Understanding testing: Early-stage breast cancer

Transcript

Eleonora Teplinsky, MD, FASCO (00:07):

So we’re going to talk about biomarkers in early-stage breast cancer. There is a lot to cover, and so I’m going to do the best I can to go through as much as we can, and then we can answer some questions. These are my disclosures.

(00:23):

First of all, when we start to think about biomarkers: What are biomarkers? Biomarker, the simple definition is that it’s a measurable molecular feature, either a gene or a protein that essentially signals how a cancer is going to behave or how it’s likely to behave or how it will respond to treatment.

(00:44):

Biomarkers also have other names. So sometimes people will say, “I didn’t have biomarker testing, but I had molecular testing,” or “I had next-generation sequencing, or I had mutation testing.” And all of that is in the same category. So you might be thinking, “Oh, I haven’t heard biomarker before,” but it’s really kind of a broad umbrella.

(01:01):

And biomarkers can be one of two things or both. They can be prognostic, meaning it’ll tell you what is the risk of your cancer coming back, for example. And again, here we’re focusing on early-stage breast cancer. There are lots of biomarkers in metastatic disease as well. We’re going to focus on early stage. So either prognostic or predictive, meaning how it will respond to a treatment, whether a specific treatment will work. And biomarkers can also be both. So what we’re going to discuss today is what we test, what we don’t test, and then very importantly what’s coming and what the future looks like.

(01:34):

First let’s talk about the biomarkers that we check in everyone with early-stage breast cancer. So you’re newly diagnosed. First thing that we’re looking at for any invasive breast cancer, so I’m going to take ductal carcinoma in situ or stage 0 DCIS out of this. So for every stage I through III breast cancer, we’re looking at your estrogen receptor and your progesterone receptor. And these are our hormone receptors that predict whether someone will benefit from endocrine therapy. So tamoxifen, aromatase inhibitors. We check HER2, which tells us if you will benefit from HER2-directed therapies like Herceptin. We look at Ki-67, which is a marker of essentially how rapidly the cells are growing. It’s a marker of proliferation or how aggressive the tumor is. And then we can also use genomic assays for hormone receptor-positive, HER2-negative breast cancer to really help us make decisions about chemotherapy. So we’re going to talk a little bit more about this. These are tests like Oncotype and MammaPrint, Prosigna, and others.

(02:38):

Let’s first start by talking about genomic tests that help us omit chemotherapy. This has been around for a long time. And so the reason I’m talking about it now is because there’s been some newer studies that are really kind of guiding how we think about it.

(02:52):

So this is for our hormone receptor-positive, HER2-negative. So if you have triple-negative breast cancer, this does not apply. We generally give chemotherapy for triple-negative breast cancer unless it’s very, very small. And then we combine that with immunotherapy for stage II and III triple negative. For HER2 positive, I’ll talk a little bit about an ongoing genomic assay that is in development. But for now we’re really going to talk about our hormone receptor positive, HER2 negative.

(03:24):

These are some of the genomic assays that are available. Who’s heard of Oncotype? So Oncotype is the one that we most often use. We also have MammaPrint, which is very widely used as well. And then there is Prosigna, which we have not used as much, but there’s some new data that I’ll talk about for young women that’s kind of making it more applicable. And EndoPredict, which is available. We don’t use it as much, but it is another genomic assay. And then we’ll pivot to Breast Cancer Index, which we can use to really help us make decisions about endocrine therapy and the duration of endocrine therapy beyond the 5-year mark.

(04:02):

Oncotype Dx is a 21-gene assay. It looks at 21 different genes with your tumor and it gives you a score. And the higher the score, the higher the risk of recurrence and the more likely it is that you’re going to benefit from chemotherapy. This is what a sample report looks like. And it will tell you what is your distant risk of recurrence. This sample report here says 5 years, but they also have ones that will say 9 years. The reason this one is 5 years is because it’s premenopausal lymph node positive.

(04:35):

There’s a lot of nuance with it, but it’ll tell you your distant risk of recurrence. And when we talk about distant risk, we’re talking about cancer coming back anywhere in the body. So a lot of my patients will say, “Well, this number is this, but my radiation oncologist gave me a different number.” And that’s more looking at local recurrence, so in the breast. We’re talking distant, coming back in the liver, bones, lungs, and so forth. And then it’ll tell you what is the benefit of having that lowered with chemotherapy. So can we add chemotherapy and will we lower that recurrence risk? And there’s a lot of nuance about how we decide where we draw the line.

(05:14):

Years ago when I was in training, if you were really low risk, you didn’t need chemo. And if you were really high risk, you needed chemo, with the numbers. And then if you were anywhere in the middle, they were like, “I don’t know, you decide.” It was completely a gray area and no one knew what to do. And so finally they said, “All right, enough with the gray areas. Let’s do a study.”

(05:34):

This is where TAILORx came. And this was a study that put the middle at a score of 11 through 25, where they used more conservative numbers just so they didn’t want to undertreat or overtreat anyone. And what they found was that if you were between 11 through 25, you did not need chemotherapy. Chemotherapy did not benefit.

(05:58):

They then said, “Well, is that the case for everyone or do postmenopausal and premenopausal women behave differently?” And so what they found was that if you were postmenopausal and you had an Oncotype score of 25 and under and you had negative lymph nodes, you did not need chemotherapy. So that was great. In women who were premenopausal, younger than 50, there started to be a lot of nuance in that. And I’m not going to go through each number here. We’ll make sure we share the slides so you can have the statistics for you if you are interested in that. But what they found was that if you were premenopausal, there was a benefit to chemo.

(06:34):

But we started raising the question, is it the chemo that was the benefit or is that chemo was putting women into menopause, shutting down their ovaries, stopping the estrogen production, which could then kind of not feed any residual cells.

(06:49):

We started asking those questions. So then they did a similar study called the RxPONDER trial in patients who had 1 to 3 positive lymph nodes. First they said, “We don’t need chemo. It does not help in node negative. If you have under a certain number, let’s look at it in 1 to 3 positive lymph nodes.” And we saw the exact same thing, same idea. Postmenopausal women, 25 and under, 1 to 3 nodes, no benefit for addition of chemotherapy, just continued hormone medication, endocrine therapy alone. But if you were premenopausal, again, there was this benefit to chemotherapy, again, raising the question: Is it the chemo or is it the ovarian suppression? I’m going to come back to this.

(07:32):

Here we have the ongoing OFSET trial. And this is the trial that is really the pivotal trial that is hopefully going to answer this question once and for all. And what this study is doing, it is taking premenopausal women who either have 1 to 3 positive lymph nodes or if they’re lymph node negative, they have an Oncotype between 16 and 25, and it’s going to randomize them into two groups. One group is going to get endocrine therapy with ovarian suppression. So these are drugs like Lupron or Zoladex, which shut down ovarian function. And the other group is going to get chemotherapy, endocrine therapy and ovarian suppression. So they’re really going to answer this question of does chemo have an additional benefit beyond the fact that it puts someone into menopause. And so hopefully with this study, we will have some answers.

(08:23):

It’s kind of hard to accrue to this study though, and so it’s been a little bit slower than I think everyone would have hoped for, but we’re hopeful that this will answer some questions for us. Because right now, if I have a woman who let’s say is 43 and she has one positive lymph node and she has an Oncotype of 20, it’s still a gray area. I have to tell her we can do the trial or we could do chemo, we can omit chemo and we go through all of that, and there’s not really a great answer. I’m going to tell you about a recent study that might help us. So we’re in this kind of gray spot. We’ve got good biomarkers, but we need to refine them a little bit.

(09:04):

MammaPrint is another assay that we can use. And I’m not going to go through all of these in such detail, but again, this is here for you. And so MammaPrint is a 70-gene assay and it kind of categorizes people either into genomic low or genomic high risk. And a lot of this is based on the pivotal MINDACT trial. And what they wanted to do in the MINDACT trial was they really looked at this key group of someone who was high clinical risk, meaning when you look at their tumor size and lymph node status and grade, they looked like they were high risk just on those clinical and pathologic features alone. And so clinical high risk, but what if they came out as low genomic risk? So generally when MINDACT was developed, if you were high clinical risk, you were getting chemo, that was it. We weren’t looking at anything else. So then they asked the question: But if you’re really molecularly behaving like a low risk cancer, is there a benefit for chemotherapy?

(10:03):

The way that I like to think about low genomic risk is if you have two children who are 4 years old standing side by side, you don’t know which one’s going to color nicely and which one’s going to color on the walls. Right? We don’t have that. That’s what the genomic testing gives you. It gives you the behavior of that cancer.

(10:21):

So on paper, high clinical risk, low genomic risk. And they randomized those to chemotherapy or no chemotherapy. And what they found was that in that group, in that high clinical, low genomic risk, there really wasn’t a benefit to the addition of chemotherapy. And again, it gets a little bit more nuanced when we talk about the premenopausal women. And so we’re seeing a trend with, again, we don’t really totally know how to approach the premenopausal women. But it further supports what we’ve seen with Oncotype.

(10:54):

MammaPrint also gives you the blueprint, so kind of the molecular signature. So is it a Luminal type, which tend to be more kind of what we think of are better behaving hormone receptor positive? Is it HER2 type? So it behaves like a HER2 positive. Or basal type, which behaves more like a triple negative? So that is a helpful tool of MammaPrint to really give you that signature.

(11:20):

And then lastly, I’ll talk about PAM50 or the Prosigna assay. And this is a 50-gene signature. It’s been around for a long time, and it gives you a risk of recurrence as well as risk groups — low, intermediate, high.

(11:35):

The big thing with Prosigna, and the reason I’m talking about it, is very recently at ASCO this year they presented the OPTIMA trial. And the OPTIMA trial looked at over 4,000 patients. What they did was they really wanted to answer this question of, again, if you are low risk by Prosigna, does it make sense to add chemotherapy. And they looked at it in premenopausal women who were 40 and over and up to nine positive lymph nodes. So this is very different because all of the other studies have only looked at up to three positive lymph nodes. And finally, we have this start to have this answer about our young women because if they were premenopausal, they required that they have ovarian suppression.

(12:23):

So they asked this question, again, low risk by Prosigna, ovarian suppression, endocrine therapy, and chemo or ovarian suppression, endocrine therapy. And what they found was there was no benefit in the addition of chemotherapy. So very exciting because now we have maybe up to nine positive lymph nodes ee don’t need chemotherapy. Maybe in our 40-year-old women and up we don’t need chemotherapy. And so this is now really starting to change the conversation about how do we think about more lymph nodes? How do we think about our younger women?

(13:02):

Everyone’s very excited about the OPTIMA trial. There’s a couple of caveats to that though. It was presented at this year’s ASCO meeting in June, made national headlines, but they still have short follow-up. So I am not rushing yet to utilize this in my practice because I want to see that the benefit of not adding chemo holds up beyond just a few years. We know these are cancers that can have late recurrences. They can recur 10, 15, 20 years down the road. And so before we rush to omit chemo, I want to make sure that if let’s say we have somebody who has eight positive lymph nodes, which we think of as very high risk, I want to make sure that we have that longer-term follow up.

(13:43):

The other thing that we have to keep in mind is that you can’t, so people are saying, “Well, what about if they have a low risk Oncotype, can I use that?” And Prosigna and Oncotype are very different tests. The genes that they look at are somewhat different. And so there’s discordance between the two. So you could be low risk on one and high risk on the other. We’re cautioning people if they’re going to use Prosigna as a chemotherapy decision tool that we don’t extrapolate that and then use Oncotype as a decision tool in somebody who has 5 or 6 positive lymph nodes.

(14:15):

And then of course it raises the question of how are we going to think about SERDs, which are coming. We’ll talk a little bit about those. How do we think about CDK 4/6 inhibitors? So these are our ribociclib, abemaciclib, and these are medications that we give in addition to endocrine therapy. So in combination with your aromatase inhibitor to further reduce the risk of recurrence. And when all of these studies were done, CDK 4/6 inhibitors didn’t exist. And so one of the challenges is how do they impact and how do they affect the chemotherapy. I think we have a lot more questions now than we actually did a few years ago as we start to get more data and more treatments.

(14:56):

Let’s pivot a little bit to extended endocrine therapy and Breast Cancer Index. Who has heard of Breast Cancer Index? So some, not as many. Breast Cancer Index is a tool that we can use to help us make decisions about what to do for extended endocrine therapy. So meaning you’re on your aromatase inhibitor for 5 years and you get to the 5-year mark and these are not easy drugs and you have joint pain or you have hot flashes and you don’t feel great on it and you say to your doctor, “Can I stop the medication?” How do we decide whether you need to be on it for 5 years or if there’s a benefit to being on it for 10 years?

(15:35):

We used to give it for everyone. Everyone used to get it for 5. Then came a bunch of studies said, no, no, 10 is better. Then came a study said, “Well, maybe 7 is OK.” And so 5 to 10 has really been like, again, what do we do?

(15:47):

Breast Cancer Index is an approved tool that is endorsed by a number of societies to help us make this decision. And what it is, it’s a gene expression assay. It looks at two different biomarker panels, the molecular grade index, and then this two-gene ratio of HOXB13/IL17BR. But the idea is that it gives you two pieces of information. One is: Are you likely to benefit from extended endocrine therapy? So is there a benefit to you to take it from 5 to 10 years, to stay on that aromatase inhibitor for 5 more years? And what exactly is that benefit going to be? And so that you get two things in that report. And it’s very helpful because it’ll tell you there is a benefit, and it’ll say your risk of recurrence without the medication is 10% and it goes down to 5% if you take the medication. Sometimes it’ll say there is a benefit, but the benefit is from 1% to 2%. And so my patients will say to me, “Well, OK, it’s a 1% benefit for 5 years. I’m not sure I’m willing to make that commitment.” And so you want to look at both of those things. It’s not just is there a benefit, you want to look at what that benefit really is.

(17:03):

This is what a report looks like. So again, you get those two pieces of information, are you likely to benefit and then what that benefit is. And historically, we have sent that test around the 4, 4 1/2 year mark, kind of as we’re getting to 5 years. And a lot of patients have asked, “Well, can we send it earlier?” And we could, but we never did because it was really that tool at that 5-year mark.

(17:28):

But now, just recently, Breast Cancer Index has expanded indications. This is some of the data that, again, is here for your reference to go through. I’m going to skip that in the interest of time.

(17:42):

So this is the new expanded use of Breast Cancer Index. They now have a 0 to 10 year report, so you can send it at the time of diagnosis, and it’ll give you two things. For postmenopausal women, it has a new category called “minimal risk” for which maybe patients don’t even benefit from being on endocrine therapy at all. And I’ll show you what that report looks like. And so if you’re minimal risk, they found that your risk of recurrence is about 2% to 3%. And for some patients, they might say, “It’s not worth it to me to be on this for a 2% to 3% benefit, and I’m going to decide not to take it.” I think it could be helpful also in some of our older patients that have a lot of medical issues and already have bad osteoporosis, and we’re worried about making their bones worse and their blood pressure worse and their cholesterol worse. So it could be a tool for that.

(18:38):

And then the premenopausal women, what they’re looking at is actually, can Breast Cancer Index tell us if someone needs ovarian suppression, which is something that I’m very excited about. It’s new and we’re not totally there to use it broadly yet, but it might help us to tell a patient, “You don’t need ovarian suppression and we don’t need to put you into menopause,” which has really significant implications.

(19:07):

So this is what the graphs look like for that minimal-risk category. And you can see that the minimal-risk category is the lowest line at the bottom and getting about a 3% risk of recurrence, which is quite low. And it might be enough for a postmenopausal woman to say, “I don’t want to be on a medication for a 3% benefit.” On the other hand, some people will say, “I want to be on that. I will do anything in my power to not have my breast cancer come back.” And so it’s all about risk tolerance and everyone has a different risk tolerance.

(19:40):

This is what the new report looks like. So you get two in the 0 to 10 report, you’ll get that: Do you benefit at all? And then you’ll get the, what’s the benefit in the 5 to 10 years? So you can now send that report at time of diagnosis rather than waiting to the 5-year mark.

(20:02):

This is the data in premenopausal women, hard to see here, but what they showed was that if you did Breast Cancer Index and it was the opposite of what they expected. They expected that premenopausal women who had a high score on Breast Cancer Index, they should be on ovarian suppression, but they actually found the opposite. They found that if you were BCI low, low risk on the BCI, those are the women that benefited from ovarian suppression. And you can see in the numbers here, just to give you an idea, for the BCI-low tumors, the addition of ovarian suppression to tamoxifen had a 7.3% benefit in reducing the risk of recurrence, and the addition of exemestane to ovarian suppression compared to tamoxifen alone had an 11% benefit in reducing the risk of recurrence. So this is very helpful. It’s again, opposite of what we thought, but it showed that if you were BCI low, you benefited from ovarian suppression.

(21:10):

So it’s something that they are now reporting. When you get your report, it’s going to look like this for premenopausal women, and it will show you what your risk of recurrence is with or without ovarian suppression. And I think it’s a tool that we’re going to start using.

(21:27):

I will say it’s not “the” tool. So I am not going to use this as my only decision-maker as to whether to offer ovarian suppression. It’s one study. We need more data. We need larger — not larger, it’s a large study — but we need more data. It’s not yet endorsed by guidelines. This is new, so the guidelines have not come out yet and said we should be using this for our ovarian suppression decision-making. And we don’t know how this plays a role in people who are on the CDK 4/6 inhibitor. And as SERDs are about to get approved, we don’t know how this will play out in SERDs.

(22:05):

So I’m thinking of this, it’s very new. The updated report just came out. I’m going to think about it as a tool, but I’m not going to base my decision 100% on the Breast Cancer Index. I think it’d also be helpful if someone starts ovarian suppression and is not tolerating it. I think it could be a tool to help us maybe de-escalate on some of those treatments.

(22:27):

So are SERDs coming? Who’s heard of SERDs? OK. So SERDs are, if you have not heard of them, these are selective estrogen receptor degraders. So your aromatase inhibitor blocks estrogen production. There’s no estrogen to fuel a cancer cell that might be there. But with an aromatase inhibitor, you live in the state of estrogen deprivation. There’s estrogen receptors all over our body, and so we get the joint pain and the vaginal dryness and mood changes and brain fog and high blood pressure and so forth. SERDs are a little bit different. They will degrade the receptor rather than blocking estrogen production. And so some of the questions have been are: How is that going to be different? Because there’s estrogen receptors everywhere, and if you’re degrading the estrogen receptors, are you going to get the same effect?

(23:17):

And the thing is that in the study, they showed the people who took SERDs for early-stage breast cancer in the clinical trial tolerated them better and had a lower rate of discontinuation of the drug. And it’s likely because estrogen receptor alpha, which is what our cancer cells fuel on, there’s other estrogen receptors. Another one is estrogen receptor beta, and that tends to be more of a tumor suppressor rather than ER alpha, which is a tumor promoter. So one of the thoughts for why the SERDs are better tolerated is you’re kind of sparing the beta estrogen receptors.

(23:55):

We already use SERDs in metastatic breast cancer. We have a number of SERDs approved. We have imlunestrant, elacestrant, camizestrant, but in MBC, these are all for patients who have an ESR1 mutation. With early-stage breast cancer, the FDA is expected to make a decision next month on the drug giredestrant, and it will not require ESR1 mutation testing. I’ll tell you why in a second. It’ll be for anyone, but it will be done with ovarian suppression. So for our premenopausal women who maybe only need tamoxifen, this would not be the drug for them because we don’t necessarily want to add ovarian suppression. But in the studies, using giredestrant compared to your standard-of-care endocrine therapy reduced the recurrence by 30%. So pretty promising.

(24:45):

Again, the study was without your CDK 4/6 inhibitor, so we don’t know what that’s going to look like. And we wouldn’t use the two together. So there’s a lot of nuance to it. But the FDA is expected to make a decision on this, and it’ll be interesting to see cost and availability. There’s going to be a lot of people who want the drug when it’s approved. And so there’s a lot of questions about manufacturing and accessibility and insurance coverage. So I think more to come, but this is what I am most excited about right now.

(25:19):

The big question that I get asked all the time is: If SERDs are approved in metastatic breast cancer and people need to have an ESR1 mutation, why don’t we check for that ESR1 mutation in early-stage breast cancer? ESR1 mutations are essentially a marker of resistance to an aromatase inhibitor, and to tamoxifen as well. What they mean is that the estrogen receptor essentially is just turned on. It is always active. So blocking estrogen doesn’t really matter because the estrogen receptor is just on, on, on.

(25:49):

When we monitor for the ESR1 mutation in metastatic disease, it tells us that someone has developed resistance to an aromatase inhibitor and we can actually switch them to one of these drugs that are approved in MBC.

(26:05):

So I’ve gotten a lot of questions: If ESR1 mutations are a marker of resistance to, let’s say an anastrozole, why don’t I do that in early-stage breast cancer to find out am I at risk for recurrence or why are we not going to use that in early stage. And the thing with the ESR1 mutations is that they don’t develop right away. They develop, these are mutations that the cancer cells develop as a result of exposure to an aromatase inhibitor. Remember, cancer cells, their whole goal in life is they want to travel and they want to grow. And so we try to block them with something and they go, Well, how are we going to overcome this? They will find a way out. And so one of the ways that they try to develop resistance is by turning on this ESR1 mutation.

(26:51):

A way I like to think about it is if you’re trying to go somewhere, let’s say you’re trying to come to the LBBC Summit and you are driving here and there is a detour, you’re not going to go, “I’m going to go home.” You’re going to find your way around the detour. Now it’s going to take you longer, you might be an hour late, but you’ll get there. And it’s the same thing with the cancer cells. We try to block them with the aromatase inhibitor and they will find a way. They’re like, All right, what else can we do? And so this is their way of overcoming the blockages we have set up for them.

(27:19):

The ESR1 mutations are not present right away. They emerge as a result of treatment with an aromatase inhibitor. And about 40% of patients with metastatic breast cancer on an AI will develop an ESR1 mutation. But in early stage, when you are taking an aromatase inhibitor, most people do not have active disease. And so that ESR1 mutation is not going to develop, and we wouldn’t check for that. We could consider, and we’ll talk about that next, is the role of circulating tumor DNA, which is looking for active tumor DNA in the blood, and that is appropriate for some people. But for ESR1, that is not something that we will check for or currently check for in early-stage breast cancer.

(28:04):

Before we talk about circulating tumor DNA, I want to briefly touch on HER2DX. This is a new biomarker for HER2-positive, early-stage breast cancer. It is in a lot of ongoing validation trials. So the thing with biomarkers, you have to prove that they work and you have to prove that they’re predictive and prognostic. We have a lot of data for this biomarker. It is a 27-gene expression assay, but we have to validate it. We have to show that it prospectively impacts outcomes. And so that’s what’s going on right now. So it’s available, but not endorsed by any of our major guidelines just quite yet.

(28:43):

For HER2-positive breast cancer where historically we’ve always given chemotherapy and anti-HER2 therapy, it gives you your risk of recurrence. It gives you a chance of your risk of what’s the likelihood of developing a pCR, meaning all the cancers gone at the time of surgery, as well as an ERBB2 messenger RNA expression score. So it’s going to really help us make some decisions about maybe where we can de-escalate treatment, where we can escalate. And I think in the next 5 years, it will be a bit of a game changer for HER2 positive.

(29:21):

Moving on in our last topic is we’re going to talk about circulating tumor DNA. Hot topic. Who has heard of ctDNA? Who has questions about ctDNA? I do too. Lots of questions. Essentially what circulating tumor DNA is, is its tiny fragments of tumor DNA that are shed into the bloodstream. So as all of our cancer cells die, they shed DNA. And so if there are any cancer cells, they will die and they will shed DNA and we can measure them. There are two ways to measure circulating tumor DNA. You can do what is a tumor-informed assay. So this is a test like Signatera, which actually takes a sample of your original tumor, and it creates an assay that you can measure in the blood. So that personalized test for you is based on your tumor. So that’s tumor informed.

(30:11):

And then there are tumor-agnostic tests that don’t require your original tumor, and they look for patterns in the blood that we see with cancer cells. So tumor agnostic is helpful for maybe somebody who wants to do a test, but they were diagnosed 10 years ago or 8 years ago somewhere else. The pathology is nowhere to be found, and you still want to get that test done. Those tumor agnostic tests can be very helpful.

(30:38):

How do we think about ctDNA? We know that it is prognostic, that having the detection of circulating tumor DNA in your blood generally reflects minimal residual disease or molecular residual disease. And that has been associated with a higher risk of recurrence and worse prognosis. The challenge right now is we don’t know what to do with this information.

(31:03):

This is just an example of the difference tumor-informed versus tumor-agnostic assays.

(31:11):

If you have, for example, I’ll show you, there’s a recent analysis that looked at 18 different studies, nearly 1,700 patients, and they found that patients who had a positive ctDNA had nearly a seven-times-higher risk of recurrence. And then if you break it down like at which point you have the ctDNA. Was it negative then became positive? Was it positive then became negative? Those numbers differ, but kind of as a whole, nearly seven-times-higher risk of recurrence. And we know that you will see that recurrence in the blood on average about 6 to 15 months before you see it on a scan.

(31:48):

This obviously sounds very promising. Why wouldn’t we want to find something earlier? There’s a couple of challenges to that. We don’t know yet that finding something earlier and starting someone on a treatment earlier actually makes a difference in the long run. Are we impacting outcomes or are we just putting someone on treatment for an extra year? So that’s number one. We don’t know what treatment to put someone on.

(32:12):

So if I get a positive ctDNA, so blood test is positive, and I do a PET scan and I do a brain MRI and I do all my scans and I don’t find any cancer on the scan, I know that sometime in the next, on average, 6 to 15 months, that cancer is going to develop on that scan, that eventually we’re going to see something on that scan. So what do I do in that year, sometimes up to 3 years? Do we put someone on a treatment? Well, what kind of treatment? That’s a lot of questions. Or are we scanning them every 3 months waiting for something to show up on a scan and imagine living with that anxiety of it’s going to come back, but I can’t do anything about it yet.

(32:53):

And so that’s why it has not yet been routinely for everyone integrated into practice. There are a number of clinical trials. A couple of clinical trials that we recommend. So if someone says, I do want to do ctDNA, there’s a number of ongoing trials, these are just some of them, that are changing treatment. So if you get a positive ctDNA and nothing on a scan, can we intervene with maybe a different CDK 4/6 inhibitor, maybe with a SERD, maybe with a antibody-drug conjugate for different HER2 treatment? Can we intervene early and delay or postpone that recurrence on a scan? So for people who are doing ctDNA testing, who have a positive test but a negative scan, we really try to get people into clinical trials to hopefully answer that question. And I know there’s going to be a lot of questions on ctDNA and I’m happy to answer them.

(33:52):

Why it’s not yet routine. Again, because we don’t know what to do with the results. We haven’t yet shown that if we act early on molecular or residual disease, so meaning positive ctDNA negative scans, that we can improve survival. We’re putting people on treatment that has a lot of side effects early and we have to show that that makes sense. It doesn’t work as well for some disease types. So it’s not as good in lobular. It’s not as good in hormone receptor positive. It’s better in a triple negative or a HER2 positive. Those are tumors that shed more cells and DNA into the bloodstream. So you can have a false negative, meaning you get a negative ctDNA and we’re excited and we’re reassured by that, but it’s not actually false. And rarely you can see false positives as well. But if we are using it, we do want to recommend a clinical trial.

(34:46):

And I do have patients who’ve said to me, I talk about it with everyone and I have some patients who say, “I don’t want to know because I can’t do anything about the results right now and I don’t want to live with this fear.“ And other people say, “I need to know. It helps me to get as much information. And if I’m going to recur in a year, I need to know that I need to prepare. I need to make plans.” And so for them, we do it. And so I think it’s really at this point as of today in 2026, a very individual discussion. Our guidelines do not recommend it routinely outside of a clinical trial, but I recognize that it might be a right choice for some people.

(35:25):

These are some of the ctDNA questions. How do we act on the results? How do we interpret the false positives and the false negatives? Will clinical trials help us to answer these questions? Can we turn a positive result into a negative? So can we change the trajectory? And does it impact long-term outcomes?

(35:43):

So we need trials to help us answer these questions. And until we get that, we won’t probably transition into using it routinely for everyone.

(35:53):

Take-home messages, and I think we have some time for questions. Biomarkers, and I hope that you’ve seen, are really helping us personalize breast cancer treatment more than ever. But as a result, we have more questions than we used to have before, and that is a function of research evolving and new data evolving. Genomic assays can help us determine chemotherapy, who needs to do chemo, who may omit chemo, where we need to do more and where we need to do less.

(36:20):

Biomarkers can help us personalize endocrine therapy as well, as we saw with Breast Cancer Index. Lots of questions about ctDNA.

(36:28):

But I will tell you two things. So years ago, everyone got the same treatment and probably more people didn’t need it and some people needed it and it was very black and white. And what we’ve seen in the last decade is we’re really personalizing it — where we can escalate, where we can deescalate. But biomarkers are just one piece of the puzzle. Everything else matters. Who you are, your goals, your clinical status, your medical conditions, what your priorities are. Biomarkers are just one piece of it. So we should never make a decision solely on the presence of one biomarker. We have to take everything into account.

(37:08):

Thank you for listening. I know there’s a lot of information. Please connect with me. My book is out. Thank you all for your support for that. Thank you. It really is more of a guide to all the things, diagnosis, treatment and everything that comes after. It’s available wherever you buy books. And then feel free to connect with me on social media on Substack. I do a lot more deep dive into the science on Substack. And now I think we’ll do some questions. Thank you, everyone.

Jean Sachs, MSS, MLSP (37:38):

Thank you. It’s so complicated. I mean, I’m just sitting here listening, remembering when there was just tamoxifen as the only option for any kind of prevention after an early-stage diagnosis. So if you’re feeling a little overwhelmed, and I think one thing that you made really clear is there’s so many exciting tests that are happening that could impact things, but we just don’t know the answers yet. When you run to your doctor and say, “I heard Prosigna’s available,” as Dr. Teplinsky said, yeah, the data looks good, but we don’t have the long-term data. So it’s hard to be patient because we just want to do this. All right.

(38:18):

So Charlotte and Chris are going to help me with these questions, but I might as well just get the SERD question out of the way because I know everybody’s really excited about the impending approval of gira and they want to know, we know the survival data looks better, but what are you thinking about the side effects.

Eleonora Teplinsky, MD, FASCO (38:38):

Yeah, so I think this is what everyone’s really excited about. Are SERDs going to be better tolerated? I will say where we have the experience with them currently is in the metastatic setting. And in the metastatic setting, I will tell you that they are better tolerated than the aromatase inhibitors. So that’s something that I’ve seen, less side effects, people just do better with them. In early-stage breast cancer, the big study that we have is the lidERA study. That’s what giredestrant was studied in. And they showed, when you look at the numbers, the side effect profile actually seems fairly similar, but they had less people discontinue the drug because of joint pain.

(39:21):

When you have a clinical trial, that’s not always reflective of what things will happen in the real world. And so we have to be mindful of that and that’s why real world data is really important. Once a drug’s approved, then they study it and see how does it do in the real world. So I’m excited about it. I think it will hopefully be better tolerated, but we’ll need to see once it’s approved what our patients are saying on it.

Jean Sachs, MSS, MLSP (39:45):

Yeah, that’s a really good answer. Charlotte or Chris, do you want to ask the next question or?

Chris Jefferson (39:52):

Yes. Let’s see. Is there any benefit to repeat genetic testing if you were tested 5 years ago and has the panel of genes, could it have changed since then?

Eleonora Teplinsky, MD, FASCO (40:06):

I would say if you were tested 5 years ago, you probably do not need to repeat it. Years ago, kind of at this point, probably 15, maybe 10 years ago, even more like close to 15, they were only doing very limited genetic panels or maybe people were just getting even tested only for BRCA. And that changed, I would say around 2015 where we started doing these very large panels. So if you were tested 5 years ago, you probably do not need to get it repeated. What I would look at is what was done. So ask your team: Did I have panel testing? And was it an expanded panel? If you only had a panel for 3 to 4 genes, yes, you should get it repeated, but realistically, no one 5 years ago was getting those narrow panels done anymore.

Jean Sachs, MSS, MLSP (40:51):

Dr. Teplinsky, do you think it would be helpful to just distinguish between genetic testing and biomarker genomic testing just so people aren’t confused?

Eleonora Teplinsky, MD, FASCO (40:59):

Yes, that’s a great point. So genetic testing, that is testing where we’re looking at the DNA in your genes that were inherited from your parents. So this is present in every cell of your body. So for example, the BRCA mutation. That is inherited from mom or from dad, and that can increase the risk of developing breast cancer and ovarian cancer and other cancers.

(41:22):

That is different than genomic or somatic or biomarker testing where we’re testing the genes or proteins in the tumor. So those are the two differences, something that you’ve inherited and is in every cell of your body versus tumor testing.

Jean Sachs, MSS, MLSP (41:39):

So important to understand the difference. And for the metastatic community, this is something they’re looking at a lot, but I know for early stage it’s not as familiar.

(41:48):

We might as well go to the ctDNA. One question is: If you test positive for some circulating tumor DNA, does that mean you’re metastatic?

Eleonora Teplinsky, MD, FASCO (42:00):

No. If you have a positive ctDNA, so first of all, we have to think about where in the time course is that test done. Generally, we are testing after someone is done with active treatment, once they finish chemo and surgery and radiation, or at least after chemo and surgery. But if you’re testing when you’re newly diagnosed, we know that that positive can become a negative. And so it really depends on where in the timeline you’re testing. So let’s say you test, you get a positive number, positive value, and you get your PET scan and all your scans and they don’t show any active disease. We would not say that is metastatic. We would say that is MRD, minimal residual disease. To have a diagnosis of metastatic breast cancer, we need to see something on a scan. And we need to ideally have that biopsy proven as well because you can see things on scans that do not turn out to be cancer.

(42:57):

So it’s really more MRD, that minimal residual disease that could become and has a high likelihood of becoming metastatic, but it’s not a definition yet. And again, it’s where in your time course you’re getting that test done.

Jean Sachs, MSS, MLSP (43:12):

Right. Charlotte, do you have a question?

Charlotte Safrit (43:19):

So this question is about HER2-low diagnosis. They are asking if those patients are reconsidered for additional treatment.

Eleonora Teplinsky, MD, FASCO (43:28):

So HER2-low, let me explain what that is. It kind of is more prevalent right now in MBC. We think of it as always binary, HER2-positive or HER2-negative. And HER2-low is everything that is not a complete positive, but has some HER2 expression. Because for HER2 positivity, it’s not just any HER2 expression, it’s a very set level. So essentially HER2-low falls in the middle. HER2-low is very relevant in metastatic breast cancer because we have trastuzumab deruxtecan, or Enhertu, which is approved for HER2-low metastatic breast cancer. Currently, we do not have drugs approved for HER2-low in early-stage breast cancer, although some studies are going to be ongoing. And so you might not hear that term in early-stage breast cancer, but you can actually, if you’re interested, you can look in your pathology report and there’s clear guidelines for what falls as to HER2 low. But we don’t use it as a marker currently in early stage.

Jean Sachs, MSS, MLSP (44:33):

OK, that’s helpful. You talked a lot about the Breast Cancer Index test, and these are exciting changes. So for someone who has not had the test yet, can they get it? Can they ask for it anytime, if they’re at 2 years, 3 years?

Eleonora Teplinsky, MD, FASCO (44:48):

So the expanded indication for Breast Cancer Index really means you can get it anywhere between 0 and 10 years. So you can ask for it at diagnosis, and we believe that it should be covered. You can ask for it at 4 years. You can even get it at 7 years. Let’s say you’ve been on your tamoxifen or aromatase inhibitor for 7 years and you’re deciding: Should I go to 10? You can get that Breast Cancer Index even at 7 years.

(45:16):

Now with this expanded indication, you can get it anywhere from diagnosis up to the 10-year mark. Again, we have to be mindful with the expanded indication, how we’re using it. And I always think of BCI as a tool. It’s not the only tool.

Jean Sachs, MSS, MLSP (45:33):

I know. I have to say it’s a little scary to think about getting it right when you’re diagnosed because it’s predicting your risk of recurrence when you haven’t even started treatment yet. I don’t know if that’s a good thing.

Eleonora Teplinsky, MD, FASCO (45:50):

I think that’s the key, right? It depends on how everyone processes some things. Some people cope with intellectualization. Give me all the information. I’m going to do the deepest dive into everything, and that will help me. Other people are more, I like to have things as they come. And so I do think if you get that test at diagnosis to now be told you have a really high risk of recurrence and you need to be on an aromatase inhibitor for 10 years. Imagine if you’re at year 2 and you are struggling and you have to now mentally prepare for that 8 years, I think that can be really hard. And so I think for some people knowing, OK, our goal right now is to make it to 5 years and then I’m going to make it to 5 years and then we’re going to kind of cross the next bridge. I think to me that I find that sometimes more helpful.

(46:40):

And the other part, remember, so BCI does not look at CDK 4/6 inhibitors. All those data were before that. It will not have any data currently on SERDs, so they will need new studies with that. So it’s also hard to say you need 10 years because it doesn’t take into account more modern day treatments. So I still kind of like to do it at that 4 or 5 year mark, but I can see how for some people doing it early will be helpful.

Jean Sachs, MSS, MLSP (47:08):

Yeah, I do hope. There’s a lot of really good training with doctors to sort of figure out just what you’re thinking about psychologically when is it good. Because if you’re also getting the test results about Oncotype or MammaPrint, about is chemotherapy needed, it’s just a lot of testing at a time when you’re really new to breast cancer. So just like the good, the bad of all of this.

Eleonora Teplinsky, MD, FASCO (47:30):

Well, exactly. I mean, information is great, but you have to think about where. It’s the same thing I talk a lot about, about how you consume social media information. You have to be in the right mindset to do that. And I think this is very similar. You’re getting five different tests and how do you make sense of all of that?

Jean Sachs, MSS, MLSP (47:46):

Yeah. OK. Lots to think about. Do you want to take a question?

Chris Jefferson (47:51):

Sure.

Jean Sachs, MSS, MLSP (47:51):

Go ahead.

Chris Jefferson (47:53):

How does accuracy of tests differ between lobular and ductal breast cancer?

Eleonora Teplinsky, MD, FASCO (47:58):

Well, that’s a great question. Lobular and ductal cancers are different. Lobular is the second most common type of breast cancer histology, and the incidence of lobular breast cancer is rising. We know that lobular breast cancers do not respond as well to chemotherapy than ductal cancers. So there are a lot of questions about how do we use the molecular assays, the genomic assays for our lobular cancers. There’s been a big push for lobular specific research, and I think that we need that because for a long time we’ve kind of clumped the two together, but we know they behave very differently. And so I’m hopeful that some of the research, there’s been a huge support for Lobular Breast Cancer Alliance and other lobular based organizations that are really committing to lobular-specific research, so I’m hoping we’ll have more answers on that.

Jean Sachs, MSS, MLSP (48:55):

So then to switch back to another genetic question is someone is asking: What can I tell my daughter in her 20s? I don’t know if she’s a BRCA carrier or not. But what kind of testing should people be considering when they’re in their 20s?

Eleonora Teplinsky, MD, FASCO (49:12):

So if someone is a genetic mutation carrier, so let’s say someone has a BRCA or a CHEK2 or PALB2, any mutation that increases breast cancer risk, a common question is when should my children get testing. And it depends on really three factors. So one is it depends on when you were as the patient diagnosed. If you were as the patient diagnosed at 50, there’s not an impetus to test very early on. You don’t have to test at 20, for example. But if you were diagnosed at 30, that may be something that we need to think about.

(49:45):

The maturity level of the child matters. Generally, we say around age 25 to test, but people have to be emotionally ready to sit and carry those results. It’s not just getting the information, it’s what are you going to do with it. Are you going to make decisions about risk-reducing surgeries? About additional screening?

(50:09):

Some people can handle that at 20; some people cannot handle that until 25. So those are the factors that we want to keep in mind. This is why genetic counseling is so important before you get testing, because one of the things that genetic counselors will do is really understand the emotional readiness of a young person to get that test done.

(50:35):

For people who do not get tested, so there are some patients who will be even close to 30 and say, “I don’t want to know. There’s a BRCA mutation in my family and I’m afraid of the results and I’m not ready to process those.” And so for that population where we know they may be at risk, but they’re not ready to get testing, we will almost treat them as if they’re a mutation carrier with the screening. So we’re not pushing risk-reducing surgeries, but we would suggest an MRI. We would maybe suggest the pelvic ultrasound. So acting as if they have the mutation because we don’t want to miss something, but waiting until they’re ready to get tested.

(51:12):

For anyone who does not have a genetic mutation and wants to know what their children should be doing, which is going to be a more common question, we do say risk assessment is so important. For a long time we’ve said you start testing 10 years before your first-degree relative was diagnosed, and that still holds true, but really starting to have broader conversations about risk assessment. What are the breast cancer risk factors? And not just breast cancer, going beyond that and making an individual plan.

Jean Sachs, MSS, MLSP (51:42):

Yeah. And there are some good risk assessment tools, so I think that’s important for most people. And also I do think we’re eventually going to move to a more personalized screening that not everybody gets the same screening at the same age, but we’re not there yet.

Eleonora Teplinsky, MD, FASCO (51:58):

Slowly, but not quite there.

Charlotte Safrit (51:59):

I was just going to ask, this is going to be a question about advocating to get biomarker testing, despite all of the things that you were talking about in which we don’t necessarily know what to do with that information. If we still want to get it and our oncologist is against it, how do you suggest that people advocate for that testing?

Eleonora Teplinsky, MD, FASCO (52:21):

I think this is probably talking about circulating tumor DNA where people are really being met with a lot of pushback. For other ones, it’s in the guidelines. So I always ask people to say, “Can you please show me the guidelines? And I’d like to get guideline-concordant care.” And I think that’s one of the ways that we can think about starting to combat some of the disparities in access that we see that contribute to disparities in outcomes.

(52:43):

But for ctDNA, where it’s not in the guidelines and people are met with a lot of pushback, I think this is a hard one. There are, I will tell you, physicians that will not order the test for that reason because they’re like, “Well, what do we do with that information?“

(53:03):

First, I always urge people to understand the risks and benefits of getting that test. If it’s very important to you, one, bring someone with you. Bring someone who’s not afraid to get a little loud, and who’s going to push for that because there is, again, you’re there and the doctor is saying no, and it creates a tough situation. You want to be the good patient, so bring someone with you who’s going to speak up and say, “This is really important.”

(53:28):

Explain why you want to get it done. And you shouldn’t have to do these things, but I would say “It’s important to me to get it done because knowing the results would help me with this, and I’m aware that I can have a lot of stress from it,” and so forth. And ultimately, and I will say, look, if it’s something that is critically important to you and you are not getting what you need, that’s what second opinions are for.

Jean Sachs, MSS, MLSP (53:50):

Yeah, that’s great advice.

(53:53):

Another question about SERDs, because there’s several about who’s going to be eligible, is insurance going to pay for it? I know you don’t know the answer to all these questions, and there will be more SERDs that will be approved.

Eleonora Teplinsky, MD, FASCO (54:08):

Most likely — and I have no knowledge of any of this, I have no relationship to the study or the FDA — most likely giredestrant will be approved for newly diagnosed patients because that’s how it was studied.

(54:23):

I have a lot of patients who have said, “I want to switch. I’ve been on my aromatase inhibitor for 4 years and I am suffering and I want to switch or I want a better outcome.” I do not know if insurance is going to cover that. The reason I think it’s going to be an issue is cost. This is not going to be a cheap drug, and I have a feeling, and I do not know, but I suspect that insurance will give a lot of pushback. They might not. I don’t know.

(54:52):

Fortunately, giredestrant is not the only kid on the block. There are a number of studies with elacestrant and camizestrant and I think imlunestrant. So all the SERDs that we are seeing in metastatic are now being studied in early stage, and some of them are being studied at that switch at the 4-year, 5-year mark. And so I think this is a rapidly evolving field that it will change, but strictly with giredestrant, I am worried that we might see some pushback.

Jean Sachs, MSS, MLSP (55:17):

Yeah, that’s a good point. OK. Any other questions you have?

(55:21):

I just want to say this is very complicated. So if you’re feeling like it’s complicated, that makes sense. And Living Beyond Breast Cancer has been doing regular programming on understanding testing. Testing in early stage, especially in the prevention side is so new, but we have a lot of information on testing when you’re first diagnosed. Keep checking in, keep asking questions. I think your advice is great. Ask your doctor, read the guidelines, see what’s right. But it does seem like some of these things, even if they are approved, it may take a while to filter down into the clinic. All right. Well, I want to thank you so much, Dr. Teplinsky.