With New Classification of HER2-low Breast Cancer, Pharmacists See Major Paradigm Shifts

In an interview with Pharmacy Times, Sydney Schultz, PharmD, an oncology/hematology pharmacist at Mayo Clinic, discussed the recent shifts in breast cancer treatment. With the new classification of HER2-low breast cancer, new treatments and diagnostic approaches are primed to be a massive area of research.

Q: HER2-low breast cancer is a fairly new category. Can you explain what HER2-low means?

Sydney Schultz, PharmD: Sure. Historically, HER2 status has been defined in a pretty binary model where patients were either negative or positive. And this was based on 2 main testing modalities, the first being immunohistochemical testing, or IHC, and then that's followed up with fluorescence in situ hybridization, or FISH testing. And so, IHC testing will range anywhere from an IHC score of 0 all the way to 3-plus, where traditionally a score of 0 or 1-plus would be considered HER2- negative and then a score of 3-plus would be indicative of HER2 overexpression and would be considered positive. And then the score of 2-plus requires a bit of additional testing with FISH to assess for the presence of gene amplification. So, if it's IHC 2-plus with a negative FISH, that would be HER2-negative. An IHC score of 2-plus with a positive FISH would then be HER2-positive. But despite not meeting those ASCO guidelines for the definition of HER2 positivity, we know that some of these tumors that have historically been categorized as HER2-negative still have some expression of HER2 positivity that could be targeted with some of our drug therapies. And so that's really led to the evolution of this new category or subtype of HER2-low disease and that includes those kinds of intermediate tumors. So, the ones that are IHC 1-plus or 2-plus with a negative FISH.

Q: Why is it important and useful to differentiate HER2-low from HER2-positive or -negative?

Sydney Schultz, PharmD: Yeah, I mean, the classification of HER2-low really does represent some pretty massive paradigm shifts in the way that we think about treating breast cancer. You know, we're so used to grouping breast cancers in those 3 traditional subtypes of HER2-positive, ER-positive, and triple-negative. Really, a lot of that categorization has prognostic implications, and the same can't necessarily be said for HER2-low disease.

And this has been a topic of great debate. There were a couple of abstracts that were presented at the San Antonio [Breast Cancer Symposium] this year, really trying to evaluate whether HER2-low status has the same type of negative prognostic implications that we know that HER2-positive disease has. And from the abstracts that were presented there, as well as a few retrospective studies, they compared those patients with IHC 1-plus and 2-plus with negative FISH to those that had an IHC of 0, or truly negative HER2-status, and they didn't find any difference in prognostics. And so, I think while we can say that HER2-low is predictive of response to some of our treatments, it's not necessarily prognostic in the way that we would traditionally define HER2 positivity. So, while it's not necessarily maybe going to become its own new subtype within breast cancer, it does provide an additional layer of information that's helpful in deciding some of those subsequent lines of treatment decisions for patients.

Q: HER2-low is estimated to encompass upwards of 55% of breast cancer patients. With such a huge percentage, why have these major developments taken so long?

Sydney Schultz, PharmD: Yeah, you are correct. It is a vast majority. And I think that's 55% of patients who would have been considered HER2-negative, now are being considered HER2-low. And it is something that researchers have been trialing different medications over the last few years for this exact subset of patients. And trastuzumab, just the monoclonal antibody alone, was trialed in combination with standard of care adjuvant chemotherapy for patients with HER2-low expressing tumors, and they didn't find any significant difference in invasive disease-free survival. And so, the authors really concluded that the addition of trastuzumab to chemotherapy was futile for these patients. We had antibody drug combinations hit the market a few years ago, firstly with T-DM1, or trastuzumab emtansine, so they tested that medication in this patient population as well. And again, they saw a pretty abysmal response rates of just 5%. And so I think the main reason why we haven't seen any major developments for these patients up until now is we just didn't have the right mechanism for drug delivery until TDXd (trastuzumab deruxtecan) hit the market.

Q: The DESTINY-Breast04 trial was the breakthrough trial in this space. Can you explain a bit about this trial and its findings?

Sydney Schultz, PharmD: Yeah, definitely. So, DESTINY-Breast04 is the phase 3 randomized control trial that gained TDXd, or trastuzumab deruxtecan, its new FDA indication. And this evaluated patients with HER2-low breast cancer, so again, that IHC score of 1-plus or 2-plus with a negative FISH, and they compared that to standard of care chemotherapy. They included patients with either ER-positive or triple-negative disease. Patients with ER-positive disease did have to be endocrine therapy refractory, and then all patients had to be status post 1 or 2 lines of chemotherapy. And researchers here compared trastuzumab deruxtecan in randomized patients in a 2-to-1 fashion to receive that versus chemotherapy. Most commonly in this setting it was single agent capecitabine, eribulin, paclitaxel, or gemcitabine. And they really found pretty impressive results. I know at the ASCO meeting last summer, this trial received a standing ovation, which I'm sure was really exciting to witness for those who were in the audience.

And that was because they saw a doubling in her progression-free survival for the overall patient population, from 5 months to 10 months, and also a significant improvement in overall survival. And this benefit of TDXd was seen across all of the subgroups that they analyzed. So regardless of age, performance status, presence of visceral disease, whether they were ER-positive or triple negative, etc., the benefit was still seen for all of those patients. And I think another interesting takeaway is that there was no difference in response for patients that were IHC 1-plus or 2-plus, kind of indicating that the level of HER2 expression, as you could say, didn't really impact whether or not the patient still responded, which was really exciting information.

Q: Why is trastuzumab deruxtecan effective in HER2-low breast cancer?

Sydney Schultz, PharmD: Yeah, I kind of highlighted a little in the why we haven't had a major improvement yet that our previous antibody drug conjugates of T-DM1 was not effective in this patient population. And I think there's a few key differences when comparing TDXd to T-DM1. So, TDXd is a novel antibody drug conjugate. It's comprised of 3 main components: we have our HER2-targeted monoclonal antibody being trastuzumab, so same as T-DM1. We have a cleavable tetra peptide linker that links the trastuzumab antibody to our third component, which is a topoisomerase-1 inhibitor cytotoxic chemotherapy payload. And 1 key difference between these 2 is the drug-to-antibody ratio. So, when we look at T-DXd, for every 1 molecule of trastuzumab, we have 8 molecules of cytotoxic chemotherapy. Comparing that to T-DM1, for every 1 molecule of trastuzumab in T-DM1, it just has 3.5 to 4 molecules of that cytotoxic drug. So, when we deliver T-DXd to our HER2 cells, we're getting kind of twice the cytotoxic chemotherapy effects in that area. So, that's one key difference.

But I think that the second difference I'm going to highlight, and probably the most important difference, is what's referred to as the bystander effect. And this really hinges on the fact that TDXd has a cleavable linker attaching the antibody to the cytotoxic payload. And so, when the TDXd binds to these HER2-positive cells, that cleavable linker is able to free the cytotoxic payload from the antibody, allowing it to then have its anti-tumor effects on all of the neighboring cancer cells, regardless of whether or not they are expressing HER2-positivity. And so, I think this is really the main reason why in these low levels of HER2 expression, as long as we still have some tumor cells that are expressing HER2 we’re able to get the antibody drug conjugate there, and then have that cytotoxic chemo kind of working in that entire neighboring area.

Q: With its approval for this indication in 2022, have you seen widespread impacts and use of trastuzumab deruxtecan?

Sydney Schultz, PharmD: Definitely, we have seen a massive shift in the way that we're treating patients once they're beyond that first, maybe second line of chemotherapy. This is kind of the first thing we're looking at now, where previously all we had was just kind of a rolodex of single agent chemotherapy agents, where our progression-free survival for those agents was really in the matter of 2 to 3 months for the average patient. And now we're seeing progression-free survival of almost 10 months for these patients. So, it was a really exciting change. It's been great to be able to go back to biopsy results, look for potentially that HER2-low expression, and be able to provide an additional option. And we're even using it kind of in these later line settings to where patients are on their sixth or seventh line of therapy. And now all of a sudden, we have an extra option for them.

Q: Some patients with HR-positive or triple-negative disease could also benefit from trastuzumab deruxtecan. What does that mean for their treatments and potential outcomes?

Sydney Schultz, PharmD: Yeah, so as I mentioned, HER2-low at this time hasn't really become its own subset of breast cancer. And so, HER2-low expression can be seen in patients with ER-positive or triple-negative breast cancer. And again, as we kind of mentioned previously, about 55% of those patients that would have been negative are now in this kind of new subset within the subset, if that makes sense. And so, you know, right now we're following the FDA labeled indication from the DESTINY-Breast04, so really plugging this in after 1 or 2 cycles of chemotherapy. So, for our ER-positive patients, kind of going through the standard first line CDK 4/6 inhibitor with endocrine therapy, following that with everolimus and endocrine therapy or potentially alpelisib if they have that targeted mutation, and then chemotherapy, typically starting with single agent capecitabine. But then once they're through that, we’re immediately kind of employing this new treatment option with that TDXd. And then with triple-negative, they really don't have many targeted options available to them. And so, this becomes an even sooner line agent once they’re post their first or second line of chemotherapy plugging this in.

Q: Where is research in HER2-low identification headed?

Sydney Schultz, PharmD: A massive focus right now is on improved diagnostics. We've seen a lot of discordance in HER2 testing from site to site. The DESTINY-Breast04 trial actually utilized a centralized approach to evaluating HER2-low expression with IHC testing. And there was a great paper that was published from Yale School of Medicine last year that really highlighted the disagreements that can occur. And most of these disagreements are occurring between IHC 0 and IHC 1-plus, where prior to this indication, that difference didn't really make a huge difference for patients, it wasn't going to change the way that we treated them. But now this is really a critical decision on 0 versus 1-plus, because that decision is going to determine whether or not patients are eligible for this drug. And so, the yellow paper actually administered slides, the same slides to a different set of pathologists and they only found 20% concordance in the way that pathologists were reporting that data. And so that really highlights the need for improved diagnostics. And I think the challenge is that we really need some type of novel quantitative assay, because even HER2 0 per our current definitions can have up to 10% staining. And I think that we've seen that in some of the other trial data that's been presented. We have the DAISY trial that was recently published and that included a cohort of patients with IHC 0, so what we would think of as HER2 negative disease, and they still had a 30% response rate to TDXd. And then more to come with DESTINY-Breast06, which has yet to be published, but they're including patients with what's considered ultra-low HER2 status. And so, patients that kind of fall in between the IHC 0 and IHC 1. And so, I think, you know, if those patients find benefit as well, this whole conversation is going to become even more complex and more confusing. But I think there's potentially a whole other group of patients that may benefit from this from this medication and I think we just need to come up with a better, more centralized, quantitative approach to analyzing HER2 expression.

Q: Are there other treatments for HER2-low on the horizon?

Sydney Schultz, PharmD: Yeah, I think this is going to become a massive area of research, kind of on the coattails of the DESTINY-Breast04 and seeing what great response rates we had for these patients. So, I think, you know, a lot of questions are still going to be asked regarding TDXd. I think DESTINY-Breast06 is potentially going to answer some of those and applying TDXd even earlier in our treatment algorithms. So, DESTINY-Breast04 is just looking at patients with hormone receptor-positive disease, but they're utilizing TDXd once patients are endocrine therapy refractory, so prior to any cytotoxic standard chemotherapy. And so potentially, we're going to see TDXd kind of move its way up the treatment algorithms.

And then there are other novel antibody drug conjugates that are also being studied. We have trastuzumab duocarmazine, we have disitamab vedotin. And so, a couple of pipeline agents that we will have to kind of wait and see what their preliminary data is showing. And then I think as I mentioned, as well, just really looking into this ultra-low IHC status and there’s still benefit there because there's minimal HER2 expression that we're just not able to fully quantify as IHC 1-plus. Or is it because that cleavable linker is releasing this cytotoxic chemotherapy payload and still having anti-tumor effects? So, I think there's, you know, a number of questions being answered for TDXd, but then a couple of other medications in the pipeline as well.