Ask the expert: Early-stage HER2-positive breast cancer

Adrienne Waks, MD addresses audience questions on symptoms, side effects, treatment options and more related to early-stage HER2-positive breast cancer.

Webinar transcript

Jean A. Sachs, MSS, MLSP:

Hi. It's so nice to have you with us this evening.

Adrienne Waks, MD:

Hi everyone. It's a pleasure to be here. Thank you for having me.

Jean A. Sachs, MSS, MLSP:

Great. I'm going to start looking at the <participant> questions, but before I do that, I'm going to start off with a few to make sure everybody's really understanding this subtype. If you could, explain how doctors define what HER2-positive breast cancer is and why it's really important to understand if you have this subtype.

Adrienne Waks, MD:

Yeah, totally. HER2-positive breast cancer makes up about 20 percent of breast cancer. So, about 1 in 5 women who are diagnosed with breast cancer will get the label “HER2-positive.”

The way that HER2-positive breast cancer is defined, or sort of carved out from the rest of breast cancer diagnoses, is based on a test that the pathologist will do on your tumor biopsy. What they'll do to test the HER2 is they'll stain the protein to see if that HER2 protein is present on the surface of the breast cancer cells. And then, if needed, if they're not sure about the HER2 level based on the staining level of the protein, they'll do a follow up test, which is usually called a FISH test or a SISH test. Basically, in sort of a middle range of staining for HER2, they can do a follow up test to better quantify the number of HER2 protein copies or gene copies that are present in the cancer. So, HER2-positive breast cancer, which is defined how I just outlined, by the pathologists, are tumors where we know that the main, or one of the main, drivers of the cancer cells abnormal behavior is the protein HER2.

Jean A. Sachs, MSS, MLSP:

Great, thank you. I'm going to read this question because it's a little bit long but I think it'll be great to have it in context.

The current NCCN (National Comprehensive Cancer Network) treatment guidelines for HER2-positive tumors under half a centimeter in size and node-negative call for considering adjuvant chemo and Herceptin. But it's not a clear recommendation to provide or not to provide that treatment, because it's efficacy for tumors that small has not been well studied.

I know this is always a problem with HER2-positive breast cancer. You don't have a lot of data. In cases such as this, does small tumor size trump biology, or are there certain characteristics of the biology of the tumor that would trump size, leading to the recommendation to proceed with chemo and Herceptin?

Adrienne Waks, MD:

That's a great question. You know, I get that question a lot. It comes up at our tumor board a lot. It does bear discussion because it's not an area where there's an absolute black and white answer, which is why annoying words like “considering treatment” come up in the national guidelines like NCCN.

What the participant is asking about are tumors that are up to five millimeters – so anywhere from microscopically invasive all the way up to five millimeter cancers that don't, I'm going to presume, have any lymph node involvement. Basically the earliest and smallest variety of a stage I, HER2-positive breast cancer.

We have a number of trials that have been done in general in stage I, HER2-positive breast cancer showing, very excellent outcomes and good effectiveness of treatment regimens that are dedicated to the stage I, HER2-positive patient subset. I can go through those a little bit. We have very good data about how we approach it as a basket of stage I, HER2-positive patients. But the rub that this question is getting at is that if you're looking at all stage I breast cancers, that's any size of tumor up to and including twos centimeters. We always would recommend treatment for the 1.8, 1.9 centimeter cancer, but what about the ones that are still stage I but are quite small – one millimeter, three millimeters, five millimeter, something like that. Should we really use those data that we have from clinical trials that were done in patients who had tumors up to two centimeters, and say that we need to apply them to those cancers that are so very small?

The answer is we don't truly know because we don't have a clinical trial that was done just in those teeny tiniest of HER2-positive cancers. We don't have data specifically for that small subset. We know that if you look at all stage I cancers – but again, that's quite a bit bigger than the question asker is asking about – that there is benefit to chemotherapy plus anti-HER2 treatment. The standard in general, if you're going to consider treatment for a stage I, HER2-positive tumor, is 12 weeks of the chemotherapy Taxol, and then one year of the anti-HER2 targeted drug called Herceptin. That's called the TH regimen. The T is the Taxol, the H is the Herceptin, you put them together and that's the standard treatment for a stage I tumor.

Do we need to use that standard treatment for a one millimeter tumor, a five millimeter tumor, a three millimeter tumor? Again, we don't have dedicated data in that patient population. So I take into account a couple of different things when I talk to patients in that really small size range. One thing that's important, I would say, is the hormone receptor status of the tumor. We know that among HER2-positive breast cancers, half are also hormone receptor-positive and half of them are hormone receptor-negative. It's 20 percent of breast cancers overall that are HER2-positive enough. Half are going to also have an estrogen driven component of their tumor, and half are not going to have an estrogen driven component of their tumor.

I would say for a very small tumor that’s, let's say, a two millimeter tumor that also has really clear evidence that it's hormone receptor-positive, that there's an estrogen driven component, and the patient is willing and open to taking an anti-estrogen treatment pill for 5 years, that's a situation where I wouldn't feel pressed to do a regimen like the chemo and the Herceptin for a full year because you know that that woman has a very small tumor even on that spectrum of one to five millimeters, say a one or a two millimeter tumor, and she is also going to get an anti-estrogen medication and benefit from that anti-estrogen medication. I would say in that sort of super, super small size range, and especially in an ER-positive cancer, I would tend to steer that person away from the chemo and the Herceptin.

On the other side of the spectrum, if you have somebody in the five millimeter range who is hormone receptor-negative, so you're not going to be able to give that patient an anti-estrogen medication that's going to help reduce their recurrence risk, then yeah, I would actually lean a bit more strongly toward recommending the standard regimen, which is the chemo and the anti-HER2 treatment.

The other thing of course that goes into that calculus is that there are side effects associated with the treatment. It’s less likely to be the right fit for somebody who has other sicknesses going on, or other medical problems that they already live with, that's going to make either the long-term or the short-term side effects of something like chemo much more significant and potentially harder to handle.

So the size within the super small range and then the hormone receptor status would be the main things I would consider when I consider whether I want to give the standard treatment in that super small size range. The final thing I'll say, is we do have two big national clinical trials that are going on right now. I'm leading a national trial called the ADEPT trial which is for patients who have a stage I hormone receptor-positive and HER2-positive breast cancer – so that's only about 50 percent of this population overall –looking at using an anti-estrogen medicine with two anti-HER2 medicines with no chemo whatsoever. The trial is asking, well if it's so small and you're going to also get anti-estrogen treatments, do you really need that 12 weeks of chemo, losing your hair, you know, all that stuff you have to deal with? So hopefully we'll have some data to understand if we really need the chemo backbone at all in that population. Those data are years from giving us an answer, but there's an opportunity to participate in getting that answer.

Then, at Dana Farber, we're also leading another national clinical trial called the ATEMPT 2.0 trial that is looking at the medicine Kadcyla, or TDM-1, for six cycles followed by completing out a year of Herceptin. So again, not using a typical chemotherapy like Taxol, but more of a HER2-targeted agent like the Kadcyla. We're trying to figure out how we can individualize treatment for women who have those really small, sort of anatomically low-risk cancers but yet have this HER2 that we want to target. We often don't feel comfortable leaving a HER2-positive patient with absolutely no treatment.

Jean A. Sachs, MSS, MLSP:

That was a good, excellent answer. And you even answered some of the follow up questions. I want to make sure that I got the names of those two trials. It's ADEPT and ATEMPT 2.0, is that right?

Adrienne Waks, MD:

Exactly, yeah, ADEPT is A-D-E-P-T. And then ATEMPT 2.0 is A-T-E-M-P-T and then the 2.0.

Jean A. Sachs, MSS, MLSP:

We'll make sure to link that on our website if anyone is interested. I'm assuming they could check that out.

So, there's a bunch of questions about what are the latest stats on recurrence for early-stage, HER2-positive breast cancer. I know it really depends on a lot of factors, but in general, what do you have to share?

Adrienne Waks, MD:

That’s, of course, a very natural and an excellent question. I'm going to assume that the question asker is asking about the stats for recurrence with a modern treatment regimen. Sometimes patients ask well, what would happen if I had my surgery and I did nothing else in terms of treatment? And that's a different set of statistics, but assuming that that the person asking this question is saying, well, I'm going to get whatever standard treatment my doctor recommends, and then after that over the next 5 to 10 years, what do my recurrence risks look like?

Like you said, this is a very heterogeneous group of cancers within early-stage HER2-positive breast cancer, so there's definitely not a one-size-fits-all answer here. But generally, I break up the answer to that question between patients with a stage I, HER2-positive breast cancer, versus a stage II or stage III, HER2-positive breast cancer. And the reason to break it up in that way is simply that we treat those two entities very differently. We take a very different treatment approach for stage I cancer versus a stage II to stage III, HER2-positive breast cancer. For stage I, HER2-positive breast cancer with the modern standard treatment regimens like that TH regimen that I was just talking about, the risk of recurrence are incredibly, unbelievably, amazingly low. If you receive treatment with a standard regimen for a stage I, HER2-positive breast cancer, the chance that you experience a metastasis, a cancer recurrence somewhere else in your body, over the 5, 7, 10 years from your diagnosis is really in the very low single digits.

Unfortunately, as everybody living with breast cancer knows, there's no absolute, ironclad guarantee of avoiding a recurrence in any situation. And that's an enormous anxiety that all women with breast cancer and all people with breast cancer, men and women, have to live with. But the risks of recurrence are truly very, very low at the stage I cancer treated with one of the modern standard regimens. For stage II and stage III cancers, the good news is we also generally bring those risks very low for the overwhelming majority of our patients. But they do typically require more comprehensive treatment regimens in order to bring those recurrence risks down. For stage II and III cancers, I do think it's a little bit harder to generalize because it's such a heterogeneous group of patients.

What I always tell patients and can always say very confidently is that in HER2-positive breast cancer, we have such a good understanding of what drives these cancers and we have so many, really ever-growing, tools and treatments in our arsenal to effectively target HER2-positive breast cancer. And, if you also have it, the estrogen driven component of those breast cancers that the overwhelming majority of women with those treatments will be cured of their breast cancer. Things that can make risk a little bit higher or a little bit lower are how much cancer is there at baseline and how sensitive the cancer proves to be to the treatments we give. You know, a bigger cancer with many more lymph nodes involved has a little bit more risk associated with it. Usually, we're giving treatment before surgery in cases of a stage II or III cancer. And we know that the cancers that we see at surgery that have had a really good response to those treatments, also have a little less risk associated with them because they're a little more treatment sensitive. But there's a lot of nuance and heterogeneity there.

At the end of the day, we have such excellent treatments for HER2-positive breast cancer. We have so much hope and achieve excellent outcomes with our current regimens.

Jean A. Sachs, MSS, MLSP:

And we've made so much progress from when it was such a hard cancer to treat. If you look back, you have to say this is…

Adrienne Waks, MD:

Unbelievable.

Jean A. Sachs, MSS, MLSP:

Unbelievable.

Adrienne Waks, MD:

In just in 15 years really. Just since 2005 or 2006 when Herceptin was FDA approved for patients with early-stage breast cancer, you know, it was about 20 years ago for patients with metastatic HER2-positive breast cancer. But just in 15 years since we've understood the efficacy of Herceptin the outcomes have astronomically improved.

Jean A. Sachs, MSS, MLSP:

We have a question about biosimilars, wanting to know the difference. We know that there are biosimilars available for Herceptin. Oh, tell us about that.

Adrienne Waks, MD:

It's a great question and the answer to that is quick. There is no difference. Biosimilars are absolutely, positively fine. In my clinical practice, I don't even pay attention to if somebody's getting a biosimilar or not. They’ve been shown to be completely, entirely equivalent to the brand name Herceptin. No problem at all.

And by the same token, I'll mention another question that comes up, another sort of slight variation on the standard Herceptin and Perjeta drugs, the trastuzumab or pertuzumab drugs, are versions that are not administered through an IV but administered subcutaneously. So, in your thigh, with alternating shots in the thigh you can receive either Herceptin by itself as an injection, which is called Herceptin Hylecta , or you can receive trastuzumab and pertuzumab together as an injections in one single vial, which is called Phesgo.

Many patients find that to be a very convenient mode of administration. It takes a lot less time to get, takes literally somewhere between 2 and 5 minutes to get a shot in your thigh as compared to an hour, it could be two hours of getting different IV drugs, infusions, things like that. Those aren't biosimilars, they are the brand name drugs technically, but they're just being administered in a different way. But that's another, sort of cousin root of administration that we also talk about with patients in the clinic. But you know, biosimilars for Herceptin, many of them exist and they're absolutely 100 percent equivalent in terms of effectiveness.

Jean A. Sachs, MSS, MLSP:

That's good to hear. Because we certainly hear from a lot of women, often metastatic, who have been on Herceptin for a long time and are very concerned when they switch. I'm really happy you mentioned subcutaneous Herceptin, because I know, sometimes, we have participants who live far away from their hospital and this can be an option.

There are a lot of questions about side effects and maybe you could talk about heart toxicity or any other side effects of anti-HER2 medicines that people need to be really attentive to?

Adrienne Waks, MD:

In early-stage, HER2-positive breast cancer, there are three, HER2-targeted drugs that are FDA approved. One is trastuzumab, or Herceptin is the brand name of that one, one is pertuzumab, or Perjeta, and then the third one, which we’ll put in a different category, is the drug TDM-1 or Kadcyla, which is used in more of a subpopulation of early-stage, HER2-positive breast cancer. I should say these are the three antibody drugs that are approved. Herceptin with or without Perjeta is probably the regimen and the drugs that most of the people on this call have received and have familiarity with. By and large for both of those drugs, day-to-day side effects, generally the side effect burden is pretty minimal.

You know, I think any cancer treatment can cause a little bit of fatigue. A little bit of skin dryness is pretty common, like some eye dryness or eye watering, those sort of things can happen. Those are the pretty common things with the Perjeta, or the pertuzumab, when you add that to the Herceptin. And we never use Perjeta by itself, it's only with Herceptin. When you add Perjeta to Herceptin there can be a little bit more rash, sort of like acne. Rash on the face is reasonably common, but it can cause rashes anywhere else. It can definitely cause some diarrhea. Then Herceptin by itself usually doesn't cause diarrhea. So there's a little bit of additional day-to-day side effects that can come up with the addition of the Perjeta.

Those are by far the most common day-to-day things that women experience. But you know, what you're also implying in asking the question is, obviously, top-of-mind for physicians and for many women getting these drugs: that much less common, but much scarier side effect of heart damage or a negative heart impact from the Herceptin or the Perjeta. What we know, and we've known this for decades since these drugs were first developed, is that the anti-HER2 drugs, like Herceptin with or without Perjeta, in very rare cases can compromise the squeeze of the heart muscle. We measure that usually with echocardiogram, sometimes with other types of testing, but usually with echocardiograms, which are ultrasounds of the heart that help us assess how effectively your heart muscle is pumping blood.

What we know is that in general, for women who are getting, say, a year, which is the standard duration of Herceptin for an early-stage, HER2-positive breast cancer, we know that in women who are getting Herceptin for that duration of time in the overall population, there's something like a few percent risk. It's around, at most, probably a 3 percent risk of Herceptin with or without Perjeta impacting that squeezing function of the heart muscle and the strength of the heart muscle and reducing what's called the ejection fraction, the effectiveness of your heart pumping out blood. That's very uncommon, but it is scary and we always have to talk about it with our patients. It's going to be on every consent form you ever sign about this drug, and it's rare, but scary.

A couple of things about those very few women who will experience that compromise in heart function. One thing is that even in that very small percentage of women who experience this, it's usually asymptomatic. It's usually something that we pick up because we're doing echocardiograms about every 3 months in a woman who's on a year of Herceptin. So usually, this rare side effect is asymptomatic, but is picked up on these echocardiograms. It's in an even a smaller percent, more like 1 percent, where they actually have any symptoms related to their heart. In addition, it's almost always a reversible problem. So even in the very scary, undesirable situation that you're in that unfortunate few percent of people who experience this, it's almost always reversible.

In fact, what we usually do is we hold a dose or two of the drug, we repeat an echocardiogram to look at the heart again, and usually it has recovered and we can reinitiate the drug in that setting. Obviously, we do that after careful conversation with a cardiology specialist and often with the addition of some sort of heart protective medications. But it is usually totally reversible. So, it's rare, it's usually reversible, and it's usually asymptomatic. But nonetheless, a source of concern. We know that the population of women who are a little bit more likely to experience that rare side effect is women who have some other risk factors for heart damage or heart troubles to begin with, women who have things like long-standing high blood pressure, or who have a history of a heart attack in the past or have really high cholesterol with diabetes, or something like that. It's not that we can't use these drugs in that population, we absolutely can, but we know that those women are at a little bit more risk of these heart side effects. Those might be women who are watching particularly carefully, or we're trying extra hard to control your blood pressure while you're on a medicine like Herceptin. We know it's even less likely if you're a 30 year old woman who is running marathons – nothing is impossible – but then you're really unlikely to be getting these heart side effects.

Jean A. Sachs, MSS, MLSP:

Just some questions related to that, and then we'll move to a different topic. Once you've finished your Herceptin, how long should you be monitored with an echo?

Adrienne Waks, MD:

That's a great question and the answer is, we really don't. It's really not a side effect that happens after you stop the drug. So we generally do the final echocardiogram within the final few weeks or maybe even the final 2 months or so of the Herceptin regimen. And then we don't check again unless, of course, you're having some pains or some shortness of breath or something like that. But this is not a long-term side effect that impacts women months or years later. And that's been looked at very carefully in long-term follow up of the trials of Herceptin with and without Perjeta. There's been a decade, two decades of follow-up looking at the original cohorts of women who got these medications and watching carefully to see if the group that got Herceptin in the past is slowly accumulating heart events or heart problems in the years after the treatment completed, and that is clearly not the case. The risk is posed while you're on the treatment and it's really not after the fact.

That is not the case for a chemotherapy drug that is probably on the minds of many on this call, that's also associated with a different mechanism and a different situation of heart damage, which is the chemotherapy drug Adriamycin, or doxorubicin. That is a drug that we use pretty frequently in women with HER2-positive breast cancers. It’s a drug we use frequently in all subtypes of breast cancer. And that can also be associated with heart damage, and that is a heart damage that can occur 5 years, 10 years later after the chemo has already finished. But, but that's not the case for Herceptin.

Jean A. Sachs, MSS, MLSP:

Okay. We have talked to some women who have an allergic reaction to Perjeta, and so they have to discontinue that. How does that affect the efficacy of their treatment if they're losing the benefit of Perjeta?

Adrienne Waks, MD:

You know, any drug we use to treat breast cancer can cause allergic reactions, though rarely. That's not super common with Herceptin or Perjeta, like it can be with some chemotherapy drugs like Paclitaxel or Taxol. But absolutely it's something that a small percentage of women experience with the Herceptin or the Perjeta. Often we are able to manage it with increased anti-allergy medications, or slowing down the infusion, or something like that. Having something on the spectrum of a mild-to-moderate allergic reaction, we can usually still get past that and manage it. But as the person is implying, there are unfortunately some cases where yeah, we can't feel comfortable continuing the drug if an allergic reaction was really so severe and so scary.

I can certainly say that Perjeta is a standard part of the management of HER2-positive breast cancer. It’s not the most important part by any means. And just as an example of that, it's actually not approved for use in Europe in a lot of the situations where we use it in the United States. Europe is always a little bit more judicious than the United States when it comes to approving new drugs and what their threshold is for the amount of benefit that they need to see. So just to say it is a drug that has effectiveness, it is FDA approved in the United States, but it's in some cases kind of a cherry on top of what are already very effective regimens.

It's not as important as, for example, the Herceptin or something like that. And there are other add-on drugs that we can use in early-stage, HER2-positive breast cancer. Like instead of just Herceptin and Perjeta, you use Kadcyla or TDM-1, or you add the drug neratinib or Nerlynx at the end of a year of anti-HER2 antibody treatment. So in situations where we're limited by an allergy or anything else in giving the Perjeta, there are other add-ons that we can certainly consider. But the good news is it's not the most important drug in the regimen.

Jean A. Sachs, MSS, MLSP:

Right, that is good to know. I'm going to have a Kadcyla question in a minute, but first I do want to ask this, because several people are asking what is the right duration for Herceptin? Six months, nine months, a year, a year and a half? It seems like in this group that's the span. What is your recommendation?

Adrienne Waks, MD:

You know, in some ways it's a very short answer to the question and in some ways it's a very long answer. The standard duration, and the duration that I recommend in all of my patients for Herceptin with or without Perjeta, is one year. There is a subset of patients who are going to switch to the drug Kadcyla, or TDM-1, and in that case you'll shorten the Herceptin duration because you're making it up with a different drug. But the standard duration is one year. There's been a big important trial that compared one year and two years, and two years was no better than one year.

A lot of patients ask, well maybe I should keep going, I'm willing to keep going, when they get to the one year mark. But no, one year versus two years has been looked at and two years was no better. We really don't have any evidence for going longer than a year. So then the question that comes up is all the time is, well, could I go shorter than a year? Six months is the standard duration that has been studied. And six months has been compared to the standard 12 months in many, many different studies. And then those studies have been collected together and the data has been looked at together in what’s called a meta-analysis. There's been a lot of work put into understanding if we really need the full one year of Herceptin or if we can get away with six months.

In general those data have been mixed, but they tend to point to the fact that six months is at the very least nearly as good as 12 months. It's not clear that it's every bit as good as 12 months, but it's nearly as good as 12 months. So, in a patient who's gotten to month six or month seven of Herceptin and is having some terrible trouble with it, like developed some heart damage or something and can't continue, or just some sort of side effect or outside life forces just make it really, really hard to get past that six, seven, eight-month mark, I'm never heartbroken if we can't get out to the full 12 months.

But 12 months really is the standard. And the other thing I'll say is, typically in the United States – and again, you'd actually get a different answer if you ask these questions in Europe – but typically in the United States, the only time that we use Herceptin by itself is for a patient with stage I, HER2-positive breast cancer. In that case we're usually using it with just one chemo, which is the Taxol. And none of the trials that compared six and 12 months looked in that stage I population who only got the one chemo. In the United States, we actually use Herceptin with Perjeta in virtually all stage II or stage III patients. That's not to say all, it's not totally one-size-fits. I don't want anybody sitting in the audience saying, “Oh, I only got the Herceptin.”

There are certainly exceptions, but by and large for stage II and stage III breast cancers, we do use the Herceptin with the Perjeta. And when the Herceptin is paired with Perjeta, given together there, there's never been a clinical trial comparing 12 months to six months. So, we can't really use the data that looked at Herceptin for six versus 12 months and say that we can then use those for people who are getting both drugs together for six versus versus 12 months. That's another limitation of the data that we have. Even though six months really looks almost as good as 12 months, it may be just as good as 12 months. Those data were not obtained in a stage I population. And we don't really use, usually use just Herceptin in a stage II or stage III population. That's for many other reasons and I could go on and on. Twelve months is really still the standard.

Jean A. Sachs, MSS, MLSP:

I hope that was helpful to the group, but that really makes people understand the data is only as good as the data, the information you get. I'm going to ask you a question. There's been obviously a lot about being HER2-low. This is in early-stage, not metastatic. If you have a low FISH test ratio, are you less likely to respond to Herceptin in the early-stage setting? And is it still given?

Adrienne Waks, MD:

I think what this person is asking is about HER2-positive cancer, right? Among HER2-positive cancers there is a spectrum of positivity. Some people are really, really, strongly HER2-positive and some people are a little HER2-positive, but they do meet the criteria for being HER2-positive. The answer is that it makes some intuitive sense. I think it has been shown that if your cancer is less strongly HER2-driven that you may derive a bit less benefit from Herceptin. But that doesn't mean that those patients don't do as well in the long-term, because we're often we're making up that benefit with anti-estrogen medications, because often those are cancers that are a little HER2-positive because they're also estrogen receptor-positive.

That's a very common population where we see a little less strong HER2 positivity – still positive, but it's a little less strong probably because there's sort of mixed behaviors of those cancer cells where some of them are estrogen-driven and some of them are HER2-driven, so they're not as HER2-positive, but they're getting their fuel in other ways and we can target that in other ways. The answer is that yes, it is pretty clear that the patients benefit a little less from Herceptin if they're less HER2-driven, which makes sense. But again, that doesn't translate into worse outcomes in the long-term. It just means that we have to think about it, look at the cancer sort of holistically and figure out are there other medications and other ways that we can use to target those cancer cells.

So it doesn't mean that you have a worse outcome, but yes, in a randomized trial of Herceptin, which was done back, you know, 15 and 20 years ago, there is a little less benefit from Herceptin in those populations. But that doesn't translate into worse outcomes. I will say to as a follow up, which was maybe your original question, yes, Herceptin is still the standard. Even if we know that your benefit from it is a little bit less, that doesn't mean that you don't benefit from it. And absolutely receiving Herceptin is still the standard of care. So there's still benefit, and it's absolutely a standard of care. Even if your FISH ratio is low I would unequivocally still recommend it. But yes, the benefit from that particular component of the treatment regimen is a little bit lower.

Jean A. Sachs, MSS, MLSP:

Thank you. There's a couple of questions about the timing of do you do adjuvant chemotherapy or surgery? The specific question is if you are HER2-positive, what are the other criteria to have chemo first and then followed by surgery if you're going to have a mastectomy or a double mastectomy?

Adrienne Waks, MD:

So again, there's a short answer to that question and a very nuanced, middle ground answer to that question. But the short answer to that question is that, at least in the United States, typically if you have a stage I, HER2-positive breast cancer, which is a tumor that's up to two centimeters and the lymph nodes are not involved, then you would have a surgery first and then you'd get your chemo and your Herceptin in the postoperative setting. You'd do your surgery first and then everything else would happen after surgery. Whereas if you have a stage II or a stage III HER2-positive breast cancer, which is any tumor that's bigger than two centimeters, 2.1 centimeters and beyond, or any tumor that has any lymph node involvement, then you get some chemotherapy with anti-HER2 treatment first, before you go on to surgery.

If it's helpful, we can go through the reasons why we would do things in that order, but it's somewhat cut and dry. Stage I, you go to surgery, for stage II and III, you have some preoperative chemo and other medicines. However, there is sort of a controversial middle ground that can go both ways, which is the bigger stage I cancers that are not quite stage II, but are bigger stage I. Those are cancers where the tumor size is in the T1 C range which is a tumor between 1.1 and 2.0 centimeters where we don't suspect lymph node involvement. There's honestly a lot of controversy. That is a stage I cancer, but it's a little bit of a bigger stage I cancer.

I would say in many cases it's a little bit more of an individualized discussion and could go in sometimes both ways. In a very broad guidelines, stage I will typically go to surgery first, especially if we're really convinced it's stage I. You've had all the imaging, we've really felt really hard in your underarm and we're really confident it's going to be stage I, and generally those will go to surgery first. And stage II and stage III would have medications first. There are exceptions in the other way, too. There are absolutely patients who have a stage II cancer, usually not a stage III cancer, but a stage II cancer where, for various reasons it turns out to be best to have their surgery first. But as a broad guideline, we break up stage I versus stage II and III.

Jean A. Sachs, MSS, MLSP:

Okay, that's helpful. There are a lot of questions, so I'm just trying to figure out where to go next. There are a lot of questions about risk of recurrence and how often should you get scans, should you get scans at all. But before we get into that, there is a question. There is a woman who finished her chemo and was told, “Keep your port in because we're actually now going to do immunotherapy.” And she was wondering, is it common for people with HER2-positive breast cancer to have immunotherapy?

Adrienne Waks, MD:

It's not common. No, it's not common for patients with HER2-positive breast cancer to receive immunotherapy. The immunotherapy that I'm talking about here, because it is a very broad definition, the immunotherapies that we're thinking about using in breast cancer are drugs that are targeting either PD-1 or PDL-1. The most common one that is approved in triple-negative breast cancer is pembrolizumab or Keytruda. We use that all the time in women with both early-stage and metastatic triple-negative breast cancer. It's FDA approved in both of those cohorts. That's a drug that's targeting PD-1. Immunotherapy is a type of drug that's working totally differently from chemotherapy. Immunotherapies are working not by killing cancer cells directly, but by sort of unmasking your tumor for your immune system so that your immune system can basically fight your cancer for you.

It's unmasking your tumor and activating your immune system so that the immune system can hopefully kill off your cancer for you. That's the idea. It's a totally different mechanism of immunotherapy compared to chemotherapy or anti-HER2 treatments. I get questions about this all the time in clinic. Immunotherapy in HER2-positive breast cancer specifically, unfortunately, hasn't had effectiveness yet. I absolutely have hope. We have so much progress to make in the way that we use immunotherapy in HER2-positive breast cancer, and so many new immune pathways that we can exploit and so many new drug combinations that we need to explore. I really am hopeful that we'll figure out a way to use immunotherapy in HER2-positive breast cancer. But at this point, to be honest, it's been a little bit of a disappointment so far.

There was a recent trial that was published called Impassion050 that was published just within the last couple months that did a comparison for women who had HER2-positive breast cancers that were lymph node positive, sort of later stage II or stage III, HER2-positive breast cancers where a women got a standard chemo regimen, they got standard Herceptin and Perjeta and they were randomized to receive an immunotherapy drug or not. And that trial didn't show a benefit to receiving the immunotherapy drug for those women. That really was the most important test we've had so far about whether we should incorporate this type of immunotherapy drug into our treatment of early-stage, HER2-positive breast cancer.

The treatment and the trial was negative, unfortunately, it didn't show benefit. Now the good news is we get really good benefit from the existing treatment, so that's great, but the bad news is we didn't add on additional benefit with immunotherapy. That was true for women whose tumors didn't express the marker PDL-1 and did express the marker PDL-1. Those results didn't look great for immunotherapy.

I obviously don't know the particular question asker’s situation, but you know, there might be some cases where you think a cancer is closer to a triple-negative subtype, and that might be a situation where you talk to somebody about going a little outside the textbook and incorporating immunotherapy, because in triple-negative breast cancer we do incorporate immunotherapy as a standard of care. But for a true HER2-positive cancer, it's not part of the current standard.

Jean A. Sachs, MSS, MLSP:

Let's get to ongoing surveillance. There are a bunch of questions for women who have finished their treatment. They want to know, why aren't I getting scans? Wouldn't it be good for me to know something early? What do you, what do you recommend with your patients?

Adrienne Waks, MD:

I have nothing but the most frustrating, unsatisfying answer for you here. I totally acknowledge that. I see breast cancer patients in clinic all the time. I was in clinic for the whole day yesterday. I probably answered this question 10 times and I would ask it too, you know? That's just a very, very common question and worry, and absolutely, understandably so for breast cancer survivors. The reason that anybody is asking that question – when you're out in the mall, somebody's asking you like, “Well, what, what did your last scan show? You know, how did it look?” It comes up all the time, every day. And you know, the reason that you're asking that question is because the hope would be, well, if I could get a PET scan or I could get a CT scan, or I could get, you know, my liver function test, or I could have tumor marker proteins checked in my blood like they do in colon cancer survivors, if I could have some of those markers checked, then maybe my doctors would find a recurrence of my cancer sooner and then they could treat it more effectively.

Maybe I would live longer, maybe I would have fewer symptoms, or something like that. That's an absolutely, positively natural thing to wonder. All of our patients are looking for, we're looking for an early detection marker, like a PET scan or tumor marker protein, something that we could do to detect a recurrence of breast cancer and treat it sooner, so that you would have a better outcome, so that their recurrence wouldn't be as big of a deal and would be more effectively treated. And unfortunately what has been done is we've done a number of clinical trials looking at scans and looking at lab tests and looking at tumor markers to understand if they fit that bill and check that box as early detection markers, and unfortunately, what all of those data have shown is that they're not early detection markers. Even though it is true that when you do CT scans every six months or every 12 months or something like that, or you check tumor marker proteins, you can pick up breast cancer recurrences slightly earlier than if a woman developed a symptom, that unfortunately doesn't translate into treating that woman better so that she has a better quality of life or does better in the long-term with her cancer. They've been looked at, they've been explored, but they're not early detection markers that help us treat you better in the long-term. They're detection markers, but they're not early detection markers. What you really want, what we really want, what we all really want, is a marker that we could test that would tell us before we could see it on a scan or before it made a tumor marker show up in your blood, tell us that there could be microscopic sort of cancer debris in your blood, so we could treat you then and improve your outcome.

We would want to make you live longer or better. That's like a holy grail in breast cancer to find an early detection marker like that. I'll talk about one in a second that looks promising right now. But the current tools that we have are unfortunately not good enough to do that. CT scans, PET scans, tumor marker proteins in the blood, they're detection markers, but they're not early detection markers. They don't allow us to pick up recurrences soon enough to change the course of the breast cancer in any way. We need an early detection marker.

The most promising one that there's a lot of hope and excitement about right now is called circulating tumor DNA. And you know, I share that patients are super excited about that. There was just an article about it in The New York Times like three days ago or something like that, and I totally agree, that looks promising and interesting for sure. But we don't have enough data yet in breast cancer, or in almost any cancers. They use it a little bit in colon cancer, but certainly not in breast cancer, in almost any cancer. We don't have enough data to tell us that it's going to do what we want to do, which is be that early detection marker. I think in next few years, there will be an opportunity to participate in trials that are looking at that marker. I absolutely encourage patients to get involved with those trials. But even those trials, we're not going to fully understand their results for another number of years. At this point absolutely we want to hear about your symptoms, we're going to 100 percent do a scan if there's something that just isn't adding up or if there's a symptom we can't explain, but as just pure surveillance, unfortunately the tools we have are too crude to have the benefit that you want them to have, and we want them to have.

Jean A. Sachs, MSS, MLSP:

Yeah, this is always a hard question and it's a common one. There's a couple people asking how do your patients tolerate Kadcyla?

Adrienne Waks, MD:

Well, Kadcyla, which is TDM-1, is what's called an antibody-drug conjugate. The T in TDM-1 stands for Trastuzumab. Kadcyla is Herceptin, it's the exact same molecule, Herceptin, but it's attached to a molecule called DM-1, which is where you get the TDM-1. And the DM-1 is a chemotherapy, so it's an antibody-drug conjugate, it's the anti-HER2 antibody Herceptin attached to, or conjugated to, the chemo molecule DM-1. So, it’s kind of a hybrid between a Herceptin-like medicine and a true chemotherapy. And it doesn’t quite have as minimal side effects as just Herceptin, but it usually doesn't have as many side effects as a standard chemotherapy like adriamycin or carboplatin or paclitaxel.

It's kind of in-between, and so some women have more trouble tolerating and experience more side effects with the TDM-1, or the Kadcyla, than with just Herceptin or even Herceptin with Perjeta. One of the most problematic side effects is that it can cause neuropathy. Basically, all of our patients with HER2-positive breast cancer have already gotten some sort of chemo medicine that can also cause neuropathy. And usually we're layering the Kadcyla, or the TDM-1, onto it. That can be really a particularly difficult side effect. You can lower the dose of TDM-1. herTe are two different dose reductions that are standard. It's just like a chemo in that way, but there are also standard dose reductions. Just because you have trouble with side effects at the standard highest dose, we still may be able to control them better by going down on the dose, unfortunately. It's usually not as hard as chemo, but, but it's definitely harder than just Herceptin.

Jean A. Sachs, MSS, MLSP:

Thank you. And there's someone who's asking, and I'm sure everybody wants to know, the circulating tumor cells, what trial were you referring to? They want to look that up.

Adrienne Waks, MD:

What, what one could they participate on? I see.

Just to draw distinction, I'm talking about circulating tumor DNA, which is like literally, genetic debris from your cancer that's floating in your blood. Circulating tumor cells, which is not just the DNA, but the whole cell, those were looked at about 10 years ago in many, many different trials to see if they were an early detection marker. And the bottom line is that in breast cancer, they again, just weren't that helpful, unfortunately. Now circulating tumor DNA is trying to take over from them and do a better job. At this particular moment, I'm not aware of the trial that I'm thinking of, although I'll tell you a little more about it being open to patients. I don't have a number or a specific name. But the trial I think is going to be for HER2-positive breast cancer patients, I think it's going to be all three subtypes of breast cancer. It's definitely triple-negative. That trial is being run through a big cooperative group in the United States called the Alliance for Clinical Trials and Oncology. It’s not open yet, so I don't know what the number is going to be, but if you looked up something like “Alliance for Clinical Trials in Oncology” and “breast cancer” and “circulating tumor DNA,” you might find more information that way. But to my knowledge, it's not actually open yet.

Jean A. Sachs, MSS, MLSP:

Okay, great. And thanks for the distinction between circulating tumor cells and circulating tumor DNA.

So, there are a couple questions about mammography screening after being treated. Particularly if you have dense breasts, which is getting a lot more attention. Should it be every six months, every 12 months? Do you recommend MRI? What's the protocol?

Adrienne Waks, MD:

The answer is pretty individualized, I would say. Sort of the bare minimum that our patients always get if they're breast cancer survivors and still have breast tissue – so this doesn't apply to you if you had a bilateral mastectomy – but if you still have breast tissue on one or both sides, then the most important screening tool that we have is an annual mammogram. Just a once-a-year mammogram. There isn't any data telling us that we do better if we do those mammograms every six months, you know, once a year is the standard interval. And again, this gets very individualized, you really would want to talk to your medical oncologist and your surgeon and maybe even also your radiation oncologist about what's right specifically for you.

There are some situations where we do the mammograms once a year, but we alternate them with an MRI of the breast tissue that's also once a year, but on the opposite six months. So every six months you're getting one or the other, either a mammogram or an MRI. There really isn't a situation where we do screening mammograms alone every six months unless, of course, they're following some abnormality or something like that. But if we're going to do every six months screening, then it would be with an MRI alternating with a mammogram. The main group where we do MRI alternating with mammogram is women who have BRCA1 or 2 or certain other mutations like PALB-2 mutations that would presumably cause them to get breast cancer in the first place. So we always recommend doing the MRIs as well as mammograms, but in other groups like dense breast tissue or women whose original cancer wasn't seen on their mammogram for example, then you know, it's a very valid question, but one that I would sort of bump back to the individual care teams because it's pretty individualized there.

Jean A. Sachs, MSS, MLSP:

So a question here, is neratinib prescribed for early-stage, HER2-positive breast cancer after completing the year with Herceptin and Perjeta?

Adrienne Waks, MD:

In some cases, yes. The medicine neratinib, or Nerlynx, which is a once a day oral medication, has been shown it's an anti-HER2 pill type of medication called a tyrosine kinase inhibitor. It has been shown in a randomized clinical trial that was called the ExteNET trial. It has been shown for women who are completing a year of just Herceptin. That's the important thing. They weren't getting Perjeta, they were just getting Herceptin. But in women who are completing a year of Herceptin after they had gotten whatever chemo they needed, finished their year of Herceptin, got their surgery, got their radiation, if they were randomized to either get the neratinib or to get a placebo, there was a little bit of a benefit, a little bit of a lower recurrence risk for the women who got the year of neratinib pill.

It's not even something to think about until after you've finished your year of everything else. But it is an oral medication that's been shown to add some additional benefit when you take it for one year after completing that year of Herceptin. We don't use it that widely, however, and there are a couple of reasons for that. One is that even though it looked like it had a little bit of benefit, it wasn't a lot of benefit and it really seemed like the benefit was limited to the patients who had both hormone receptor-positive and HER2-positive breast cancer. We really almost never consider it in a woman with a hormone receptor-negative, estrogen receptor, progesterone receptor-negative, HER2-positive breast cancer, but we might consider it in somebody who's estrogen receptor or progesterone receptor-positive and HER2-positive.

That's one thing. The second thing, which I already highlighted, is that it was actually studied before Perjeta was the standard and it was also studied before TDM-1, or Kadcyla, was part of the standard. So, we have no idea, those are already adding on different anti-HER2 drugs to that Herceptin backbone. It's entirely plausible that maybe you don't need the neratinib anti-HER2 drug. If you've already gotten all this additional benefit from your Perjeta drug, and potentially also Kadcyla, then you're already using three anti-HER2 drugs. It's really not clear that a fourth one is going to add anything in that case. That's just because the trial was done before those additional drugs were part of the standard. In general now, when we consider using it, it's in a population of patients who have already received and presumably benefited from more than just Herceptin.

That's the second big reason why it's hard to know if patients really need it at this point. The final thing is it causes pretty significant diarrhea. It's not a totally side effect-free year of your life, and at that point you've already been through probably well over a year of chemo treatments and other drugs and surgery and radiation. It's a hard year to add on at the end of what's already a very long course of treatment. So yes, we do use it. I do use it, I use it in women who have hormone receptor-positive and HER2-positive breast cancer who had disease where I'm really worried about them, like they had a lot of lymph nodes involved or something like that. They didn't have as good of a response as I hoped to treatment that they got before surgery, and maybe had trouble, like where they couldn't tolerate the Perjeta and couldn't finish it. Maybe that's somebody where since they couldn't get the standard anti-HER2 add-on drug, that would be a time to think more about adding something on like the neratinib. So, it is used, but it's not used super widely for those reasons.

Jean A. Sachs, MSS, MLSP:

Right. Great. I can't believe it, but we're close to being out of time and I do want to ask you what is new that may be coming out of treatments for metastatic HER2-positive breast cancer that may become applicable in the early-stage? What should we be looking out for?

Adrienne Waks, MD:

I think the two most exciting trials that are going on right now, and this is not a comprehensive answer, but I'll highlight what I think are the two most exciting trials that might bring us in new directions. For early-stage, HER2-positive breast cancer there are two trials that are trying to borrow from drugs that have been really successful from metastatic HER2-positive breast cancer. For a population of patients who had some chemo and anti-HER2 treatments first and then when they got to surgery, still had some cancer left in either the breast or the lymph nodes, we know that that's a way of picking cancers when you get to your surgery and there are still some cancer cells left. We know that's a way of your cancer showing us that it wasn't optimally sensitive to the treatments that you got in that first portion of your treatment.

There's a lot of clinical trials that are going on to help us understand, once that woman has finished her surgery and maybe finished her radiation, what should we do in the postoperative setting? How can we do better than the standard as we try to bring that woman's risk down as low as possible? Two trials that are important that are going on right now, one of them is called CompassHER2 RD, where the RD stands for “residual disease.” This is women who have residual disease where the preoperative treatments didn't kill all the cancer cells. That trial is taking women and all of those women get Kadcyla, that's the current standard, but it's randomized to Kadcyla with or without the drug tucatinib or Tukysa which is an anti-HER2 pill that has looked extremely effective in metastatic, HER2-positive breast cancer.

So that's one important trial and if that trial's positive then we would change to not just using TDM-1 but to using TDM-1 with the Tukysa or the tucatinib pill. So that's one trial that's going on that's important. That's CompassHER2 RD, looking at the Tukysa, or tucatinib, pill. And then the second trial that's going on that's very important and exciting is called DESTINY-Breast05. Whenever you hear a clinical trial that has the word “destiny” in it, you know that it's a trial of the drug and Enhertu, or trastuzumab deruxtican, which has been a revolutionary, exciting drug for women with metastatic, HER2-positive breast cancer. So now, of course, we want to know if we can bring Enhertu from the metastatic setting and have it benefit women with early-stage, HER2-positive breast cancer.

There are going to be all sorts of trials in Enhertu in early-stage, HER2-positive breast cancer. But the one that's going on right now that I think will result first and will be very exciting to see is that same population of women who have residual cancer left after they've gotten their preoperative treatment and then their surgery, and randomizing them to either the standard, which is TDM-1, or Kadcyla, versus the Enhertu drug. The question that's asking is, can we do better than TDM-1? Can we actually replace it with Enhertu and achieve better outcomes for those women? Both of those trials are enrolling now, they're enrolling nationally, so there's an opportunity to participate on either of them. And those will be, I think, really interesting results.