Breast Cancer | Clinical Medicine

What's up, ninja nerds? In this video today, we're going to be talking about breast cancer. Again, this is a part of our clinical medicine section. If you guys like this video, it makes sense, it helps you, please support us. You can do that a couple different ways. Hit the like button, comment down the comment section, subscribe, or become a premium member on our website. We have a link down in the description box below. Go check that out. We have our notes, illustrations, quiz questions, everything that you would need to truly succeed in all of your courses. All right, let's get into it. Let's talk about the pathophys of breast cancer. All right, friends, let's start talking about the pathophys. When we talk about breast cancer, it's really important to understand that when you look at the basic anatomy of the breast that there is, you know, all these mammary glands and really it's made up of ducts and lobules. That's really all it is and that's what helps us to make these the milk is those cells. That's where cancer arises. Cancer arises from those lobbules are from those ducts and from those epithelial cells. They unfortunately they undergo mutations of sort. They become malignant. They start to proliferate. they grow and you get these clumps of abnormal malignant cells within the lobules or within the ducts and then eventually they can spread. That's what generates breast cancer. Now the reason why these cells start to abnormally proliferate, why they gain the capacity to become abnormal and they continue to grow and they break past the basement membrane. They get into the blood. That comes down to a couple different things we'll talk about later. It could be that the estrogen exposure over a long period of time is a little bit higher than normal. They could develop mutations in specific genes that predispose them to this cancer. Or there could be other scenarios where we don't really have a good reason, but for some reason these patients overexpress specific receptors that increase the signaling for proliferation and survival of malignant cells. So let's take a look here at the breast. Let's say it again. When cancer arises, they usually arise in two locations. They arise in the lobule or in the duct. And so let's imagine here that we kind of just zoom in on the structures here and say here's what we're looking at. We're looking at a zoomed in version here. And here we're going to see we have a lobule and there's going to be a mass in this lobule. Or here we're going to have a duct and there's going to be a mass in that duct. And these are the tumors that are basically making up a patient's breast cancer. So this right here is a duct. This is a ductal tumor, right? And here is a lobular tumor. And these are the two different ways that we can really think about breast cancer as it comes down to a tumor that arises in the duct of the you know memorary gland or arises from the lobules. What really helps us to kind of dig in a little bit more into this is let's say that we take for example we we take like a section here of this duct right we zoom in or we take a section of this lobule and we zoom in here and we look at the progression. So whenever we take like this cross-section and we zoom in on the lobule or on the duct how do these actually become tumors really how does that occur? And so let's say that we take for example this is a normal duct or a normal lobule. All right. So this is a normal duct lobule. Right? So when you look at the cells there they look normal. Have they invaded this red structure called the basement membrane? No. It looks pristine. However, over time the patient develops mutations. And these mutations cause the cells to become a little bit more atypical and they don't look as normal cells. And so then they progress. All right? And so from here we start to see what's called atypical hyperplasia. And this atypical hyperplasia, it usually can result in two different locations, right? So look at these cells. Look how jacked up and funky these stinking things look. Look at that. This dude has got some kind of like little goober hanging off the top. That's an atypical appearing cell. It doesn't look normal. And again, this can occur in the duct or it can occur in the lobules. Now, out of these, which one's most common? Most of the time when malignancies arise, they arise in the ducts. That's usually the most common location. Lobules, it can occur. It's just not as common. Let's say now atypical hyperlasia is kind of like a premolignant condition is the way you want to think about it. patients who have a atypical hyperlasia on their biopsies when you look at them they have a very high risk of that converting into cancer. How? Let's say that these patients experience more mutations cuz really everything that happens here is it's a mutation. Mutations. You get the point. They experience more mutations. Every single time there's abnormalities here that are causing mutations to arise that are causing proliferation. All of these things are occurring right now. When that happens, these cells continue to become abnormal and become malignant. Now, we technically have a cancer. This is technically as defined as a cancer at this point where you have cells that have accumulated and taken up the entire concentric portion of the duct or the lobule. They're confining that entire lumen. This is now referred to as a carcinoma incitu. And what this cancer tells us is that this cells, these malignant appearing cells have not broken past that red structure, which is the inbasement membrane. So they're proliferating. They're not dying. They're surviving, but they haven't developed the point of where they have a lot of blood supply coming to them, angioenesis. They haven't released the matrix metallic proteinases yet that are breaking through the basement membrane. They're not there yet. But once they acrew more mutations and they become abnormal then they gain that capacity to do that. And then from here this started off as a carcinoma and site too. And again where could it be guys think about it? It could be in a duct which is going to be the most common or it could be in a lobule. Now from here once it actually does get to the point where these things start these cells start releasing matrix metalloproteinases they break down the basement membrane and they get a lot of blood supply coming to them and they can spread. At this point this thing is invasive. This thing has the ability to spread and this is now referred to as an invasive carcinoma. It's no longer incitu. It's an invasive carcinoma. And again, out of the two locations, where would this occur? It could be in the duct or it could be in the lobules. The thing that I want you to think about here is look at the normal trend. Most of the time when we think about a patient developing breast cancer, they develop a mass in their breast. Most of the time it's ductal. So usually starts off as you have a normal cells within that duct. you acrew mutations or abnormalities that cause proliferation and eventually it turns into atypical ductal hyperlasia. Then they acrew more mutations and it becomes carcinoma and site but it's ductal carcinoma and situ that's technically we'll talk about these you technically can write these we'll write them later ductal carcinoma and site and lobular carcinoma and site too. Then from ductal carcinoma and sight too if it occurs more mutations becomes abnormal and eventually gains the capacity to break past the basement membrane. It's now invasive ductal carcinoma. That's the most common progression that we think about with these cancers. Now the scary thing about cancers is that from here these cells they can start to become a little bit more liquid and they don't become solitary in the sense that they're staying in one location. they can start to spread. And once they do that and they break off and these things get into the circulation or they get into the lymph nodes, now we're having cells break off and go into different locations in the body. At this point, we refer to this as metastatic breast cancer. So, this is referred to as metastatic breast cancer. And we'll talk about the most common locations that these things go. Usually they start at the lymph nodes, but they can go to the lungs, they can go to the liver, they can go to the bones, they can go to the brain. And this can cause a lot of havoc on the body. So you get the point here. When we talk about breast cancer, which is the most common cancer in women, you see that a cancer can that arises in a duct or in a lobule really starts off normal, becomes atypical. This is a marker for a significant high risk of developing breast cancer. Then they become carcinoma and cyitus and then they become invasive. Then they break away from that local region, go to nearby lymph nodes or they can get into the bloodstream and spread to other organs. Then we have metastatic breast cancer. What I want to do now is I want to take a little bit of time to talk about what is the true difference in ductal carcinoma and site 2, lobular carcinoma and site 2, invasive ductal, invasive lobular carcinoma and then also talk about a couple other variants like padets and inflammatory breast cancer because there's some slight differences in those pathophysiologically. Let's do that now. So let's think about this at this point. We've developed an understanding of the progression kind of like microscopically hystopathologically of breast cancer that it's normal atypical carcinoma site to invasive metastatic. So when we talk about these I want to break cancers down of the breast into non-invasive and invasive. Most of the time whenever we see these patients and they come in with symptoms they're usually at the stages of invasive. But let's talk about some of the non-invasive ones that you need to be able to recognize and consider that they do carry that risk of becoming an invasive cancer. So non-invasive cancers, one of them, we talked about it, it's a carcinoma and site. What's the most common one that I told you that the cancers usually start off in? It's in the ducts. So we're going to start off and talk about ductal carcinoma in sightu which again is DCIS. So with this one where does the cancer actually arise? Think about this. It arises in the ducts. So there's going to be some type of mutation that occurs where the cells start to proliferate and grow but they do not break past the basement membrane. Now when this happens because they do not invade past the basement membrane how will these patients usually present? Well the thing with ductal carcinoma and situ is that they don't usually present with a breast mass or symptoms most of the times these patients are pretty much asymptomatic. Most of the time they have they are asymptomatic. How do we usually find this? Then it's usually an incidental finding. And so what happens is a patient goes they get an ultrasound or they get a mammog. Usually it's a mammogram and on the mammogram they see calcifications like microalcifications. That's somewhat indicative that it could be a patient who has ductal carcinoma and you would biopsy that if you had some concerns and you would find that type of hystopathology that we talked about that it would be these cancer cells confined to the duct not you know invading the basement membrane. So often times it's micro calcifications on mimography that is usually how this presents. It's almost always asymptomatic and it's incidentally found as microalcifications on mimography. Now one of the big things with this cancer is that again it can have that risk of developing and converting into invasive ductal carcinoma. So it carries a very high risk of uni or ipspsyateral breast cancer. That's really really important. So I want to add one more thing into this one is that there is a increased of ipsyal breast cancer. Now you might be wondering why I'm telling you that. I promise I'll tell you a little bit later. It's going to come into play with lobular carcinoma in site too. But again big thing to remember for ductal carcinoma incitu is again it's a cancer that arises in the duct and it does not invade the basement membrane. It usually doesn't produce palpable or any kind of mass lesion that's going to be symptomatic. They're asymptomatic and often times it's an incidental finding. So, let's add that last thing in there is often times it's a incidental finding. Whenever you get a mimography during your screening process that we'll talk about later, that's when we find it and it may have some concerning features to it. We may biopsy and find that. The next one that I want to talk about is called Padget's disease of the breast, but I'm just going to put it down here as Padget's disease. So Padet's disease is kind of like, it's actually kind of interesting. It starts off as a ductal carcinoma in sight to. So imagine this. Imagine it's kind of like you have a cancer right here in the duct. It's confined to it. But then what happens is the cancer cells start migrating. They don't they don't invade past the basement membrane, go into the surrounding fat tissue or anything like that. Look at this. They move along the lactiferous ducts and sinuses and they move out here onto the breast. So now you see how these cells are kind of migrating. So look, it actually starts to in a way, you can think about this, it's migrating towards the nipple and then outwards from the nipple onto the skin. That's weird, right? So that's one of the big differences with this one is that this starts off as a ductal carcinoma incitu. So we can say it's a ductal carcinoma in SYU and then spreads to the nipple and the lactiferous sinuses which are kind of right around that area. So that's really what happens. It doesn't invade the basement membrane, which makes it non-invasive, but it does move along these and then move onto the skin. And so really what happens with these patients is they have a characteristic picture. They often time have what's called nipple eczema. I'm I'm not even kidding. It literally can look like a red, inflamed, itchy nipple. For these patients, it looks actually a little bit like this. So whenever you see that type of picture, a very itchy, a little bit red, inflamed nipple, you should be thinking about pages disease. Here's another concerning thing. Not only can it cause nipple eczema, but these cells, they may start to ulcerate the nipple. Isn't that sad? It is, man. And so if it does do that, sometimes these patients can also get bloody nipple discharge. That's another thing that you want to watch out for. So, another thing here is watch out for bloody nipple discharge. Bloody nipple discharge. Okay, so we got it. Padet disease is kind of like a ductal carcinoma in sight. Sometimes it can even actually be truly I'm not even kidding. Sometimes you can actually get invasive ductal carcinomomas and they can also spread. But often times it's ductal carcinoma and sight tube that moves through these ducts to the sinus to the nipple to the areola and causes an axe lesion to appear. Itchy red inflamed nipple with sometimes associated nipple discharge. Now one of the things actually is important to remember here is you'd think oh I got to do a core needle biopsy. do. But sometimes what's actually kind of high yield to think about here and I want to add in for this is that sometimes with pages disease we can just if we see son of a gun if we see that a patient has this nipple eczema we can take a skin biopsy and so if we do a skin biopsy of this lesion right around where that eczema appears and it produces page cells that's almost diagnostic when it comes to the USML exams. So definitely think about that that they may present a patient who has nipple eczema maybe some occasional bloody nipple discharge they do a skin biopsy and it shows page cells that's a duct carcinoma site that's spread to that nipple areola region all right cool so when I say non-invasive I got these two the last one some people don't really consider this to be a cancer um they consider it more of like a very high risk kind of marker it's like a marker of badness so it's called lobular carcinoma and site and you're like what do you what do you mean Zach can't this kind of like it's the same thing like Zach you said that these can go normal atypical carcinoma and site to into an invasive that's the funny thing for some reason when you think about this this is a cancer it's confined to the lobules yeah doesn't spread past the basement membrane usually same thing completely asymptomatic so they don't really present with any kind of symptoms But it's usually often times it's an incidental finding. It's the same thing. You actually go you get a mammogram and it shows like this weird appearing lesion. However, there's not microalcifications. So it appears sometimes like a fibroatenoma. So it's not a classic mimog mimography finding but it is something that is an incidental finding. So usually it's a finding on mimography or sometimes there's a thought that this is a fibroatenoma and they get a biopsy and it comes back lobbular carcinoma in sight too. The whole point I'm trying to make of this is is that lobular carcinoma it's pretty much never going to be one of those that goes from lobular carcinoma in sightu to invasive lobular carcinoma which is odd right? One thing that this disease tells you and they can try to test you this on the exam is if you see lobbular carcinoma in sight too. This is what you should be kind of telling your patients. These patients have a high risk pretty scary risk a pretty high risk of bilateral cancer. Whereas ductal carcinoma and situ carry a risk of ipsilateral. It's usually that same side. this if a patient has lobbular carcinoma in sight 2 on their left breast they have a high risk of developing invasive carcinomomas in both breasts why is that important because sometimes on the step two what they could do is they could say hey you have a patient who has lobbular carcinoma in sight too they're at high risk for bilateral breast cancer what would be a preventative strategy get rid of both breasts that's something that could come up on the exam and so that's what they'll try to say is that to consider this you may need to remedy this that's the big kind of like telltale thing for this one is you may have to do a bilateral mastctomy and by doing that and this is prophylactic you're trying to prevent them from developing that bilateral breast cancer that's the big thing I want you guys to take away from this all right non-invasive breast cancers done we have a pretty good idea out of these non-invasive which one is the most common ductal carcinoma and site 2 that's the one that you're going to see it's usually microfalifications page Agit is a weird variant of that that usually causes nipple eczema lobular carcinoma and situ it's not symptomatic. It's usually diffuse and it's more likely going to affect both breasts that because of that you have a high high risk of bilateral cancer. Consider it for these patients talking to a surgeon about removing both breasts. Now invasive breast cancer is the next big thing that we have to talk about with invasive breast cancer. There is really two types and we talked about them a little bit over here that you have what's called invasive ductal and I'll write both of these ductal carcinoma. Now when I talk about breast cancer dude like most of the times I probably 70 to 80% of cases is this. That's the most common. Another one is um invasive. So we'll talk bring this one down here. invasive lobular carcinoma, but this one is not very common. We'll talk about one more. And this one is really, really, really sad. It's super, super scary. Usually when patients present, they're already stage three, getting ready to go to the point of stage four. And so, this is a really, really important one that I want to talk about. So, let's differentiate these because we were able to differentiate these, right? Let's differentiate these. With invasive ductal carcinoma, you're going to start off with this cancer here. It's in the ducts, but guess what it's going to start to do? It's going to break past the basement membrane. Do you get the difference there? It's spreading beyond that. Is that going to produce a palpable mass? It definitely can. So, this one definitely can present as a palpable mass. And sometimes if you think about this, if you present with a palpable mass, what's the most common location? So when you think about the breast and you cut them into four portions, the upper outer quadrant is the most common. 55% of the time, it's usually going to present in the upper outer quadrant of the breast because there's a little axillary component here called the tail of Spence. That's usually right in those areas there is where you're going to have most of these cancer starting to arise. That's one way that a patient will present. Sometimes they may present on their screening mimography. So it can be a palpable mass or this could be an incidental finding on mimography. Most of the time when you think about a patient having breast cancer, that's the type that you're going to be thinking about. All right. This is the one that can start here and it can spread outwards. What you'll see later is that these patients usually because of that mass it latches on to suspensory ligaments and then the suspensory ligaments become tethered and fibrodic and they pull on the skin and the nipple and then the skin becomes retracted. The nipple can become retracted. And then the other thing is that sometimes these cancers can cause a little bit of nipple discharge. It's not as common, but the biggest thing is is looking for a palpable mass with associated dimpling of the skin in the nipple. That can be kind of a a tellt tell sign. Again, invasive ductal carcinomaomas, these are the most common. What about inflammatory breast cancer? Inflammatory breast cancer is interesting. So, usually at the terminal ductal lobular unit, kind of like right here is our cancers. From here, here's where it's different. They break off like little tumor micro emblei, let's call them. They're like little tumor emblei and they can get out and spread but they don't do it in chunks. They do it in like little micro emblei from here. These tumor microi, guess where they go? They go right over here to your your lymphatics in the dermis. When they get into these areas here, they start clogging up your dermal lymphat lymphatics. And so you get lymphatic obstruction. Now imagine you obstruct these lymphatics because naturally what's supposed to happen is is the lymph should drain some of this interstatial fluid and take it out, right? That's naturally what should happen. But guess what you're going to do if you have these obstructions there. You're not going to be able to do that. And so what happens here? This gets inhibited. This fluid builds up. Oh dude, if I obstruct my lymphatics, I'm going to cause a lot of edema. So then a lot of this fluid will start accumulating and accumulating and accumulating here and you'll get a lot of swelling of the breast. So that's what you're going to start seeing is you're going to see breast swelling. And dude, it's usually bilateral. It can present bilateral. It can present unilateral. But you're the the key characteristic features here is you're going to get a lot of breast swelling. And whenever you have a patient here who has that breast swelling, it's going to look like mastitis. And that's one of the biggest things that they'll try to talk to you about with inflammatory breast cancer is that when you look at these patients, they're going to have basically um let's say swollen, red, and painful breasts. And so when you look at this, if you actually see what this actually looks like, it actually can be really problematic with inflammatory breast cancer. can look like mastitis which is an infection of some of the mammary gland tissue. All right. What would happen is is you would take this you would say oh I think it's mastitis and if you gave these patients and usually with mastitis there's maybe some fevers there's maybe an elevated white count but what you would do is you would say okay let me give this patient antibiotics and if it if you gave them antibiotics and it gave a positive response with antibiotics and they got better it's probably mastitis but If you had this patient with swollen, red, painful breasts, you gave them antibiotics and it didn't get any better and if anything it continued to progress, poor response, this suggests inflammatory breast cancer more often. That's something that they can try to mess with you with on the exam is they'll say, "Hey, a patient came in, they had swollen, red, kind of like really painful breast. I gave them antibiotics. They didn't get any better. What's your concern?" I'm concerned for inflammatory breast cancer. Now, one of the big things that is important to remember is that with this cancer, because of the dermal lymphatics getting so obstructed, they get swollen. This the skin when you look at it, I'm not even it looks like an orange peel. You get all like these little dimples and it's called a pud orange, which is kind of an orange peel appearance to the breast. It looks a little bit like this. With inflammatory breast cancer, it is really, really important to remember that this is often characterized by lymphatic obstruction by tumor microi. This one is a big palpable mass. It's cohesive. It can spread, can become metastatic. But this is the one that's really scary. And when these patients are found, here's what's sad about this one is they present usually at stage three. They present at stage three. And I'll tell you what stage three means when we get to it. But with invasive ductal carcinoma, you may catch a patient at stage one. You may catch them at stage two. Usually when inflammatory breast cancer, when you have these tumor micro emblei and they're in the skin, they're in the mammary gland tissue. That's already at that point the tumor has spread and metastasized. That's how they get these symptoms. So usually by that time it's in the the actual skin chest wall area. That's why these patients usually have stage three breast cancer. All right, invasive lobular carcinoma. This one's not very common, but again, you can kind of imagine here that it's a cancer that starts off in the lobules and then eventually it breaks out. And you might want to kind of go the route and say, "Oh, this is a lobular carcinoma in situ that became invasive." For some reason, that's not usually the case. It's very rare, very, very, very rare for that to happen. Often times it's just a cancer that usually arises there and it starts to really really again spread beyond that. But it's uncommon for lobular carcinoma and site when you find it to become invasive lobbular carcinoma. Now with invasive lobular carcinoma there's something really really weird about this one because sometimes when you look at these and you think okay lobular carcinoma ductal carcinoma how would they really test me? Well, with this one again, these patients are often times going to be asymptomatic and therefore because of that they would have usually this is a incidental finding on their imaging usually a a mammo so mimography right and so this is usually going to be asymptomatic. It's usually going to be you know more of a diffuse multicentric and lobular involvement. They'll appear very abnormal. Here's what's really important and this is how they will try to test you on the exam. When you think about invasive lobular carcinoma when you look at the cancer, all right, and this is really what's interesting is let's say that I take a piece of that cancer here and here's the cell and it's all starting off here where you're having all this buildup inside of the lobules, right? And then what it wants to do is is it wants to break past the basement membrane. And so it gains those matrix metallic protein aces. Right? When it does that, it helps it to move. And they move in a single file fashion. That's the characteristic thing that you guys want to take away from invasive lobular carcinoma is that when it spreads and it breaks past the basement membrane, it moves in a single file fashion. So when it moves in a single file fashion, so it migrates in a single file fashion, you have to ask yourself the question, okay, so it doesn't do that for ductal. Why? And the reason why is when you actually look at their microscopic structure uh and some of the proteins, there's a specific protein that actually helps these cells to kind of be linked together and it's called ecadherence. What happens is these patients lose they have a loss of ecadherence. That's the big difference. They have a loss of ecadherence. So they develop some type of mutation or change that causes them to break off those proteins between cells and move in a single file fashion past the basement membrane. So when you think about this and this is that lobular cancer right here. We're kind of just zooming in on it here to look at this in a cross-section. These things lo they move in a single file fashion. That's because of a loss of the ecadherence. Reason why I tell you that is that sometimes what you can do is you can actually check an ECAD test on these patients and if they have that loss of ecadherence it supports more of a lobular carcinoma that's invasive as compared to a ductal. All right. So again that's the big thing to think about for these things. Now that we've talked about our non-invasive and invasive breast cancers and we have a pretty good understanding that most often the time whenever a patient presents they start off with dto carcinoma and situ and they progress to this but sometimes the scary one that you could miss and it's already too late is inflammatory breast cancer. Another way that they could present from dto carcinoma is the variant of pageantss but these two are not very common. This one very high risk of bilateral breast cancer. This one it's mo most often times an incidental finding and really one test that we consider is the ECAD hearing testing. All right. Now from here what I want to ask ourselves is how in the heck what in the same heck is causing these cells to mutate and to grow and to proliferate. The reason why I tell you this is these patients can either present in a bunch of different ways. no mass incidental finding on screening, bleeding from the nips, they can have eximitus lesions, a lot of different things. You have to be able to look into the patients history and say what puts them at high risk because sometimes you may need to screen these patients earlier, use specific modalities or do specific types of therapies. That really is key to know. Let's talk about that. Now we've really established a baseline on how these kind of cancers particularly within the breast you know grows how it actually starts. So when we think about this what are really the triggers what's kind of the risk factors that are associated with kind of like jumpstarting these cells to become atypical to become you know malignant to really spread. And so one of the big ones that we talk about and and that's why we have to do really good histories. We have to assess a patient's risk and that comes with estrogen exposure over time. And so let's kind of have an understanding as to why this happens. Your ovaries are responsible for producing something called estrogen. So I'm going to write this out, right? But there's another way that you can write out estrogen. There's because estrogen comes in like estrone and estradiol. The most common form is estradiol. And so I'll also write this as E2 which is estradiol. Now that's one way. So the ovaries for females will produce estrogen. Now whenever the uh ovaries produce estrogen, what happens is is estrogen can go and work on the breast tissue. It works on a bunch of different tissues, right? It's a hormone. It can go and work on breast tissues. It can work on the muscles. It can work in the bones. It can work in the brain. All the kind of areas that you can think of. One of the big things with estrogen is that it has to work especially in the breast. It can work on two different ways. One, it's its primary way is intracellular, but you do have some small amounts of extracellular receptors, but estrogen is primarily going to cross the cell because it's a lipid soluble type of medication. It's a steroid. And so it'll cross over and I'll represent this as a E2 with like a circle. And what happens is E2 will bind onto a a receptor, an intracellular receptor. And then once this happens, this E2 and receptor uh will then move into the nucleus. All right? And it'll basically bind on to specific genes. When you bind on to a specific gene here, this will cause this gene, usually it's the cycl D gene. That's usually the primary one is the Cycl D gene. you'll activate this Cycl D gene and this will cause these patients to kind of increase the expression of Cycl D and Cycl dependent kinases and so really what it'll do is it'll increase the expression of what's called cycl dependent kinases CDK and this is usually four and six and what these things do is dude they like ramp up your proliferation right because think about it estrogen can kind of cause some of the breath breast tissue to grow. That's why usually breast tissue starts to rise when a patient hits their, you know, their their point of where their actual ovaries are producing estrogen, right? That's why breasts usually develop during those the secondary sex characteristic staging. So whenever this happens, the CD4 and six, basically this will cause the cell to proliferate. Dude, I mean these cells go ham and so you get cell proliferation. Now, here's the problem with cell proliferation. Every time a cell proliferates, what's the issue with that? How in the heck does that cause cancer? It doesn't. It's just the more that a cell proliferates, the more chances a person develops the risk of developing cancer. So, every time a cell proliferates, the DNA has to replicate. Every time the DNA replicates, there's a chances of DNA damage. And every time the DNA is damaged, there is the risk that that could actually become mutated if you don't repair it properly. And with that, that mutation can cause normal cells to become cancer cells. So every time a cell proliferates, you all you essentially do is you increase the risk of mutations. That's all it is. And every time you increase the risk of mutations, you turn a normal cell. So let's say here I have a normal cell. You take this normal cell and you turn it into an atypical or malignant cell. That's really what is happening is that every single time a cell mutates, it can become the high risk of that cell becoming malignant. And that's what you get scared of is now I have a malignant cell as compared to me originally having a normal cell. So that's where we get scared. And so if estrogen is being produced consistently and consistently over time, what's the issue? All right, it's constantly being produced due to prolonged exposure to having high estrogen levels. So the higher the estrogen levels are over time, the more it stimulates this intracellular and extracellular receptor, the more it activates the genes to increase the expression of CDK46, cause cell proliferation. Over time, there may be other things that can occur besides the proliferation. You may cause the cells to stop undergoing apoptosis. You may cause the cells to trigger angioenesis and cause more blood flow to the area. You may cause them to gain the capacity to release things to break down the matrix and spread. So, you get the point. What would be a reason that the ovaries would be producing a large amount of estrogen over time? So, here's what I want you to think. We usually see this. So, let's say here we think ovarian. So, the ovarian estrogen is up. So, you have an increase in the ovarian estrogen. What are a couple different reasons for this? And I want you to think about it not necessarily as an acute increase. It's a estrogen increase over a longer period of time than normal. So one reason is early monarchy. What in the heck does that mean? Well, that means that your first menstrual cycle was really, really young. So think about this, dude. If a menstrual cycle was at 11 years old and then you go into menopause at like 55 or something like that, that's the amount of time that you had estrogen levels. these consistent times during the follicular period, the ludial phase where you had estrogen levels that were up. That's more proliferation of the breast tissue. That's more chances that they acquire mutations. What if the menopause was really really late? You see the thing with that one? So, what if menopause was late? That's another thing. So, if you had early monarchy or if you got into menopause way later than you were supposed to, that's extend expanding your time frame of prolong estrogen exposure. So late menopause is another really really important one to consider as a risk factor. Another one is a patient who never has breaks in their menstrual cycle. So you know when there would be a break in the menstrual cycle is whenever you get pregnant. When a woman gets pregnant they have a period where they're not having this abrupt rises in the estrogen production as compared to during their normal menstrual cycles. And so that affects their their breast tissue, right? So that's another really important one is a patient not undergoing pregnancy. And so nulliparity is a really really important one. So when we think about this, these are potential things that really can cause ovarian estrogen exposure levels to be high over a period of time. Sometimes even late par. So if you have a child later in life, that also can potentially increase that risk as well. Another reason is it could be due to um atapose. So atapose estrogen is really high. So you know atapose tissue it's kind of really interesting when we think about this. So normally we have different hormones that our body makes. One of them is called androgens. And so this can happen um also kind of in even the adrenal cortex too. But androgens are actually things like testosterone or dihydrotestosterone um androstine dione all of these different types of androgens. So dihydro epiandrosterone um androstine dione testosterone all of these things. So what happens is we can take these and the fat tissue contains an enzyme called aromatase. So there's an enzyme here and it's called aromatase and that enzyme stimulates the conversion of androgens into estrogen. And technically this estrogen is uh you know estrone but I'm just going to again I'm going to kind of say here that this is going to be estrogen. It's technically not going to be as much the E2 but you're still going to have this increase in estrogen. And so I'm just going to write here E2. But the thing is is that the mechanism is all the same. So the same thing would happen here that this would do what? Well, the estrogen would then go and again it would can bind onto this receptor but more often than not it's going to go intracellularly and stimulate this pathway. Question is is why in the heck would atapose estrogen levels be high? What's going to cause an uptick in the aromatase expression or activity that's going to continue to convert androgens into estrogen? If you got a lot of atapose, you'll have a lot of these enzymes. That's a really big thing to that to actually remember. So, morbid obesity definitely contributes to a risk of developing breast cancer. And so, this is important because sometimes we think about in the step two, they'll ask you exam questions and they'll say, okay, they'll present the clinical vignette and they'll say, this patient is at risk for breast cancer. Which one of these risk factors with regarding to estrogen exposure is modifiable? Obesity. You can't change when you have a period and start. You can't change when you go into menopause. Technically, nulliparity you that is a modifiable risk factor. You technically you could actually get pregnant, but obesity is a true modifiable risk factor as well. The other things that are important to remember that can increase the risk of any kind of mutation is alcohol. So alcoholism definitely is a modifiable thing that actually increases the risk of developing breast cancer as well. But nonetheless, the last thing that I want to talk about here is what if it has nothing to do with the um atapose? What if it has nothing to do with the ovary? What if this is exogenous estrogen is high? So exogenous estrogen is high for longer periods of times. And usually this is in patients who are post-menopausal and who are on a drug that is trying to replicate estrogen and progesterone. What would that be? Hormone replacement therapy. I'm going to put HRT. So HRT. And usually they've been on HRT for a decent amount of time, 5 10 years. So they're prolonging their estrogen exposure except this it's a pill, right? So this scenario here, we'll represent it as though this is a drug and this drug contains estrogen and progesterone. And so all this is doing is it's just getting into the body and acting like this. You get the point here. All of these things are leading to an increase in cell proliferation. So whenever a patient has these particular risk factors, you have to consider that. Now this is really really important because guess what? Not only can these patients when you think about it let's say here we take this is this is their cancer that starts here in the upper outer quadrant when you really look at this and you examine this again it starts off normal becomes atypical becomes carcinoma and situ and becomes an invasive breast cancer the real reason this is happening is is the estrogen levels over time so they're having elevated E2 elevated E2 elevated E2 and at stimulating the increased proliferation and therefore mutations that cause you to go from normal to atypical to carcinomy to invasive. You get the point. That's why it's actually super critical when a patient has cancer, we biopsy their tissue and we look to see because guess what happens with high estrogen exposure? Guess what you do to these receptors? You upregulate them. You overexpress them. That's another thing. We'll talk about that down there. But often times we'll biopsy these areas. We'll send it off for amunohystopathology and see is there an overexpression of estrogen and progesterone receptors. All right, that's the increased estrogen exposure. Let's move to the next reason that a patient can also develop these risks of causing a cell to become cancerous and especially in the breast and that's a decrease in tumor suppressor activity. All right. So now we move on to the next component here which is again what are causing these cells to either proliferate become abnormal gain the capacity to break past the basement membrane and another really important one is the genetics. So tumor suppressor gene activity is really critical in preventing malignancies right and there's a lot of different genes but there's really really important ones that are critical to discussing in breast cancer. So let's say here I have a normal cell, a normal ductal cell, and all of a sudden this cell experiences some type of DNA damage. So here we're going to cause some damage to the DNA. So there's some DNA damage, gets hit with whatever it may be, you you cause some damage to the DNA. Now, I'm going to represent that with an X. That's a damaged DNA. Maybe there's a break in the DNA. And so we need DNA repair genes to come into play and say, "Okay, cool. I'm going to go ahead and fix this." So let's say that you have these DNA repair genes and they're going to go ahead and fix this. So if there's good DNA repair, so we're going to have DNA repair going on here, then we'll have these enzymes come in and basically help us to fix that actual damaged DNA. And so we can take and generate a normal cell. All right, this is a cell that's not going to undergo mutation now. All right, this here is our damaged cell. And if you repair that DNA, there's less chances of it mutating and becoming a cancerous cell. But if you don't have DNA repair occur, right? And there's a lot of genes that are critical to DNA repaired. Uh P-53, the TP53, um the which is like the tumor suppressor p-53 and BA genes. There's P10. There's a lot of them. Um, but this is a really, really important concept that if you don't have those genes working to undergo DNA repair, what's going to happen? That damage will not get fixed. So, here, this one, we're good. We fixed it. Look, it went from a damaged DNA to normal. Here, we're still going to have that damage. And maybe it progresses and it becomes like a double stranded DNA break instead of a single. And then from there you end up causing mutations to occur because you don't allow for this cell to really undergo the normal process that it should. So now that I have inadequate DNA repair, now I take this cell and I increase the risk of causing gene mutations. And eventually this right here is where we can see issues where we start off with the normal cell. Here's a normal duct. Here's a normal duct. And this is these cells. You cause increased risk of gene mutations. Now what's going to happen? Because I didn't fix that damaged DNA, I can increase the risk of the mutation. That mutation can cause my cells to transform and to become malignant. And then from here, this is where I see cancer starting to rise. Right now, I've taken this cell which was normal, it's become abnormal, and now I have cancer. I have a cancer cells all riddled within these ducks. And then from here, this thing is going to build up in the breast tissue and you're going to get this breast mass here. So that's the problem with this. And so we have to ask ourselves the question, what's really playing a role in this? And so there's the tumor suppressor genes are really what are aiding in our DNA repair process. There's two really, really important ones that get tested. One is the BA one and the BA 2 genes. If you have mutations in these genes, this can be a problem. These are natural tumor suppressor genes which aid in DNA repair. So if you have abnormalities or mutations in the BA 1 and BA 2, guess what's going to happen? You're going to have no adequate DNA repair. So that's one problem. So let's say here I have a BA one or a BA 2 mutation. That's going to lead to this problem here. So if you have mutations in these potential genes then guess what that can actually lead to the inhibition in DNA repair which causes this risk of malignancy. And the question that comes here is these are tumor suppressor genes. Yes. But when we talk about this obviously family history is key because this is an autotosomal dominant condition. So since this is something that can be autotosomal dominant you really have to look at this as being a factor that can come with a family history. So a patient who has a very strong family history of breast cancer, you really want to be thinking about Bracka 1 and Bracka 2. Here's the other thing about Bracka 1 and Bracka 2. The other thing is here is not only is it a familial thing, but also it increases the risk for breast and ovarian cancer. So it's not just breast cancer that becomes a little bit of a higher risk. It significantly increases the risk of breast and ovarian cancer. Now, sometimes when patients find out that they have the BA one or BA 2 mutation, they may say, "Oh my gosh, I'm very very high risk for developing breast cancer um and especially ovarian cancer." And sometimes these patients, they'll go the route of maximum prevention and they'll remove their breasts bilaterally and they'll remove also their ovaries. And so that's called a bilateral mastctomy and a bilateral salpingo ooerectomy. And that's something that's relatively common if you have this bracket mutation. The reason why is with bracka mutations. Not only does it carry this risk and not only is it seen with a family history, but here's the concerning feature with bracka mutations, they cause breast cancer. They cause breast cancer at a young age and younger patients. And the other thing with this one is it's very very a it can be very aggressive. So that's a really really important thing to remember is that we'll see this breast cancer being a little bit more common in younger patients and also being kind of aggressive. That's one thing I want to think about when I talk about uh to a patient I say hey what's the family history? Does your mom have breast cancer? The grandma have breast cancer. This is going to show an autosomal dominant pattern. So it's really really important to take into consideration and you can go as far as testing for these and doing gene testing. The next one that is also really important they they like to ask this on the exam just because of like sometimes there's big like names. So whenever you hear the name of something, it's actually helpful. And so so this next one is actually we'll see with a TP 53 mutation. And so this is something that we see in a disease. It's called Lee Frameni syndrome. Now Lee Frmani syndrome is really important. It's a genetic mutation in the TP53 gene. Now the TP53 gene is a tumor suppressor gene. So, if you have a mutation in the TP53, guess what? You don't allow for adequate DNA repair. If you don't allow for adequate DNA repair, this can cause those cells to no longer be able to survive as normal and become malignant because you don't repair those damaged DNA. With leaf for many syndrome, one of the biggest things to remember is that this presents not just as this one is usually breast ovarian. That's a big thing to remember with leaf mini. Remember the pneummonic blast 53. Blast 53 is that these patients can have a high risk of breast and brain cancer. They have a high risk of lymphoma leukemia. They have a high risk of adrenal carcinoma. They have a high risk of saroma. and they have a high risk of the TP53 mutation. So this is something that is a really helpful pneummonic. So if you see a patient who has multiple cancers, think about the blast 53. Do they fit that category, it may make me think about leaf for many syndrome. This one really bad. These patients have a very very very aggressive and young cancer. So they have they present with cancer at a very young age. These often times fit, we'll talk about this a little bit later. I don't want to get too far ahead, but these types of mutations cause a patient to often times present with triple negative breast cancer, which is a very aggressive type of cancer. Meaning that these cause mutations in the cells and it has nothing to do with estrogen exposure, progesterone exposure, her two signaling. It's all due to these mutations that cause these cells to again not undergo this repairing. And then they can cause these damaged DNA to cause mutations that lead to these cancer cells just going haywire. This can be very a very aggressive cancer. So these are usually your triple negative ones that we think about here. All right. So we've gotten down to risk factors is think about estrogen exposure over time whether it's ovarian exogenous or atapose. Think about mutations with these. Think about younger patients. Look for family history. look for other types of cancer risks in them or in their family. The last thing I want to talk about is receptor overexpression. All right, so the next component here that I want you guys to think about is receptor overexpression. Really, this kind of goes handinhand with like estrogen exposure to a degree, but there's also maybe some mutations that are playing a role in this. So, when we talk about again looking into risk factors, this is one of these things where we don't really like look into the history for this. This actually comes from a biopsy to really determine this. But there may be a lot of epigenetic, there may be mutations. This could be due to estrogen exposure. There could be a lot of different reasons why this is happening. But what usually happens in this scenario is that you have different types of receptors. You have hormone receptors. And so let's actually categorize this. So you have hormone receptors on the breast and then you have what's called your growth factor receptors. Now the hormone receptors, there's actually two types here that are really important. Um the most important one is the estrogen receptor and we're going to represent that as ER. And the other one is the progesterone receptor. The other one for the growth factor receptors is going to be her two. All right, her two or herb two but her two is the big thing here. Now what happens if these receptors you increase the number of them? I increase the expression or upregulation of these receptors on the cell membrane. So here we have the estrogen receptors. We'll just use these as estrogen receptors here. So you have some kind of extra extracellular parts, but here you're going to have the intracellular. That's primary the way that these receptors will present. So here E2, which is going to be the example we we used. It can bind here, but most of the time it's going to bind intracellularly. And then when it does that, you have this combination of them. And then these will then do what? Well, they'll use this kind of like, you know, receptor um lian complex and then they'll move downwards and they'll bind on to a specific gene in the DNA and increase the expression usually of the cycl D genes, right? So, we know that and so basically the overall effect that we're going to see from this is that you're going to increase like the cell proliferation. That's going to be a really really important one via the cycl dependent kinases, right? You can also um potentially see other effects here which is you can see some decrease in apoptosis as well. So you can even see some decrease in apoptosis from some of these genes because you're trying to cause the cells to proliferate. So therefore you don't want them to die. And this basically allows for increased survival of these tumor cells and cancer cells. So that's one way that we can think about this. If you increase the number of receptors basically you're increasing this response. So if a patient already has increased estrogen exposure and you increase number of receptors, you're facilitating this type of process. You're really amplifying it and that's going to increase the risk of these cancers becoming pretty pretty rough. If you have an increased estrogen exposure and a lot of receptors to tolerate that increase, you have a recipe for a lot of proliferation in cells that don't die. Her two is actually a little bit more scary though. So this is basically for growth factors. And so her two, if you have a mutation or you increase the expression of these HER twos, they're supposed to bind on to what's called epidermal growth factors. And so epidermal growth factor can bind on to these HER two receptors. When they bind onto the HER two receptors, they activate a bunch of different pathways. I don't I don't really want you to go crazy, but it can activate like the Jackstat pathway. It can activate the Raz like MAP kynise pathway. So there's a lot of different pathways, but either way, these are going to be kind of like tyrroscen kinus receptors where these epidermal growth factors bind on causes the tyrroscine residues to get phosphorolated and then activates these pathways and then these pathways will send signals down to the genes, right? And then whenever you do that, you trigger these cells to undergo proliferation to decrease apoptosis. And on top of that, you want a lot of blood flow. So this can even cause a lot of vascular endothelial growth factor to get released from the cell and cause more blood flow which can cause that tumor to really get a lot of oxygen nutrients and also to metastasize. And so this can also increase angioenesis. The whole point here is that if you have increased expression of those HER two receptors basically you're going to stimulate these receptors more intensely. You're going to increase your intracellular signaling pathway. you're going to really activate these genes to cause proliferation, drop in apoptosis, and increase in androgenesis. This is going to cause these cells to become super super super scary. That's the important thing to remember. So, let's say that I take a patient who has breast cancer. We diagnose that from their mimography, maybe a combination of ultrasound. We see that it's a suspicious lesion. We say, "Okay, we got to go and biopsy. We do a coral biopsy." When we do that corinal biopsy, we send off that tissue to look at it to see if it's lobbular or ductal carcinoma and if it's other kinds of features like pageets or inflammatory breast cancer. But we kind of get to the bottom of the type and then from there we also want to know which receptor type is most particularly overexpressed because that determines the way that we'll treat them and also determines their prognosis. So let's say here I took a biopsy and I have these different types of cancers and what I find is I find that I have my different receptors. I have my estrogen receptor, my progesterone receptor and my her two and let's say for this cancer it's increasing the expression of your hormone receptors. And so they're positive for the estrogen and progesterone but they're negative. They're not overexpressing the her too. This is hormone receptor positive cancer. This is a specific type of treatment that we'll give them. Things like tmoxifen, aromatase inhibitors, lupralide, CD46K inhibitors, things like that. What if I took another tissue and I biopsied it, looked at the amopenotyping, and I found that their estrogen receptor really wasn't overexpressed, their progesterone receptor wasn't predominantly overexpressed, but the one that really was is the her two. If that's the case, this is a herto positive cancer. This is a very specific type of treatment. It's more aggressive than this one. And this is going to need something like tstuzumab and maybe even chemotherapy. The last one, this is the scary one. This is the worst prognosis. What if I look at it, I look at the estrogen receptors, the progesterone receptors, the heru receptors, and I want to see which ones are overexpressed. But all of these are not overexpressed. This is called triple negative breast cancer. All right. So there's different types here. So again, this is our hormone. This is basically the estrogen receptor, progesterone receptor sensitive. This is our her too. This one I really want you to know the name of. This one we call triple negative breast cancer. This has the worst prognosis. Very very very aggressive. Usually we see this with the bracka 1, bracka 2, p-53 mutations. All right, very important to remember. The big thing to take away from this is this determines prognosis. But again, it also determines the likelihood of these of or it kind of explains to a degree why these cancers are actually arising. What's actually happening? Well, if you have more receptors, they can bind to estrogen. They can bind to growth factors and they can trigger the proliferation, shut down apoptosis, and get a lot of blood flow to them. And that's how you get these cancers. All right. All right. Now that we've really talked about all these different aspects of the pathophysiology and how breast cancer arises, we need to now say how will they present? Let's do that now. All right. So, let's now discuss the classic findings of breast cancer. When we think about breast cancer, funny enough, when you say classic findings, I'd say more often than not, breast cancer is usually asymptomatic. It's found on imaging. So that's why we do screening is unfortunately during a screening process we see oh there is an abnormal or suspicious lesion um that we found on mimography or we found on ultrasound. Um sometimes though unfortunately the breast mass if it becomes large enough um and it's in the right spot it can cause symptoms to occur. So what are some of those symptoms that you should be readily thinking of? So one is a breast mass. Now location-wise we already talked about it. it's usually going to be in the upper outer quadrant. So, that's going to be the biggest thing is look for the upper outer quadrant to be one of the locations. So, again, we kind of like we cut the breast into different sections here. And when you do that, you're going to find that the most common location is going to be in this vicinity. Now, another thing that's also really important to remember about this breast mass is that usually it's going to be firm. It's going to be palpable. it's going to be usually um most of the time painless. And so that's something that you want to be thinking about is when we think about the breast mass, it's usually going to be firm, it'll be palpable, and it'll be painless. The only reason I say most of the time is that, you know, you think about inflammatory breast cancer, usually it's not like a mass. It's the entire breast is enlarged. It's swollen. It's really painful in those patients. The next thing to also consider is that whenever these masses, they start to encroach, right? So they start from a duct, they start from a lobule, they start to expand and invade. When they do, they can start to invade onto these like ligaments. Do you guys know what these ligaments are called from your anatomy? They're called the Cooper's ligaments. And if they can enlarge and they get tethered to those Cooper ligaments, what can happen is it can cause them to generate a little bit more tension because they kind of get shortened. And if they get shortened, they pull. And when they start to pull, what could this do? Well, this could start retracting on the skin or on the nipple. And so that's what you see here is you see that the Cooper's ligaments. So these are your Cooper's ligaments that are kind of getting tethered by these tumors and that's causing retraction or pulling of the Cooper's ligaments which retract the skin or retract the nipple. And so that's what you can start to see here is you could see retracted skin or a retracted nipple. And I think it's important to understand what these look like. So retracted skin looks like this. And then retracted nipple looks like this. So if we have a patient coming in, they have a palpable breast mass, they come in with a retracted nipple, retracted skin, these are important things to consider. Now one other thing that I want to talk about is nipple discharge. I'd say that this is something that you can see. It's not as usually common with truly invasive breast cancer. Sometimes what can happen is you can have an intraductal papilloma and this can kind of ulcerate and it can cause bleeding here or pageants disease can also present like this. So usually it's bloody nipple discharge. It's often times going to be more likely bloody. So bloody nipple discharge. So bloody discharge is a really really important one to think about. This is often times seen more likely in a patient who has padets or an intraductal papilloma. So we can write that down here. Really you're only going to see this one in two different types. You're going to see it in pads and they'll also have that associated what? Nipple eczema. That's really really important to remember. Please don't forget that. And the other one is an intra ductal papilloma. We'll talk about this a little bit more when we get into um OB/GYN and some of the other types of like benign appearing breast masses. Now, if a patient has nipple discharge, definitely be thinking about this one. Pages a little bit easier because you're going to see that nipple eczema associated around it. And again, if you did the skin biopsy around that area, what would you get? Pages. Putin orange is going to come up on your exam one way or the other. With this one, it's again, you have that tumor that's occurring here. It's at the terminal ductor lobular unit and then it starts to get these tumor microi and these tumor microoli start to spread and they get into the lymphatics and whenever they get to the lymphatics they cause lymphatic obstruction. When you get lymphatic obstruction we already kind of talked about this with that lymphatic obstruction comes a lot of backflow of lymphatic fluid. And when you get that backflow of lymphatic fluid that's going to cause all this swelling to occur. And this is going to cause a very very enlarged orthemitus painful occurrence of the breast tissue. And when you look at it, it can have this orange peel like appearance. It's kind of like little dimpling that may be evident there. This is what you would see in inflammatory breast cancer. And it looks like this. So we've seen now that if a patient has this type of appearance where they have the pit orange, they have the nipple discharge, they have the breast mass, they have the nipple skin retraction. That's important to remember. But again, what did I tell you? Oftentimes, more than not, the patient will come in asymptomatic. They'll get screening and we'll find the breast mass. With that being said, when a patient has breast cancer, there's a complications that one needs to think about. And the first thing is lymphenopathy. That's usually the first place. I mean, come on, imagine here you have a breast cancer that's occurring in the upper outer region of the breast. What is literally right next to it? The axillary lymph nodes, dude. So these tumors cells can actually spread to the axillary lymph nodes. That's going to be the most common. They can spread to the internal mammary lymph nodes. They can spread to the superclavicular and infraicular lymph nodes. But by far most often, axillary lymph nodes are going to be most often affected. The next one, again, I'd say this is way less likely, but you could see them spreading to the internal mammary uh lymph nodes. And then another area that they could potentially spread is the uh clavvicular ones. And so you can have two different types here. I'll write them all as though as they're kind of like one entity, but it's going to be the supra or infraicular. Now, out of these, which one is by far going to be the most common? It's going to be the axillary lymph nodes. Now, these can become enlarged, right? So, a patient may present with a breast mass, maybe some nipple skin retraction, but then what's the next thing that you want to look for? Look in the axilla to see if there's any large, palpable, firm, um, and usually painless lymph nodes. That's something that you definitely want to be assessing for. And if that happens, that's really, really important because it determines the staging. And it's also really important to know that if you have axillary lymph nodes that are getting hit and involved and they're getting enlarged, you want to know if they're mobile or if they're fixed. And so because the reason why is this kind of also adds to prognosis and staging. So you have to ask yourself the question, is it mobile? That means it's not really as bad, right? Or is it fixed? So that's also really really kind of helpful in thinking about that. So now that we have lymphodenopathy is a really really important thing. This is usually the first area where a cancer can start to metastasize. other areas of like distant and usually hematogenous metastasis is going to be the brains, bone, liver, and the lungs. So, let's say here you have a cancer. And again, what's the most common type? It's usually going to be ductal. That's going to be the most common type. And it's going to invade past the basement membrane and it's going to start seeding. When this cancer starts seating, so here we're just taking a kind of zoomed in look at this cancer. You see how it broke past the basement membrane and it's starting to seed these cells, these cancerous, malignant cells into the bloodstream. And from here, they're going to go all over the place, man. These things are just going to go haywire. One area that they're going to go is the brain. when they get to the brain. This is uh something unfortunately as working in a neuro ICU I've seen a lot is that these masses they get into the brain and they can definitely cause what we would say is brain mets. But one of the big issues with these is that sometimes they can bleed. So you can get the risk of this mass bleeding kind of around that vicinity. So some of the things that I've usually seen with these brain mets from breast cancer or renal cell carcinoma or lung cancer or melanoma or thyroid cancer is that they can bleed. And so one thing that you could see is a mass. And these masses do have the potential to do a couple different things. One is they can bleed and they can become an intraanial hemorrhage. Another thing is that usually these masses can be near the cortex and so they alter the cortical activity. So they increase the risk of seizures. and also they increase your intracranial pressure. So these are the things that you get worried about when you have this mass that's kind of like in these areas is you can get an right you can get seizures or you can get a bump in the intraraanial pressure and so seizures are obviously pretty simple to see how they would present they could present with focal neuro deficits and headache and increase ICP they can present with headache, nausea, vomiting. So these are definitely things to be thinking about. Also, they can present with focal neural deficits, too. And so, you can see how this can become problematic when you have what we refer to as brain mets. Now, these are pretty sad and often times we'll find this if a patient has breast cancer and they present with headache, nausea, vomiting, uh blurred vision, they present with seizures, they present with a bleed and therefore present with focal neuro deficits or let's just add this on. It's confining an area where normal tissue is supposed to be and you can get focal neuro deficits. if they present with these symptoms, you need to get imaging. And so what we would often times do is we would say, "Oh, this is definitely not normal. We need to proceed with a brain MRI with contrast, find that mass, and say, "Ah, dang it. It's metastasized to the brain." And that changes the management. Another thing is that these tumor cells, these dang pesky tumor cells, they can get into the bone. When you get bone mets, the problem with this is is they like to activate, you know, these cells here. What are these cells here? These are your bone eating cells. What are these called? Your osteoclass, right? So these are called your osteoclass. These cells will activate the osteoclass. They can secrete osteoclass activating factor. They can do a lot of different things. There may be other kind of cytoines but these osteoclass will start chewing away at the bone and when they chew away the bone they liberate calcium and they lead to lesions and so you can get these things called litic lesions and you can also get hypercalcemia and so that's another thing that you want to be watching out for is does the patient have any hypercalcemia do they have the presence of litic lesions so with litic lesions they can present a couple different ways one of the concerns is that with litic lesions, what can they do? Well, if that happens to a bone and you start eating away at the bone, you're going to cause pain, right? So, that's a couple ways that they can present. One is they can present with pain, bone pain. Another thing is that this bone now is eaten apart and you got chunks missing out of this dude. You know, it could fracture, dude. It could fracture. So, you could get pathological fractures. The other concern is that if these litic lesions are near the the the vertebrae. So a really scary area is when you get what's called spinal mets and these spinal ms give you like these litic lesions. These dudes man they cause pain obviously but one of the concerning signs is that if it's enough in that area that it can start to compress on the spinal cord. So that's where I usually would get worried is the spinal cord compression. So you could have a patient coming in and their presenting signs are going to be, you know, that they have weakness in their lower extremities, they have urinary incontinence or they have feal incontinence, they have loss of sensation down there. And so these are definitely concerning features from these these litic lesions. So that's something I would want to watch out for is a patient presenting with a lot of bone pain. Um they're presenting with history of pathological fractures. I get imaging, I see spinal mats or I see lesions all over the dang place or they come in and they present with like a cod aquinus syndrome kind of thing. That's scary. Another thing I would also consider is that whenever you break down bone and you get a lot of bone cell turnover, there's an enzyme that's released. This is called alkaline phosphatase. And so that's another one where if you have alkos that's really really elevated in combination with calcium, you can think about a a malignancy there as well. But if I see the presence of these bone mats, then usually what you got to do is you got to go as far as to say, okay, I need to consider for this patient, I got to go uh far and really evaluate them with what's called a bone scan. So then I I got to get a a bone scan. And sometimes we'll just get like a CT scan of their chest, abdomen, and pelvis. And you'll probably find these litic lesions by doing that workup. Now, if these puppies metastasize to the lungs, you know, then then you get these kind of lesions that occur usually near like the the bronchi and stuff like that and in some of the lung tissue near the periphery like near the plura. And so often times if it's near like the bronchi, you can kind of compress on the bronchus. And so, you know, these symptoms are usually super vague, but you can get things like cough and dysnia. So, that could be one thing. I'd say the the other thing is that if a patient keeps getting plural eusions so you get inflammation right or this deposition near the this malignancy near the plura you can definitely cause increased capillary permeability here and so this can definitely cause plural eusions pretty like recurrent ones. So plural eusions and a patient who has like underlying history of breast cancer, I definitely consider has it spread? And so usually for this, we'd have to go as far as to say, okay, we got to look for this. Let's get a a chest CT really to find this. And then finally, uh these these dang pesky tumor cells, man, these little puppies, they can deposit here and they can get all up in the liver, all up in that sungun. And when they do that, it usually doesn't do too much. It may make the liver a little bit bigger. Maybe you get a little bit of hpatomegaly. But often times they're not really symptomatic. If it if it is big enough and if it's affecting liver tissue, sometimes you may see a bump in their LFTs. But I'd say that that's not always going to be the case. It may be a little bit mild bump in the LFTs. But oftentimes, I'm telling you, you get an imaging for one of these things because usually what happens is for this, you get like a CT um of the chest, abdomen, pelvis, and you may find these, you know, these lesions here. So, this is where you may progress and say, "Okay, let me get a um a CT of the abdomen and pelvis." So, the whole point here is like looking for metastasis. And we don't order these tests unless they present with symptoms because it's unnecessary. Just like for axillary lymph node involvement, guess what? The only way that we truly want to know is if they have lymph node involvement is we biopsy that. And so usually what happens is we'll talk about this a little bit later. We can do something for these patients called sentininal lymph node biopsies. And so for example, if I have an axillary lymph node that I'm really really concerned is is really it's inflamed, it's bigger, it's larger, sometimes what we can do is and we'll talk about this. We do something called we'll do what's called a sentininal lymph node biopsy. So there's two different types. You can do what's called a sentininal lymph node biopsy or an axillary lymph node dissection to really see if these axillary lymph nodes have a lot of tumor cells in them. Right? So these are the things that we'll talk about as we get into our diagnostics, which is super crucial. So let's do that now and really say, how do I put all of this together? How do I really look for those patients who are high-risisk and screen before they have these symptoms or these classic findings? What if I have a person who comes in with classic findings or complications? How do I really get to the diagnosis of it? Once I've diagnosed it, how do I know the receptor types? How do I know what to do with these patients? and how do I stage them? That's what we got to talk about. All right, my friends, let's move into the diagnostic approach now. So, we got to put everything together. Everything that we talked about on the whiteboard, let's really have a good way of summarizing it. So, the first thing, you always got to be getting a history and physical. You got to ask the good questions. You want to know particular things because it determines their risk. So, you're going to be on the computer. You're going to be plugging these things in. You want to know, okay, do you have any family history of breast cancer? Oh, you do? Okay, cool. Um, do you have any personal history of breast cancer? Okay, let's put that down as another risk factor. Okay. Do you have any BA mutations? We see this a lot in the Ashkanazi Jewish population, right? That's another potential risk factor. Did you have an early menstrual cycle? Oh, you did? Okay. Did you have late menopause? All right. It's another one. And then the other thing is, have you ever had a baby? No. All right. So, no parody. That also adds risk. And so, there's all these different things that become a big big ball of risk that we plug into something called the Tyrus score and it spits out a number or percentage and tells us where the patient falls, if they're average or high risk. So that's one thing we have to think about. The physical exam is going to be key. Obviously, the patient should be examining themselves. If they notice any kind of abnormalities, they should come to a doctor and say, "Hey, this is what I'm noticing." When you physically evaluate them, do you see or palpate a breast mass? Do you see any nipple or skin retraction anywhere in the vicinity of that mass? Is there any discharge that's either intermittent or while you're there? Do you notice any diffuser, edema, hot, tender? Those could be potentially mastitis. So then what you do is you start them on antibiotic, they don't get better. Ooh, could this be inflammatory breast cancer? That's a classic clinical vignette. And do they have any nicle eczema that just doesn't seem to go away? That could be pageantss disease. Right? So these are all things that you're thinking about. So what you want to know is does their physical exam suggest any classic presentation clues? If it does and they have any of the things that we just talked about, you go straight to diagnostic imaging. You're trying to figure out is there a lesion that supports these symptoms? If they're less than 30, because of the more density of the breast tissue, the likelihood of seeing cysts or fibroidomomas, probably better to go with the targeted breast ultrasound. But if they're 30 or plus that, you can get enough primarily with a diagnostic mammogram. And you could consider adding adding in a targeted breast ultrasound as well. But again, less than 30 ultrasound greater than equal to 30, it's going to be a diagnostic mammo. That's the way I want you guys to think about this for the exam. Now, if a patient does not have symptoms, but they have all those big risk factors, and you plug it into the Tyrusic assessment and it spits out a percentage that's high, greater than equal to 20%. That's a high-risisk patient, man. We got to we got to do something where we got to do screening mammograms to see if we can find these masses. But we want to go a little bit better. And so, we're going to add in a breast MRI. And that's really only for your high-risisk patients. And then on top of that, we're going to screen them per guidelines, which is it's going to be earlier than most patients and it's going to be more frequently than most average risk patients. Now, if they fall within the average risk of less than 20%, we just do a screening mammogram. We don't need the MRI and we can do things a little bit differently. We don't need to screen them every single year for a long time. So, let's discuss what these screening guidelines truly mean. So, it's funny enough in 2024, I think it was like late maybe it was either September, October, um the USPSTF actually came out with new guidelines. They used to be 50 to 75 years of age. We'd screen them every two years and then stop at greater than 75. Um now it changed and so now they're going earlier. So, this is the most commonly tested one is USPSDF. They say 40 to 75, stop at greater than 75 and do it every two years. ACS is kind of stuck with their guidelines that you go 45 to 54 every year. So we'll be aggressive upfront and then once we get to greater than 55 we'll go to every two years. Then you stop when you think that less than 10 years of life is expected in that patient. Obviously this could be based upon just if they're an 85y old patient can they still get breast cancer? Yeah. But do they also have congestive heart failure? Do they have other potential things that are going on that potentially could shorten their lifespan that's not going to make truly that much of a difference? All right. then we probably shouldn't even do any of these assessments because we're going to find something and then do nothing about it and and then just kind of expose them to unnecessary risk. And so that's why we kind of stop at that age range. Now high risk, we got to be aggressive. We got to catch this thing early. So we do MRIs, breast MRIs at like 25 years of age and then once they get to 30, we do add on the mammogram. And so that's what I want you guys to remember. We're doing this every single year. So the big numbers is USPSDF 40 to 75 stop greater than 75 every two years high risk breast MRI at 25 annually. Once you get to 30 add in the mammogram annually all right now from here the next thing is once we've found these lesions let's say that we get the mammogram we get the MRI we get the ultrasound they show some concerning findings. Usually a BAD score is always reported by a radiologist on these. And so a bio ads of zero probably just means it was like not conclusive. Wasn't a good image. You should probably just repeat it. Usually when you get to like one to three, it's like it's likely benign, but it does carry a risk of malignancy. Probably just screen them a little like scan them again a little bit in like maybe 6 months, 3 months if it's really concerning. But if it's greater than equal to four, that's high risk of malignancy and you can't ignore that. You can't just like wait and say, "Hey, we'll come back. We'll screen in a little bit later." No, you got to biopsy this, right? Right. So if you see things like on the ultrasound where you appreciate here a hypocoic lesion next to the nipple and then down here we're actually kind of taking a better look at it. You can see this is a little bit more concerning. This is definitely an ultrasound that shows a kind of hypocoic leion that could be suspicious for a breast mass especially a malignant one. And then here we can appreciate in the MRI you can see kind of like this coin shaped lesion pretty bright opacity that you can appreciate that's pretty suspicious as well. So if they reported that this would come out as a greater than or equal to four then you got to go to the next step which is biopsying that mass. So you're going to do a coral biopsy. The benefit of this is it's going to tell you the type of breast cancer that we discussed. Is it invasive ductal carcinoma, lobular carcinoma, ductal carcinoma and situ, inflammatory breast cancer, pad cells? Do they have estrogen receptor, progesterone receptor overexpression? Do they have her to overexpression? Do they have no expression? All of these things come into play when you get that coral biopsy. So that's why it's so clutch. So you're going to go ahead do an ultrasound, find it over the mass. Once you find the mass, you're going to stick a needle down and take out a chunk of that tissue that you're going to send off to histopathology. pathologist is going to take his you know thing he's going to look under oh yeah okay I see everything it is going to be if it's a tumor confined to the ducts and hasn't broken past the basement membrane that's DCIS right ductal carcinoma site tube if it's in the ducts and then it's actually broken outside of the basement membrane then that's an invasive ductal carcinoma this is the most common 80% of the time it's this one if it's in the lobules and it's broken past that then that's when we get the lobular carcinoma site too right but here we can appreciate before we actually do that look you can see here here's going to be the duct. You can see a mass confined to that kind of extending outside of it. And here's the lobules. Right? So this is going to be the invasive ductal carcinoma. And the next one was again if you see it in the lobules invading the basement membrane that's invasive lobular carcinoma. So I'd expect it to be in one of these guys. And so here you can see it's kind of like enlarged there. Right. Next one is if I see tumor cells that are in the dermal lymphatics. It's kind of spread throughout the chest wall, the skin, the dermal lymphatics. This is pretty much like pathommonic for somewhat for the inflammatory breast cancer. So kind of you know showing this is kind of indicative of that. And the last one is if it's kind of confined to the nipple the skin the areolar area that we did a biopsy we found these things called padet cells that'd be concerning for pages disease of the nipple. All right so these are ways that we can determine in kind of the the overall type of breast cancer but that's not always like super helpful. What is helpful is the amunoistochemistry. So I want to look at the tissue cells in that tumor and say hey what kind of receptors are they overexpressing? And so if I see estrogen receptor progesterone receptors that are really really overexpressed but not any her too that's hormone receptor positive breast cancer. So ERPR positive breast cancer. If I see that they have no ERPR positive but they have lots of HER two expression that's her two positive breast cancer. The reason why this is so important to remember is because this is different therapies. We can do tmoxifen if they're premenopausal. We can do aromatase inhibitors if they're postmenopausal. if they're getting really towards the like end stages where they're getting really really bad uh like stage four we can add on things. So we can do things like adding on CD K46 inhibitors which I'll talk to you guys a little bit about. We can do LHR agonist like Lupralide. So there is alternative options here that we'll discuss. When it comes to her too we really only have one drug and that's Tusmab. You can do chemotherapy sometimes but Tusmab is going to be the one that they'll test you on the exam. So you see her two anywhere I think trstuzzmad. Now ERP negative and her two negative tells me that none of the receptors all three of these receptors are negative. That's called triple negative breast cancer. This is a very aggressive one. Her two breast cancer her two positive breast cancer and triple negative breast cancer have a very high risk of recurrence. They're aggressive. They're nasty ones. And so we just really want to be able to identify that. Now, if a patient has breast cancer and they're pretty young, less than 45, that brings about a concern of like them having a genetic, you know, susceptibility to this like a BA or a TP53 mutation like a leaf for many syndrome. If they have triple negative breast cancer that also carries the risk of a BA mutation of some type of like genetic problem and I think a really big one is a strong family history, right? So, strong family history where multiple first-degree relatives or relatives in that kind of like chain or generation have recurrent episodes or episodes of breast cancer. So that's something I would actually go ahead and get genetic studies for. I would test for BA 1 and BOA 2. I would test to see if they're coming back positive. The reason why is not only do these carry the risk of breast cancer, they carry the risk of ovarian cancer as well. A lot of patients, we'll talk about later, they may elect if they know that they have these to do a bilateral mistctomy to remove the breast and a bilateral subpingotomy to remove the ovaries just because they want to reduce their risk completely of developing breast and ovarian cancer. If they have the TP53 mutation, that could suggest leaf for mini syndrome. We see that these patients have risk of not just breast cancer but like lymphoma, leukemia, they have adrenal cortical carcinomomas. They have sarcomomas and so these are really really important to remember as well. A lot of times we can even do these things called an enkot type. It's a little bit beyond the scope of like what you'll need to know for the step two but the enkotype diagnosis can kind of help us to guide how we'll treat patients with adgivant chemotherapy. And so it really kind of helps us to say, "Okay, we should we should kind of modify our therapy plan because their enkotype diagnosis diagnosis tells us this." Now, either way, after we've done genetic testing, it's just telling us, is there a hereditary, is there a familiar, is there a genetic potential cause to this that I need to address? That's what it's going to tell me. But from here, I've diagnosed breast cancer. I've determined the type of breast cancer. I've determined the receptor type of breast cancer. I've taken the time to consider, could there be a genetic cause to this patient's breast cancer? What's the next thing to determine? What's the stage of the breast cancer? And so, the first thing I got to do is go back to my imaging and assess the tumor size and look at the T for the TNM staging. Is it less than 2 cm? That's T1. That doesn't necessarily determine the stage, but it helps us. Is it 2 to 5? That's T2. Is it potentially greater than 5 centimeters? That's T3. And then lastly is it invaded the chest wall, the skin. That's T4. And this is all really helpful because it's going to come into play at the end to tell us what type of stage this patient falls in. All right. So here we can have a less than 2 cm. Here's two to five. Here's greater than five. And here we got it a decent size mass, but it's a kind of all over the place in the chest wall, in the skin. That's something that we got to think about. Now from here, we've determined the size. Next thing we need to know is the lymph nodes. any of the lymph nodes enlarge or they have lympadenopathy because if you can palpate those great if you can't you don't know that those tumor cells haven't spread from the breast to the axillary or the clavvicular nodes yet and so what we'll do is we'll do something called a sentininal lymph node biopsy we often dur this dur we do this during a lumpctomy so we're in there we're cutting out the tumor and then what what we'll get ready to do is we'll say okay here's the tumor what I want to do is I want to take a radior die inject it into the tumor and see which lymph nodes it goes to and I want to take that lymph lymph node, right? So, I'm going to inject it in. I'm going to see where the radio tracer goes. Okay, it goes to these lymph nodes. Let me test these lymph nodes. And then what I want to know is do any of the lymph nodes have tumor cells in them? Because if they do, that's concerning. But I need to have a specific number. And if it's three or more of those lymph nodes that are just infiltrated with tumor cells, a shoot son, we got to cut these puppies out. So, we got to do an axillary lymph node dissection. So, again, no nodes that are palpated, sitting lymph node biopsy, usually done during the lumpctomy. Inject it, see where it goes, test it. Oh, we got tuma. Boom. We got to cut them out. All right. Especially if there's three or more. The next thing is if they do have palpable nodes, you probably want to test those to make sure that they're actually consistent with breast cancer. They don't have some kind of other cause. And so we'll actually do a core needle biopsy on those and see if they come back with tumor cells. What you want to know is how many kind of like nodes are being involved. And so the way that we kind of do this is we say, do they have one to three axillary nodes involved? This is very arbitrary, but if they do, it's called N1. Do they have potentially four plus axillary nodes involved? That's N2. And the last one is we say do they have any clavvicular nodes like superclavicular inclavicular nodes involved? Okay, that's N3. And the reason why is we've now developed the T, we've got the N. The last part is the M. And so from here, all I want to know is is there distant metastasis? Has this cancer got into the bloodstream and spread to the other areas like the brain, the lungs, the adrenal glands, the bone? That's what I want to know. And so we often look for symptoms. So do they have a headache? Do they have focal neural deficits on one potential side? Do they have new onset seizure? You got to get a brain MRI, man. You got to look to see, do they have a mass? And if you see something like this, you're like, ah, you got brain mets all over the place, man. This is something that would be very, very concerning for a metastatic disease. And that would probably be in this case, in this patient's scenario, from their from their primary breast tumor. The next thing is if they have presentation of bone pain and maybe some pathological fractures. You check their calcium level. It's through the roof because they're having lots of osteolyis. You check their alkos. That's high because there's lots of bone cell turnover. Maybe the tumor even got near the spinal cord and it's extra dural and it's mashing on the spinal cord and they got some some uh neurode deficits or they have some weakness, some paristhesas, they have fecal urinary incontinence. These are all things that we got to be concerned about. So we get bone scans oftent times and look to see do we see any big radioracer uptake. Oh yeah I got multiple areas here in the spine that it's getting taken up from and that's another common area that the breast cancers like to go to to the bone. All right apatomegaly increased LFTs. This is something that's probably not often you're going to see it's probably incidental that you're getting a CT scan for the patient of their chest maybe their abdomen their pelvis and you happen to find some hypatic lesions that could be present. But if they do complain of like right upper quadrant pain, their liver feels a little enlarged, they you're getting some baseline labs and you find that their LFTs are bumped, I would get the CT, abdomen, pelvis, and see if you find any apatic mets. This is a really big one to find as well. All right. And the last one is do they have any cough, dysnia, recurrent plural eusions that just you keep tapping and draining and it's not getting better. That's something I'd be really really concerned about especially even like hmopticis too uh about getting a CT test to see if they got any mets that spread um from their primary breast cancer to their lungs. All right, this is a really big one. You can see they got tons of these all over the place. All right, so these are all really things that make me think about metastatic breast cancer. So we determined the type of breast cancer. We even diagnosed breast cancer based off the coronal biopsy. We determined the type and we determined the receptor type off of that. We then looked at the size of it based upon the T. We then looked at if there's any node involvement and I can really do that by palpating if I have palpable ones biopsy those if I don't have them sentininal lymph node biopsy and then scans based upon symptoms to see if it's spread from here now I've determined the TNM stage so let's kind of like take and put this all together if I really say that a patient has ductal carcinoma and situ or there's stage zero is what we kind of say then the tumor is it's not really com something that you're looking at the size of it you're looking to see if it's confined to the ducts. If it is, that's Dr. Carsonu. But stage one, that tumor size is usually less than or equal to 2 cm. So that would be consistent with this one. The node involvement though, you shouldn't see really any node involvement with stage zero or stage one. So they're not going to have any node involvement. All right. If we go to stage two, well, now let's think about it. What's the next size? 2 to 5. So now we got a tumor that's about 2 to 5 cm. Do we have any node involvement? Well, it could. And usually at this one it's about one to three axillary nodes that are usually involved. If I have that that's N1, right? And that's going to be suggestive of stage two. When I get to stage three, this could be greater than 5 cm, right? Or it could be a tumor that's invaded the skin, the chest wall. It's more diffuse. That's very common of inflammatory breast cancer. Nodes. Well, now we got to go N0 N1. Guess what N2 is? N2 is if they're getting to like, you know, greater than or equal to four axillary lymph nodes or any clavvicular nodes. All right? So, we can have an N2 and an N3 here. That's going to be your stage three. Stage four is really easy. And the reason why is any of these, stage 0, 1, 2, three, they shouldn't have any distant metastasis. But guess what? Stage four has stage four, we don't care really what size it is. If they had node involvement, that doesn't matter as much. What matters is did it spread to a distant organ? And so that's why I want you to think about these breast cancers. Again, if it's less than or equal to two and they have no node involvement, that could be stage one. If it's two to five, one to three nodes, that's going to be stage two. If it's five cmters or greater or it's invading the skin in the chest wall and they have any kind of N2 and three, multiple four plus axillary nodes, clicular nodes, it's stage three. And lastly, if they have distant metastasis, it's instant stage 4. This is the one that you can probably get tested on because it's the one that's pretty obvious. All right. Now, really, really important note because this is another thing they like to do is because when you think about inflammatory breast cancer, it is a tumor that usually is diffuse. It's widespread. It involves the skin, the dermal, lymphatics, lots of different parts of the chest wall and the breast. So, whenever a patient has inflammatory breast cancer on diagnosis, it's stage three. Always make sure that you remember that inflammatory breast cancer is always stage three upon diagnosis. All right, so we've diagnosed breast cancer. At this point, we then need to say, how do we treat it? Well, there's so many different therapies, and oftentimes we can look at this a couple different ways, and then we'll put it together at the end. So, targeted therapies, you're looking at really trying to target estrogen is really the key thing. Tmoxifen is a really beneficial one. Um, especially in those who are premenopausal. And so the concept behind this is that when a patient has androgens, all right, androgens usually can get converted into estrogen. And and this is going to be helpful to remember because estrogen then what it does is it actually binds onto a receptor, right? And this is usually inside of the cell. So this is actually the plasma membrane. This is going to be the nucleus. There's going to be a receptor, probably intrauclear receptor or at least some type of intracellular receptor for estrogen. It's going to bind onto that estrogen receptor. What it's going to do then is going to help to activate a specific cycl enzyme cycl D1. When it activates this enzyme that then is going to be really really important because it couples with another one called CDK cycl dependent kynise 46 who then phosphorolates other different types of proteins. One of them is called RB retinol protein. when it phosphorolates this protein, that protein gets rid of E2F. E2F is a very powerful transcription factor that stimulates the cell cycle to undergo the proliferative phase to go from G1 to GS, I mean to G1 to S to G2 and to go through mitosis and to split and make a cell. So, it's going to trigger that cell proliferation response. Right? When you give a drug like tmoxifen or even one like relaxophene, what they do is is they block the estrogen receptor. So if estrogen is present, it's blocking it. That blocks the cycl D1 signaling that blocks this phosphorilation reaction. This blocks this transcription factor from triggering the cell cycle. And now you're not going to have that cell proliferation. aromatase inhibitors which are commonly utilized in post-menopausal women. Right? So these here are going to be beneficial because what they're going to do is they're going to shut down this pathway. So aromatase inhibitors are going to be things like let anastrizol and they're going to inhibit the conversion of androgens into estrogen. That means less estrogen to bind onto the estrogen receptor. That means less of that cycl D1 pathway. That means less phosphorilation. That means less E2F release. That means less of this cell proliferation. So this is going to be something I really need you guys to remember. Really important for you guys to remember these. Now, what do we use them for? Again, we use them in patients who have ERP PR positive breast cancer. They have lots of estrogen receptors, progesterone receptors that they're very sensitive to, and you're going to try to block that pathway. Another thing to think about is we can use this in chemrevention. So patients who have a high risk of breast cancer, they get that greater than equal to 20% tier accusic score, we could actually put them on this because it may slow the progression of that disease. So that's something that we can think about and slow the risk of it actually causing high estrogen exposure leading to cell proliferation leading to the risk of mutation and malignant transformation. So that's why we can consider these especially again sticking with the premenopausal and post-menopausal uh separations. CDK46 inhibitors. You can imagine where that's going to go. That's going to go right here. Right? So, this is gonna be pal p I wouldn't even try to say this name. I can't even say the dang thing. But, uh, palo cichlib. All right. So, these ones you're not going to be tested too often on them. Often, if you get a name like this, you're probably going to see more likely the drug category, the CDK46 inhibitors. Um, but these are going to be drugs that I want you guys to remember particularly as an add-on. And what they're going to do is they're going to inhibit the CDK4 and six. And when they inhibit this enzyme, that's going to inhibit the phosphorilation process. If you don't phosphorolate retinoplasto, you don't release the E2F. You don't then trigger the cell proliferation. So you stop and stunt that cell proliferation process. All right. So these are drugs that I think are usually good as an add-on. All right. So if a patient has a metastatic ERPR positive breast cancer, this is one that you would add on. Usually you add it on to an aromatase inhibitor. All right. So if a patient has metastatic breast cancer that's ERPR positive, we'll put them on letol which you can see here to block this pathway and we'll put them on CDK4 and six inhibitors which are going to inhibit this pathway and that kind of provides a mutually benefited action. Now one other important note that I didn't mention is relaxophene. It also is mentioned in the textbooks that relax can be used as a chemre preventive agent but we use it as an alternative to aromatase inhibitors in post-menopausal women not premenopausal. Tmoxifen is the only one for chemoprevention and premenopausal aromatase inhibitors and relaxophene which has the same mechanism as tmoxifen which is kind of interesting is going to be for post-menopausal women chemrevention. All right so that covers this. So again we got all of these drugs and how they work in this process. These two ERP positive breast cancer chemrevention this one add-on to the aromatase inhibitor and the metastatic erpr positive breast cancer and relaxine can be an alternative to this guy and post-menopausal women who you want chemrevention. Now LHR agonist this is going to be things like lupide. It's also good in ERP positive breast cancer. All right. Again, usually patients who have that high risk and again they're premenopausal. So this is something that I would add to tmoxifen. So premenopausal tmoxifen. So this would be an add-on if they're really at that ERP or a positive breast cancer high risk and they're premenopausal. I'll add this one on to tmoxifen. The concept behind this one's actually kind of interesting. So here you have the hypothalamus and makes something called G&R. G&R then stimulates the pituitary gland to make something called luteinizing hormone which goes to the testes and males and triggers testosterone production which then goes to the prostate where it can be converted the UVA into what's called DHT and DHT is really helpful for the prostate growth right the other one is going to be follical stimulating hormone and luteinizing hormone and these really go to the ovaries where they'll stimulate the ovaries to make things like estrogen and progesterone but estrogen is the primary one and then estrogen will go to the breast and the breast is going to be really really critical here, right? So, whenever you give someone what's called an LHR agonist, you're acting like G&RH. Another name for this is a G&RH agonist. And so, what it's going to do is it's going to stimulate the pituitary gland to increase the production of luteinizing hormone to increase the production of FSH and LH. When you do that, and we're focusing here on the female side, it's going to then tell the ovary to increase the production of estradiol. and in males it would increase the production of testosterone. The whole point here is that in this scenario it's going to create a high level which creates a negative feedback mechanism. The reason why this is in both is because you can use this drug in prostate cancer and in breast cancer because it's going to shut down these hormonal pathways. It's like a chemical castration for males and it's basically shutting down the estrogen pathway in females in a sense. So now watch what happens when they're elevated. It's going to then do a negative feedback and shut down that pathway. negative feedback, shut down that pathway. So, now that you've done that, what's going to happen to the luteinizing hormone, the FSH levels? It should drop. And if they drop, what happens to the testosterone in males and the estradiol in females? It drops. If your estradiol levels drop, what's that going to do? It's going to cause less proliferation in the breast, less chance of that tumor getting any worse and bigger. That's the benefit of this. And it's the same thing for males who have prostate cancer. if they have really really advanced prostate cancer will put them on LHR agonist because what it's going to do is it's going to shut down the testosterone and that's going to reduce the recurrent and consistent growth of that tumor while we also consider other therapies for that patient usually in states like where they're not metastatic radical prostatectomies is usually the option right all right so that's what I want you guys to think about here is again LHR agonist is an add-on to tmoxifen in certain cases like erpr positive breast cancer. Tstusmab the big thing is just you you hear this you got to think her two positive breast cancer her two positive breast cancer we're giving trstuzumab the concept behind this is here you have a breast cancer cell and you have a herto receptor when this thing's active it's sending tons and tons of different pathways to cause cell replication so many your goal is to give a drug that blocks that receptor and by doing that what you're hopefully doing is you're basically telling these receptors to get internalized and get broken down so now you have less of them exposed. You're also going to stimulate apoptoic pathway so that the cell can die. And then on top of that, you're also going to shut down the cell replication process so that that breast cancer cell stops continuing to grow. So you're either going to lower the receptors, kill the cell, or stop it from continuously replicating. That's the job of trustmab. Now pebrlymab is another one that we can consider. Um it's usually a triple negative breast cancer. So we'll check the PDL1 and see if they have that high PDL1 kind of activity and that's really going to play a big role in how we're going to treat this patient. Right? So pimberlymab is really going to be something that we give chemotherapy and pimberlymab for triple negative breast cancer. Now pimberlymab is kind of cool. It's an immune checkpoint inhibitor. So here let's say you have a tumor cell and here's a T- cell. uh T- cells will interact with tumor cells via a T- cell receptor and on the tumor cell they should have an MHC complex that expresses an antigen. Now what happens is this TE-C cell it wants to be active and it wants to start killing this tumor cell if it appears that it's abnormal or foreign. But what happens is the tumor cells express something called PDL1 and if that PDL1 interacts with the PD1 that's present on the T- cell it shuts the T- cell down and it can't kill that tumor cell. What I want to do is I want to give something that either binds to one of these two and so that they can't interact with one another and it can't shut down the T- cell. Keeps the T- cell active and that T- cell is going to start [ __ ] beating the snot out of the tumor cell. And so that's what we do. We give a drug that binds to the PD1. It's an antiPD1 inhibitor. It's pimberlymab. When it binds, these two can interact T- cells like all right, Floyd Money Mayweather's in the house. Boom. And it's going to explode this cell. Right? So that's the concept I want you guys to remember. Now PARP inhibitors is not a common one that we actually talk about much for the exams. All I really want you to know is we really only give it in patients who have BA positive breast cancer. Concept behind this is that usually with these patients who have breast cancer or any kind of person who gets cancer, there's always a risk that they have breakage in the DNA and they have to repair it. And if they don't repair it or if there's a problem with that, you're going to have issues. So Bracka plays a really really big role in repair. So if you get a single strand of DNA break, PARP enzymes are supposed to come in and help to repair that. Well, if I give a drug that then let's say I get a break, PARP is supposed to come in, but I give a PARP inhibitor that comes in and blocks that, can I can I allow me to fix that single stranded break? No. So then guess what ends up happening? You end up with like double stranded DNA breaks. This is even more catastrophic because what happens here is that if a if a patient did have normal mismatch repair genes or they had DNA repair genes and they could fix a lot of this kind of issue then cool we'll be okay and the cell will survive if they have good bracka muta bracka genes they don't have mutations in them right so if they have the ability to cause what's called homologous recombination repair then they'll be okay the cell will survive but if they don't have the ability because they have mutations in their bracka 1 and bracka 2. Guess what? They can't do that homologous recombination repair and then that leads to death of the cell in this case. So that's what I want you guys to remember here is that we're giving something to hopefully kill that cell who doesn't have that ability to fix the DNA. All right? And that's when we would give this in a patient who has metastatic breast cancer with BA1 BA 2 mutations. Now chemotherapy is something that we give to these patients as well and it's usually neoagguant meaning that we give it before a particular therapy like surgery um or even before radiation therapy and that's usually stage three breast cancer because you want to try to shrink the tumor the best that you can before you go to do the surgery. Adgiant chemotherapy you're doing it after a particular set of therapies. So you're doing it after surgery, after radiation therapy, maybe even in combination with targeted therapies. You're doing this in patients who have breast cancer that got treated with a lumpctomy or a mistctomy, radiation therapy, and they're on a targeted therapy, but they have a high risk of recurrence, and you want to try to kill some of those like micro metastases, kill some of those remaining cells, tumor cells to prevent recurrence. This is usually any patient with triple negative breast cancer. Any patient with her two positive breast cancer, you're giving them adgiuant chemotherapy. All right. Now, the specific agents I don't think are super critical, but they are going to be kind of things like anthroycans, like doc rubicon um or taxes like um like pacataxel. All right. So, these are things that I want you guys to consider is neoagivant or adgivant chemotherapy. It'll all come together because we're going to put all of this together in a nice table. The next thing is surgical intervention. Obviously, this is the best case scenario for anything from like, you know, stage zero. So, ductal carcinoma and site 2 all the way up to like stage two. We can we can kind of like cure this with minimal kind of invasive strategies. So, what's called a lumpctomy. Uh, and so it's going to cut tissue, but it's not going to cut out the entire breast. It's breast conserving. And this is really good for ductal carcinoma and site 2 or stage one and two breast cancer because you're finding where the tumor is. You're going to make an incision. You're going to pull out that that tumor and you're going to suture it up. Done. That would be the best case scenario. But if you get to where it's a bigger tumor, it's more involved. It's getting into the, you know, a little bit more diffuse, then we might have to unfortunately go to a myctomy. All right? And so that's when we get into like usually stage three. stage three breast cancer will probably go into the route of a mistctomy unless you still can conserve it. Uh usually if you get like a diffuse tumor that's all over the place or a really really big one there's not much to conserve. Um especially in these kinds of scenarios where they have lots of node involvement too. You may just have to go the route of doing mistctomy. All right. And these could be like you're just cutting out the actual breast tissue itself and leaving the nodes. All right? or it could be very radical and you're cutting out the breast tissue and cutting out the nodes and even some of the muscle tissue. Um, and then there's even a nipple sparing mectomy where you can still kind of do like a total mistctomy but you're just sparing the nipple tissue itself. So these are different ways that we can try to cut out the tumor and also just reduce any kind of remaining tumor that resides after that. So that's our goal in stage three. Now bilateral mistctomy sounds pretty aggressive but we do consider this as a prophylactic option in patients who have brack one bracka 2 mutations um you can do a bilateral mistctomy because yeah you do carry that risk and so cutting them would would definitely reduce that risk but you also have the risk of ovarian cancer and so these patients also consider opting for a bilateral sophenolctomy where they remove the breast and then with the sophenolctomy they remove the ovaries and the fallopian tubes to reduce the entire risk of ovarian cancer as well. So that's kind of the really really aggressive route that some patients will go if they have bracka one bracka 2 mutations. Now we talked a little about sentininal lymph node biopsies that it's it's in the diagnostic section where if a patient doesn't have palpable nodes we're going and doing a lumpctomy during that process we're also doing a sentinel lymph node biopsy to see if some of the tumor cells spread to the nearby nodes that we don't see and if they do we go about that right but this is a test again where you're doing it during a lumpctomy or during the surgical procedure where you're going to inject that dye look to see if it's spread okay found the node let me go ahead and check this see if there's any tumors in there all there tumors in there okay we're going to have to do an axle lymph node dissection if there's a bunch of them three or more. All right, with that being said, a lymph node dissection really the reason why we would go to this one is you got tons and tons of nodes that come up positive on sentininal lymph node biopsy or your stage three because at that point you probably have four to 10 axillary nodes some that are involved at that point. So that's a really really big one and inflammatory breast cancer is most likely going to be very diffuse. It's going to involve the dermal lymphatics. So you're going to want to take those out as well. All right. And so again you're kind of just taking and you're literally cutting away axillary nodes. So you're showing here the kind of lymphatics where there's the axillary going into kind of the to the area of the armpit. You can appreciate some nerves and vessels that you want to be careful with especially the long thoracic nerve. You don't want to hit that one especially during this process. You can end up with winging of the scapula and things like that. So there is a lot of different risk with this one but the goal is to try to cut out as much of the axillary nose as possible. So this is the surgical interventions that we talked about. All right. So the next thing I want to talk about is radiation therapy. So when we use radiation therapy, it's primarily adgiuant. It's not anything that we usually ever do neoagivant meaning that we do it before some type of surgical procedure. It's usually always after the surgical procedure like a lumpctomy or a messctomy. So adgiant radiation therapy is going to be great for those who have you know Dr. Carson site two after they get a lumpctomy. Uh same thing for stage one, stage two after a lumpctomy. Stage three again after a mistctomy. So, it's usually going to be something after we've had some type of removal of the tumor cuz you're trying to prevent micro metastasis. You're trying to prevent any of the remaining tumor cells. If you didn't get the best margin or if you didn't completely remove some of the the small little tumor cells that were residual afterwards, you're trying to kind of kill those and prevent recurrence. And so, that's the goal of that. And again, you're just kind of taking radiation therapy, pretty decent dose, and you're hitting that right at the tumor or in the area, the vicinity of where the tumor was, and you already performed the procedure. Obviously, this runs the risk of like radiation necrosis and other associated problems, but that's something that it's kind of worth the risk um when you're doing this after a surgical procedure. So, there's a lot, right? It's definitely a lot. And so, I want to try to put it together for you in a way that makes sense where we put everything step by step. If a patient has dto carcinoma and situ, you always want to think surgery first. So, doing a lumpctomy is going to be the best way here. Radiation therapy is going to reduce the risk of micrometastases and then chemrevention should be offered like tmoxifen and premenopausal right or aromatase inhibitors and post-menopausal or you can also consider relaxophene if they're tyrusic score is high greater than equal to 20%. All right, stage one, stage two kind of similar. These ones, they can have tumors that are decent size, but hopefully they're not involving the skin, the chest wall. They're scattered. And so for here, lumpctomies is the desirable goal. Right after that, well, during the lumpctomy, we're also kind of basing it upon if they have nodes or not. So, what sometimes is likely being performed during this procedure, a sentininal lymph node biopsy, right? To see if it's kind of involved multiple different nodes. And if it does, okay, we go axular lymph node dissection. If it doesn't do that then we don't do actually lymph node dissection if there's not three or more. But after we've done the lumpctomy with the sentininal lymph nobi biopsy during that process what's afterwards it's the same thing as DCIS radiation therapy. We don't do chemobion here because at this point the patient has cancer. We technically don't consider DCIS like breast cancer. It's like it's in route. It's very high risk. they're kind of like at that point where they definitely if if we let it go, they can convert and grow to invasive um ductal carcinoma. Now, at this point, radiation therapy, we've hit them with cutting out the tumor. We check to see if it spread to the lymph nodes. If it did, we cut out, especially if there's a lot of them, we'll cut those out. And then we're going to kill or prevent any kind of micro metastases. At this point, you then can consider targeted therapies. You can consider them. So things like tmoxifen things like aromatase inhibitors could be considered in this scenario. So if I have a patient who has premenopausal I'll give them tmoxifen and if especially if it's erpr positive if they're postmenopausal I'll give them an aromatase inhibitor. If they have her two positive I'll give them a trusimab. Right? So those are definitely things that you can add on. What's really important is this next step which is variable which is chemotherapy. You can do chemotherapy but it's based upon their risk. So for example, let's say that a patient had triple negative breast cancer. We're doing lumpctomy. We'll do this. We'll do this. For triple negative, we don't really have any targeted therapy. We're going to go straight to chemotherapy. If a patient has her two positive breast cancer, we'll do lumpctomy, sentinel biopsy, radiation therapy. We'll start the bunchusmab and we'll add on an adgiant chemotherapeutic agent. So those are the kind of things where we would add that on. It's based upon the enkotype diagnosis. With this point, the patient has a tumor that either could be greater than five centimeters, could be kind of diffused scattered throughout the chest wall of the skin. Um, they could have four plus axillary nodes, some clicular nodes, it could be pretty extensive. And so, a lot of the times doing a surgery right away is kind of challenging. So, you want to try to shrink the tumor or tumors the best that you can. And so, doing neoaguvent chemotherapy first is usually the go-to. We're going to try our best to shrink the tumor down. After we've done that, then we're going to try and do a mastctomy. If there's any possibility of a lumpctomy, always try that, but a mastctomy may unfortunately be the way to go. Because there's so many axillary nodes that are likely involved, you're going to have to dissect those out. After you're done with this, you want to reduce the risk of micrometastasis. So, you're going to hit them with radiation therapy. Targeted therapy should always be considered. if they have ERPR positive and they're premenopausal, tmoxifen, right? And add something on at this stage like LHR agonist if they're ERPR positive. If they're post-menopausal, you can do something like an aromatase inhibitor plus an LHR agonist, right? But you're doing targeted therapies. If they're her two positive, it's trusimab. So again, you think about these scenarios here. All right? If they're ERP positive, you're going to go with this. Now, here's where the next step comes in. The adgiant chemotherapy. So, if I have a patient with triple negative breast cancer, I'm doing chemo first. Going to cut out the tumor. Going to cut out the nodes. Going to prevent the risk of micro metastasis. No targeted therapy specifically going to chemo. Her two positive, hitting them with this, cutting out the tumor, cutting out the nodes, trying to prevent micro metastasis. Tristimumab and chemotherapy. All right. So, those are things I want you guys to consider. Now, we get to the last stage. Stage four. this is spread. It's spread to potentially the bones, the brain, the liver, right? Um, and at that point, that's a that's a scary scenario. So, what we need to start considering is, do we even do surgery at this point? No, surgery is not really an option. So, we don't usually go to that. What we like to do is just target a therapy. That's really going to be the go-to in this potential scenario. So for example, if the patient was ERPR positive, right, you'll do an aromatase inhibitor plus a CDK46 inhibitor. That would be your go-to if they're metastatic. If they're triple negative breast cancer, pimberlymab, and if they have bracka positive mutation, it'd be a PARP inhibitor. If they're her two positive, it's going to be tristmap. You get the point. And lastly is we can consider adgivant chemotherapy for these patients if they have things like her two positive if they have things like um triple negative breast cancer. Those are times where we'll add on the adgivant chemotherapy. My friends that was a ton dude that was a lot. I really hope it made sense. I hope that at the end of this you feel just a little bit more comfortable or even hopefully a lot more comfortable with breast cancer. I hope that if you see it on the exam you're ready to crush it, dude. And um I just love you guys. Thank you guys so much for hanging around, listening to the video, and love you. Thank you. And as always, until next time. [Music] [Music]