Sacituzumab Govitecan in Hormone Receptor–Positive/ Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer - Episode 2

The Role of Trop-2 in mBC and the Rationale for Use of Trop-2–directed ADCs

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Dr Vidal elaborates on the role of trophoblast cell-surface antigen 2 (Trop-2) in metastatic breast cancer and discusses the rationale for using Trop-2–directed antibody-drug conjugates (ADCs), including sacituzumab govitecan (SG), in patients with the disease.

Dr. Sara Tolaney: Now as you point out, we do actually have some antibody-drug conjugates. You mentioned trastuzumab deruxtecan targeting the HER2 receptor really making us need to figure out which patients do have HER2-low disease and then Sacituzumab targeting Trop 2. Maybe, Gregory, I could turn to you in terms of the role of Trop 2 in breast cancer in general, and then we can maybe circle to the ADCs targeting that.

Dr. Gregory Vidal: Trop 2 which is the target of that antibody on Sacituzumab really it more serves here more as a target than a disease driver. What we know about Trop 2 which is a membrane protein receptor is that it's expressed more in malignant tumors than non-malignant tumors. It has, according to some preclinical data, probably a role in tumorigenesis, but it doesn't appear to be a direct driver. In the case of Sacituzumab, it serves as the target that brings with it the payload in case of Sacituzumab which is the SN-38 chemotherapy, which internalize then releases that chemotherapy to have its impact on the cell and the neighboring cells, which is really a unique design of this drug. As far as all we know and we're learning more and more about it, Trop really doesn't play any direct role there as far as anti-cancer in breast cancer.

Dr. Sara Tolaney: I think that's so helpful because it's interesting, it's kind of a paradigm shift in the way we think about targeting cancer in general because we've always thought about finding an oncogenic driver, figuring out a way to turn off that driver kind of like the way alpelisib is turning off PI3 kinase. That's kind of the way we've thought about drug development but now with examples that you both have pointed out, like T-DXd for HER2-low and HER2 low having low HER2 expressions, not driving that cancer. It's just that we found that there's a little bit of protein to deliver that ADC. I think similarly with Trop 2 as you point out that just knowing that there's that target there is allowing us to have targeted delivery of chemotherapy, which has proven to be so useful now in breast cancer. Maybe it would be helpful to dig into a little bit of the data and get your guys' thoughts on what we're seeing. I think with Sacituzumab as you pointed out, it's an ADC targeting Trop 2 with this topoisomerase 1 payload SN-38.