Selecting an Appropriate Treatment Regimen for Patients With HR+/HER2- mBC

Virginia Kaklamani, MD: Now, returning to this patient: she was involved in a trial, and there's an expectation that at some point she will experience progression of the disease. So, what should we do? Well, she has HER2 (human epidermal growth factor receptor 2)-low breast cancer. We can't forget the potential use of tDCS (transcranial direct current stimulation), which is approved for HER2-low breast cancer. We possess data from clinical trials showing its efficacy and improvement, especially when compared to single-agent chemotherapy for such patients. With that in mind, tDCS would be my second-line treatment choice.

One critical aspect to ponder upon is the mechanism of resistance when you're using sacituzumab govitecan and when you're considering tDCS. With antibody-drug conjugates, there could be multiple resistance mechanisms. The primary one relates to the antibody itself. For example, with trastuzumab—an anti-HER2 antibody—a known mechanism of resistance is the mutation development within HER2. This mutation makes it so the antibody can't bind to its receptor. This resistance pattern observed with trastuzumab might suggest it could be seen with similar drugs. However, since sacituzumab govitecan is a distinct antibody-drug conjugate and binds to TROP-2 (trophoblast cell-surface antigen 2), if a patient had been responsive to sacituzumab govitecan but later develops resistance, it's unlikely the HER2 receptor would already possess a mutation. As such, drugs like trastuzumab deruxtecan would remain effective.

Another potential resistance mechanism is the attached payload—the chemotherapy component of these antibody-drug conjugates. Both sacituzumab govitecan and trastuzumab deruxtecan have topoisomerase I inhibitors as their attached chemotherapeutic agents. However, they use distinct topoisomerase I inhibitors. Hence, the prevailing thought is that in most instances, even if a tumor develops resistance to one drug, it might still be sensitive to another. It is, therefore, a prudent approach to sequence these drugs. As we continue our research, we anticipate gathering more data on this sequencing strategy, but it's certainly an important aspect to keep in the forefront.

That's the methodology I employ when evaluating these patients, aiming to pinpoint the most effective treatment regimen for them.