Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here’s your host, Breastcancer.org Senior Editor, Jamie DePolo.
Jamie DePolo: Hello, I’m Jamie DePolo, senior editor at Breastcancer.org. I'm podcasting live from the 2024 San Antonio Breast Cancer Symposium. I'm joined by Dr. Aditya Bardia, director of the Breast Oncology Program and Translational Research Integration at the UCLA Health Jonsson Comprehensive Cancer Center, where he is also professor of medicine in hematology/oncology at the David Geffen School of Medicine at UCLA.
At this conference, he presented results from the DESTINY-Breast06 study, which looked at Enhertu, also called T-DXd, versus doctor’s choice of chemotherapy for people with hormone receptor-positive, HER2 low or -ultralow metastatic breast cancer that grew after they received one or more hormonal therapy medicines. Dr. Bardia, welcome to the podcast.
Dr. Aditya Bardia: Thank you so much. Thanks for having me.
Jamie DePolo: So, could you please summarize the results you presented for us?
Dr. Aditya Bardia: Yes, at SABCS 2024, we presented additional results from DESTINY-Breast06, which looked at T-DXd versus standard-of-care chemotherapy for patients with hormone receptor-positive HER2 low and -ultralow metastatic breast cancer. And essentially, T-DXd outperformed standard chemotherapy, capecitabine, or taxanes. Median progression-free survival about 13 months with T-DXd, versus about eight months with standard chemo.
So, more than a year, or more than 12 months, of median PFS with T-DXd. We then also looked at how patients did based on prior duration of CDK4/6 inhibitor. So, for example, if there's a patient who receives CDK4/6 inhibitor in the first-line setting and has disease progression within four to six months, that's a setting we worry that patient, likely, has endocrine-resistant disease, and sometimes, physicians use chemo after that, which was allowed in this trial, as well. And in that setting, the median progression-free survival with T-DXd was 14 months versus about six months with standard chemo.
So, that's a setting where T-DXd can be used as the next line of therapy. But it also worked in other patients who had longer duration with their CDK4/6 inhibitor. We also looked at disease burden, patients who had, say, two sites of metastatic disease versus five sites of metastatic disease, and in both these settings, T-DXd outperformed standard chemo. So, it's an effective option that works in ER-positive breast cancer and as seen in DESTINY-Breast06, both for HER2-low as well as -ultralow.
Jamie DePolo: So, that leads perfectly into my next question, which is about HER2-low and -ultralow. Many people with breast cancer I've talked to are really confused about that designation. How is it determined? If they, say, were diagnosed with metastatic disease maybe four or five years ago, should they be retested? What do we know right now? What can we say to these folks?
Dr. Aditya Bardia: The answer is yes. The retesting should be done, because HER2-negative is not negative, in the sense that there could be some HER2 expression present, which could be low or ultralow.
So, low is defined as, if based on IHC, we see 1+, 2+ expression, and ultralow is if there is less than 1+, so what we call 0+ expression.
So, absolutely, anyone who has HER2-negative disease, the question should be, do I have HER2-low or -ultralow disease because that could be actionable.
Jamie DePolo: And am I right in understanding that pretty much every cancer would have some HER2 protein on it? There is really no such thing as...when we say HER2-negative, that does not mean HER2-zero. Is that correct?
Dr. Aditya Bardia: For majority of hormone receptor-positive breast cancer, yes, there is some HER2 expression present, and it becomes an issue of how the testing was done and what the threshold is of detection by IHC, but majority of hormone receptor-positive breast cancers would have HER2 expression.
Jamie DePolo: But not hormone receptor-negative? Is that different?
Dr. Aditya Bardia: Hormone receptor-negative, the expression is lower in some subsets.
Jamie DePolo: So, that's my next question. Are scientists working on more refined HER2 testing? Or I guess I'm wondering, do we need HER2 testing at all if we see that some of these newer-developed antibody-drug conjugates, like Enhertu, seem to work on cancers that have very, very low expression of HER2? Is it still as important to test for it?
Dr. Aditya Bardia: I think both are good points. Yes, scientists are working on better methods of testing for HER2, more refined, more analytical in terms of how HER2 is measured, rather than immunohistochemistry. And drugs like T-DXd do work, even at very low expression levels of HER2, and if we look at another example, which would be sacituzumab govitecan, or Trodelvy is the trade name, that's used regardless of Trop2 levels. We don't look at the Trop2 level for selection of this drug, and maybe for hormone receptor-positive breast cancer, it could be a similar situation with T-DXd. That's more of, like, my personal opinion.
I think, ultimately, we have to follow the FDA label, but you know, looking at the amount of HER2 that's present in hormone receptor-positive breast cancer, it makes sense to use this drug in this setting.
Jamie DePolo: Perfect. Thank you, because it just seems like, as things move along and if we do get more refined testing, I could see there being so many different levels of HER2. I mean, if we're looking at the low, but then, we could have more levels of positive, too, I'm assuming, correct?
Dr. Aditya Bardia: Absolutely. Absolutely, and so, the question would be, how low do you go, in the sense that what's the lowest threshold below which T-DXd is not effective? And then, if we have other HER2 ADCs in the future and approved, as well as other ADCs, there, maybe once we start comparing ADCs to ADCs, the thresholds might change again.
Jamie DePolo: Dr. Bardia, thank you so much. This has been very helpful. I know we don't have all the answers, but I'm hoping this provided some more information for people.
Dr. Aditya Bardia: Thanks so much for having me.
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