The Emerging State of HER2-low Breast Cancer


Dr Geyer and Dr Krop discuss key data and the evolving standard of care for patients with HER2-low breast cancer.

Dr. Charles Geyer: So, I guess then we should wrap up by touching on this new entity of sorts, HER2-low cancer. Clearly, a very heavy poster load to San Antonio came in from major centers who've been doing genomic sequence, looking at their HER2-low patients to try to get a sense of the- addressing, is this HER2-low population a biologically unique subset, or is this a group of patients that just respond very, very well to this targeted agent. And there's a lot there to go through. My impressions are, and they had a debate, Sara Tolaney I think did a nice job presenting kind of the idea that, no, this is probably not a new subtype of cancer overall. Clearly we have issues regarding what is HER2-low mean with the initial use of an assay that was designed to detect three plus staining on IHC for overexpress trastuzumab. We had this scale that had zero, one and two that kind of guided reflex FISH. That was used to identify a cohort that was studied in DB04, and we saw really impressive results with T-DXd in that cohort. So there is the question on the lower end. We know there's DB06, we'll be taking that second line study. That DB04 was basically patients with HER2 positive, HER2- excuse me, ER positive, HER2-low cancer who had had one chemo regimen. So DB06 is going to say, let- when it time- comes time for chemo in patients with ER positive, HER2 negative therapy, where we would normally be doing capecitabine or taxane, let's randomize to T-DXd. I think we're going to be seeing those results next summer. So, I think that's going to have a real big impact on how we manage the cohort. But I- and I- we're going to see continue- that study will include some of patients with HER2-zero. We're going to, I think, continue to see refining. But at the present time, I think all we can do is rely on the assays that are currently available for identifying potential candidates for the therapy.

Dr. Ian Krop: I agree. And in some ways the whole discussion of whether it's a new subtype versus a new molecular marker of predicting benefit of a drug is a little bit of a semantic argument, at least, I think, in the clinic right now. I think that the take home message is that these are- that we- that it's important to identify which of our patients are HER2-low versus HER2-zero. Since prior to the DB04 data, we grouped all those people together from a clinical standpoint. But with the current technology, differentiating the one plus, two plus FISH negative patients from the HER2-zeroes, which makes them eligible for the use of trastuzumab Deruxtecan in the post-one line of chemo setting is the important message. I don't think there was anything at San Antonio this year that changed that. I think what - I completely agree with you. What the highlights were, the point that the testing is not probably ideal and needs to be improved, and what the lower limit of sensitivity is. Is it really one plus and the zeros are fundamentally different and don't benefit or is there some zone between one plus and zero that still benefits? Or even if--there probably aren't any completely zero cancers, these ultra-lows between one and zero are the group that's also going to be looked at in a small number of patients in the DB-06 data. So more to come on the zero patients, but clearly, the one plus, two plus seem to benefit from- or at least a subset of them benefit from T-DXd. From a clinical standpoint, I think many of us - and I'd be interested in your thoughts on this, Chuck--let's say you have a patient whose primary breast cancer was two plus FISH negative and their metastatic disease is HER2-zero by your local labs testing, and they've now progressed on first-line capecitabine, do you entertain the use of T-DXd in that patient?

Dr. Charles Geyer: Yeah, my perspective on that is, in that case, I would, but I wouldn't go just asking for staying after staying after staying until I get a one plus. I think if it's, as you described, they were two plus and now the metastatic disease has just come back zero, there's enough technical questions and things, and the study was designed largely off that original tumor. So I wouldn't use that as a reason not to assess the activity of T-DXd in those patients.

Dr. Ian Krop: Yeah, I agree 100% that if they're HER2-low at some point and you have one biopsy that shows that they're not, just use your treatment decision based on the original sample and just go with that, because again, for all the reasons you talked about, the test is just not as precise as we would like it to be yet. So hopefully, that will change.

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