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FAQs: ADCs in Breast Cancer
FAQs: The Expanding Role of Antibody–Drug Conjugates in Breast Cancer

Released: July 21, 2023

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Key Takeaways
  • Currently, experts do not recommend using trastuzumab deruxtecan for patients with HER2 IHC 0 MBC outside of a clinical trial.
  • Trastuzumab deruxtecan has shown evidence of intracranial activity in patients with active brain metastases, and sacituzumab govitecan is being evaluated in this setting. 

In this commentary adapted from a discussion among Sara Hurvitz, MD, FACP; Aditya Bardia, MD, MPH; and Shanu Modi, MD, the experts address important clinical questions about how to integrate the currently available antibody–drug conjugates (ADCs) into treatment strategies for patients with breast cancer.

Are you using the ADC trastuzumab deruxtecan (T-DXd) for patients with previously treated estrogen receptor–positive, IHC 0 metastatic breast cancer (MBC)? What are your thoughts on the future of T-DXd in early-stage, HER2-low breast cancer?

Aditya Bardia, MD, MPH:
For a patient with estrogen receptor–positive MBC, I would test for HER2 expression in tissue specimen, ideally last biopsy, before making a treatment decision. If the patient has not recently undergone a biopsy, I would consider a repeat biopsy, particularly if prior results revealed HER2 IHC 0, because HER2 expression can change over time, and HER2-low breast cancer is therapeutically actionable. If HER2 expression is consistently IHC 0 in the primary and metastatic tumors, I would consider therapy with sacituzumab govitecan but will not administer T-DXd because there is no approval for T-DXd in the IHC 0 MBC setting. T-DXd is approved for patients with unresectable or metastatic HER2-low breast cancer who have previously received ≥1 prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. We are looking forward to the results of the ongoing phase III DESTINY-Breast06 trial of T-DXd vs chemotherapy for patients with HER2-low, hormone receptor–positive, locally advanced or metastatic breast cancer after disease progression within 6 months of starting first-line therapy for MBC or after ≥2 previous endocrine therapies in the metastatic setting. This trial also includes patients with HER2 IHC 0+ (ultralow) advanced breast cancer.

Sara Hurvitz, MD, FACP:
I agree. Despite the promising results seen in the phase II DAISY trial, which demonstrated an overall response rate of 30% in heavily pretreated patients with HER2 IHC 0 MBC, as yet, I would not recommend the use of T-DXd for patients in this setting.

Shanu Modi, MD:
I also agree. The results from the DAISY trial are provocative. It was a great surprise to see a response rate of 30% in the cohort of patients with HER2 IHC 0, which begs the questions of whether T-DXd is specifically targeting HER2 and what minimum threshold level of HER2 IHC expression is required to activate T-DXd. There is great interest in knowing more about the specific characteristics of the disease and the patients participating in the DAISY trial. In addition to the ongoing DESTINY-Breast06 trial, which is looking at T-DXd in patients with ultralow HER2 expression, there are plans for clinical trials to specifically test the activity of T-DXd in patients with HER2 IHC 0 breast cancer to gain a better and larger experience in this setting.

Aditya Bardia, MD, MPH:
Overall, T-DXd has been a game changer in breast oncology because it improves overall survival vs chemotherapy (DESTINY-Breast04 trial), and it led to the new subclassification of patients with HER2-positive breast cancer as HER2 low. There is a lot of interest in moving T-DXd to the earlier setting. As previously indicated, the DESTINY-Breast06 trial is investigating T-DXd in patients with advanced HER2-low breast cancer who are chemotherapy naive, including patients with HER2 IHC 2+/ISH-, IHC 1+/ISH-, or IHC 0/ISH- disease. Also, the randomized phase II TALENT trial is evaluating neoadjuvant T-DXd either alone or in combination with anastrozole for patients with HER2-low hormone receptor–positive early-stage breast cancer. In the initial analysis of the TALENT trial, T-DXd demonstrated activity that appears to be higher than would be historically expected with traditional chemotherapy. So, it is likely that in the future T-DXd will be used in the neoadjuvant setting either alone or sequenced with chemotherapy, or even in combination with other agents. It is clear that these ADCs will replace chemotherapy in the future. In other words, I think that wherever chemotherapies are currently being used, such as in early-stage breast cancer, we likely will start using ADCs in the not-so-distant future.

Is there a clinical biomarker associated with response to sacituzumab govitecan?

Aditya Bardia, MD, MPH:
Although sacituzumab govitecan targets Trop-2, it also has a bystander effect and can affect Trop-2–negative cells. Accordingly, even in patients with Trop-2–low disease, we observed better progression-free survival with sacituzumab govitecan vs standard chemotherapy in the TROPiCS-02 clinical trial. Of note, Trop-2 is an epithelial antigen. Whether sacituzumab govitecan would be effective in a patient with predominantly mesenchymal cancer, such as breast sarcoma, is unknown and needs further evaluation.

Sara Hurvitz, MD, FACP:
Finding a biomarker of response will be clinically useful. Ongoing studies are investigating potential biomarkers in tissue samples collected at the time of progression on ADCs. 

Aditya Bardia, MD, MPH:
That is correct. We currently are investigating the mechanisms of resistance to ADCs by comparing genomic profiles in samples collected before treatment is initiated and at the time of disease progression. Clinically, we have very little data currently on potential mechanisms of resistance to ADCs.

Are the ADCs T-DXd and sacituzumab govitecan able to cross the blood‒brain barrier?

Sara Hurvitz, MD, FACP:
Our initial understanding was that T-DXd and sacituzumab govitecan are large, bulky molecules that will not be able to affect brain metastases. However, now we have some data showing that T-DXd is able to penetrate the blood‒brain barrier and that it has activity in patients with active central nervous system (CNS) metastases. In the phase III ASCENT and TROPiCS-02 trials of sacituzumab govitecan, however, only patients with treated, stable CNS metastases were eligible.

Shanu Modi, MD:
The DESTINY-Breast04 trial included patients with treated, stable brain metastases. We performed serial CNS imaging of these patients and observed good activity. T-DXd seems to be active in patients with stable CNS metastases. The phase II TUXEDO-1 trial (NCT04752059) has shown that T-DXd elicits intracranial activity in patients with HER2-positive breast cancer and active brain metastases. The multicohort phase II DEBBRAH trial also showed that T-DXd has intracranial activity in patients with HER2-positive stable untreated or treated progressing CNS metastases. Anecdotally, I have seen really dramatic CNS responses with T-DXd in patients with HER2-positive MBC and active CNS disease. I was involved in an interesting study performed at my institution in which we analyzed tumor tissues from patients with HER2 IHC 0 MBC, and we found that approximately one half of these patients had brain metastases expressing low levels of HER2. So, there is a real need and a potential solution for these patients, especially with the availability of T-DXd. With regard to sacituzumab govitecan, its activity in patients with active CNS metastases remains unclear. There is an ongoing phase II trial of sacituzumab govitecan in patients with HER2-negative breast cancer and brain metastases (NCT04647916). Even though these ADCs are large, it appears that they are able to cross the blood‒brain barrier. Whether they are able to do this after the blood‒brain barrier has been breached with procedures such as radiation therapy to the brain or because there is a passage for these big molecules remains unclear.

Your Thoughts?
What challenges do you experience in your practice when it comes to using T-DXd and sacituzumab govitecan for managing patients with MBC? Answer the polling question and join the conversation in the discussion box below.

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Have you used the ADCs T-DXd and/or sacituzumab govitecan for patients with breast cancer and CNS metastases?

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