Emerging data about the use of antibody-drug conjugates (ADCs) in breast cancer highlight the importance of target quantification, unresolved sequencing questions, and the evolving balance between targeted and cytotoxic effects, according to David Rimm, MD, PhD.
In an interview with OncLive® during the 2025 San Antonio Breast Cancer Symposium, Rimm distilled major points from a session he moderated during the meeting about the translational role of ADCs in breast cancer management. In the session, key breast cancer opinion leaders outlined the limitations of immunohistochemistry assays that are currently FDA approved for pathologist use in interpreting HER2 expression levels, noting that these assays are not optimized to accurately discriminate between HER2-low and HER2-ultralow cases.1 Additionally, they debated whether ADCs should be considered similar to targeted therapy due to the fact that target expression levels and mutations mediate ADC efficacy and mechanisms of resistance, or whether this class of agents is more akin to an advanced form of chemotherapy, owing to these drugs’ inability to spare normal cells and antitumor activity that is not well correlated with target expression levels.2,3
“In some settings, and [maybe in] more settings in the future, there will be more than one ADC available to patients, and oncologists will have to choose which one to use first,” Rimm contextualized in the interview.
Rimm is the Anthony N. Brady Professor of Pathology and a professor of medicine (medical oncology) at the Yale School of Medicine, as well as director of the Tissue Microarray Facility, director of Yale Pathology Tissue Services, and director of the Physician Scientist Training Program at the Yale Cancer Center in New Haven, Connecticut.
OncLive: What clinical and biological factors might influence the decision to use an ADC for patients with breast cancer?
Rimm: I'm on the side of [ADCs] being a targeted therapy. My lab has worked, in the last 2 or 3 years, on measuring the target. That is what the pathologist does: read the target and give a score. My lab has focused on how to measure [targets] using concentration units of attomoles per square millimeter. We're interested in trying to prove that those assays are important and that measuring the target is important for predicting patient response and deciding which ADC is best for the patient.
In what clinical scenarios might traditional cytotoxic therapy remain preferable over other emerging treatment modalities, such as ADCs?
There's a place for traditional chemotherapy. No one really knows how to sequence it, ultimately. When you get to higher-line metastatic settings, there are a lot of different opinions on what should be first.
Key Design Elements of the Ongoing TRADE-DXd Trial4-
- TRADE-DXd is investigating the efficacy and safety of sequencing T-DXd followed by Dato-DXd, or vice versa, in patients with HER2-negative locally advanced unresectable or metastatic breast cancer.
- Patients in group 1 will be randomly assigned to receive either T-DXd or Dato-DXd; if they progress on the study drug they are initially assigned, they will cross over to group 2 and receive the other study drug. Patients will be eligible to enroll directly to group 2 if they already received the first study drug.
- ORR in groups 1 and 2 serves as the primary end point. Key secondary end points include PFS, OS, clinical benefit rate, time to progression, time to response, duration of response, safety, and change in HER2 expression level from baseline.
Some people think you should give one ADC first. Some people think you should give another [ADC after that]. Some people think you should give ADCs in sequence, and some people think you should put chemotherapy between the two ADCs. There isn't much evidence for any of those methods at this point. As some trials mature, like the phase 2 TRADE-DXd trial [NCT06533826], we'll see evidence developing for which order you should give the drugs in, and whether you should splice in chemotherapy.
What main message should clinical oncologists know about the current role of ADCs in breast cancer management?
It's not definitively shown whether ADCs are either chemotherapy or targeted therapy. There's evidence showing that they're just chemotherapy and that the ADC gets cleaved externally, so it's just a lower or different type of dosing of the chemotherapeutic payload. There's also plenty of evidence demonstrating that the target makes a difference, that bringing the payload to the target makes the drug much more effective.
In my experience, when there's a controversy like this, both parties are correct. That's probably going to be the case here. We'll [likely] see that there's some contribution [to the activity of ADCs] from targeted therapy and some contribution from non-targeted or more traditional chemotherapy. It's not definitively known which [argument] is correct, but both probably have some merit. In my opinion, it's important to consider the target, but that's not the only consideration.
References
- Sgroi D. HER2 low/ultralow: what the pathologist sees. Presented at: 2025 San Antonio Breast Cancer Symposium. December 9-12, 2025. San Antonio, Texas. Abstract CTI-01-03.
- Chandarlapaty S. Evidence that ADCs are targeted therapy. Presented at: 2025 San Antonio Breast Cancer Symposium. December 9-12, 2025. San Antonio, Texas. Abstract CTI-02.
- Hurvitz S. Evidence that ADCs are chemotherapy. Presented at: 2025 San Antonio Breast Cancer Symposium. December 9-12, 2025. San Antonio, Texas. Abstract CTI-03.
- Treatment of ADC-refractory breast cancer with Dato-DXd or T-DXd: TRADE DXd (TRADE DXd). ClinicalTrials.gov. October 24, 2025. Accessed February 13, 2026. https://clinicaltrials.gov/study/NCT06533826
