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ADCs for HER2 Low or Negative MBC
Optimal Integration of ADCs Into the Care of Patients With HER2-Negative/Ultralow/Low Metastatic Breast Cancer: A Call to Action

Released: October 28, 2025

Laura A. Huppert
Laura A. Huppert, MD
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Key Takeaways
  • Trastuzumab deruxtecan (T-DXd) is now approved by the FDA for specific patients with HER2-low or HER2-ultralow metastatic breast cancer; sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) are approved for specific patients with previously treated HER2-negative metastatic breast cancer.
  • ADCs have unique AE profiles; specific AEs should be monitored and managed during treatment, including interstitial lung disease (T-DXd and Dato-DXd), diarrhea and neutropenia (SG), and ocular toxicities and stomatitis/mucositis (Dato-DXd).

Antibody–drug conjugates (ADCs) have now received FDA approvals for the treatment of patients with HER2-low, HER2-ultralow, and HER2-negative metastatic breast cancer (MBC), significantly altering therapeutic paradigms for these patients. In this commentary, Laura A. Huppert, MD, discusses opportunities and challenges to the integration of ADCs into optimal care of these patients, as well as key areas of education for patients who might receive these agents.

Opportunities and Challenges in Integrating ADCs for MBC
The use of ADCs for HER2-low, HER2-ultralow, and HER2-negative MBC is an evolving space, with multiple agents demonstrating both progression free survival (PFS) and overall survival (OS) benefit and significantly improving outcomes for our patients. However, it can be hard to keep up with the constantly changing landscape in MBC, and there are many unanswered questions. Currently, there are 3 ADCs FDA approved in this space (as of October 2025).

Trastuzumab deruxtecan (T-DXd) has indications for patients with:

  • Unresectable or metastatic hormone receptor (HR)–positive/HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer that has progressed on ≥1 endocrine therapies in the metastatic setting
  • Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy

Sacituzumab govitecan (SG) has the following indications for patients with:

  • Unresectable locally advanced or metastatic HR-positive/HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received endocrine-based therapy and ≥2 additional systemic therapies in the metastatic setting
  • Unresectable locally advanced or metastatic triple-negative breast cancer who have received ≥2 prior systemic therapies, ≥1 of them for metastatic disease

Datopotamab deruxtecan (Dato-DXd) is indicated for patients with unresectable or metastatic, HR-positive/HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.

HER2 Low/Ultralow MBC
One challenge related to the discussion of HER2-ultralow/low MBC is that HER2 ultralow is not a standard pathology term. HER2 ultralow is defined as HER2 IHC between 0 and 1+ and FISH negative. Historically, that has not been something noted in pathology reports. In the clinic, when we are trying to decide if patients are eligible for T-DXd with HER2-low or HER2-ultralow disease, we can look back through their prior pathology reports to determine if they have ever had a HER2-low or -ultralow reading

(even with early-stage disease). If HER2 low/ultralow has never been reported, it can be helpful to email the pathologist to ask them to re-evaluate for these. This is an extra step for our pathologists, but if HER2 low or ultralow is observed, it allows for the use of T-DXd in that patient, so it is very important.

ADC Sequencing for HER2-Negative MBC
Another challenge with the current clinical use of these ADCs is that T-DXd, SG, and Dato-DXd all have topoisomerase I inhibitor payloads, and none of the pivotal phase III studies with these agents allowed the use of prior ADCs, so the optimal sequencing of these ADCs is unknown. Specifically, is it best to give chemotherapy in between ADCs, or can you give them back-to-back? There are retrospective data that suggest that, in general, patients derive more benefit from their first topoisomerase I inhibitor ADC than their second topoisomerase I inhibitor ADC; however, we do not have prospective data at this time. There are multiple ongoing prospective trials that are evaluating this question (eg, TRADE-DXd, ENCORE, and SERIES), so hopefully there will be more data to help us address these questions soon.

In the meantime, in patients with HR+/HER2- MBC, I tend to prioritize the use of T-DXd first given the impressive data from the DESTINY-Breast04 and DESTINY-Breast06 trials. I often use a chemotherapy “sandwich” after T-DXd and then another ADC, either SG or Dato-DXd. In other patients, I sometimes give ADCs back-to-back depending on the patient’s sites of disease, comorbidities, and prior treatments. For triple-negative MBC, I tend to use SG first given the data from ASCENT, and then T-DXd after that, either after a line of chemotherapy or directly in sequence. I do sometimes change the preferred sequence based on patient preference, comorbidities, or other factors, so ultimately, I make these decisions on a case-by-case basis. It is also not yet clear whether T-DXd should be used as the first- or second-line chemotherapy in patients with HR+/HER2- MBC; both DESTINY-Breast04 and DESTINY-Breast06 showed that T-DXd outperformed chemotherapy in the first- and second-line settings, respectively, but OS is immature for DESTINY-Breast06. I tend to use T-DXd in the first-line setting in patients with more aggressive disease, those who are symptomatic, or those with a short disease-free interval on endocrine therapy, whereas it may be very appropriate to use capecitabine as the first chemotherapy in patients with more indolent disease and then T-DXd in the second-line setting. Again, I tend to make this decision on a case-by-case patient in discussion with each patient.

Adverse Event Management
It is important to also understand and optimize the management of adverse events with these agents. With T-DXd, we have learned a lot during the past few years about monitoring for interstitial lung disease (ILD): getting more frequent CT scans; counseling our patients to let us know about any cough or shortness of breath; and counseling our multidisciplinary teams to be able to recognize early symptoms and optimally manage ILD. In addition to managing ILD, fatigue and nausea are also AEs that can require more careful management. For nausea, I typically use a triplet IV antiemetic regimen. I also use olanzapine at night for the first 5-7 days after each treatment, which can significantly help to mitigate nausea. 

For SG, it is important to carefully manage neutropenia and diarrhea. Growth factor should be used to mitigate neutropenia. For diarrhea, counseling patients about the use of antidiarrheal medications is critical, with dose reductions of the ADC if needed. SG can also cause fatigue and alopecia. Dose reductions can be effective for fatigue.

For Dato-DXd, mouth sores/stomatitis can be the most difficult AE to manage. I recommend that my patients use prophylactic dexamethasone mouthwash 4 times per day, which can significantly mitigate this AE. Dato-DXd also has a low risk of ILD. There is also a low risk of ocular AEs with Dato-DXd, so patients should see an ophthalmologist around the time treatment starts and are advised to use saline eye drops and avoid contact lenses during treatment.

Shared Decision-making and Discussing ADCs With Patients
Whenever I discuss a new treatment with a patient, it is always a situation where shared decision making is critical. I see my job as an oncologist as providing my patients with information about what treatment options are available, reviewing the efficacy and safety data, and then helping to decide what is the right treatment for them. Often, a discussion may be as follows: “There are several different options, and here are the data for each. What are your preferences? What side effects are you worried about? Is there a schedule that would be easier or harder for you?” Then we decide together what is the right treatment for that patient. Having this open discussion and shared decision making is so important to providing the best care for each patient.

Because ADCs are a newer class of medication, some HCPs may not yet have as much experience with some or all of these agents. There are many resources online now to help provide education so that HCPs can feel more confident administering these agents. There are also patient-centered materials to provide information about ADCs. .

Your Thoughts
Have you recommended ADCs for HER2-low, HER2-ultralow, or HER2-negative MBC? What was your experience with these agents? In your practice, how do you communicate with your patients about ADCs? Please join the discussion by leaving a comment below or answering the polling question.

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