Welcome back to an introduction to breast cancer. I'm Dr. Anees Chagpar. You remember in our previous sessions, we talked about staging, a really important concept that helps us to understand how a breast cancer will behave and ultimately, how patients will do. We talked about a staging system called the AJCC, the American Joint Commission on Cancers staging system. This is one of the most universally used staging systems, so that all of us can understand each other when we say somebody is stage one or stage two or stage three. Well guess what, that staging system has been revised. And so, I wanted to share with you the updates to the new staging system. Let's get started. The AJCC eighth edition incorporates many of the things that we talked about in the AJCC seventh edition. Anatomic Staging, the concept of TNM, remember, tumor size, lymph node status, and metastasis to distant parts of the body, brain, bone, lungs, liver, is still incorporated in the eighth edition. But there's something new and that is Prognostic Staging. So, we're taking all of TNM and adding in other components, things like grade. Remember, we talked about grade and that was how do the cancer cells look under the microscope? Are these well differentiated, moderately differentiated, or poorly differentiated cancers? Or what I called good looking, medium looking, or ugly looking cancer cells? Well, that's now incorporated into this prognostic staging system because we know that as cancer cells get more deranged and start looking less and less like normal tissue, they have higher grade and that can impact prognosis. The new staging system also incorporates hormone receptor and HER2 receptor status. Remember, we talked about that too. Patients who have tumors that are fed by estrogen and progesterone tend to do better than people whose cancers are not fed by these receptors. And that's because we have drugs that can block the estrogen and progesterone receptor and starve cancer cells. That piece of information is important when we think about how patients will do and so has also been incorporated into the new staging system, similarly for HER2. Remember HER2? That's that tyrosine kinase receptor and we have drugs like trastuzumab, pertuzumab, they can block HER2. And that influences prognosis too. And the other big thing that has happened in the AJCC eighth edition is that we're now including genomics. This whole concept of a genomic revolution, the idea that we can now biopsy cancers and see what genes are turned on, what genes are turned off, that gives us an idea not only about how this cancer will behave, but will it respond to drugs like chemotherapy? We talked a little bit about that in another segment. So all of this information is now being incorporated into the AJCC eighth edition. Now, the wonderful thing about this course is that I know that so many of you come from all different parts of the world and there may be some of you out there who are in less developed countries, who don't have access to some of these newer genomic tests. Not to worry. In your situation, you will still use the anatomic part of the staging system which is essentially exactly like AJCC seven. For the rest of you who are in the U.S. or in more developed countries, you will incorporate prognostic staging as part of your routine staging for patients. This is really exciting, but somewhat intimidating too because the entire staging system which used to be fairly simple has now become a lot more complicated. Let's take a look and see how that really works. A few key changes in a AJCC eight. One is that LCIS is no longer classified as Tis. What does that mean? Well, remember back to when we talked about LCIS? LCIS means lobular carcinoma in situ and we talked about in situ cancers as being kind of inside a pipe. Remember, we talked about the breast being made up of ducts and lobules? Well, that hasn't changed. And we talked about the fact that if you think about ducts like pipes and if you had a corrosive inside a pipe, if you put water down this end of the pipe, the water goes out that end of the pipe, nothing leaks. If you take the same pipe and you put some corrosive inside the pipe and you either let it sit there for a while so that, that corrosive starts corroding through the pipe or maybe you just pick up an old rusty corroded pipe to begin with, that's got these little holes in it. Now if you put water down this end of the pipe, the water could leak out the little holes, doesn't have to, but it could, it has that potential. We talked about the fact that cancer works exactly the same way. This first situation is what I call a pre-cancer, but we call this in medical terms in situ. In situ, inside the pipe. This situation is what we call invasive because the tumor invaded through the pipe or infiltrating because it infiltrated through the pipe. These are the ones that have the ability to spread. These are our true cancers, but the in situ cancers are what I called pre-cancers. They don't have the ability to spread, but they do have the potential to turn into invasive cancers. We talked, however, about the fact that this is really the case in the ductal system. So, ductal carcinoma in situ is still considered a pre-cancer. And in the staging system, we call that Tis, is for in situ. Remember that T1, T2, T3, only refers to these infiltrating or invasive cancers. Tis so long as the lymph nodes are also negative, is automatically a stage 0 cancer. Well, you would think that LCIS, lobular carcinoma in situ would follow the same paradigm. But wait, it doesn't. So remember back to when we talked about lobular carcinoma in situ? Lobular carcinoma in situ is not like ductal carcinoma in situ. It's not a pre-cancer. In it's classic form, it's simply a marker of increased risk. It increases your risk of developing cancer in either breast. So truthfully, it should never have been classified as a pre-cancer. It should never have been in the staging system, but up until AJCC seventh edition, it was. So good news, it no longer is classified as a cancer. So for all of those people who had lobular carcinoma in situ who were scratching their head wondering, is this a cancer or not, be assured it's not a cancer. Not to worry, at least not in its classic form. What's another change that happened in AJCC eight? Well, they really invented a new marker for us to identify which patients have multiple synchronous tumors. What does that mean? Let's suppose you have a specimen that you took out and in that specimen you have a couple different cancers and these are separated by some space. There was never a way for us to designate before that these are all there, that there were multiple different spots, now there is. And we use the marker m to designate that there are multiple tumors in the same specimen. The other thing that's been clarified is how do you measure. Do you measure across all of these? The answer is no. You only measure the size of the largest tumor. So when you're trying to figure out is something a T1 less than two centimeters or a T2 two to five centimeters, instead of adding up all of these distances, you'll only measure the biggest one. So, some good clarifications for us in the AJCC eighth edition. So, remember back to AJCC VII shown here, it was really a very simple classification. We took our T, our N, our M, we put it together and we had stage. But now, what about this prognostic staging system, where we're starting to incorporate other things? Let's take a look at how some people's stage may change with the addition of this new information. So first of all, there are many genomic tests that have been incorporated into the new staging system. Oncotype DX, Mammaprint, PAM50 Breast Cancer Index, and others have all been incorporated into the staging system. If you look at the lowest risk group in any of those tests, and for Oncotype DX that is being defined as a recurrent score of less than 11, if you take a patient who is hormone-receptor positive, that is to say their estrogen or progesterone receptor positive, her2 negative, and have negative nodes, regardless of tumor size. So you could have a patient, who had a five-centimeter tumor, node negative, ER positive, PR positive, her2 negative, node negative. If they had a low recurrent score or a low risk for any of these tests, automatically, in the new staging system, they are staged as though they had a T1a or T1b N0 tumor stage one. So, no longer is somebody who has got a five-centimeter tumor or 5.1-centimeter tumor classified as a T3, which would make them at least a stage two, if not, a stage three, they would now be back down to stage one. So, really, the new prognostic staging system incorporates the information about the genomics of the tumor, and helps us to use that information to really predict their prognosis. Which, in somebody who's got a low risk tumor by genomic sub-typing, would be really low risk. Let's look at some other examples. So, let's suppose you had somebody who had a T1 or T2 tumor. They had a positive lymph node. So that made them N1. They didn't have any signs of distant metastases, they could be any grade, ER positive, any progesterone receptor, negative for her2. In the AJCC seventh edition, they would be classified as stage two. Either stage IIa if they were a T1, or stage IIb if they were a T2. But if now, they're Oncotype DX is less than 11, you'll see they're back down to a stage Ib. Similarly, if you had somebody who had a T0 to a T2 tumor, so anywhere up to five centimeters, they had 4-9 positive lymph nodes, so that made them N2, no distant metastases, any grade, ER positive, any progesterone receptor either positive or negative, they were her2 negative, in the seventh edition, that would be stage IIIa. They may be really scared about that. But because their archetype was low, less than 11, they are now stage one, stage Ib, which is really great. So you can see how much of a difference this is going to make for patients, because we're now incorporating that information about the genomics, about the biology of how these cancers work, and how people will respond to therapy to really guide their staging. Even without the fancy genomic tests, the inclusion of biomarkers, things like grade, ER, PR and her2 status is making a difference for staging. So, let's look at some examples. If you were a T1, N0, M0, so AJCC just based on those three, means your stage Ia. If you had a low grade, all good. So these patients may think, "Oh, right. I'm home free." But let's say you were triple negative, remember estrogen receptor negative, progesterone receptor negative, or her2 negative. When we talked about medical oncology, we said that those patients won't respond to endocrine therapy, because we can't block estrogen receptor, they don't respond to that. We can't block her2. They're negative for her2. These patients require chemotherapy. Well, in the AJCC eighth edition, because of their triple negative status, they get upstaged to stage IIa. Again, taking into account more information about the tumor biology. If you similarly had a patient T1, N0, M0, stage Ia, but now you make them high grade. Similarly, they moved from being a stage Ia to being a stage IIa, because we know that people who have high grade tumors do worse than people who have low grade tumors. What about people who have large tumors? Say you have somebody who has a seven-centimeter tumor. There at T3. Let's say they have nine positive lymph nodes, N2, no distant metastases M0, in the AJCC seventh edition, that's bad news. That's stage IIIa, and that's what we would normally think, just thinking about the anatomic burden of disease, big cancer, lots of lymph nodes, and that's all true. But if you add in the fact that they had a grade one tumor and that they were triple positive, so you can treat them with endocrine therapy. You can treat them with a her2-directed therapy. And we know that these therapies are really effective. Now all of a sudden what was a stage IIIa becomes a stage Ib. So you see, the incorporation of all of these new pieces of information, understanding more of the biology of the disease, the genomics of the disease, and how patients respond to newer therapies is helping us to more accurately predict how they are going to respond to these therapies. And that is what's being put in to prognostic stage. I know that a lot of this is really confusing, and for many clinicians who are starting to use this staging system as of January 2018, the concept of incorporating all of this information is getting to be from big data to humongous data. But the good news is, we'll be more able to accurately predict how our patients will do. So, until next time, this is Dr. Anees Chagpar
