HER2-Low Metastatic Breast Cancer and Use of Trastuzumab Deruxtecan

Centering their discussion on the HER2 low setting of HR+ metastatic breast cancer, medical oncologists review data behind trastuzumab deruxtecan therapy.


Eva M. Ciruelos Gil, MD, PhD: Sara, now we are talking about HER2-low. Does HER2-low exist? I don’t know. The first question is how do you measure HER2 expression in histochemistry with quantitative analysis or not? It’s really difficult to capture HER2-zero, or very low, or ultra-low. I’m getting crazy with this.

Sara M. Tolaney, MD, MPH: I wish I had a good answer. I think it’s obviously a very important question. Now that we have T-DXd [trastuzumab deruxtecan] for our HER2-low patients, figuring out how to select which patients are candidates for T-DXd is really important. In DB04 [DESTINY-Breast04], they selected patients who were 1+, or 2+, and not FISH [fluorescent in situ hybridization]-amplified. This sounds very straightforward, but the problem is that we’ve seen a lot of discordance in testing, particularly when looking at HER2-zero and HER2-one disease, where it’s such a critical distinction because it determines whether you get the drug or not. There is a very nice publication by David Rimm’s, MD, PhD, group at the Yale School of Medicine in New Haven, Connecticut, that shows there’s only about a 20% concordance amongst pathologists when given the same slides to read.

Eva M. Ciruelos Gil, MD, PhD: That’s true.

Sara M. Tolaney, MD, MPH: That is actually pretty disturbing. We had a discussion with the pathologists at our institution about this because we wanted them to realize that these assays were originally developed just like patients for trastuzumab [Enhertu], but it didn’t matter if you were 1+ or a zero. It didn’t have any treatment implications.

Eva M. Ciruelos Gil, MD, PhD: Sure.

Sara M. Tolaney, MD, MPH: But now it matters. I think it’s really important to discuss these implications with your pathologist and hopefully be able to figure out what the correct result is. I think the challenge is that we need a quantitative assay because even HER2-zero disease has up to a 10% staining. Having a quantitative assay will be more important. We’ll have to see what the results are from DESTINY-Breast06 study which was including some ultra-low patients—meaning they could have any staining between zero and one. If that group has benefit, this is going to get even more confusing.

Eva M. Ciruelos Gil, MD, PhD: Sure. I think that we have a pathologist problem here. In Spain, we are performing HER2 predictions at SOLTI, trying to guess what the 1+, 2+ HER2 expression means versus mRNA expression in the majority of patients who are participating in clinical trials with T-DXd. Maybe this is the way to move forward and try to have a quantitative study that could be robust, reproducible, and be proceeded as the companion diagnostic. Why not? If there’s a very effective track behind T-DXd, then we should work very hard on selecting patients. This is the first step. What are your feelings on HER2-negative? Do you think that we are ready to begin to use T-DXd? T-DXd has recently been approved by the FDA for this indication. Are you ready to treat your HER2-low patients with this drug right now? What is your sequencing to this treatment landscape for ER-positive disease?

Sara M. Tolaney, MD, MPH: I don’t know. I mean, when those data came out at ASCO [American Society of Clinical Oncology] from the DESTINY-Breast04 study I got a standing ovation. I think it was deserving, not just because use of T-DXd is improving both progression-free survival [PFS] and overall survival [OS], but it’s also a paradigm shift in the way we think about treating breast cancer. We’re so used to thinking about subtypes, such as ER-positive, HER2-positive, and triple negative. I don’t think HER2-low is a new subtype of disease. I don’t think it’s biologically unique and associated with a different prognosis. I think it’s just trying to find a marker as a target for a drug to get drug delivery in. But it’s a completely different way of thinking because if you can find that marker on the cell to deliver your chemotherapy, it works irrespective of subtype. I think it’s really going to change the way we do drug development in general. Again, it was very deserving of the ovation that it got and, given how active the drug is, as soon as we got approval from the FDA, the USA started using it right away. In essence, T-DXd is doubling PFS and dramatically improving OS. I think the only challenge that we’ve had is the toxicity in trying to balance benefit with potential risk. We know that about 10% of people can get interstitial lung disease [ILD] from T-DXd, and there were 3 deaths in DESTINY-Breast04 from ILD. I don’t take that lightly. I think our group has made sure that we are getting routine high-resolution CT scans. I restage people a lot more often than I would normally if they’re getting T-DXd. Usually, I am reimaging patients every 6 to 9 weeks to make sure that I’m not seeing greater pneumonitis on imaging. I think it’s really important that we’re aware of that, and that we inform patients about that risk. But in terms of where I’m placing it, DESTINY-Breast04 was meant for someone who had had 1 or 2 prior lines of chemotherapy in the metastatic setting, post-endocrine therapy. Similar to your algorithm where you give your CDK4/6 and then endocrine therapy plus fulvestrant [Faslodex]—fulvestrant plus everolimus [Afinitor] or alpelisib [Piqray]—after that, I am usually moving to chemotherapy quickly because not much works at that point in time. Usually, as you pointed out, capecitabine [Xeloda] is a wonderful option there. But if the patient is post-capecitabine, and if they’re HER2-low, I’m thinking about T-DXd at that point in time. Then the question arises: Can you use it earlier than that? Certainly, we don’t have the data from DESTINY-Breast04 to support using T-DXd earlier, but DESTINY-Breast06 will address that question because it’s immediately post 2 lines of endocrine therapy prior to chemotherapy.

Eva M. Ciruelos Gil, MD, PhD: Sure.

Sara M. Tolaney, MD, MPH: We’ll have to wait to see and continue to watch the toxicity to balance that risk-benefit.

Eva M. Ciruelos Gil, MD, PhD: Sure.

Sara M. Tolaney, MD, MPH: But I think I’ve been mostly utilizing it after 1 line of chemotherapy.

Eva M. Ciruelos Gil, MD, PhD: This is an important issue. As patients have been treated with oral drugs for many years, with a nice quality of life, their status was good until they suddenly needed an IV [intravenous] therapy that could potentially risk their lives because of ILD. This is a big change for them, especially if they come from hormonal treatments or capecitabine. This is not HER2-positive disease because many came up before in this higher-risk patient. This is an issue.

Transcript edited for clarity.

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