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HER2low and HER2ultralow mBC: FAQs
Challenging Treatment Paradigms in HER2-Low and HER2-Ultralow mBC: Experts Answer Your Questions

Released: July 02, 2025

Expiration: January 01, 2026

Nadia Harbeck
Nadia Harbeck, MD, PhD
Ian Krop
Ian Krop, MD, PhD
Sarah L. Sammons
Sarah L. Sammons, MD
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Key Takeaways
  • Experts suggest that it is key to perform repeat HER2 testing because of changing tumor biology during the course of disease, improved assay sensitivity, along with new guidelines on result reporting.
  • In patients with estrogen receptor–positive disease and HER2-low or HER2-ultralow status, experts recommend evaluating disease characteristics like time to disease progression on endocrine therapy and retesting for hormonal status and other actionable biomarkers to better assess eligibility for trastuzumab deruxtecan (T-DXd).
  • Although limited data exist, experts recommend caution when pursuing T-DXd in patients with prior pneumonitis because of unrelated prior therapy and comorbidities of asthma and chronic obstructive pulmonary disease.

In this commentary, breast oncology experts Nadia Harbeck, MD, PhD; Sarah L. Sammons, MD; and Ian Krop, MD, PhD, answer frequently asked questions posed by an audience of healthcare professionals (HCPs) at a live satellite symposium on the current recommended management of patients with HER2-low and HER2-ultralow metastatic breast cancer (mBC) held at the American Society of Clinical Oncology 2025 annual meeting.

HER2 Testing in 2025

When assessing a patient’s tumor for HER2 status, would you repeat testing over time? 

Nadia Harbeck, MD, PhD:
Yes, I repeat HER2 testing in patients with mBC who are progressing on endocrine therapy. A study conducted in 547 patients with breast cancer showed a discordance for HER2-low status from primary tumor and that of the later developed metastases. Another study by Tarantino and colleagues showed that HER2 status can change over time. For instance, in that study some patients whose primary tumor had been HER2-low could become HER2-zero over time (22%), and some patients who were initially HER2-zero based on primary tumor had become HER2-low (44%) or even HER2-positive (by immunohistochemistry [IHC] assay score of 2+) using matched biopsy samples from advanced disease. This trend was seen regardless of whether the patient was estrogen receptor positive or had triple-negative status. This might not just be a biological phenomenon but may be a result of improvements in staining methods and updated guidelines on result interpretation and reporting.

Whether a patient was considered HER2-zero or HER2-low did not matter as much before, but now that we have treatment options approved for these patients such as trastuzumab deruxtecan (T-DXd) for those with HER2-low and HER2-ultralow status it is key that we know this information for the appropriate management of advanced mBC. T-DXd has FDA approval for patients with HER2-low and HER2-ultralow as follows:

  • For adult patients with unresectable or metastatic hormone receptor–positive/HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer as determined by an FDA-approved test that has progressed on ≥1 endocrine therapies in the metastatic setting
  • For patients with HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer as determined by an FDA-approved test for patients who previously received chemotherapy in the metastatic setting

What do reports for HER2-testing look like at your institutions? Do you get the percentages or do you get the immunohistochemical qualifier? 

Nadia Harbeck, MD, PhD:
I practice in Germany, and with regards to HER2 testing results reporting, we may ask our pathologist to report the overall IHC stain results and the pattern and positivity of staining (ie, a ≤10% membrane staining, which now has been reclassified as HER2-ultralow disease).

Sarah L. Sammons, MD:
At my institution, we order IHC assays for all of our patients with breast cancer, which includes HER2 status assessment. Our pathologists routinely report HER2-ultralow as well, although I know that is not the standard practice everywhere in the United States. In addition, we do get the semiquantitative score on everyone who has been tested for HER2 status.

Ian Krop, MD, PhD:
We should note that based on the IHC data that have been presented for assessment of HER2 status, distinguishing HER2-zero from HER2 1+ can be challenging. Distinguishing HER2-ultralow from those 2 can add to the difficulty, especially when also trying to quantify things more with results that may not be reproducible. I would not personally rely too much in a number and I think it more practical to assess results based on the various categories we know (HER2-zero, HER2-ultralow, HER2-low, and HER2-positive). The current tests are not strongly conclusive as some patients who are classified as HER2-zero may still respond to T-DXd. This observation is supported by data from the phase II DAISY trial of T-DXd in a group of patients with variable HER2 expression (HER2-overexpressing, n = 72: cohort 1; HER2-low, n = 74: cohort 2; and HER2-nonexpressing, n = 40: cohort 3). What that study ultimately showed was that approximately 36% of patients who were classified as HER2 IHC of 0 (defined by HER2 results below the median) had a confirmed objective response compared with 30% of patients with HER2 expression above the median. The ongoing phase IIIb DESTINY-Breast15 study of T-DXd in patients with unresectable and/or metastatic HER2-low or HER2-zero breast cancer (N = 250; NCT05950945) should provide results from a bigger sample size for a better assessment of the HER2-zero population. For instance, if that study shows a significant tumor response in patients with disease classified as HER2-zero, then it would validate the results from DAISY and hence there would not be a need to test for HER2 status as an indication for T-DXd. That being said, we should continue to follow the current FDA-approved indications as detailed above.

What are your thoughts on whether the Ventana assay validated the 4B5 HER2 pathway for HER2-low and HER2-ultralow, and its approval as a companion diagnostic for T-DXd?

Nadia Harbeck, MD, PhD:
In Germany, we do not have the concept of a “companion diagnostic.” We rely on quality assurance testing throughout the pathology community and we are more flexible regarding which individual test(s) HCPs are using. I know that in the United States things are a bit different. The Ventana PATHWAY HER2 4B5 assay is approved as a companion diagnostic for treatment with T-DXd. And it has also been validated for the HER2-low and HER2-ultralow detection. But as mentioned, this might not be applicable to some of the testing that is performed outside of the United States.

Selecting Treatment for HER2-Low and HER2-Ultralow mBC After Progression on Endocrine Therapy

How does the presence of other biomarkers, in addition to HER2-low of HER2-ultralow status such as the ESR1 or PIK3CA alterations, inform your therapy selection? 

Sarah L. Sammons, MD:
This is a very important question. When I think about in which patients I would recommend an antibody–drug conjugation (ADC) (ie, T-DXd, sacituzumab govitecan, or datopotamab deruxtecan) or chemotherapy, I am really thinking within the setting of endocrine resistance. Here, we also need to consider biomarkers like ESR1 or PIK3CA alterations when I am considering a second-line endocrine therapy. And after excluding biomarkers that would suggest for an endocrine therapy (eg, ESR1 mutation, for elacestrant; and PIK3CA/AKT1/PTEN-alterations, for fulvestrant and capivasertib), I would consider ADCs to be a reasonable option.

Nadia Harbeck, MD, PhD:
We all have patients from before elacestrant was approved as well. I can think of 1 patient where we had exhausted the endocrine therapies available at the time and we gave her T-DXd. We also gave sacituzumab govitecan in that setting. Based on the positive results from the phase III EMERALD trial of elacestrant vs investigator’s choice of standard-of-care endocrine therapy in patients with estrogen receptor–positive/HER2-negative mBC who had ESR1 mutation (HR: 0.55; 95% CI: 0.39-0.77; P = .0005), we started to test for ESR1 mutated and transitioned those patients to elacestrant. I would say that this patient had disease that was progressing slowly, and after the switch to elacestrant, she remarked that she had a “wonderful year” in reference to her quality of life while receiving this treatment.

My takeaway from this is that if the disease is not progressing rapidly or overly aggressive (symptomatic, visceral crises, etc), then it is ok to consider elacestrant if we had not had a chance to use it before.  

Another thing that comes to mind is whether it matters if disease with multiple actionable biomarkers is HER2-low or HER2-ultralow.

Sarah L. Sammons, MD:
I do not think we have an answer for this. Data from the phase III DESTINY-Breast06 of T-DXd compared with physician’s choice of chemotherapy (consisting of capecitabine, paclitaxel or nab-paclitaxel) in patients with hormone receptor–positive mBC and progressive disease on ≥2 previous endocrine therapies with or without previous targeted therapy and HER2-low (IHC 1+, or 2+/ISH-) or HER2-ultralow (IHC >0 to <1+) status based on central IHC assessment the median progression-free survival (PFS) (HER2-low and HER2-ultralow modified PFS: 13.2 months, 95% CI: 11.4-15.2, and 13.2 months, 95% CI: 9.8-17.3) were nearly identical. As stated earlier, we now have an FDA approval for both of them. I should also mention that I do use T-DXd in HER2-ultralow patients at this time, but I do not use T-DXd for the truly HER2-zero patients evidenced by consistent HER2-zero on all of their biopsies. Thus, if they received capecitabine in the first line and then they are HER2-ultralow at recurrence, I think it is perfectly reasonable to consider T-DXd in the second-line.

In patients with mBC and HER2-low and HER2-ultralow status, what would your preferred local therapy be if the patient also has central nervous system disease present? Thoughts on Gamma Knife radiation or stereotactic radiotherapy?

Sarah L. Sammons, MD:
If the patient has disease that is truly HER2-positive and we were very inclined to avoid radiation therapy and that patient had asymptomatic brain metastases, we might consider holding off on radiation because the intracranial response rates seen with T-DXd for HER2-positive disease is approximately 70% to 80% based on data from the phase Ib/II DESTINY-Breast07 study of T-DXd with or without pertuzumab in patients with advanced mBC, including with previously treated/stable brain metastases. However, I would not feel comfortable doing that for a patient with HER2-low or HER2-ultralow mBC. In patients with HER2-low or HER2-ultralow disease, I would recommend local therapy with stereotactic radiosurgery because I am not comfortable enough with an intracranial response rate of 25% as seen in the DESTINY-Breast04 trial of T-DXd vs chemotherapy for previously treated HER2-low advanced breast cancer.

What are your thoughts on using T-DXd earlier, such as after the CDK4/6 inhibitor, to potentially attain an even better response because of how potent this agent is? Or would you always go to the endocrine therapy first?

Sarah L. Sammons, MD:
Because these patients have mBC and will be on treatment for the rest of their lives, we always make an attempt to maximize the number of therapy options that they can receive. Unless I have a reason to put them on intravenous chemotherapy earlier in their disease course causing them to lose their hair and be subjected to the serious adverse effects associated with T-DXd, I opt for maximizing my endocrine therapy options first. That said, if I have a patient who has rapid disease progression (eg, ≤6 months of their CDK4/6 inhibitor and symptomatic progression) and we need to get the disease under control via a rapid response I might use T-DXd in that case. Often when I have these rapid progressors on first-line CDK4/6 inhibitors, rebiopsy shows a substantial loss of their ER (approximately 25%). And for such patients, I hesitate to give a second line of endocrine therapy and might consider using T-DXd instead.

Managing the AE Profile of T-DXd

In patients with concomitant lung diseases (eg, asthma or chronic obstructive pulmonary disease [COPD]), would you expect an increased risk of interstitial lung disease/pneumonitis with T-DXd? Are there any contraindications for T-DXd? 

Ian Krop, MD, PhD:
Patients with low ejection fraction were not eligible for any of the clinical trials evaluating T-DXd. Patients with substantial histories of pneumonitis in the past, particularly pneumonitis requiring treatment, were often excluded from many of the trials as well. For this reason, we do not have very robust data on whether there are increased risks of pneumonitis in patients who previously had pneumonitis for another cause. This topic may arise when we come across a patient who has had radiation treatment–related pneumonitis. And this is something that I do not worry about too much. By contrast, if you had a patient who experienced pneumonitis from another drug like everolimus, I might consider not giving T-DXd to this patient for concerns of a resurgence of treatment-related pneumonitis. As I said, we do not have much data to inform you regarding this because these patients were often excluded from the trials evaluating T-DXd.

Regarding asthma and COPD, the data we have on predictors of interstitial lung disease do show a modest increase in incidence with patients who have lung comorbidities, which include asthma and COPD, but not a dramatic increase. Furthermore, you have to weigh the risks and benefits for a drug that can be beneficial for many of our patients.

Your Thoughts
What are your thoughts on the current treatment landscape in HER2-low and HER2-ultralow mBC? Answer the polling question and leave us a comment. Visit the program page to access the slides associated with this program and watch an on-demand webcast from the live event.

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