Advertisement

Advertisement

Role of HER2 Expression in Hormone Receptor–Positive Metastatic Breast Cancer

Posted: 8/31/2023

This is Part 2 of Novel Therapies for Advanced Breast Cancer, a three-part video roundtable series. Scroll down to watch the other videos from this Roundtable.

 

In this video, Drs. Aditya Bardia, Sara Tolaney, and Antonio C. Wolff discuss the role of HER2 expression in hormone receptor–positive metastatic breast cancer. The patient is a 55-year-old female with metastatic hormone receptor–positive metastatic breast cancer (HER2 IHC = 1). She has experienced disease progression various endocrine-based therapies, and recently capecitabine and paclitaxel. She has a good performance status, is negative for germline BRCA mutations, and is PIK3CA and ESR1 wild-type.

 

The faculty review the shifting understanding of HER2 expression categories—particularly “HER2-low”—in breast cancer in the wake of the DESTINY-Breast04 study, best practices when it comes to distinguishing IHC 0 from IHC 1+, and current antibody-drug conjugates available and in the pipeline for metastatic breast cancer.



Transcript

Disclaimer: This video transcript has not been proofread or edited and may contain errors.

Dr. Aditya Bardia: Welcome to the ASCO Post Roundtable Series of Novel Therapies for Advanced Breast Cancer. I'm Aditya Bardia, breast medical oncologist at Massachusetts General Hospital, Harvard Medical School. Joining me today are two of my colleagues. Dr. Tolaney. Dr. Sara Tolaney: Hi, good morning. I'm Sara Tolaney, I'm a breast medical oncologist at Dana-Farber Cancer Institute and thanks so much for having me today. Dr. Bardia: And Dr. Wolff. Dr. Antonio Wolff: Hi everybody, my name is Antonio Wolff. I am a breast cancer medical oncologist at Johns Hopkins in Baltimore. It is a treat to be here with all of you today. Dr. Bardia: Great. Today we'll be discussing recent updates in the treatment of advanced breast cancer and integrating these new developments in three patient scenarios. Our second installment will focus on the role of HER2 expression in hormone receptor–positive metastatic breast cancer. So let's start with the case. This is patient FR. FR is a 55-year-old female with metastatic hormone receptor–positive breast cancer. HER2-negative, HER2 IHC expression of 1+. She has experienced disease progression, various endocrine-based options and more recently capecitabine and paclitaxel. She has excellent performance status, no organ dysfunction, germline BRCA status negative and in terms of tumor genotyping, both PIK3CA and ESR1 wild-type. So I'll start with the first question to Antonio. Antonio, this patient has HER2 IHC 1+ disease, some would call it HER2-low. Can you update us on whether we should be using the term HER2-low and the recent ASCO guidelines? Dr. Wolff: Thank you Aditya for this question. And I am certain that everybody knows about the terminology that is being used by some, of HER2-low. And this is just driven by the amazing, very impressive results that we had at ASCO last year on the activity of trastuzumab deruxtecan in patients without HER2 amplification or HER2 over-expression. And you may know that the drug T-DXd or trastuzumab deruxtecan is essentially an antibody-drug conjugate that uses as antibody trastuzumab. And we have until now known that targeting HER2 matters in tumors that are HER2-addicted or have disease that is HER2 driven. But I think what is forgotten is that HER2 is expressed essentially in all breast cancers and the terminology HER2 IHC 0 is actually, maybe, a false construct and it could be a fixation or effect in the sense that formalin fixation can hide the expression or the presence of the antigen for antibody detection. And you have heard about, from a methodology standpoint, something called antigen retrieval, which is usually done by warming up the tissue specimen or microwave antigen retrieval, which is part of the procedure for HER2 testing, exactly because formalin fixation can hide HER2. So if you go back a number of years in the 2000s, when initially trastuzumab was approved in patients with metastatic disease, this is 1998, New England Journal of Medicine, Dennis Slamon. And at that moment, yes it was a dramatic change in what we could do for patients but we were dealing, still, with an incurable disease. The conversation changed completely back in 2005, ASCO in Orlando, when an amazing session with the first results of the potential lifesaving, life-altering results from the clinical trials from NCCTG and at that time at the NSABP and also the BCIRG, the trials showing that adding trastuzumab in the adjuvant setting to combination chemotherapy could alter clinical practice and could improve survival. So now you have such an important decision to be made on the basis of a single biomarker, that's so determinant of therapy selection, to give trastuzumab or not. And that was the genesis of an effort at a organizational level from ASCO and CAP, because HER2 testing at that time was not just for an adjunct to pathology to help the pathologist make anatomical determinations, but now this is a biomarker with clinical utility, accuracy is key, false-positives and false-negatives are essentially not acceptable even though they still happen. So if you go back to the first ASCO CAP guideline back in 2007 and until now the HER2 testing guidelines have focused on identifying HER2 protein over-expression or gene-amplification to identify therapies that would disrupt HER2 signaling. And we now need to recognize that since the data from the DESTINY-Breast04 in patients with tumors, that the company called HER2-low, we now have an FDA approval for the use of trastuzumab deruxtecan in tumors where HER2 is not overexpressed, it's not amplified, but is immunohistochemistry 1+ or 2+ without amplification by in situ hybridization. So the challenge is that the trial DESTINY-Breast04, and I can understand that there was a developmental strategic decision by the drug companies that own and are developing T-DXd to essentially exclude patients with so-called IHC 0 from DESTINY-Breast04 even though we do have some parallel data from a trial that was finally recently published in mid-2023, the DAISY study, showing that even patients with IHC 0 may have some expression by other measures but also you see clinical activity, today we have no evidence that tumors that are, let's say, IHC 1+ and 2+ and potentially IHC 0 behave differently or do not respond similarly to some of these new HER2 antibody drug conjugates. And I think, unfortunately, or we need to be cautious that despite all of this, despite evidence that IHC 0 is different than so-called IHC-low biologically, we need to recognize that these data are relevant simply because of the trial entry criteria that supported the new regulatory approval. So traditionally you could argue that markers matter if they can help us identify disease that behaves differently and that therapy could modulate that clinical behavior in HER2 amplification over-expression is so critical. This does not appear to be the case in terms of HER2 so-called low, different than HER2 IHC 0. But we have, at this time, an artificial construct in that patient with IHC 0 were not eligible for the clinical trial and could not get regulatory approval today if we're trying to make a clinical decision in the clinic whether we can give the antibody drug conjugate T-DXd, we need to know that information. So this is relevant because of the trial we have the criteria and the new regulatory approval. So even though it is premature to create new result categories of HER2 expression, including HER2 low and HER2 ultra-low, I think the pathologists need to do their best to try to differentiate IHC 0 from IHC 1+ because of the FDA approval. But we need to remember that IHC was never developed to distinguish among tumors with low levels of expression. It does not have dynamic range to operate in the low end of the spectrum, was purely developed to differentiate over-expression and the amplification usually from not over-expression. So that's a big challenge and it could be that at some point in the near future this becomes an exercise in futility because if we see that the drug has activity in so-called IHC 0 or if we have better quantitative markers that can look within IHC 0 and even IHC 1 and 2+, different levels of HER2 that could be associated with differential clinical benefit, those biomarkers become relevant and these categories may become important. But today it's hard for me to understand how we can use these categories other than simply to find out can I get insurance approval for my patient to receive this new ADC or not. Sorry for the long answer. Dr. Bardia: That was very helpful. Thank you so much for the thoughtful review Antonio, this is a complicated topic, so very much appreciate you explaining where we stand and the nuances related to HER2 definition. And for this patient, this patient did have HER2 IHC 1+ so clinically it's actionable. Maybe we will ask the question to Sara, what should we do next? As a summary, this is a patient who's received various endocrine-based treatments and two lines of chemotherapy and has metastatic hormone receptor–positive, HER2 IHC 1+ disease. Dr. Tolaney: So knowing that this patient does have HER2-low disease and has progressed on two lines of chemotherapy in the metastatic setting, I would be thinking about trastuzumab deruxtecan here for this particular patient. Antonio alluded to the great data from DESTINY-Breast04, really demonstrating that, in essence, T-DXd really led to about double the PFS compared to standard chemotherapy in this setting. And so I do think T-DXd represents a very attractive option for this patient at this point in time. Certainly one could also say there are other ADCs also available like sacituzumab govitecan, which also has had activity in metastatic hormone receptor–positive disease. I think when trying to think about which drug to use, I do like to think about the space in which each of them were studied because DB04 really looked at T-DXd in patients who had had one to two prior lines of chemotherapy in the metastatic setting and were HER2-low, whereas TROPiCS-02 had looked at sacituzumab govitecan in patients who'd had two to four prior lines of chemotherapy. So it was a much more heavily pretreated group of patients. And so technically this patient very nicely fits into both categories, would've been eligible for either study. But again, because T-DXd fell a little bit earlier, I do tend to use T-DXd earlier and then I try to sequence sacituzumab, for example, subsequently though I realize we have absolutely no data on how sacituzumab would actually work and someone who's progressed on T-DXd knowing that, in essence, they have very similar payloads with T-DXd having deruxtecan a topo-1 payload and sacituzumab having SN-38 also a topo-1 payload, but different targets. And so it'll be interesting as we learn more. I know, Aditya, your group had some very nice data that had been presented at ASCO trying to look at performance of these ADCs in sequences. So I'm curious how you think about it now, knowing your data. How have you been thinking about using these ADCs in this setting? Dr. Bardia: Yeah, it's a similar algorithm, Sara, starting with trastuzumab deruxtecan for a patient who has HER2 IHC 1+ disease and then after that considering sacituzumab govitecan because in TROPiCS-02 it was better than standard chemotherapy, so we'd be more interested in using SG or standard chemotherapy, but we need additional data, particularly data from clinical trials before we can definitely answer this question. Dr. Wolff: So because we are talking about data, but obviously the folks who are watching us, they want to know, “what do you guys do?” And, we see a little bit more breast cancer patients perhaps than the community oncologists who may see 25, 30% of their practice in breast cancer. Have you guys had the experience, anecdotally, of using SG after T-DXd? And what have you guys seen? Dr. Bardia: Yeah, I can start first and we'll love to hear from Sara as well. We have used SG after T-DXd in hormone receptor–positive breast cancer. And, anecdotally, it does work in some patients, not all. This was a summary at ASCO this year in poster discussion where the response to the second ADC was less as compared to what had been seen in clinical trial. So it looks like there's a subset of patients where it works, but there's another subset where it doesn't and we need more biomarkers to understand that. But till we get those results, I think at this time it's reasonable to consider one after the next. I don't know, Sarah, what's your practice and what have you seen? Dr. Tolaney: Very much similar to what you've seen and actually what your data has shown. I do think we're seeing not probably the same level of activity of sacituzumab post T-DXd as we would've seen in a T-DXd–naive patient, for example. But as you also point out, there's some people who get great benefit and others who progress immediately. And I think it does speak to the fact that we don't fully understand ADC resistance that well. And Antonio pointed out the very impressive work done in DAISY, for example, that had looked pre-post T-DXd and it did show that there are some potential mechanisms of resistance including downregulation of HER2, looking at genomic mutations that could be payload-resistant mutations. So in this case, I think, there probably are some cases where people are developing resistance to topo-1 inhibition, maybe why they're not responding to sacituzumab as well, whereas maybe in other cases they don't have that topo-1 resistance and maybe that's why they're okay. And so I think we have a lot more to learn here, but as you said, we're doing it clinically. I do like to offer it sequentially and kind of see what happens because at this point we don't have great biomarker predictors to tell us who should sequence and who should not. Dr. Wolff: Yeah. And Aditya, if I may push you a little bit further, I don't think you have formally published your data yet, but you have presented it publicly. So based on the analysis thus far, because I know that this is a question that our colleagues will have, did you see any association between duration of progression-free survival or duration of prior T-DXd therapy and likelihood of response or clinical benefit from second additional ADC in this case, saci-govi? Dr. Bardia: That's a good point. We've not formally looked at this question. We did create what is called a butterfly plot, looking at prior duration of first ADC and then duration on second ADC. Visually, there did not appear to be a strong correlation, but we've not done formal statistical analysis to answer this question about does the duration of ADC-1 impact PFS on ADC-2. Dr. Wolff: Great. And we know there are a couple of studies that our various groups are going to be doing in the very near future and asking exactly this question, not just with the approved ADCs, but also with the new investigational ADCs. So this is a perfect example of stay tuned with still a lot to be learned and let's get access to the biomarkers. If I can make a plea here. It has been very difficult. A lot of these biomarkers are controlled by the industries, by the companies that own the drugs and ran the studies, and it's not been very easy for investigators to get their hands on these tissues to start looking at predictive biomarkers of response to these incredibly helpful drugs. Dr. Bardia: That's a great point, Antonio, and look forward to these upcoming studies looking at the question of ADC after ADC and biomarker work as well. Excellent. So I'll summarize the key clinical takeaways. It is now clinically relevant to distinguish HER2 IHC expression 0 from 1+. Currently there are two ADCs approved for patients with hormone receptor–positive metastatic breast cancer. Trastuzumab deruxtecan or T-DXd is approved for patients with HER2-low metastatic breast cancer, HER2-low has an IHC 0 or 1+ in patients who received at least one prior line of chemotherapy or within 6 months of completing adjuvant chemotherapy. Sacituzumab govitecan is approved for patients who've received endocrine based therapy and at least two prior lines of systemic therapy in the metastatic setting, regardless of HER2 or tropo-2 expression. Additional studies are looking at novel agents and targets and also looking at this important question of ADC after ADC. Thank you so much for joining today. This brings us to the end of the case. Please see the other segments for future discussion about the latest data in metastatic breast cancer or visit ASCOpost.com. Thank you.

Advertisement
Advertisement