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Everything You've Always Wanted to Know About HER2

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Published on December 14, 2020

What Should Breast Cancer Patients Know About HER2?

The human epidermal growth factor receptor 2 (HER2) protein has been a common element of breast cancer research, diagnosis, and treatment for decades – but what exactly does it mean? In the Answers Now segment, a renowned breast cancer expert shares everything you’ve always wanted to know about HER2 including an in-depth explanation of the HER2 protein, how and why it occurs, what it means for patients, the available treatment options, and more. 

Dr. Sara Hurvitz, MD, is the Director of the Breast Cancer Clinical Trial Program at UCLA Medical Center. She is joined by host, patient advocate, and writer Andrea Hutton and breast cancer survivor and patient advocate Amy Hash. Together, they will discuss what everyone should know about HER2, whether you’re positive or negative, and how emerging research is improving our understanding of these proteins. 

This program is supported by an educational grant from Daiichi Sankyo. This organization has no editorial control. It is produced by Patient Power and Patient Power is solely responsible for program content.

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Transcript | Everything You've Always Wanted to Know About HER2

Andrea Hutton: Hello, everyone. I'm Andrea Hutton. I'm your host for this installment of Answers Now. Today's show will focus on what it means to be HER2-positive with breast cancer in 2020. I was diagnosed myself with HER2-positive metastatic breast cancer in 2009. So, this topic is very personal to me. I am extremely pleased to have one of the world's most renowned HER2 experts join us today, Dr. Sara Hurvitz. Dr. Hurvitz, welcome. Dr. Hurvitz is the Director of the Breast Cancer Clinical Trials Program at UCLA Medical Center, and Associate Professor of Medicine at David Geffen School of Medicine. Welcome, Dr. Hurvitz.

Dr. Hurvitz: Thank you so much for having me.

Andrea Hutton: We also have our HER2-positive patient advocate joining us today, Amy Hash. Amy is joining us from San Francisco. She's currently finishing her TDM1 treatment and is scheduled for reconstructive surgery in early 2021. Amy, thank you for joining us.

Amy Hash: Thanks for having me. I'm excited to be here.

Andrea Hutton: Amy, I'd love to have you start our conversation. Can you tell us a little bit about the moment when you first learned that you were HER2-positive? Did you understand what that meant? Can you tell us how you felt that day?

What Was Your Reaction to Finding Out You Were HER2-Positive?

Amy Hash: Right. So, this was the first time I met my oncologist, and this was after two weeks of all of the tests and the biopsies and the scans, and all of the things that someone goes through when you get diagnosed. And I was told I was triple-positive. And I did not know what that meant. I had never heard of HER2. And I thought, "Oh, there are three options for cancer and lucky me, I got all three of them," was my initial thinking.

Andrea Hutton: It's a very intense thing when you first get diagnosed and you have to learn all of these new terms and go down that rabbit hole of finding out all of the information. So, Dr. Hurvitz, can you review for us exactly what the HER2 protein is and how it's important in breast cancer?

What is the HER2 Protein?

Dr. Hurvitz: In the 1980s, Dr. Slamon at UCLA found that about 20% or 25% of breast cancers are characterized by having too many copies of a certain gene called HER2. So, if you remember, you have two copies of every gene in your body, one from mom and one from dad. So, every cell should have two copies. Well, something happens in the cell and too many copies of that gene for that protein called HER2 are made. And that leads to way too much of the protein being expressed on the cancer cells. And that distinguishes the cancer cells from normal cells that have a low level of expression of that protein.

And he went on to show that those patients who had HER2 amplified or HER2 over-expressing breast cancer had a much worse prognosis. They had a higher likelihood of developing metastases, a shorter long-term survival, even with Stage 2 breast cancer, which should be highly curable. And so that would have been a really sad ending to the story had he and other scientists not gone on to develop therapies that specifically target that problem, that protein on the cancer cell, one that you just mentioned, trastuzumab, otherwise known as Herceptin. And a number of other molecules since have been made that specifically go after that abnormality in the cancer cell.

Andrea Hutton: So, Herceptin, trastuzumab, is the standard course of treatment for HER2. And I was diagnosed now 11 years ago, and a lot has changed since then.

Dr. Hurvitz: Absolutely.

Andrea Hutton: Yeah. So maybe Amy, you're on a newer treatment. Do you want to talk to us about what that is? And I'm sure you have questions for Dr. Hurvitz about that as well?

What Was Your Experience Receiving Targeted Therapy for HER2?

Amy Hash: Sure, absolutely. So, I started like many people, I did Herceptin, Perjeta (pertuzumab) and actually did Abraxane (paclitaxel) rather than Taxol because I had an allergy to that drug. And then I did AC. And then I finished that treatment, had a lumpectomy and I did not have a pathological complete response. The tumor had less than 1% cellularity in it. So pretty darn close to a complete response, but not totally. So, what that meant was that after my lumpectomy, I would be doing Kadcyla (ado-trastuzumab emtansine), or TDM1. And I read up on the KATHERINE trial, which was part of Kadcyla TDM1 becoming a treatment option, and really saw, "Wow, I'm really lucky that I actually didn't have a pathological complete response," because now I get this ability to have this really great drug. And how wonderful is that?

However, as I was getting ready for radiation, I had a mammogram and they saw something. And they took a biopsy and saw that there was still cancer and it came back positive for HER2. So, then I did three rounds of TDM1 and then had a mastectomy, a unilateral mastectomy. And from that pathology, again, it still had one millimeter of cancer left of HER2. So now, I'm getting ready to finish the TDM1 and I'm looking at my oncologist and I'm saying, "This HER2 was obviously very persistent in me. It does not want to quit. It does not want to die from all of the drugs that we're giving it. So, what's next?" So, I state it to Dr. Hurvitz, my question is what's next?

Dr. Hurvitz: Yeah. So, you present a very interesting situation. I tell patients it's never fun to be an interesting patient case. But there are some things that should be gleaned. First of all, it sounds to me like you have curable breast cancer, early-stage breast cancer. So, this is in contrast to Stage 4 breast cancer where the breast cancer has gone elsewhere in the body. And so, you received neoadjuvant chemotherapy or chemotherapy plus Herceptin and Perjeta prior to surgery. And about half of patients who undergo neoadjuvant therapy that have HER2-positive breast cancer will have what you call a pathologic complete response, but half do not. And if you look at the patients who do not achieve a pathologic complete response or where the therapy doesn't do that for you, you have a higher chance of being in that group of patients with residual disease if the tumor co-expresses hormone receptors.

The hormone receptors, estrogen, progesterone receptors, make the tumor a little more slow growing and less amenable to chemotherapy. And we think that patients with ER-positive, HER2-positive breast cancer benefit the same amount from Herceptin, it's just that the likelihood of having a complete benefit by the time you get to surgery is low. The way I think of it is these tumors are a little slower to develop and grow and they're also slower to regress and completely respond. So, I think the treatment you received with the TDM1 was spot on, and I am not worried that you had a millimeter left at the time of mastectomy. I'm glad that it was taken out, that it was discovered by mammography. And hopefully, if there's any residual cancer that's microscopically present elsewhere in your body, all of this therapy, including the hormonal directed therapy, the anti-estrogen therapy that you'll likely be receiving, is going to address any of that.

Andrea Hutton: So, all of these treatments that we're talking about are specifically targeted to HER2. And I mean essentially, trastuzumab, Herceptin, was the first targeted therapy there was for breast cancer, and this is one of the first things that was discovered. And now, we have all these other options. We have a question from the audience. Why isn't testing for HER2 standard procedure in DCIS?

Why is Testing for HER2 Not Standard Procedure in DCIS?

Dr. Hurvitz: I started practice as an oncologist in 2006 and we only had Herceptin. So that was our one tool, and we were really excited when we had the availability of lapatinib, or Tykerb, FDA approved in 2007. And now in 2020, we have seven FDA approved HER2 targeted therapies with three approvals in the last year. So, because we know what's driving the cancer in HER2-positive breast cancer, that has enabled scientists to develop multiple different ways to target that abnormality. Now in DCIS, DCIS is pre-cancer, it's not an invasive cancer. It doesn't have the ability to metastasize elsewhere in your body. So surgically removing DCIS should be completely curative. You can do radiation to the breast tissue to reduce the chance of a new breast cancer in that breast. But it is a curable disease with surgery alone.

That said, there are some studies that indicate maybe half of DCIS, especially higher grade, is HER2-positive. So, the NSABP, a big cooperative group, recently did a trial where they gave a couple doses of trastuzumab, or Herceptin, with radiation after a patient had a lumpectomy or surgery for DCIS. And they showed there was no benefit to use of trastuzumab in those patients. In other words, it didn't reduce the risk of breast cancer coming back, a new diagnosis in the breast or a breast cancer recurrence. And so, given that we don't want to commit somebody to extra therapy that they don't need, we don't test for HER2 because we don't have a therapy that we're going to use against it that's been shown to benefit patients in that setting.

Andrea Hutton: So, with all these treatments, is possible for cancers during treatment to change from HER2-negative to HER2-positive, from HER2-positive to HER2-negative? Is it usual for it to go one way versus the other? And how typical is it to change status? And how often do you recommend that patients have their metastases or tumors re-tested? How important is that?

Is It Possible for HER2 Status to Change from Positive to Negative, and Vice Versa?

Dr. Hurvitz: So, there are two clinical scenarios. The first is in the early-stage setting. So, Amy's type of setting, where she's got a curable breast cancer and she has a core biopsy that shows she has a HER2-positive breast cancer. She starts therapy prior to surgery. And then at the time of surgery, if there's any residual cancer, typically pathologists will retest the ER and PR in HER2, but not always. HER2 can change, but it's uncommon. Usually, I'd say 90%, 95% of the time, the HER2 level is consistent before and after treatment. However, I do have cases. In fact, one case just last week where the patient clearly had HER2-negative disease prior to her neoadjuvant chemo. And at the time of surgery, had clear HER2-positive breast cancer. And when we went and looked at the pathology samples and had an expert look at them both, there were clearly two separate populations.

So, the chemo we gave killed the HER2-negative population and left behind the HER2-positive breast cancer because we hadn't used Herceptin. So that's a rare situation. In the metastatic setting, there are studies that indicate anywhere around 15% of patients, if you sample the metastatic tumor, the HER2 status is different from the time of their original diagnosis of breast cancer. And that may be for a variety of reasons. One of them is HER2 testing has evolved over the years. We've gotten better. Our guidelines have gotten better.

The way the labs test for HER2 has become more stringent and standardized. And so that may account for some of the differences we're seeing when we compare a patient's original diagnosis five years ago to now. And sometimes, there's a situation where truly there is tumor heterogeneity, meaning the tumor's a mixture of different kinds of cancer, HER2-positive and HER2-negative. And as you treat with one form of therapy, it allows the untreated type of cancer to grow up. That's less common, but it is reported.

Andrea Hutton: And that's what Amy was expressing happened in her case. The specific piece of the tumor that they take in the biopsy, how often can that be a mistaken identification of the characteristics?

Dr. Hurvitz: There's a false result probably on the order of 5% of the time, if you're at a good laboratory. We feel that the gold standard at UCLA is to test the tumors by FISH and by immunohistochemistry. So, immunohistochemistry is testing the protein level on the tumor and FISH is testing, it's actually counting the numbers of the gene copies in the tumor. So, the FISH is a more objective way of doing it. You're just counting the copies. Whereas the immunohistochemistry, the protein, it's a pathologist who stains the tumor cell and then says, "Oh, it looks like this many cells have light staining. This many have moderate staining." So, the FISH testing, I believe, should be the gold standard way to look at HER2 testing. And by FISH, there really should be less than a 5% false negative, false positive.

Now, a question has come up from the KATHERINE study and that is if the patient's tumor starts as HER2-positive clearly in the core biopsy, and then you get the Herceptin, Perjeta chemotherapy regimen and go to surgery and the tumor left at the time of surgery is HER2-negative or HER2 low, does a patient still benefit from TDM1? And the answer we have so far, based on some of the samples studied in that KATHERINE trial, is that yes, TDM1 still benefits patients even if there appears to be loss of expression of HER2, as long as the tumor was originally HER2-positive.

Andrea Hutton: We've gotten a lot of questions too about whether or not it makes a difference where those metastases occur. So aside from the obvious radiation treatment can be effective in different places, but as far as what your results might be, whether the metastasis is in bone, soft tissue, brain, what are the options for people now? How are you looking at patients and the different places where they find metastases? What differences are there?

What Are the Treatment Options for Metastatic HER2-Positive Breast Cancer?

Dr. Hurvitz: Yeah, that's a really good question. Breast cancer can metastasize literally anywhere. But the treatment that we use, the systemic treatment, systemic treatment meaning medicine that we either give by mouth or intravenously, should treat the cancer regardless of where it is in the body. That's with the exception of brain metastases. Brain metastases are a little more challenging to treat because the brain environment is protected by this netting called the blood-brain barrier, which is a capillary network with very tight junctions to try and prevent anything harmful getting into the brain since the brain is the control center of a human body. So, it's been challenging to find therapies that pass through that blood-brain barrier and can actually be effective against metastases there.

However, we do have a new FDA approval of a drug called tucatinib, or Tukysa. And it is a pill that actually does penetrate that blood-brain barrier and target specifically HER2 and has demonstrated very, very promising results. And so, this year, it was FDA approved in combination with Herceptin and chemo called Xeloda (capecitabine) for patients with metastatic breast cancer, with or without brain metastasis. We have a number of other systemic therapies, very, very effective therapies, for patients with metastatic HER2-positive breast cancer that treat - if you take it intravenously or orally, it goes throughout the body to treat the cancer wherever it is.

Andrea Hutton: I know when I spoke to you about a year ago about the study for tucatinib, and the hope was that there would be reduced side effects as well. And how's that going?

Dr. Hurvitz: This is a unique molecule. It's hard for scientists to figure out how to make a pill therapy that's against cancer really specific to the target you want. The problem is that a lot of the therapies that are pills that target HER2 also hit a bunch of other important receptors that are important in normal cells. So, we get a lot of toxicity like rash, and diarrhea, and nausea, and that's been really difficult.

Andrea Hutton: Yeah, I have all of those. Yeah.

Dr. Hurvitz: Yeah, exactly.

Andrea Hutton: Can you talk maybe a little bit about how the side effects from HER2 targeted treatments are maybe different than chemo side effects?

What Are the Side Effects of HER2 Targeted Therapies?

Dr. Hurvitz: Yeah. So, for the pill therapy, neratinib (Nerlynx) and lapatinib, what we call them are tyrosine kinase inhibitors, they hit HER2 which is good, but they also hit something called epidermal growth factor receptor, or HER1, and that causes a lot of diarrhea and rash, skin problems. Tucatinib specifically hits HER2. And so, we don't really see much more in the way of diarrhea. It looks a smidge greater, a smidge higher rate of diarrhea when you add tucatinib to Xeloda and Herceptin compared to just Xeloda and Herceptin. But it's pretty well tolerated therapy. Now, there are other classes of drugs called antibodies. The antibodies are just protein antibodies like we have in our immune system that target HER2, and those include Herceptin and Perjeta. And those are pretty much well tolerated. Very low side effects because there's no chemo component. But the problem is we usually have to give it with chemo. So, then you get the chemo side effects by the chemo you're combining them with.

And then we have this new class of therapy called antibody drug conjugates, which is the antibody stably linked to a chemo payload. And so, the antibody carries the chemo like a smart bomb, delivers the payload to the HER2 over-expressing cancer cell and specifically delivers the chemo to the cancer cell with the idea being that that will spare normal cells. So TDM1's a great example of that. Amy has got hair. It sounds like she's still working and pretty busy. And TDM1 generally allows for that. It does have some side effects, some low platelets and neuropathy and fatigue. But it's so much better than the chemo she went through. I'm sure she can attest to that.

And a newer one is called trastuzumab deruxtecan, or Enhertu, that one has some more side effects just because the payload, the chemo is released around the tumor cell, so it's not as specific. So, you can have things like hair thinning and nausea and diarrhea that are more consistent with what you would see with chemo.

Andrea Hutton: Are there updates from any of the clinical trials, HER2, and other studies that are out or about to be out?

Can You Share Any Information on HER2 Clinical Trials?

Dr. Hurvitz: It's an incredibly exciting time. I mean the tucatinib data really blew us all away. It's very exciting. So, they now have a number of ongoing trials of looking at tucatinib in the early-stage setting. So, adding it to TDM1 for patients who are really high risk and looking at it in earlier line setting in the metastatic setting for stage four breast cancer, because right now it's approved for second and third line and beyond.

There's this other drug in Enhertu that we briefly mentioned just a few moments ago, which is showing just profound activity in patients who are heavily, heavily pretreated with metastatic disease. In this study, half of the patients had more than five prior lines of therapy. There was a patient enrolled in this trial called the DESTINY-Breast01, who'd had 27 prior lines of therapy for her metastatic disease.

And what they found, when we give a patient a study drug on a clinical trial like this and they are so heavily pretreated, we get excited if we see 10% of them have their disease shrink. And in this trial, 61% had their disease shrink. So, this is FDA approved last December based on these very, very exciting data. It was a single arm study, so we're waiting for the randomized trials that are comparing it to standard of care. But I think we're going to be seeing a lot more information about that drug as well.

Andrea Hutton: Well, that's, I mean, very encouraging for all of us. I know Amy was diagnosed young; we're getting a lot of people commenting about how long they can stay on drugs. How long can you expect to be on a treatment?

How Long Can a Breast Cancer Patient Remain on the Same Treatment?

Dr. Hurvitz: Yeah. So just to distinguish, in the curative setting, so stage 1, stage 2, stage 3 breast cancer, there is going to be a finite length of therapy given, typically one year of HER2 targeted therapy like Herceptin and chemo, maybe TDM1, maybe five years of endocrine therapy like tamoxifen (Soltamox) or an aromatase inhibitor if the tumor also has estrogen receptor. Sometimes we use a drug called neratinib in the early-stage setting. So, we have all of these agents from which to choose, but patients aren't on it forever because we assume a pretty large proportion of these patients are cured. So, you want to just give enough therapy, find that sweet spot and then stop, and then get on with life. And in the metastatic setting, however, that's incurable disease. It's a chronic illness, but it is a disease that is highly, highly treatable.

There was data presented at the European Society of Medical Oncology about a month ago with over 20,000 patients from the Netherlands, I believe. Dr. Suzette Delaloge presented these data. Looking at the outcomes of patients based on whether they had HER2-positive, triple-negative, or hormone receptor positive HER2-negative breast cancer, just show that HER2-positive... And it's all metastatic. So, all stage 4. HER2-positive patients are able to live much, much longer and receive many more lines of therapy.

In my own clinic, I have patients who've been living over 15 years with metastatic HER2-positive disease, some of whom don't have any evidence of disease, but we maintain them on Herceptin to keep our foot on the brakes of the breast cancer so that it doesn't hopefully come back or progress. So, the answer is yes, if you have metastatic cancer, you should be on therapy in perpetuity, as long as you're tolerating it well and as long as it's working to control the disease. But in the curative setting, stage 1 to 3, there is an end in sight.

Andrea Hutton: So, Amy, how do you feel now?

Amy Hash: I feel good. It's nice to hear an oncologist say this. After I got diagnosed, again, I was like, "Oh God, I'm triple-positive. I have all of them." But I went home and talked to my father-in-law, who was a scientist curing basal cell carcinoma cancer. And when I told him I had HER2, when I was triple-positive, he was elated. He was like, "That's great because they have lots of drugs they can give you. They have so many drugs they can give you." That's not the case with the other ones. And honestly, I didn't really believe him. But now that Dr. Hurvitz has explained it this way, it does give me some hope that there are lots of options.

Dr. Hurvitz: I would just close with one remark. When I started in practice, as I said, in 2006, Herceptin had only been available under a year for early stage HER2-positive breast cancer and only eight years for metastatic HER2-positive breast cancer. And I was used to seeing these survival curves showing that patients diagnosed with HER2-positive breast cancer had the shortest survival. And I'm so fortunate to now, 14 years later, be seeing curves and papers coming out showing that if you're diagnosed with HER2-positive breast cancer of any stage, your chances of long-term survival are higher than any other subtype of breast cancer.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.


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