S16 Ep35: T-DXd Trials Transform Treatment for HER2-Positive Breast Cancer: With Sara Nunnery, MD, MSCI; and Kelly E. McCann, MD, PhD

Breast Cancer Briefing, hosted by Sara Nunnery, MD, MSCI, a breast medical oncologist and the director of Breast Cancer Research at Tennessee Oncology in Nashville, is a podcast series that breaks down the latest news in breast cancer research, one conversation at a time.

In today's episode, filmed live onsite at the 43rd Annual Miami Breast Cancer Conference, Dr Nunnery sat down with Kelly E. McCann, MD, PhD, a breast medical oncologist in the University of California system.

Their conversation centered around the evolving HER2-positive breast cancer treatment paradigm. The experts highlighted that although this disease was once associated with a poor prognosis, targeted therapies like trastuzumab (Herceptin) have revolutionized management, making these cancers highly curable.

They noted the role of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), an antibody-drug conjugate (ADC) that delivers chemotherapy directly to cancer cells and uses a bystander effect to kill neighboring malignant cells. The phase 3 DESTINY-Breast11 trial (NCT05113251) evaluated T-DXd in the neoadjuvant setting for patients with high-risk, HER2-positive early breast cancer. Results showed significantly higher pathological complete response rates with T-DXd followed by docetaxel, trastuzumab, and pertuzumab (Perjeta) compared with standard chemotherapy. Responses were even more pronounced in patients with hormone receptor–negative disease.

Furthermore, they spotlighted the phase 3 DESTINY-Breast05 trial (NCT04622319), which examined T-DXd as adjuvant therapy for high-risk patients with residual HER2-positive disease. In this study, T-DXd generated an improvement in invasive disease–free survival compared with standard ado-trastuzumab emtansine (Kadcyla). They noted that a significant benefit of T-DXd is its ability to cross the blood-brain barrier, offering the potential for preventing brain metastases. However, the experts expressed caution regarding interstitial lung disease, a potentially fatal adverse effect associated with T-DXd. Because of this risk, patients who receive T-DXd require frequent, expensive CT monitoring, which Nunnery and McCann explained can pose logistical and insurance challenges in standard practice.

Although adjuvant T-DXd has been added to the National Comprehensive Cancer Network Clinical Practice Guidelines for HER2-positive breast cancer, the neoadjuvant regimen has not yet been included, likely awaiting more mature survival data. Both oncologists conclude that although ADC-associated toxicities require vigilant management, these treatment advancements provide powerful new tools for potentially curing high-risk patients with HER2-positive breast cancer.