Welcome back to an introduction to breast cancer. I'm Dr. Anees Chagpar. So far, we've talked a lot about breast cancer. What it is, and we've started to talk about how to treat it. Today, we're going to take that one step further, and talk about medical oncology. This is a really important aspect, in terms of the management of breast cancer. We're going to talk about the drugs that we used to actually fight cancer. Let's get started. So you remember this table where we talked about the different stages of cancer and the different treatment modalities. So today, we're going to talk about chemotherapy and hormonal therapy, and you can see that for almost every stage, this is a big maybe. Except, of course, for people who have stage 0 disease. That is to say, in situ disease. That precancer that's still within the pipe. Those people don't need chemotherapy. But just about every other stage of breast cancer might. So let's think about that. How do we make the decision of who needs chemotherapy and who doesn't? Let's talk a little bit about the drugs that we're going to use. We'll talk about hormonal therapy, and then we'll talk about some novel therapies as well. Now I want to really hit home this one point, which is that there are local therapies, and we've talked about some of them. Surgery and radiation which are really focused on dealing with the cancer locally in the breast. Then there are systemic therapies. These are therapies that go all over the body that prevent cancer cells from breaking off and setting up shop somewhere else. In the bones, in the lungs, in the liver, distant metastasis. These two are separate entities. So it's not like, if you do maximal local therapy, you don't need systemic therapy. They serve different purposes and therefore they're often complementary. That's really important. Today, we're going to focus on the right hand side of this graph. On systemic therapies. Chemotherapies, biologic or targeted therapies, hormonal therapies, and a little bit on some novel therapies, like Immunotherapy. So why is Systemic Therapy so important? Well, take a look at how cancer works. If you have a cancer, it's going to start to grow. And then, as part of that process, it's going to undergo a process called angiogenesis. That is to say, it's going to recruit blood vessels to be where it is. And why do cancers do that? Because those cancers want to break off, invade into the blood stream, and start spreading all over the body. So that's where we see invasion, intravasation, survival in the circulation. Finally, what they'll do is when they get to an organ or a distant site where they are comfortable, these cancer cells will arrest in that organ, extravasate and take up a new home. Now, it's important that you understand that just because we might not see cancer cells in a particular distant organ, you may not have distant metastasis in your bones or your lungs or your liver. It doesnt' mean that there aren't cancer cells floating around in the circulation just waiting for that perfect time to set up shop somewhere else. And it's that reason that we need to think about, Systemic Therapy to kill off those cancer cells in that circulation. It's also possible that you have undetected metastasis. So cancer cells that have actually set up shop somewhere else in the bones, in the lungs, in the liver but we haven't been able to detect them yet. Here too, Systemic Therapy can be of help but we want to do something about this disease before you have distant metastatic disease that is clinically detectable. Remember that, that situation is what we call stage four disease, and in stage four disease it's really only Systemic Therapy that can be helpful. Because surgery or radiation in the breast itself will not take care of these distant metastatic sites. And we know that your prognosis, how well patients do is really determined on the basis of those distant metastasis if present. So, let's focus on who needs chemotherapy. What are the factors to consider? For the duration of this lecture, I'm going to be focusing primarily on people who have stage one to stage three disease, why? Because you know that stage zero won't require distant chemotherapy, and you know that people who have stage four disease often will. They'll need some form of systemic therapy anyways. But in the middle, how do you decide whether a patient needs chemotherapy or not? Many patients ask their physicians this question as well. There are many factors to consider. Some things you already know about. Remember when we talked about stage? We said that stage really helps us to understand the patient's prognosis and dictate treatment. So, how big is this cancer? Is it in the lymph nodes? That gives us a sense of the probability that this cancer has broken off and is in the circulation. So those patients may require systemic therapy. Other things, how about tumor grade? Remember, grade is how ugly do those cancer cells look under the microscope. And when we talk about how ugly they look, it really is, how much are they proliferating? How fast are they dividing? That also goes along with this term Ki67 which is a marker of proliferation. There were other markers that we look at too, things like PR and HER2. These are receptors that are often found on cancer cells, so estrogen receptor, progesterone receptor, and HER2 are receptors that we always look at. And we look at them for a variety of reasons but one of the main ones is that we have targeted therapies. So agents that can go and block the estrogen, starving cancer cells, or they can block HER2 and the downstream pathways. These are very effective therapies, and so oftentimes our systemic therapy is really geared around whether patients are Positive or not, whether they're PR positive or not, and whether they're HER2 positive or not. This goes into looking at genomic profiles. Now that we have the ability to look at a whole range of genes that are expressed or not expressed in a given tumor, we're now beginning to come up with novel therapies that really look at those genomic profiles. Now, so far many of these things have looked at the tumor itself. But it's important to remember that a tumor is just part of an individual. And it's important to consider your patient, the patient's age, their comorbidities, their other health status. Because that will make a difference in terms of the treatments that you may prescribe. Let's take a closer look at these Molecular Subtypes. Remember we talked about estrogen receptor, progesterone receptor, and HER2? Well, when you combine those you get, oftentimes, a surrogate for molecular subtypes, and there are four. So Luminal A tend to be ER/PR positive and Her-2 negative. These are patients who are going to benefit from hormonal therapy. Now, they may benefit from chemotherapy, as well. But, because they're Her-2 negative, Her-2 directed therapy won't be a benefit. Then, there's Luminal B, which is ER/PR positive and Her-2 positive. So these are patients who benefit from hormonal therapy and Her-2 directed therapy. Her-2 Rich, as the name implies, are people who express Her-2, but don't express And PR. So this means that they are not going to respond to hormonal therapies that block estrogen receptor, or progesterone receptor. But they'll do very well with Her-2 directed therapies. And then there is the basal type. Some of you may have heard about this type called triple negative. And it's called triple negative because it's estrogen receptor negative, progesterone receptor negative, and Her-2 negative. Well, what do you do now? These patients don't respond to hormonal therapy because they're ER/PR negative. They don't respond to Her-2 targeted therapy because they're Her-2 negative. So what do we do? Well, these are patients who will respond to chemotherapy. So don't forget that you still have added things in your toolbox, just because you don't have targeted therapies necessarily. And, of course, in all categories there are novel therapies, and we should always be thinking about clinical trials. Remember, patients who participate in clinical trials tend to do better than patients who don't, because you're always comparing standard of care to what we think is better. So always think about clinical trials. You can see here, however, that the vast majority of patients, 40%, are Luminal A, 20% are Luminal B. And it's really only about 15 to 20% who fall into this triple negative category. As you think about how to predict how well your patient is going to do with different therapies, you have a number of tools in your toolbox. One of them is statistical models. This is one called Adjuvant Online and as the name implies, it is online, where you can plug in your patient's criteria. How old are they? What's their comorbidities? What is the factors associated with their tumor? How big is this tumor? How many lymph nodes are involved? Was this estrogen receptor positive or not? And then you can compare different regimens. If you're going to give them hormonal therapy, say, with tamoxifen, or you're thinking about chemotherapy, say, with a third-generation regimen. We'll get to what that means in a minute. And then you can see how patients will do. So this is a hypothetical example. With no added therapy, you can see that statistically, by prediction modeling, this patient, if you took 100 patients, 63.5 would be alive in 10 years. Now if you give this patient hormonal therapy, you add an extra 9.5%. If you add chemotherapy, you'd add 17.1%. And if you added them both, well then it's 22%. What do all of those numbers mean? Well, that's a conversation that you're going to have with your patient. How much bang do they want for their buck? How much risk are they willing to take for the benefit? And having these personalized conversation is really where cancer medicine is going. The other place where cancer medicine is going is in terms of genomics. Rarely these days will you open a medical journal without seeing a red and green plot like you see here. These are where we take genes, some that are turned on, some that are turned off, that give us a sense of how this cancer is doing. There are some tests now that have actually pulled out significant genes and put them together into a test. So here, for example, is a test, this one happens to be for a 21-gene assay called Oncotype DX. But there are others, Mammaprint and others, that will give you some information as to how your patient will do. So this is, for example, just an output score of the recurrence score from Oncotype Dx. And you can see that, if you are in a low risk category, you have indolent disease. You are more likely to do very well, have a long survival rate, and do well just with endocrine therapy or hormonal therapy alone. You don't get that much bang for your buck with chemotherapy when your tumor is in this low risk score. Now, if we happen to take a biopsy of your tumor and we look at this genomic profile and you have high risk score, well then you're going to do much better with chemotherapy. And you can see the graphs here, on the right hand side of the slide, that illustrate that. So we've talked a little bit in passing about different kinds of therapy. But I want to dig a little bit deeper into what these actually mean. So hormonal therapy, also called endocrine therapy, is really targeting estrogen and progesterone receptor. You've heard about these already, when we talked about risk reduction. Remember, we talked about Selective Estrogen Receptor Modulators, things like tamoxifen, which block the estrogen receptor. And things like aromatase inhibitors that block aromatase, this enzyme that converts steroids into estrogen in peripheral fat. Well, the aromatase Inhibitors inhibit that enzyme, so essentially reducing the amount of estrogen. And when you've got cancers that are estrogen fed, that's a good thing. Well, just as these work in risk reduction, they also work in therapy. But they only work in therapy when you've got a cancer that responds to them, that is to say, an estrogen or progesterone positive cancer. We've also talked about Her-2 directed therapy. This is another form of targeted therapy. Her-2 is a little receptor that sits along the cell membrane. And when it's activated, it yields a whole downstream path of other factors that turn on that engine that makes cells divide. Remember back to our very first lecture, when we talked about what cancer was? And we talked about Calvin and Hobbes going down the hill at full throttle, all accelerator, no brake. Well, that's what Her-2 does. It pushes on that accelerator and takes away any brakes. What do Her-2 directed therapies do? Well, they put a brick under that accelerator, right? They block Her-2, and by so doing, they stop that acceleration. There are a couple of commonly used drugs that are used in this setting. One is called trastuzumab, the other is called pertuzumab. And you can see in these graphs here, and I've given you the references for a couple of New England Journal of Medicine articles that really show that by blocking Her-2, patients do better. But remember, they only do better if they express Her-2. If they don't, all you're doing is adding toxicity. And it's important to consider the toxicity. Because for example, trastuzumab does have significant cardiac toxicity. This isn't to say, that if you have a HER2 targeted agent and you have a HER2-positive cancer that you should not treat, you should. But you should just be aware to make sure that your patient has got their cardiac function assessed before you start that therapy. That's important to keep in mind when we start talking about chemotherapy. Now remember, chemotherapy is simple drivers that have been in our tool box since the beginning of time. Well, maybe not since the beginning of time, but you know what I mean, long before we had targeted therapies. Chemotherapy is really directed at blocking that acceleration pedal any way we can, and it's not necessarily with a targeted agent. A couple of the most commonly used chemotherapeutic agents are shown on this slide. The first class is anthracyclines. These are drugs like doxorubicin or epirubicin often times we'll call this Adriamycin, that's a trade name. And the way that Adriamycin works is it prevents DNA replication. DNA that building block that we have in all of our cells, is really what needs to be replicated when cells divide. In order to do that, that double helix needs to unwind. The enzyme that does that is topoisomerase II. So what do these agents do, they block that enzyme. If you can't unwind the DNA, you can't replicate it. And if you can't replicate it, you've now essentially put another brick under that accelerator pedal, preventing these cancers from dividing. And when they can't divide, they can't grow. That's good news, but remember the other side effect that you with this class of drugs in particularly is cardio toxicity. So when you're using an Anthracycline combined with a herto targeted agent. You have to be weary about cardiac toxicity, again a lot of people do really well with both agents combined. It's just something to keep in mind. Now another class of drugs that has had huge benefit in breast cancer are the taxanes. The taxanes are drugs like docetaxel or paclitaxel, and these also prevent cells from dividing, but they work in an entirely different way. So imagine a cell, maybe the DNA has already unwound and it's already replicated itself. Great, but now the cell itself needs to pull apart and divide. Well in order for that cell to pull apart and divide, it relies on these things called microtubules. Those microtubules are blocked by this class of drugs. Well if the cell can't divide, again that's another brick underneath that accelerator pedal, that's going to prevent it from getting stuck. The side effects here are peripheral neuropathy. So this is where patients can get numbness and tingling of their fingers and toes. Oftentimes, they can get a little black as well. It's important to warn your patients about the potential toxicities that they can experience. Now while these two classes of drugs are clearly the work horses, they aren't the only ones in our toolbox. There are a variety of other common chemotherapeutic agents that we use in breast cancer. Things like cyclophosphamide, methotrexate, 5-fluorouracil. We'll often use these in combination with some of the anthracyclines and taxanes that we already talked about. They are other agents like Gemcitabine, the platanins like Cisplatin or Carboplatin, Capecitabine, Vinorelbine, on and on and on. Some are used more first line, as our first line of defense against these cancers. Some are used if the first line doesn't quite work. Now, how do we figure out which agents we're going to use, which combinations we are going to use? This is where we often turn to guidelines, the NCCN guidelines in particular. The NCCN is the National Consortium of Cancer Centers that have formed a network that get their heads together to think about all of the evidence and what agents or what combinations of agents we should use. They've divided these into HER2-positive disease and HER2-negative disease. So in patients who are HER2-negative, the most common regimens that are used are dose dense AC. AC is adriamycin and cyclophosphamide, followed by paclitaxel weekly or every two weeks. Another regimen is TC, so this is a taxane with cyclophosphamide. Other regimens are listed here. So you can see that these are all permutations and combinations of different agents that are put together for HER2-negative disease. One thing you'll notice in this slide, there isn't any trastuzumab or pertuzumab listed. Let's see what happens when we look at HER2-positive disease. Now, in every single regiment, you've got a HER2 directed therapy, why? Because if you have a HER2-positive cancer, HER2 directed therapies are incredibly effective. But they're often used in combination with all of the chemotherapy regimens that we've previously talked about. So here are the guidelines for, HER2-positive cancers. Now what about, we haven't really talked about hormonal agents. Well sufficed to say, that after you've finished your chemotherapy with either a HER2 directed therapy or not, based on the cancer type. You'll take a hormonal agent, something like tomoxaphin or a neuromatase inhibitor afterwards, if your Or PR positive and if you're not then you won't. Okay, what's new on the horizon? Some of you may have heard about this excitement that's going on with immunotherapies. People have often wondered. How come my immune system can take care of viruses and bacteria when I get sick? How come my immune system can't take care of cancers? It's a great question. The reason is because cancers are pretty darn sneaky. And they figured out a way to have an invisibility cloak, very much like Harry Potter's invisibility cloak that allows them to sneak under the radar to avoid detection by the immune system. Well now, people have started to look at these immune checkpoint inhibitors. Things like CTLA-4 and PD-1, these are receptors that help the immune system to see what's foreign and what's not foreign. And now we have agents that really help kind of take away that invisibility cloak, and help the immune system fight cancers. So there are a lot of immunotherapies coming into play. A lot of these are still in the clinical trial phase but they are important to keep in mind. Because many people think that they may actually be the next bastion of care in terms of cancer management, which brings me to clinical trials. Now because I think this is so important, we're going to have a whole lecture dedicated especially to clinical trials. You've seen it as we've gone along that I continue to refer back to clinical trials, data that we've achieved by looking at these clinical trials. So clearly clinical trials help us to understand what works and what doesn't and what are best therapies? But clinical trials also help patients, why? Because essentially you're getting tomorrow's therapies today. And we know that we're always comparing standard of care to what you think is better. However, it never fails to amaze me. Patients often find that clinical trials are associated with some trepidation. They don't want to be consider human guinea pigs. They appreciate the benefits of clinical trials, but everybody is still a little bit scared about participating. Well I hope after hearing this lecture and lecture in clinical trials that's to come that all of you fell much more confident about participating in clinical trials knowing that this really is how we get the best therapist and patients you participating in this trials of said tend to do better. I love this cartoon. The guy says, I just heard there's a drug that might stop my cancer. And she says, great, are you going to volunteer to participate in the trial? And he says, of course not, why would I do that? And she says, I would either, sure hope they find some results soon. So again, you can help us to get those results and knowing that, you can also benefit from getting tomorrows therapies today. One of the huge proponents of clinical trials and a very good friend of mine, who also happens to be a giant in this whole field of breast medical oncology, is Dr. Lajos Pusztai. He's the Chief of Breast Medical Oncology here at Yale. He also is the Translational Working Group Leader for breast cancer and our disease team. And he is Co-Director of Cancer Genomics and Genetics here at Yale Cancer Center. I am so excited about having him with us. We're going to talk to him about, how do you figure out who gets what therapy, what he thinks is coming on the horizon? I'm so excited, I hope you will join me for that. Well until next time, this is Dr. Anees Chagpar.