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Expert Perspectives on HER2 ADCs
FAQs With Expert Perspectives on HER2-Directed ADCs in Breast Cancer: Treatment Selection, Sequencing, and Patient-Centered Care

Released: July 01, 2026

Sara A. Hurvitz
Sara A. Hurvitz, MD, FACP
Ian Krop
Ian Krop, MD, PhD
Adrienne G. Waks
Adrienne G. Waks, MD
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Key Takeaways
  • Recent approvals and clinical trial data have expanded the role of T-DXd across HER2-positive early-stage and metastatic breast cancer, requiring healthcare professionals to individualize treatment selection based on disease risk, prior therapy, treatment goals, and patient preferences.
  • Recent clinical trial data highlight the importance of individualized treatment sequencing based on clinical features and patient characteristics.
  • Safe and effective use of HER2-directed ADCs requires proactive toxicity monitoring, early patient education about ILD/pneumonitis symptoms, and clear communication with pathology teams to support accurate interpretation of HER2-positive, HER2-low, and HER2-ultralow disease.

In this commentary, Sara A. Hurvitz, MD, FACP; Ian Krop, MD, PhD; and Adrienne G. Waks, MD, address key questions raised during a recent live symposium titled, “Integrating HER2-Directed ADCs Across Early and Metastatic Breast Cancer: Practical Strategies for Testing, Sequencing, and Patient-Centered Care.” During the symposium, the expert faculty discussed common clinical questions related to the use of HER2-directed antibody–drug conjugates (ADCs) across the HER2-positive breast cancer continuum. The following is based on questions from the audience and highlights the panel’s perspectives on applying recent clinical trial data to treatment decisions, sequencing, toxicity monitoring, HER2 testing, and patient-centered care.

Which patients with high-risk HER2-positive early breast cancer are candidates for neoadjuvant trastuzumab deruxtecan (T-DXd) followed by paclitaxel/trastuzumab/pertuzumab (THP)?

Ian Krop, MD, PhD:
For patients who fit the eligible DESTINY-Breast11 patient population criteria, a neoadjuvant T-DXd–based approach is a reasonable option. This includes patients with HER2-positive stage II or III disease with higher-risk features, such as clinically node-positive disease and/or tumors larger than 5 cm. The important caveat is that we still need to determine how best to manage residual disease after neoadjuvant T-DXd because this is a clinical scenario we have not had to manage previously.

Sara A. Hurvitz, MD, FACP:
Although the DESTINY-Breast11 trial results are encouraging, I remain cautious about broadly adopting neoadjuvant T-DXd for every patient. The trial did not include a docetaxel/carboplatin/trastuzumab/pertuzumab comparator arm, making it difficult to determine the incremental benefit of the T-DXd–based regimen compared with current standard neoadjuvant therapy. I also question whether 4 cycles of neoadjuvant T-DXd before transitioning to THP are sufficient for all high-risk patients, since use of adjuvant T-DXd is not indicated in a patient who received neoadjuvant T-DXd-THP. Until longer-term efficacy and overall survival (OS) data are available, these uncertainties make me hesitant to replace current neoadjuvant standards for all patients.

Adrienne G. Waks, MD:
For young, fit patients with high-risk HER2-positive early breast cancer, I would favor a neoadjuvant T-DXd–based approach. The trial reported impressive pathologic complete response rates with the investigational regimen and other data raises important questions about whether all patients require carboplatin as part of neoadjuvant therapy. Although longer-term follow-up is needed, I believe the DESTINY-Breast11 trial results support incorporating T-DXd into the neoadjuvant treatment strategy for patients with node-positive disease. Lower-risk patients may not need this level of escalation, and we need longer follow-up and better biomarkers to refine who benefits most.

How should adjuvant T-DXd be discussed for patients with residual invasive HER2-positive disease after neoadjuvant therapy?

Adrienne G. Waks, MD:
The DESTINY-Breast05 trial is highly relevant for patients with residual invasive disease after neoadjuvant trastuzumab-based therapy and taxane-based treatment, particularly those with higher-risk residual disease. In that setting, adjuvant T-DXd reduced the relative risk of an invasive disease–free survival (IDFS) event by approximately one half compared with trastuzumab emtansine, with a 3-year IDFS rate of 92.4% vs 83.7%. That is a clinically meaningful benefit, but it should be discussed alongside the higher rates of gastrointestinal toxicity, cytopenias, fatigue, and interstitial lung disease (ILD)/pneumonitis observed with prolonged adjuvant T-DXd.

Ian Krop, MD, PhD:
I would emphasize that the adjuvant indication is specifically for patients with residual invasive disease after neoadjuvant trastuzumab, with or without pertuzumab, and taxane-based treatment. This is not the same question as what to do after residual disease following neoadjuvant T-DXd. As T-DXd moves into the neoadjuvant setting, we will need additional data to define the optimal postneoadjuvant strategy for patients who have already received T-DXd before surgery.

Sara A. Hurvitz, MD, FACP:
The strength of the DESTINY-Breast05 trial is the IDFS endpoint, which is more clinically meaningful than pathologic complete response alone. At the same time, in potentially curable patients, we need to be very clear about risk–benefit tradeoffs. Adjuvant therapy with T-DXd for 14 cycles is not a trivial treatment, and counseling should include ILD/pneumonitis risk, nausea prevention, fatigue, cytopenias, and the importance of early symptom reporting.

How do the findings from DESTINY-Breast09, PATINA, and HER2CLIMB-05 trials inform the selection of first-line induction and maintenance therapy for HER2-positive metastatic breast cancer?

Ian Krop, MD, PhD:
All 3 studies demonstrated meaningful improvements in progression-free survival (PFS), but they do not point to a single optimal treatment strategy for every patient. Instead, these data highlight the importance of individualized treatment recommendations, taking into account disease characteristics, patient preferences, treatment goals, and the anticipated balance between efficacy and toxicity.

For patients with hormone receptor (HR)–positive/HER2-positive disease, I find the PATINA data particularly compelling because they support incorporating endocrine therapy and CDK4/6 inhibition into first-line maintenance. This is now an NCCN recommendedoption: Palbociclib may be used in combination with trastuzumab, with or without pertuzumab, and endocrine therapy as maintenance treatment after induction therapy for adults with HR-positive/HER2-positive locally advanced or metastatic breast cancer.

Sara A. Hurvitz, MD, FACP:
I am concerned that we may overtreat some patients in the first-line setting. Some patients can remain on maintenance trastuzumab/pertuzumab for many years with excellent quality of life, particularly those with HR-positive/HER2-positive disease, where endocrine therapy and CDK4/6 inhibition as part of a PATINA-based approach may provide meaningful disease control.

I am not yet convinced that T-DXd/pertuzumab should be used routinely as first-line therapy for every patient, especially because T-DXd remains an effective later-line treatment option. I am eager to see mature OS data and the T-DXd monotherapy arm from the DESTINY-Breast09 trial; if those data demonstrate an OS advantage, I would be more compelled to use T-DXd earlier in a broader group of patients.

My approach differs for HR-negative/HER2-positive disease, where I am more inclined to consider first-line T-DXd. In the future, biomarkers, including PIK3CA mutation status and HER2DX, may help refine selection, and the role of T-DXd as induction therapy followed by maintenance therapy remains an important unanswered question.

Adrienne G. Waks, MD:
I agree. For a patient with de novo HR-positive/HER2-positive metastatic breast cancer, I often favor a PATINA-based strategy after THP induction. This allows us to incorporate endocrine therapy and CDK4/6 inhibition early while preserving T-DXd for later use, where it has demonstrated meaningful progression-free survival benefit.

My threshold for first-line T-DXd plus pertuzumab is lower in more individualized scenarios, including HR-negative disease, tumors with PIK3CA mutations, early relapse after prior HER2-directed therapy, or clinically meaningful central nervous system (CNS) involvement. Some patients may still achieve durable outcomes with THP alone, so validated biomarkers will be important to better refine patient selection.

At present, I would not routinely prescribe a predefined course of T-DXd plus pertuzumab followed by maintenance therapy because prospective data supporting that strategy are lacking. Instead, I would continue T-DXd plus pertuzumab while it is well tolerated and consider transitioning to maintenance earlier if cumulative toxicity becomes a concern.

How do you approach treatment for patients who develop metastatic disease after exposure to T-DXd in the early-stage setting, including possible T-DXd rechallenge?

Sara A. Hurvitz, MD, FACP:
This is an important clinical question, and we have very limited data to guide T-DXd rechallenge after prior T-DXd exposure. In the absence of prospective evidence, I think the duration of prior benefit, the interval since T-DXd treatment, and the reason treatment was discontinued should all factor into the decision to rechallenge. If progression occurs soon after T-DXd, I would generally favor a different HER2-directed regimen, clinical trial, or another evidence-supported approach rather than immediate rechallenge.

Adrienne G. Waks, MD:
I would rechallenge with T-DXd-based therapy for patients who stopped it after a pre-defined neo/adjuvant course and then remained off T-DXd for approximately 12 months before recurrence or progression. However, I would be less inclined to rechallenge if a patient developed metastatic disease within 6 months of prior T-DXd treatment. For patients whose disease recurs between those time points, I would individualize the decision based on the clinical scenario and how well the patient previously tolerated T-DXd.

Ian Krop, MD, PhD:
I generally agree with that approach. A treatment-free interval of approximately 1 year is a reasonable threshold to consider when deciding whether to rechallenge with T-DXd, although that cutoff is somewhat arbitrary. Until more evidence becomes available, these decisions should be guided by clinical judgment and each patient’s prior experience with treatment.

How should T-DXd and tucatinib-based regimens be considered for patients with HER2-positive breast cancer and brain metastases?

Adrienne G. Waks, MD:
Brain metastasis management is multidisciplinary, and local therapy remains important for symptomatic, large, dominant, or limited lesions. From a systemic therapy standpoint, the DESTINY-Breast12 trial results increase my comfort using T-DXd in patients with HER2-positive metastatic breast cancer and brain metastases, particularly because the CNS-PFS and overall PFS in the cohort of patients with baseline brain metastasis were similar and response rates were in a similar range in the body and brain. However, the DESTINY-Breast12 trial was not a randomized first-line trial, and the brain metastasis patient data from the randomized phase III HER2CLIMB trial are also very compelling for the efficacy of this regimen for patients with HER2+ breast cancer brain metastases – showing a 9.1 month OS improvement with tucatinib specifically for patients with brain metastases.

Sara A. Hurvitz, MD, FACP:
The tucatinib, trastuzumab, and capecitabine regimen remains an important option especially because the HER2CLIMB trial uniquely enrolled many patients with active or stable brain metastases and demonstrated survival benefit in this population. In practice, treatment choice depends on the line of therapy, whether CNS disease is active or treated, extracranial disease burden, prior T-DXd exposure, symptoms, and patient preference.

Ian Krop, MD, PhD:
For isolated CNS progression with otherwise controlled extracranial disease, the HER2CLIMB experience supports considering local therapy and continuation of the patient’s current systemic therapy in select patients. That clinical principle remains useful even as systemic options evolve, but these decisions should be individualized with radiation oncology and neurosurgery input.

How do you counsel patients with early-stage breast cancer about the risk of T-DXd–associated ILD/pneumonitis, particularly when radiation therapy is planned?

Sara A. Hurvitz, MD, FACP:
I strongly emphasize this risk when counseling patients, especially in early-stage disease where treatment intent is curative and effective non-ILD–associated alternatives may exist. Close monitoring with chest imaging, similar to the surveillance used in clinical trials, may be warranted, although implementing serial CT scans in routine practice can be challenging. Patients should understand that even low-grade or asymptomatic findings require prompt evaluation and that therapy may need to be held.

Ian Krop, MD, PhD:
Close monitoring with chest CT scans is critical for the early detection of T-DXd–associated ILD/pneumonitis. Of equal importance is educating patients to report new respiratory symptoms, such as dyspnea or cough, promptly. Patients may otherwise seek care outside their oncology team, where ILD can be mistaken for pneumonia, delaying appropriate management and allowing toxicity to worsen. Healthcare professionals must remain vigilant and ensure that patients understand the importance of reporting symptoms early.

Your Thoughts
What are your questions about the rapidly evolving management of patients with early-stage and advanced-stage HER2-positive breast cancer? Have you had any interesting experiences with your patients with HER2-positive breast cancer that you would like to share with your colleagues?

Be sure to visit our HER2-positive metastatic breast cancer Interactive Decision Support Tool to get expert treatment recommendations for your patients!

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And stay tuned for our new early-stage breast cancer Interactive Decision Support Tool coming soon!

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With the recent FDA approvals of T-DXd as both neoadjuvant and adjuvant therapy for early-stage HER2-positive breast cancer, are you planning to incorporate these options into your clinical practice?

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