Biomarker testing for early-stage breast cancer

Biomarker tests are key in making informed treatment decisions. They can help determine whether to pursue chemotherapy and what a patient's risk for recurrence is. This information can lead to some stressful conversations. While some patients may be unaware of these tests and their benefits, others arrive at appointments ready with research and questions.

Join us for a free, one-hour webinar designed for healthcare providers to gain a deeper understanding of biomarker testing and how to confidently discuss these options with your patients.

Our speaker, Seth Wander, MD, PhD, Mass General, will break down the complexities of biomarker testing, guide you through real-world patient conversations, and answer participants' questions live.

What you’ll learn

• The different types of biomarker tests available for early-stage breast cancer
• When and how each test is used in clinical practice
• Key differences between testing options
• How to effectively communicate with patients about biomarker testing results

Watch the recording below, or read the transcript here.

Transcript

Caroline Koffke (00:02:28):

Hello everyone. Welcome to biomarker testing for early-stage breast cancer. My name is Caroline Koffke, and I'm the Director of Educational Programs here at Living Beyond Breast Cancer, and I will be serving as the moderator for today's session. Up until a few months ago, I was also an oncology nurse navigator. So, I have an immense appreciation for our audience today, and I'm very thankful for you taking some time out of your busy schedules. Biomarker tests are key in making informed treatment decisions for our patients, and they can help us to determine whether or not chemotherapy, or other options might be the best for them in their trajectory and risk of recurrence. This information can oftentimes lead to some really stressful situations in the clinic. Some patients come in with a ton of awareness of these tests and their results, and others may arrive ready with questions and concerns.

(00:03:20):

Dr. Wander, our speaker, today, will unpack their intricacies throughout today's session. Please say hello to our chat host, Manager of Healthcare Provider Outreach, Stephanie Washburn. The chat box is located at the bottom of your zoom screen. Let us know where you are joining from. I know we have people from all across the country today, so feel free to drop in the chat where you're joining from either your institution or the city that you're in. This webinar is being recorded so you can watch it again and can share it, with others in your community. And I would like to take a second to thank our sponsors who are very generous in supporting this program, both Agendia and Veracyte. We could not do programming like this without their generous support. At the conclusion of today's program, we have a very brief program evaluation for you.

(00:04:09):

We'll share a slide with a QR code that will link to the evaluation, which should not take you any more than three to five minutes to complete. But this feedback is incredibly important to us as we continue to, to build out our programming. We will also have certificates of participation for those who attend the entire session today, and those will be emailed to you within six weeks of our program. Today I am incredibly honored to introduce today's speaker, Dr. Seth Wander. He is a medical oncologist at Massachusetts General Hospital with a clinical and translational research interest in breast cancer, which makes him a perfect expert on our topic today. He also focuses on cancer genomics. He has published more than forty peer reviewed manuscripts focused on precision medicine and related topics in oncology. If you would like to learn a little bit more about him, you can click the link in the bio. Dr. Wonder is going to give a slide presentation on the various aspects of testing in the early-stage setting, and we will pause periodically to take some of your questions. If you would like to ask a question, please use the Q&A feature so that we can see them. We will do our best to answer as many questions as possible, but we may not, of course, get to all of them. Welcome, Dr. Wander. Thank you so much for joining us today.

Dr. Wander (00:05:27):

Thanks. Thanks Caroline, and thanks to everybody for the invitation. It's a great pleasure to be with you all today. And my patients value the resources from the team at Living Beyond Breast Cancer. I have had a lot of patients specifically reach out to me because they saw that I was participating, and it is my honor to do so. Let me share my screen here. Hold on. Okay. Can you all see these slides, Caroline? This, Okay?

Caroline Koffke (00:05:55):

Looks great.

Dr. Wander (00:05:56):

We were just chatting about this. We could do an entire day on molecular profiling for early-stage breast cancer. So, what I wanted to do today was give a brief big picture overview of this topic and really try to focus it on what kind of material the patient is going to be interacting with. We will look at the reports for all three of these tests, and there are other assays out there. I wanted to pick the three most widely utilized tests to give you some examples. Here are my disclosures, none of which are relevant for this conversation.

(00:06:41):

We will talk about general principles and therapeutic approaches. We will go through three examples of these widely utilized tests. These are in no particular order. I just did them alphabetically the MammaPrint assay, the OncoPrint assay, and the Prosigna assay. And then we will end with some future directions. So, let's talk about general principles. Certainly, this group appreciates, as I do, how important treating breast cancer is in terms of incidence. This is by far the most common cancer type in women both in the US and internationally. But it is not the most common cause of cancer death, lung cancer is the most common cause of cancer related death in the US, and part of that is because we have developed so many of these new tools and strategies to help treat breast cancer.

(00:07:29):

We have begun to bend the curve in the right direction, and I'll show you that momentarily. This is interesting data and puts a lot into perspective about where we are in terms of treating breast cancer. This data's a little bit out of date, there are some blips here with COVID in terms of causes of death. But if you look over a 40-to-50-year period from the 1970s into the 2010s, you see heart disease a dramatic decrease in rates of death from heart disease due to various factors, better medications, screening, lipid management, et cetera. And then you see the second most common cause of death traditionally in, in older patients and traditionally in younger patients was cancer. This is not breast cancer. These are all cancers. You can see for younger patients, both curves are really shifting down.

(00:08:21):

But now clearly cancer is a more common cause of death than heart disease. Whereas in patients over 65, we have bent the curve down, maybe not as steep as the cardiovascular curve, and now it is close in terms of heart disease versus malignancy as cause of death. We have made progress for all of these issues. This is that same data and with the red arrow, I am showing you where breast cancer is. You can see over the last forty plus years we have been reducing death rates in breast cancer both for younger patients, you can see on the left, as well as for patients over sixty-five on the right. So, we are making progress here and we are diagnosing cancers at earlier stages. We have better therapies in terms of hormonal therapies, targeted therapies. We are becoming smarter about who we use chemotherapy with and how we use chemotherapy and that has been a benefit in terms of reducing mortality rates over time. This is very encouraging data.

(00:09:23):

When I meet with a patient, and we review their diagnosis, typically in the case of many of the patients we will be talking about today, they will have had surgery, and they are coming with their pathology report, and we are reviewing that. This may be the first time we meet, or it may be the second time we meet if we meet preoperatively. I go through a few general principles, which I thought would be helpful for us to review today to set the stage. The first is what is on the pathology report. So, tumor grade does not equal stage, and this can be really concerning for patients because they'll see grade three and they'll think it's stage three. It is not grade it is the pathologic assessment of the tumor by the pathologist. They are looking at how angry the cancer cells look, how fast they're growing stage takes into account various features.

(00:10:12):

Traditionally, stage has been based on tumor anatomy, the size of the primary tumor, what they call the status of the lymph nodes, positive or negative, and how many are involved and whether there is any metastatic disease. Beginning about seven years ago, they changed the staging guidelines to make them much more complex. They include those anatomic features, but now they also include the receptor status, estrogen, progesterone receptor, the HER2 status, the genomic risk score, as we are going to talk about today, as well as tumor grades. It made things a little bit more complicated, but a stage one breast cancer is a smaller tumor in the breast with no lymph node involvement. A stage two tumor might be a larger tumor in the breast or a little bit of lymph node involvement. A stage three tumor would be a more aggressive, larger tumor in the breast usually with some regional lymph node involvement.

(00:11:05):

A stage four tumor would be a cancer that has spread to any other site outside of the breast or lymph node, and that could be a spot in the bone or the liver or the lungs. That is really the distinction, stage 1 through stage 3 versus stage 4, and we might say early stage that could refer to stage 1 to stage 2 locally advanced meaning still curable as well as stage 2 to 3 with more lymph node involvement. Metastatic is stage 4. What about local therapy? When I meet with the patient, we review the pathology, we go through the grade, we go through the stage, we go through what it means to be estrogen or progesterone receptor positive or negative, and then we say, well, what are we going to do? What is the treatment plan? For curative intent treatment, which is what we are going to talk about today, these are patients with stage 1 through 3, we are going to try to cure them of their breast cancer.

(00:11:56):

We have local therapy options that go to where the cancer is, surgery, plus or minus radiation, and we have systemic therapy options. Those are drugs that go all around the body to help prevent the cancer from coming back. That is where we come in as the medical oncologist and today, we are going to be talking about chemotherapy and hormonal therapy. Let us first talk about local therapy. In general, recurrence risks are similar if you do a mastectomy - take the whole breast off - or a lumpectomy with radiation to cover that area. Who needs a mastectomy? Patients where there may be too much disease to get an optimal cosmetic outcome, meaning they can't do a big enough lumpectomy. A BRCA carrier, patients who have genetic risk where the lifetime risk of another breast cancer is so high that it makes sense to think about intervening surgically for the future.

(00:12:49):

Inability to achieve negative margins, meaning they thought they could do a lumpectomy, they are trying to get the tumor out, but the margins are positive, and they must go back in more than once or twice. Or patient preference, sometimes the patient, especially younger patients where there may be cyclical changes with menstrual cycles. Breast density can be an issue, when they are coming back and always getting called back for mammogram or MRI findings and may prefer to do a mastectomy. The counterpoint here is also important. There is a misconception that every time you get a mastectomy you do not need radiation. That is usually true, but not always. If you have a patient who gets a mastectomy, but the cancer is close to the chest wall in the back or close to the skin in the front we may need radiation to cover that area. If you have a mastectomy, but there's positive lymph nodes, we have pretty good data to cover the armpit, the axilla, even after a mastectomy to help reduce recurrence risks from the lymph nodes.

(00:13:47):

What about systemic therapy, drugs that go all over the body to help reduce cancer risk. The backbone of treatment here for our therapy are Antiestrogen Blockers, drugs that block estrogen signaling because 70% of breast cancers are estrogen sensitive. The back of the envelope calculation is for a patient with early-stage 1 through 3 estrogen sensitive breast cancer. By giving one of these pills for at least five years you get about a 50% reduction in the risk of recurrence. That is significant, and these are the two main drugs we are using in yellow, tamoxifen and the aromatase inhibitors. This comes back to basic biology about where estrogen comes from in a premenopausal patient about 80% of the estrogen comes from the ovaries. In all patients, whether you're postmenopausal and the ovaries aren't working, or in men, you get about 10% to 20% or low levels of estrogen that come from steroids made above the kidney and the adrenal gland throughout the body within fat tissue there's an enzyme called aromatase, and a small amount of those steroids all over the body gets converted into estrogen.

(00:14:59):

This is a common question for my postmenopausal patients, the majority of the patients ask why, if I am postmenopausal, do I have to take a medicine to block estrogen? It is a good question because 80% of the estrogen is gone from the ovaries. You still have 10% to 20% throughout the body from this fat tissue being converted into estrogen, we all have this happening, everybody, so the tamoxifen is an estrogen receptor blocker. So, you have the E2 is the estrogen, you have the estrogen receptor in the cancer cell, the tamoxifen blocks the ability of the estrogen to bind to its receptor, whereas the aromatase inhibitors reduce that conversion throughout the body of the steroid to estrogen. So this is why it makes sense that the aromatase inhibitors can only be used in a postmenopausal woman or in a premenopausal woman who we've shut down the ovaries either with a medication like Lupron or by taking the ovaries out surgically, because if I use an aromatase inhibitor in a premenopausal younger woman, you still have 80% of the estrogen coming kind of unencumbered from the ovaries.

(00:16:10):

This makes sense, you'll see in your clinics why we are only using the aromatase inhibitors in older patients over menopause typically over 50 to 60 or in younger patients who are on Lupron or ovarian suppression. What are the side effects? I think everybody on this call who is interacting with patients a lot like I am, you are running into these side effects so you know all of this, but just to remind ourselves, we can use tamoxifen pre or postmenopausal, we can use the aromatase inhibitors postmenopausal, they can all cause menopausal symptoms. And this is not a full list. These are just some of the common ones. Hot flashes, vaginal dryness, fatigue. The tamoxifen has some rare but serious things, rare irritation of the liver, increased risk of blood clot, or even a secondary cancer in the uterus.

(00:16:56):

Not common, but it can happen. The aromatase inhibitors have lower serious side effects, but cause more joint stiffness, muscle aches, arthritis, and bone density loss over time. Again, if you are seeing tons of patients in clinic like I am every week, this is probably the most common thing you are discussing are the side effects on these medicines and how we are managing them. What are some of the key questions? We are going to go through some of these genomic tests to help personalize care for patients. What is the recurrence risk for any given kind of patient in any specific tumor who gets benefit from chemotherapy in addition to the anti-estrogen? Because we really offer the anti-estrogen to any estrogen sensitive cancer, even the smallest stage 1 who benefits from extended duration treatment. Meaning we traditionally gave five years of these pills, the tamoxifen, or the aromatase inhibitors, like anastrozole or letrozole, but now we know we can go up to 7 - 10 years and there is some incremental benefit.

(00:17:54):

Who should get that, and then which premenopausal patients should have ovarian suppression? Again, this ties into recurrence. If the recurrence risk is higher, you want to really maximize the suppression of estrogen, so which younger patients need to have that and face the risk of more menopausal side effects like we are talking about here. These are some of the questions that these tests have put us into a position to answer these tests, they take the guesswork out of it for the oncology team by giving us a really personalized measurement of recurrence risk and potentially benefit from chemotherapy, and that's the theme we're going to go through for the next few minutes. I'm going to show you not all the data for every test, because that would take a whole day, but just an example of some of the studies that have been done to show how valuable the tests are in terms of prognosis recurrence risk, typically distant recurrence risk, meaning risk of stage 4 disease, and the predictive power of the test. Not only does it give you prognostic insight, but it also tells you who is going to benefit from chemotherapy, who should we add that extra chemotherapy on top of the anti-estrogen treatment too, and that is the theme for all these tests.

Dr. Wander (00:19:14):

Let's start with MammaPrint. Again, these are not in any order other than alphabetical and the other disclosure that I should make, every institution kind of has its own workflows. Part of this is clinician comfort. Part of it is institutional, payment and financial preferences at our institution. Historically, over the last 10 years, we have predominantly used Oncotype. I have interacted with all these tests, but in our own clinic, just based on our workflow, all these tests have in many ways equivalent capabilities, but we tend to use Oncotype. I'll frame a lot of my experience based on Oncotype, but that doesn't mean that all of them aren't excellent and all of them have many of the same predictive powers. Here's the MammaPrint test.

(00:19:59):

This is from Agendia, all these tests look at expression of genes in cancer. And the way I explain this to patients is that these are not genes that are typically inherited from parent to child. Like you're thinking about BRCA or some of these other genes. These are genes that are typically turned on or turned off in the tumor and through lots of effort over many years and decades we've developed these signatures that these companies have harnessed for these tests to use the turning on or turning off of these genes to predict the likelihood of recurrence. MammaPrint is a 70 gene panel, and it has four categories here, ultra-low, low, high one or high two, which is really two categories, right? You see green and pink, low risk and high risk. The lower risk patients have lower likelihood of recurrence, and particularly early recurrence, the higher risk patients, as you move across the spectrum in the score, have a higher likelihood of recurrence.

(00:20:57):

The second feature of the test is something called BluePrint, which is an 80 gene panel that explores signaling pathways within the cancer cell. These pathways that tell the cell to grow or survive or divide or move from one place to another and they divide the cancer into these subtypes that we'll talk more about when we get to the Prosigna test, Luminal A or B, HER2 meaning not HER2-Positive, but they have some genetic features similar to HER2 or basal, the basal tending to be a little bit more aggressive and this is all different ways of measuring the same thing. I told you about tumor grade one being less aggressive, slower growing, three being more aggressive, faster growing. There's a lot of correlation between the subtype of the cancer, luminal basal being more aggressive, the tumor grade, lower grade versus higher grad as well as the receptors estrogen sensitive, HER2-negative, triple negative, HER2-positive

(00:21:58):

These are different ways of measuring the same phenomena which is the behavior of the tumor over time and what's important is that the BluePrint test here from MammaPrint changes your understanding of about 20% - 25% of the cancer. For example, if I have a patient whose estrogen sensitive, HER2-negative, statistically about 80% of the time most of them would be luminal A or luminal B but if you use this blueprint test, you'll find about one out of five of those patients isn't luminal, they might be basal, or they might be HER2 type. It helps us understand a little bit more about the biology of the tumor and one out of five is a high number. I see about twenty patients a day so that means multiple patients a day IHC, the receptors, ER/PR and HER2might not be the most accurate measurement of this subtype of the cancer.

(00:22:57):

MammaPrint can really help predict chemotherapy sensitivity, this is from the flex study. What you're looking at here on this graph is the five-year risk of distant recurrence. This would mean somebody develops stage IV, metastatic breast cancer over the first five years after diagnosis on the X axis. You see the MammaPrint ultra-low, low, high one, and high two. As you move into the high-risk range, just focus on the blue line, this is endocrine therapy only. Let's say I have a patient, she gets a MammaPrint, she has a score, and I just give her tamoxifen or I just give her anastrozole. This is telling you what her five-year risk of distant recurrences on endocrine therapy alone. You can see for a low or an ultra-low, these are very low numbers. They tend to be low single digits, somewhere between 1% and 5%.

(00:23:47):

It's never really zero; there's always some risk of recurrence even if it's very low. Look at this patient with high risk two, if I just give her endocrine therapy her risk is getting up to 20%, even as high as 30 plus percent risk, that's very high. That is one out of three or one out of four chance if you give those patients chemo so give them a few cycles of chemo before they get the endocrine therapy, you move from the blue line to the red line. If we're in the low-risk category those lines are not significantly far apart statistically but if we're in the high-risk category, you're dropping risk from the 20% to 35% range, down into the 12% - 14% range. A significant difference, you’re cutting the risk of distant metastatic recurrence over the first five years in half, and you can see that here, in the chart, the difference in risk is on the order of 10% to 14% for the high two groups a significant clinical benefit.

(00:24:51):

What about patients with the MammaPrint low? There's good evidence that these patients can probably avoid chemotherapy. You see that here the distant metastasis free survival for these patients is 95 plus percent. When you get to five years and look on the right side, this curve is showing you every time the curve goes down there's a recurrence event and you can see that curve is staying high up well over 90% into the five-to-ten-year range. On the right side, these are patients who have low MammaPrint, meaning the genomic risk is low, but they have positive lymph nodes, so the clinical risk is high in the era before genomic testing, all of these patients got 100% chemotherapy. We know that for the patients who get, for example, MammaPrint or the other tests we're going to look at today, if they have a low genomic risk, it can trump the positivity in the lymph node.

(00:25:48):

Look at these two lines. The the lines here basically reflect whether or not they get chemotherapy. And you can see with eight years of follow up it's about a 1% difference, meaning no real statistically significant difference whether they get chemotherapy, even if they're lymph node positive, if they have a low MammaPrint. If they have a low MammaPrint even one to three positive nodes they really don't need chemotherapy. You're just getting risk from chemo side effects and long-term effects without getting benefit from chemotherapy itself. That's the whole population, so that's pre and postmenopausal women but when we, and this is a theme we're going to see also for Oncotype, what if we look based on age? Here's that same data I just showed you this data for the low risk with positive lymph nodes, one to three positive lymph nodes.

(00:26:43):

If you break that data into age over 50 or age younger than 50, which correlates with menopause the age over 50 is mostly postmenopausal. The age under 50 is mostly or is more frequently premenopausal. Look at the age over 50, truly no difference a CT is adjuvant chemotherapy or no adjuvant chemotherapy It's a 0.2% difference over eight years, no difference. Look at young women, women under 50 more premenopausal patients here, you get about a 5% benefit from chemo, even with the low MammaPrint so if you look at the whole population the MammaPrint suggests no benefit. If we look at the smaller group of women who are younger and premenopausal, there may be some benefit here. The challenge that we're running into in clinic, and this is where the conversations can get quite long, is that we don’t know for sure why this difference exists.

(00:27:41):

One possibility is because giving chemo does something to the cancer cells in the younger women that it doesn't in the older women. I think the more likely possibility is that the younger women, by getting chemo, they're getting pushed into menopause. The chemo is accelerating the likelihood of going into menopause. It has nothing to do with the cancer and by flipping them into menopause, it actually helps their cancer risk, which we could do by giving them Lupron and sparing the toxicity of chemotherapy. This is a big debate in the field right now for MammaPrint, for Oncotype, for all these tests. What amount of the benefit in the younger women is just related to chemo, kicking you into menopause with these low-risk scores, and how much of it is a beneficial effect of chemo on the cancer? Remember, we're talking about low risk.

(00:28:26):

If you have a high-risk score, whether you are node positive or negative, you need chemo. This is just looking at the low-risk patients, but it gets a little bit confusing for us in clinic. Let me end this section on the MammaPrint by just showing you what the patient and the clinician would look at in clinic. You may get questions about this, or they may be wondering about sections of this. This is the report on the top, there's information - the size of the tumor, the nodes status, the tumor grade, the patient age, then you get the MammaPrint score, and it tells you where it is, low risk or high risk in which group. Then on the front you get a lot of clinical data. What's the benefit of preoperative chemotherapy? The likelihood of a complete response.

(00:29:06):

What's the benefit of postoperative chemotherapy and the five-year distant metastasis rate? What's the benefit of extending the adjuvant anti-estrogen therapy for more than five years? So, there's a lot packed in here. You can see for this patient in particular has significant chemotherapy benefit. You know, they're in the high one group, so it's anywhere from 3% to 12%. This is telling the clinician what to talk about with the patient and then the next two pages show you more data. This shows you on the left hand, in the preoperative setting, if I were to give additional therapy in the preoperative setting, this is the magnitude of benefit I might expect for complete response. And what we're really focusing on the right hand side is the postoperative setting. What is the benefit of postoperative chemotherapy? What is the benefit of extended duration anti-estrogen therapy? This is some of the data that we had just reviewed a minute ago there. So with that I'm going to go to Oncotype.

(00:30:12):

Now you're going to see very similar data for these other tests so, you know they're going to be similarities. I'm going to try to wrap up in about maybe 15 more minutes so we have time for discussion for the last quarter or third of our hour together. Here's Oncotype and this data dating back now almost 20 years. Oncotype is a 21 gene signature, so we saw 70 genes for MammaPrint, this is a 21 gene signature. And these genes, again, have things to do with the level of estrogen and progesterone expression, how fast the tumor cell divides and grows, et cetera. You can see as the Oncotype score gets higher; there's a higher risk of distant recurrence over 10 plus years. This was valid in multiple analyses retrospectively here, so you can see, um, this is data originally as the Oncotype test was being described, if they have estrogen sensitive, HER2- negative early stage breast cancer, low Oncotype score over more than a decade, you can see these numbers look very, very good, right – single digit recurrence risks.

(00:31:18):

If they have an intermediate Oncotype score, or worse, a high Oncotype score, you can see these numbers drop significantly down into about a 30% recurrence risk over 10 to 15 years, so clear separation between the curves in terms of risk. Remember this is time on the on the X axis here, and on the Y axis is the freedom from distant recurrence. So, every time the line drops, that's a patient or a group of patients that's having a recurrence. The flatter the line, the lower the recurrence, the deeper it drops, the higher the recurrence risk so, you want to be, as close to the top line as you can here. This is that same data basically saying, what is the benefit in retrospective looking backwards studies for giving chemotherapy in the setting of these different Oncotype groups.

(00:32:08):

Now, in the old days, Oncotype used to be low, intermediate, and high. Now we just have kind of low and high, but I'll get back to that in a minute. So, look at this, the benefit of chemotherapy, the relevant benefit as you move from low to intermediate is pretty minimal but when you get into that high range, you can see it's pretty significant. Absolute increase in distant recurrence free at 10 years goes up 20% to 30% if you give chemo to the high risk patients. Look at this chart, this graph on the right, it looks very similar to what we just saw from MammaPrint. Here you've got on the Y axis 10-year risk of distant recurrence. And on the X axis, the Oncotype score is 0 to 50. The red line is what if I just give Tamoxifen alone for five years.

(00:32:56):

The blue line is what if I give tamoxifen after a few cycles of chemo. So, let's take a patient with an Oncotype score of 10, very low. You can see her recurrence risk is less than 10% on the Y axis, single digits and there's really no difference between the red and the blue line. Let's go over to a patient where she has an Oncotype of 50. So now go up, If I just give her tamoxifen on the red line, even with Tamoxifen, her recurrence risk is on the order of 30% or maybe a little higher and if I give her a few cycles of chemo, she drops to the blue line and with an Oncotype of 50, she's down to about 10%, maybe 10% to 12% so that's a big difference. We're dropping it from 30 plus percent down to 10% to 12%. That's where you get this 20% to 30% on the right hand side reduction in distant recurrence, really significant.

(00:33:47):

Here's a prospective trial, so we're not looking backwards at old data, we're getting new data forwards in time. Published in the New England Journal about seven years ago this is called the TAILORx study, this is the most widely used study for Oncotype. We use this in the clinic all the time. Here you're looking at patients who had an Oncotype below 25. So, if the Oncotype is 26 or higher, everybody got chemo - that was a high score. If it's below 25, they called it a low to intermediate score and they randomized those patients, half of them got chemo, half of them got no chemo, they all got anti-estrogen therapy. What you can see on these lines, remember the higher up the line, the better it is, the lower the recurrence risk over more than five years of follow up, there is no difference.

(00:34:38):

There's a dashed line there and a solid line. It's hard for you to see that there's two lines because they are literally on top of each other. There was no benefit to chemotherapy in the overall population in over 6,000 patients if the score was 25 or below. Of course, it gets a little bit more complicated on the right-hand side. What if the patients were younger than 50? Remember we saw this data from MammaPrint a minute ago. If the patients were younger than 50, meaning enriched for pre menopause, look at this for a minute. Just focus on the five-year risk, the rate at five years. If that patient was 21 to 25, so kind of intermediate, she had a benefit of getting chemo of about 6% improvement in recurrence risk. If you look at the distant recurrence risk, 21 to 25, it's about 3% to 6% depending on if you look at five or nine years.

(00:35:33):

If she's 16 to 20 a little bit lower, it's a smaller benefit. It's on the order of about 2% so when we look at the report, what you're going to see is if the patient is over 50 and the score is below 25, there's no benefit to chemo. That's a quick discussion, there's no debate. If the patient is under 50, and certainly if she's premenopausal or perimenopausal and her score is in that middle range, 16 to 25, 20 to 25, then it's a complicated discussion. Just like with MammaPrint, there's some evidence that there's probably 2% to 7% improvement in recurrence risk if we use some chemotherapy here, but again, we have no idea whether that's inducing menopause, which we can do without using chemo or whether there's something unique to the chemo. It's a frustrating situation to be in for our younger patients.

(00:36:27):

For the menopausal patients over 50, it's very straightforward here. This is a more recent study from about four years ago, also published in New England Journal in lymph node positive patients, so one to three nodes, same idea. If the Oncotype is above 26, everybody gets chemo. That's not in the study. If the Oncotype is 25 or below, even with positive lymph nodes, up to three patients were randomized to get chemo plus endocrine or endocrine alone, tamoxifen, letrozole, et cetera and you can see in all patients there was no significant difference. It was about a 1% benefit to chemo, so this is great. The node positive women who would've all gotten chemo 10 years ago, if their Oncotype is below 25 and the whole population, 5,000 patients here, there's no benefit to chemo. And again, if we look at postmenopausal, these lines, red and blue are on top of each other over five years, even with positive lymph nodes.

(00:37:26):

If you have an Oncotype below 25 postmenopausal, it's a 91% - 92% chance you're not going to have a recurrence and there's no benefit to giving chemo here for this population. The same thing is true if we start to look at the node positive premenopausal. So, look here, you've got about a 4% to 6% improvement from 89 to 94 in your premenopausal, younger patients with a low Oncotype, and the same debate applies. Do these patients get something special from chemo or is the chemo kicking their menopause sort of into gear, which we could do without all the risks of chemo. So again, for one to three positive nodes, younger patients, we must have a complicated discussion. Even with a low Oncotype. The guidelines suggest considering chemo because it's about a 4% to 6% improvement here.

(00:38:28):

Here is the test report, this is what we see in clinic. This is what your patients will see in clinic it looks a little different than the MammaPrint. Here you have a recurrence score, it goes up to a hundred, but most people are zero to 50, and the number you're looking for is 25. If it's 25 or below, that's low risk. If it's 26 or above, it's high risk. This gives you a risk of distant recurrence over about 10 years on hormone therapy alone and this tells you whether there's chemo benefits. So here, this patient has 13, we just talked about 25 being the cutoff, no benefit to chemo. Um, and her risk on anti-estrogen therapy alone is low. It's less than 5%. And if you look in the middle, this is what I'm talking about in terms of the table. If you look here, the patient and it says this patient's node negative, you can see on the top right of the report top left.

(00:39:12):

So, if you look at the table in the middle, if they're over 50, you can see for any score up to 25, there's no chemo benefit. It's very black and white. If they're over 26, there is a chemo benefit. Now look at under 50, you can see if you're between 16 and 20, it's a couple percent. If you're between 21 and 25, it's a couple more percent. So, this is really where we run into challenges in clinic having these conversations. At the bottom it just gives you a measurement of estrogen, progesterone, and HER2, which compliments the pathologist, It's a different measurement of the same thing. On the back of the sheet or the second page, it shows you the data I just went through. If you focus on the topic, it gives you the curves, tamoxifen alone, tamoxifen plus chemo recurrence, risk on the y axis, recurrence score on the X-axis.

(00:40:01):

So, what I'll do is I'll read the first page with the patient and then I'll show them this graph and I'll sort of point to where they are. I'll say, okay, your score is 15 so look, these two lines are not very different, the risk is under 10% no matter what,there's no benefit to chemo or your score is 45, so look, if I just give you the estrogen therapy, your risk is up here in 20 to 25%, but if I give you chemo, we drop it down here all the way to about 10%. This is a very visual way for the patients to understand the risk and the benefit. We're going to move on to the last one. I think I'm staying on time here.

Dr. Wander (00:40:45):

Let's finish with Prosigna Veracyte, this is just alphabetical, nothing to do with preference here for me, Veracyte is based on a really powerful recurrence risk score called the PAM 50. These are 50 genes that originally led to the development of our understanding of the luminal, the HER2, the basal subtypes, so these genes are some of the most well-validated genes in all of breast cancer biology. You can see the list of the genes here and I just put this up because I wanted you to see they have to do with proliferation. They have to do with cell structure and cell division, they have to do with estrogen signaling cell cycle apoptosis, which means cell death. These genes were well characterized and classified to have to do with different signaling pathways that allow the cancer cell to grow and divide over 400 publications in the PubMed database using these genes, the PAM 50 genes.

(00:41:43):

Here's the Prosigna test, this test uses the gene expression of those 50 genes to tell you the subtype, the luminal A, the luminal B, the basal, the HER2 enriched, and it gives you a 10 year risk of distant recurrence on endocrine therapy alone and very strong data for both node negative patients and for node positive patients, which you see on the right and you have a recurrence risk score zero to a hundred, that doesn't mean a hundred percent risk of recurrence it's just the score that they have their scale. Let's go through some of the data for recurrence risk for Prosigna. This is an almost 1500 post-menopausal patients with more than a decade of follow-up you can see distant recurrence-free survival. This looks similar to the patterns we're looking at for all these other tests, you can see for the low Prosigna score, for the low recurrence risk score, very few recurrences.

(00:42:41):

That line is almost up over 95%, almost up to a hundred percent, not a hundred, but almost for the intermediate score, it's pretty good, it's somewhere in between it ends around 91% but look at this high-risk score, these patients really fall off here. All of these are recurrence events, and that score gets all the way down to about 80%, you know, 79%, 80%, about a 20% increase in risk of recurrence over 10 years for node negative postmenopausal patients. Here's data that shows 10-year risk impacted by both the Prosigna score and the number of nodes. This is an interesting study where they had over 1,011 plus node negative and over 1300, almost 1400 node positive, again all postmenopausal. So here you're using both the clinical factors, the number of positive nodes, as well as the Prosigna the recurrent, the ROR, the risk of recurrence score

(00:43:38):

You can see the Prosigna score on the X axis, then you can see risk of distant recurrence on the Y axis. and the Prosigna score being modified with the number of lymph nodes on top of it so you see zero lymph node positive one, two, and three and for the same Prosigna score as you add the number of lymph nodes, you see the risk going up a little bit each of these curves jumps up a little bit. So, if we take a patient, for example, who's got an a Prosigna score of a hundred with no positive lymph nodes, unfortunately she still has a pretty high risk at about 35% to 40%. If you take that patient up to three positive lymph nodes, her risk is getting closer to 70% but look on the flip side, if you have a patient with a very low Prosigna, less than 20, even with three positive lymph nodes, her recurrence score less than 10% at single digits.

(00:44:33):

So, this is an incredible concept, and I really want to sort of drill down on this for a minute. You have all these patients who have the same number of positive lymph nodes three, but when you look at this genomic test, the recurrence risk moves all the way from 5% up to 70%, that's a massive range in terms of recurrence risk for precisely the same anatomy, three positive lymph nodes. That just tells you how powerful these genetic tests are in addition to our traditional clinical variables in predicting recurrence risk and this is also telling you indirectly which of these patients benefit from chemotherapy. Certainly, the ones where you're getting these recurrence risks up into the 30 plus percent range are going to benefit from cytotoxic chemotherapy and this is telling you PAM 50, remember luminal basal, HER2 versus our traditional assessments, estrogen receptor, progesterone receptor, HER2.

(00:45:35):

The way we would normally do this, if you look at the top graph here on the right, this is divided by our pathologist, is it HER2 positive? Is it triple negative? Is it ER positive? You can see as you move from ER positive, HER2 negative in red down to triple negative and HER2 positive and blue and purple, the recurrence risk gets worse, the curve shift down and the PAM 50 does the same thing. It probably does more accurately luminal A, luminal B basal, like et cetera. So, it's similar distribution, but I think a more accurate assessment to use the PAM 50 because it's not a subjective pathology measurement, it's a quantitative genetic measurement. So, here's the PROSIGNA report this tells you where are they low risk, intermediate risk, or high risk and then it also tells you the subtype underneath luminal A, luminal B basal.

(00:46:25):

On the bottom we're looking at that curve, it's telling you where the patient falls on the curve in terms of rate of recurrence over the next 10 years, distant recurrence. This patient with a score of 70 has a 20 plus percent risk of distant recurrence. Here on the back, they're giving you more information about the intrinsic subtype and they're giving you additional validation studies from different patient populations with recurrence risks over time based on the Prosigna score you know where this patient would fall. There's an important ongoing study that I wanted to mention, this is the Optima study. It's enrolling right now; I think it's being led in the UK where we're looking again in a prospective way at the benefit of chemotherapy as a function of the Prosigna score.

(00:47:20):

These are patients that have some risk factors. They have a tumor greater than three centimeters or lymph node positive breast cancer. As you can see in the inclusion criteria, the first group of patients just gets chemo and endocrine therapy as per usual. The second group of patients gets Prosigna, and if they have a low score, less than 60 on that risk of recurrence score, they skip the chemo. If they have a high score over 60, they get the chemo, and the patients are sort of randomized. So, they don't know exactly which group they're in here. Then we'll look at the longer-term recurrence up to 10 years to again prove that for these patients with the low recurrence score under 60, there's no benefit to chemotherapy, similar to what we've seen so far with many of these tests. So, the sample size here is very large, almost 5,000 patients.

(00:48:09):

So let me end just with some thoughts and future directions and then we should have about 10 minutes for conversation. Breast cancer is the most common cancer in women, hormone receptor positive meaning estrogen or progesterone receptor positive HER2 negative is the most common subtype. The foundational approaches to curative intent treatment, as we talked about local therapy, surgery plus radiation, plus or minus radiation, as well as systemic therapy, anti-estrogen therapy with or without chemo. That anti-estrogen therapy is critical to reducing the long-term local and distant recurrence risks. These genomic assays are extremely powerful tools to provide new insight and to really personalize care for patients. In the old days all we had was the anatomy and the age. These tests are prognostic, they show the likelihood of distant relapse and they're predictive about the benefit of chemotherapy. In addition to endocrine treatment, all these patients are getting endocrine treatment, but we have a lot of important work that we're doing right now.

(00:49:06):

How do we optimize care for premenopausal women? I showed you all this confusing data for node positive premenopausal, we have to have better insights so that we're not really guessing there. What about emerging assays? There's lots of new tools coming online, minimum residual disease. You may have heard of things like Signatera. This is a very different type of technology where we make a DNA barcode for each patient, only for that patient and you can find microscopic amounts of tumor DNA in the blood, which can then convey elevated recurrence risks. That's a really new kind of next generation tool that's being developed.

Caroline Koffke (00:49:54):

First off, thank you so much. I feel like I just learned an incredible amount. Are you speaking at ASCO?

Dr. Wander (00:50:02):

Yes, we have a talk at ASCO on different topics. We're going to be talking about metastatic disease, and we’re talking about new biomarkers to help guide therapy for stage IV, we have an educational session at ASCO on Friday afternoon.

Caroline Koffke (00:50:18):

Brilliant. I will be there. And maybe some members of the audience will be as well, or at least joining virtually. So that's super exciting to know that we can kind of continue to learn from you. So many great questions, thank you everyone for popping those in. One of the first ones that I saw as a common theme is what tumor specimen are we sending for these tests? A lot of times it's surgical, can we do the original biopsy?

Dr. Wander (00:50:44):

I was purposely vague on this point, so the standard in our practice, and again, I'm going to speak from my own clinical practice, if you put five of us here we could have a panel and debate this, you would get some different answers, but for our practice we like to use the surgical specimen when the tumors all the way out. That's not to say that you can't deploy these tests on the biopsy, there's data that's been published that shows correlation between the biopsy genomic risk score and the excision genomic risk score. These tests are generally developed postoperatively for helping to decide once the tumor's out, because then we know the nodal status, we know the grade, we've confirmed the hormone receptor status.

(00:51:29):

I will say during COVID, the height of covid, we were in a situation where the ORs were shut down. They didn't have ventilators for anesthesia. We had no choice even for stage one patients we couldn't go to the OR for months in Boston. We started to use Oncotype on the core to help decide if the patient had a high Oncotype, I'd give them chemo. If the patient didn't have high Oncotype, I'd just put them on anastrozole or tamoxifen and waited out for two or three or four months. You can imagine that was a very stressful time. But we became more comfortable deploying these tests on the core biopsy in an emergency situation like that.

Caroline Koffke (00:52:04):

Great, thank you. Super helpful. A few questions also, on AI’s versus tamoxifen. Is there specific data from any of these tests that differentiate between the two?

Dr. Wander (00:52:15):

It’s an interesting question. There's a lot of data predating these tests about who should get an AI versus who should get tamoxifen and the general rule of thumb putting these tests aside for a minute, is that outcomes are slightly better with aromatase inhibitors than with tamoxifen. Now, it's a small difference, it's on the order of a couple of percent and you have to look at thousands of patients over many years. So, my preference in general, if I can get a patient onto an aromatase inhibitor, that's better for two reasons, one, the outcomes are slightly better over time, and two, the risks of the serious stuff are lower, right? You don't have the uterine cancer risk or the thrombotic risk. So, with that being said, these tests are not perfectly suited to differentiate between tamoxifen and an AI because many of the retrospective trials that they used were really in the era of like tamoxifen, like that data for Oncotype.

(00:53:06):

I would say the higher the recurrence risk for any of these tests, the more keen I am to get them on an AI because we know that relative couple of percent benefit means more to somebody who's at a 30%, 40%, 50% risk of recurrence than somebody who might be at a 5%, 6%, 7%, 8% risk of recurrence. So I feel better about Tamoxifen for my younger patients who are node negative and have low genomic risk score because younger women, I think this is what the question may be alluding to everybody on this call who treats a lot of patients would probably agree with me that all things considered, if I have a 45-year-old with ER-positive breast cancer and I have a choice between putting her on tamoxifen or Lupron and anastrozole, she feels worse on the Lupron and the anastrozole. More estrogen deprivation, more hot flashes, more joint pain, more vaginal dryness, more hair thinning, things like that. They tend to feel better on tamoxifen. I feel better about putting them on tamoxifen if the recurrence risk score is low and then lymph nodes are negative.

(00:54:14):

It’s good for the patient to think about confronting the side effects and saying, okay, I understand my benefit is higher if I have to go through this.

Caroline Koffke (00:54:20):

Such a good point, it makes that a little bit more tangible, which is always helpful when you're not feeling good. Another couple questions, is there a benefit to having multiple of these tests? Does it give us different information that might be useful and will insurance cover it? You may not know the answer to all of that.

Dr. Wander (00:54:40):

I don't know the answer to all of that because we have our own workflows. We tend to kind of send the one. I do think there may be benefit, there are differences, right? We saw some differences between these tests. Some of these tests have better data 10 plus years out. I showed you that with the Prosigna data dating out more than a decade, and with the number of lymph nodes positive, some of these tests may give you more information. Like Oncotype doesn't give you intrinsic subtype, Luminal versus basal. MammaPrint has a little bit more granularity, ultra-low, low, high one, high two, and tells you more about extended duration, anti-estrogen therapy, which the other doesn't. So, if I could have them all, I would <laugh>.

(00:55:20):

One of the challenges though is we don't know what to do with this, what if you have a person who’s a 23 on an Oncotype, but flips over the edge on a Prosigna or on a MammaPrint, what do you do there? We don't know, it can get a little bit muddy there in terms of interpreting the data, so I think that it is an area of an unmet need, to understand what the complimentary contributions are from these tests. I do think it can be challenging in some situations for insurance to cover it.

Caroline Koffke (00:55:52):

That makes a lot of sense. I guess just for of my own thoughts too, if you're predominantly using Oncotype, which we know a lot of facilities do use, but you don't have that data about the luminal basal subtype, does that inhibit your decision making as a physician?

Dr. Wander (00:56:10):

I'm a translational research person, so I value having more data, I value understanding these things because I still think we have a lot to learn about intrinsic subtype and how it influences response to anti estrogens and CDK inhibitors and even chemotherapy. The basal tumors probably do better with chemo than the luminal A - I would like to have that info. So yes, it does limit me, but it is part of like the standard workflow for a community oncologist, probably not right at this moment. I think with our colleagues at, at Veracyte and Agendia and other places academically, I think we'd like to move that information into clinical practice because it's another tool and it's quite humbling to me that 20% to 25% that I cited where our expectation, it's ER positive, HER2 negative, it's luminal A is wrong, 20% might not seem that high, but when you have 20 patients a day, that's multiple patients where my expectation would be wrong in a day.

Dr. Wander (00:57:11):

Not to mention in a week, in a month and a year. So, I think there will come a time perhaps in the future where those sort of data points start to enter the personalized strategies that we're going to use.

Caroline Koffke (00:57:27):

Thank you. I think this is related as well, this was a great question. With the approval of CDK 4/6 inhibitors in the early stage is there a benefit and maybe it is knowing that it's a basal subtype or something like that. Is there a benefit to these tests or how are you using that data?

Dr. Wander (00:57:44):

Great question. All the data that we talked about today precedes the of CDK 4/6 inhibitors in the adjuvant

Dr. Wander (00:57:50):

A lot of the work that I've done over the last 5 to 10 years is looking at the genomics of response and resistance to CDK inhibitors in the metastatic setting and many teams have been working on this. There is good data to suggest that intrinsic subtype does correlate with response to CDK 4/6 in the metastatic setting and this is an important question that we need to answer using Prosigna, using MammaPrint other tests. My expectation would be that in the adjuvant setting, if you had a basal like tumor or luminal B et cetera, you would likely have less benefit from CDK 4/6 inhibitor therapy, but we don't have that data yet. That's extrapolating from metastatic data into the adjuvant setting so I would not hold back from treating if I had a Prosigna where a patient was basal adjuvant I wouldn't today withhold a CDK inhibitor from that patient, but intellectually, biologically, I'm thinking this may be a problem. That benefit may not be as high. We may be able to generate that data in the future.

Caroline Koffke (00:58:53):

That's huge, that is practice changing stuff.

Dr. Wander (00:58:57):

And think about the cost and the toxicity of CDK 4/6 in the adjuvant setting

Dr. Wander (00:59:00):

These are thousands and thousands and thousands and thousands of dollars a month per patient with diarrhea, with cytopenia, with fatigue. With all these things it's an important concept.

Caroline Koffke (00:59:12):

I think this might be our last one - someone asked a great question about genetic mutations. We know BRCA, CHEK2, all these other genetic mutations can sometimes lead to worse outcomes for patients. Obviously, we know some of these are also susceptible to specific medications like an Olaparib, but how do these tests take into account any of those genetic mutations and the outcomes of those patients?

Dr. Wander (00:59:41):

Great question. It's two different kinds of genetic testing, and this is an important misconception, right? People think that they had genetic testing, which means that they had genomic risk profiling, not true. There are two independent and complimentary things that you're referring to, there are inherited germline genetic tests; patient inherited a gene from parent to child, that led to some parts of the development of the breast cancer. We know Olaparib and other drugs are approved in that situation. We should use those drugs in that situation. These tests are looking at genes turned on and turned off in the cancer. Now, there may be some crosstalk in the PAM 50 and in some of the other scores, there may be crosstalk between the BRCA pathway and some of the signaling pathways that are turned on or off because of the inherited gene and the genes on the list for MammaPrint, Prosigna and Oncotype. But these tests will not tell you whether the patient's BRCA and that's the take home message. You cannot rely on Oncotype, Prosigna, MammaPrint to tell you if the patient is BRCA positive or negative, nor can you rely on the inherited germline test to tell you whether to give chemo or not. They are mutually exclusive and beneficial in my mind, so we need both for these patients.

Caroline Koffke (01:00:48):

That's super helpful. Dr. Wander, overall, I cannot thank you enough. This is an immensely complicated topic, especially with the difference between genomic and genetic testing and you really simplified it and showed some great data that I think all of us can take back with us and use in our own practices. I do want to thank Agendia and Veracyte for their sponsorship. I do want to put up that QR code for our evaluation, it truly only takes three to five minutes is even an over exaggeration of how long it will take you, but that feedback is immensely important for us so that we know what is of interest to you. Thank you, Dr. Wander. If you are joining ASCO please join his session, It's going to be incredibly fruitful. I hope everyone has a wonderful afternoon and a wonderful weekend.

Dr. Wander (01:01:35):

Great. Thanks for the invitation, great to be with everybody. Thanks for the work you all are doing for our patients. I know that they appreciate it very, very much. I hope to be able to work with you again soon.

Caroline Koffke (01:01:45):

Well, we appreciate you as well. Thank you.

Dr. Wander (01:01:47):

Thank you.