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ESMO Breast 2021 | Trastuzumab deruxtecan: a promising agent for treating HER2-low breast cancer?

Paolo Tarantino, MD, Instituto Europeo di Oncologia, Milan, Italy, discusses research advances in the field of HER2-low-expressing breast cancer, which account for almost half of all breast cancer cases. Trastuzumab deruxtecan has been identified as a promising agent for breast cancer treatment and is currently being investigated in Phase III clinical trials including the DESTINY-Breast04 trial (NCT03734029) and the DESTINY-Breast06 trial (NCT04494425). Dr Tarantino highlights recent results demonstrating that the expression levels of HER2 are similar in de novo metastatic breast cancer and early-stage breast cancer. His hypothesis behind such results is predominantly attributed to the absence of adjuvant therapy. Dr Tarantino also states that relapsed breast cancer shows higher expression levels of HER2, around 57%, in contrast to de novo and early-stage breast cancer, which show around 40-45%. Future research should employ quantitative assays to enhance our understanding of the role of the HER2 gene and the impact of HER2 mutation. This interview took place at the virtual European Society for Medical Oncology (ESMO) Breast Cancer Congress 2021.

Transcript (edited for clarity)

Before talking about the work, I’d like to highlight the background where we started, which is actually the evolving field of HER2-low breast cancers Because for decades HER2-low expressing breast cancer have been neglecting any actionability within tier two agents, because trastuzumab was not effective in these cancers. And we did not have any other effective agent. But lately at ASCO 2019 and 2018 and from that moment on, we’ve seen some very promising agents, such as trastuzumab deruxtecan and trastuzumab duocarmazine, which showed activity in HER2-low expressing breast cancers, which are about half of all breast cancer...

Before talking about the work, I’d like to highlight the background where we started, which is actually the evolving field of HER2-low breast cancers Because for decades HER2-low expressing breast cancer have been neglecting any actionability within tier two agents, because trastuzumab was not effective in these cancers. And we did not have any other effective agent. But lately at ASCO 2019 and 2018 and from that moment on, we’ve seen some very promising agents, such as trastuzumab deruxtecan and trastuzumab duocarmazine, which showed activity in HER2-low expressing breast cancers, which are about half of all breast cancer.

So, a very big population or a relevant population where these agents showed interesting activity. And now some of them, such as trastuzumab deruxtecan, are being tested in large Phase III trials, such as in the DESTINY-04 and DESTINY-06 trials.

So in the future, we could understand if these compounds are going to be more active than chemo in advanced HER2 -ow expressing breast cancer. And if this happens, it’s going to be really important to understand and characterize HER2-low breast cancer. And this is what we’re doing in a large work of characterization over HER2-low expressions in breast cancer.

And last year at ESMO Breast 2020, we have shown that the reason enrichment in advanced breast cancer for HER2-low expressions compared to early breast cancers. And this makes biologically sense because we have preclinical data showing that per tumor progression and also the activity of treatments such as chemotherapy, endocrine therapy, and target therapy and upregulate HER2.

So, this year we provided a different analysis from this work, which focused on the novel metastatic breast cancers. And what we show is that HER2-low expressions in the novel metastatic breast cancer is closer to early breast cancer compared to relapsed breast cancer.

And these also again, makes sense because the novel metastatic breast cancer are untreated, were not treated with adjuvant treatment like relapsed breast cancer. So, this could be a possible hypothesis for these observations, or it could be also to more progression itself. However, what we show overall is that relapsed breast cancers have higher HER2-low expressions, about 57% of relapsed breast cancer in our analysis showed low HER2 expressions, compared to about 40 to 45% in the early setting or the novel metastatic breast cancer.

What I would like to highlight, however, is that these analyses are performed with the standard assays for HER2. And in particular with immunohistochemistry, which is a semi-quantitative assay, and may not be the best strategy to test HER2 for the future. For instance, in the DESTINY-06 fixed trial of trastuzumab deruxtecan in HER2-low breast cancer, even immunohistochemistry zero scored tumors can be patients with these tumors can be enrolled in the trial if they show some minimal ultra-low HER2 expression. This means that in the future with more quantitative assays, we could be able to have a more granular view of HER2 expressions, and to change, probably revolutionize, the way we interpret HER2.

So with this, I’d like to thank you for the attention. And once again, thanks VJ for allowing me to give this interview. And I hope you enjoy ESMO Breast ’21. And I hope to see you in person at ESMO Breast ’22.

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