Hope S. Rugo, MD, FASCO: We also know that DESTINY-Breast04 [NCT03734029] included the HER2-low population, not a biologically identified group of patients, just not HER2 positive and not zero, and everybody in between. That's about 65% or so of hormone receptor–positive disease, they showed a benefit in the 58 triple-negative patients who had HER2-low disease too. Not complete overlap, 2 very different populations in trials. If you could give both today, how would you think about it on the clinic, Anne?

Anne O'Dea, MD: I think, as you mentioned, these are very different patient populations. I think I even had to remind myself as I was reflecting on this data, as you mentioned from TROPiCS, these were extremely heavily pretreated. As you pointed out, in the curves you see that very sharp drop-off at the beginning. That is something that we often see in later line trials, and that impacts the mean, which is something we must keep in mind. In DESTINY-Breast04, these were patients that had only potentially one chemotherapeutic, a much different patient population, theoretically much healthier. And so, it raises a lot of questions for us about where we will put this. How will we compare this to alpelisib, for example for PIK3CA-mutation carriers, where will we put it with PARP inhibitors for BRCA germline carriers? There are so many potential options for the different patients, for the different subgroups. Then also, as Dr Pegram was reminding us about tumor header… and which biopsy are we going to use to show the HER2 +1 or +2; Is it the original tumor? Is it the pre-neoadjuvant? Is it their surgical biopsy, is it their metastatic biopsy, or is any one of those OK to guide this new subtype of HER2-low? It just raises a lot of questions for us.

Hope S. Rugo, MD, FASCO: Although I think it's important to keep in mind that these patients had finished all their endocrine therapy plus one chemotherapy at least, 1 to 2 lines. Right now I would discourage people from using this instead of endocrine therapy. But Aditya, do you see a role for sacituzumab in hormone receptor–positive heavily pretreated breast cancer?

Aditya Bardia, MD, MPH: Based on the TROPiCS-02 trial [NCT03901339], I think there is a role for sacituzumab to be taken in the metastatic setting. We tend to use therapies sequentially, and if I have a patient where I have to give gemcitabine or navelbine, I would rather give sacituzumab where we've taken cost issues aside. The question is going to be if you start using trastuzumab deruxtecan in the second-line setting and a patient has disease progression, then after that should we use sacituzumab over deruxtecan. One could certainly do that based on these data but there could also be some cross-resistance. So, we'll probably need some additional data in the future to look at activity of sacituzumab over deruxtecan post trastuzumab deruxtecan.

Hope S. Rugo, MD, FASCO: It's a good point. Mark, do you have anything to add to that?

Mark Pegram, MD: It's a really robust discussion. I think the last thing we should touch on is something that Patricia LoRusso [, DO, Yale School of Medicine,] brought up in her discussion following the DVL-4 presentation, and that is, assay methodology to define HER2-low. That's in a state of flux. For example, the original HER2 diagnostic antibodies were never designed to discriminate between IHC [immunohistochemistry] –0 and +1; they were designed for the opposite reason, to find very high-level protein overexpression, so they are not the right reagents to define to too-high or too-low patient population. She showed some recent data using more sensitive, quantitative, protein measurement techniques, that you can find HER2 protein in IHC-0 clinical specimens. Moreover, my press and the group at Cepheid Diagnostics in the Bay Area published a paper a couple of years ago using real-time PCR [pathological complete response], looking at HER2 transcript and comparing IHC-O vs +1 and +2, and the transcript is not dissimilar in the IHC-Os than it is for the +1 or the +2, raising the possibility that all patients have some HER2 and that the HER2 IHC-0s as we know them now might be truly false negatives. So, all this needs to be resolved based on data. There is no right answer in the short-term. Obviously, the label language will be based on the IHC that we have right now. We'll have to suffer through that for the next little while, but eventually, we may find that there's HER2 in a lot of patients that you might not ever expect, and maybe you don't have measure it at all. We'll see. There are ongoing trials of trastuzumab deruxtecan in IHC-O patients, and anecdotally, I'm told from those investigators, they have seen some responses already.

Hope S. Rugo, MD, FASCO: Right, DESTINY-Breast06 [NCT04494425]. I think that maybe that there's a basal-like triple-negative where we're not going to see that response, but I think it will be interesting. At the moment, maybe there'll be sacituzumab in the HER2-0s, we just don't know.

Transcript edited for clarity.