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SABCS 2022 | Remaining questions surrounding HER2-low breast cancer – how low can you go?

Paolo Tarantino, MD, Dana-Farber Cancer Institute, Boston, MA, discusses key remaining questions surrounding HER2-low breast cancer, including whether the benefit of trastuzumab deruxtecan (T-DXd) to HER2-0 and whether HER2 can be better quantified in breast cancer. The Phase II DAISY (NCT04132960) trial demonstrated a 30% objective response rate with T-DXd in patients with HER2-0 metastatic breast cancer suggesting targetability for HER2-0 breast cancers. Additionally, through quantitative measurements HER2-0 breast cancers have been shown to harbour HER2 expression that cannot be detected by immunohistochemistry (IHC), suggesting quantitative measurements of HER2 expression could expand the detectability of HER2. This interview took place at the San Antonio Breast Cancer Symposium (SABCS) 2022 in San Antonio, TX.

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Transcript (edited for clarity)

So HER2 remains fundamental in clinical practice to select patients for trastuzumab deruxtecan. What we are really curious to understand if is we can expand the benefit of trastuzumab deruxtecan and maybe other HER2 ADCs to HER2-zero patients because we know that also HER2-zero breast cancers actually harbor a lot of expression of HER2 that cannot be detected with immunochemistry and in some cases it can be detected but we call it ultralow or but could be detected with better assays...

So HER2 remains fundamental in clinical practice to select patients for trastuzumab deruxtecan. What we are really curious to understand if is we can expand the benefit of trastuzumab deruxtecan and maybe other HER2 ADCs to HER2-zero patients because we know that also HER2-zero breast cancers actually harbor a lot of expression of HER2 that cannot be detected with immunochemistry and in some cases it can be detected but we call it ultralow or but could be detected with better assays. There was a wonderful presentation by David Green during the congress showing that with quantitative measurements of HER2 expression we can expand the detectability of HER2. So I think the most important question right now is how low can we go?

And so in patients with HER2-zero breast cancer, can they derive benefit from trastuzumab deruxtecan and other ADCs and the DAISY trial, a small French study that has shown that T-DXd can achieve 30% objective response rate, although with a medium PFS of four months, but still intriguing to see that HER2-zero metastatic breast cancer can be targeted with these ADCs and so I think we need to fill this gap. And one important trial that is trying to fill at least part of this gap is the DESTINY-Breast06 Phase III. That includes not only HER2-low metastatic breast cancer patient but also ultralow, so HER2-zero with some detectability. And that’s right now I believe the main question.

And the second main question that we need to answer is if novel assays can better predict the activity of T-DXd compared to immunochemistry. Because if you look at DESTINY-Breast04, immunochemistry 1+ and 2+ show the same benefit from T-DXd. But we have seen now that novel ways, for instance, digital pathology, AI assisted pathology or quantitative measurement of HER2 have more potential to dissect the patient with higher likelihood of a response to T-DXd or less likelihood. So, I believe these are the two main things we need to understand expanding the benefit of T-DXd to HER2-zero and quantifying better HER2.

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