or potentially very, very high, such as those patients who have [00:41:00] pathogenic gene mutations or prior chest radiation.

And then you wanna match the interventions to the risk level. So for average-risk patients, routine annual mammography, counsel them about healthy lifestyle modifications they can make to reduce their risk, and to be aware of any changes in their family history. For intermediate-risk patients, you'll consider s- individualized supplemental screening, such as ultrasound or MRI or contrast-enhanced mammography.

Again, discuss lifestyle modifications. And then you could start to consider chemoprevention if the risk is elevated enough and the patient is highly motivated. And then for high-risk patients, this is when we really start thinking about MRI as an adjunct, always having a profession about the option for chemoprevention, and if available to you and them, referring for high-risk follow-up.

[00:42:00] Then our very highest risk patients, so those with pathogenic gene mutations or history of chest radiation, we talk about MRI-based surveillance, chemoprevention, risk-reducing mastectomy, risk-reducing salpingo-oophorectomy where it is relevant, and consideration of clinical trials and of course, enrollment in high-risk clinic as well.

And then always, we wanna be reassessing our patients over time as things in their personal and family history changes

Amazing. Thank you for that framework. I think that that will be very helpful for all of us trainees. I also wanna add that there are several new exciting tools emerging in the risk assessment and reduction space.

First, I wanna talk briefly about Clarity Breast. So this is a project that is the first AI-guided algorithm that is FDA-approved for mammography assessment. So the twenty twenty-six NCCN guidelines have introduced the first [00:43:00] AI-guided recommendation in breast cancer risk assessment for women starting mammographies at the age of thirty-five.

Clarity Breast is a project that uses a standard mammogram, but it provides a risk score using an AI algorithm to then personalize the subsequent screening modalities and to risk stratify the patients. Based off of the risk score, these patients are then either placed into a program where there's increased surveillance or an expedited referral to a high-risk clinic where they can discuss their options downstream.

So Dr. Palusci and Dr. Danskaner, are there any other new sort of innovations in the risk reduction space you're excited about?

I'm happy to come in here. I think that there's a couple things. If we think about risk assessment in addition to AI, which is obviously emerging in all aspects of medical care that we think about, I think that will continue to grow.

We also are evaluating the idea of kind of expanded genetic risk [00:44:00] assessment. So you've seen the laundry list or heard about the laundry list of genes that we know are associated with an increase of breast cancer. But we also now are looking at polygenic risk scores. When there is not an identifiable deleterious variant in one of those high-risk genes, you may still have a patient who has an increase in hereditary breast cancer risk based on SNPs or just the overall assessment of their genetic profiling.

And so I do think that we're gonna see that rolled out in the near future. But on the other end of the spectrum are what can we think about for risk reduction? We've heard about our main buckets, right? Lifestyle intervention, risk-reducing medication, and surgery Risk-reducing medication is likely the most applicable for the vast majority of moderate and high-risk individuals.

It is effective. We have a plethora of randomized controlled trials that support its use. But what we know from the literature is that the minority of eligible women choose to [00:45:00] take these drugs, and it's because of the side effect profiles that we heard about. These patients don't have a cancer diagnosis, and so taking a medication that has risks such as blood clots and endometrial cancer and menopausal symptoms or bone loss is really taxing.

And so there's a lot of studies going on to look at novel options for risk reduction, things like topical chemoprevention. Can you apply the drugs that we know work but treat only the organ of interest and not have systemic uptake? Can we individualize the dose of those medications and find the lowest dose that works to reduce side effects?

So lots of cool stuff coming in the next five years that will help us hopefully identify risk reduction that doesn't necessarily involve a major operation, but that also doesn't carry the same side effect profile

I think it'll be very exciting to see how all of these tests collect their initial [00:46:00] data, and then we get our initial starting reports of the analysis of how these tests perform in real-world populations.

The risk counseling, I also wanted to point out, can be pretty emotionally loaded. So are there any communication pearls that you guys have that would help us sort of navigate these conversations with our patients with more ease?

I think this is an important point. You know, thinking about relative and absolute risk is complicated for all of us.

And so individuals who are not in medicine may not completely understand the terminology, and so meeting patients where they're at, I think using absolute risk when we can, can be quite meaningful for patients. So describing risk as twenty-five percent lifetime risk may be more impactful than just your risk is elevated.

The data shows that most patients misinterpret their breast cancer risk, and that has downstream impacts on adherence to surveillance, and so using numbers [00:47:00] that make sense. And when we talk about benefit of risk reduction, also thinking about absolute benefit. So if an individual has a twenty-five percent lifetime risk and risk-reducing medications reduce that by fifty percent, we can tell them that that takes us to about a twelve percent lifetime risk, which is average risk, and so putting that into context.

The other thing to consider here is that risk models are useful, but they are estimates, and they are not perfect. And so they are definitely helpful in select situations, in particular for individuals with strong family history. I will just continue to reiterate that, that, um, I typically don't recommend that we use risk models for patients who have high-risk breast lesions because of the inaccuracies that we've seen.

But it's helpful to get a number to put it on the spectrum for a patient of how close to average versus twenty percent versus fifty percent someone falls. Um, and so [00:48:00] that tool can help us, but they're not perfect. And I, I think that this came up previously. We talk a lot about lifestyle modifications, and they are important, but we also wanna keep this in perspective.

They are moderate when it comes to the risk that is added by these things, but they're things that we may have control over. And so when patients say, "I wanna do everything I can," we should absolutely counsel them on the impact of weight management and exercise and moderation of alcohol. But we don't want patients to have blame or guilt related to this, so it's important that we counsel them within the context of, you know, why we want to make these recommendations.

And then it's obviously taking patient preference into account. Particular if we think about our high-risk patients, where surgical risk reduction might be part of the conversation, this is absolutely not the right choice for everyone. We know in the United States, for women with a pathogenic variant in BRCA one or two genes, that about half of those [00:49:00] women ought to undergo risk-reducing mastectomy, which means half don't, and they continue with surveillance because it's not the right choice for them.

And so understanding what is most important, what their life looks like, what their timeline is, plans for childbearing, all of that comes into consideration. And so we talk to patients about their anxiety related to screening, their acceptance of taking medication and their risk tolerance, which all come into play for decision-making.

Lastly, and I think that we just need to highlight this really in any surgical conversation that we have, is that we continue to need to think about all of these factors from an equitable standpoint. Uh, it is clear that not everyone has the same access to risk assessment, high-risk clinics, and high-risk screening.

And as I mentioned, risk models perform differently across populations. Access is not equal, and that's an area that we need to continue to [00:50:00] focus on and ensure that we can deliver this information and care equitably across all of our patients.

Yeah, exactly. You can talk about risk all day long, but if you have no access to intervention, it's really not particularly helpful

Thank you both for that.

Let's wrap with the key takeaways for the episode. So 10 important key takeaways. If you were just looking at this episode and you had one minute to spare, Dr. Paluski, start us off with our takeaways.

Okay, 10 key takeaways. Number one, obviously breast cancer risk is not one size fits all, and so risk assessment is really paramount and is influenced by age, genetics, family history, breast density, reproductive factors, biopsy history, lifestyle, prior radiation.

The list is [00:51:00] long, but all of that needs to be taken into consideration. Number two, for those risk factors, we want to separate modifiable and non-modifiable factors for patients. Not all of these things are under someone's control, and so we can highlight those that they may be able to have more impact on.

Thirdly, we'll keep talking about this, but for appropriate patients, use a validated risk model. Use a model that fits the clinical question, but acknowledge that certain patients should not have risk assessment using a model because it can over- or underestimate their risk, in particular for those with high-risk breast lesions.

Number four, and this is just crucial, genetic testing is paramount for patients who have family history. The best thing we can do is identify patients who have genetic risk before a cancer develops so that they have, are fully educated on the options and may have access to risk reduction [00:52:00] rather than cancer treatment.

Number five, talked a lot about this, but lifestyle interventions matter. Again, they are modest in comparison to some of the non-modifiable risk factors, but we can impact them. So physical activity, weight management, alcohol in moderation thoughtful use of hormone therapy, all of these things can kind of add up and may reduce breast cancer risk and frankly, also just improve overall health, so I think important across the board.

Next, if we move on here, we're at number six, would be risk-reducing medication. They are effective and dramatically underused. Tamoxifen, raloxifene, anastrozole, and exemestane are robustly supported by the data. They are recommended by ASCO and NCCN, and are effective. And we should not only discuss, but recommend these medications for appropriate high-risk women.

And as I mentioned, [00:53:00] there are a number of ongoing trials that I think are really exciting that will continue to test novel options and my side effects. Number seven, important for everyone to just keep this in the back of your mind, that screening is important for early detection, but it does not prevent cancer.

We're getting to the end, but number eight here from the surgical audience, high-risk lesions require two decisions. Number one, do we excise now? And number two, how does this impact long-term breast cancer risk? Number nine, risk-reducing mastectomy is effective, reduces risk by up to 95%, but has significant potential risk and impact on body image and sexuality, and so really is reserved for appropriate high-risk patients after careful counseling.

And then lastly, clinical trials are essential in improving prevention strategies and broadening our options for truly millions of women at increased risk.

That was a tour de force in takeaways, but that was excellent and [00:54:00] fantastic. Any final thoughts? It's

just been really nice learning and sharing what I know, and just a reminder that our job is to quantify risk as accurately as we possibly can to help patients choose a strategy that fits them, which could be all the way from enhanced screening to lifestyle change, medication, surgery, clinical trial enrollment, or some combination.

Thank you again so much for joining us and for sharing so much of your incredible expertise in this very important topic. See you next time, and dominate the day.