Dr Yuan on the Potential Benefit of Upfront T-DXd in HER2+ Breast Cancer With CNS Metastases

"One of the [potential] benefits to using the DESTINY-Breast09 approach upfront is perhaps we can prevent some of the CNS metastasis. This gives us a lot of comfort, although…we still have a lot of myths around how the blood-brain barrier works, and why this bulky molecule T-DXd would have CNS penetration."

Yuan Yuan, MD, PhD, the director of Breast Medical Oncology Medicine and the medical director of the Breast Oncology Disease Research Group at Cedars-Sinai Medical Center, as well as a health sciences clinical professor at the University of California, Los Angeles, discussed the potential clinical benefit of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) combined with pertuzumab (Perjeta) as upfront therapy for patients with HER2-positive advanced or metastatic breast cancer with central nervous system (CNS) metastases, based on findings from the phase 3 DESTINY-Breast09 trial (NCT04784715).

This approach may offer advantages beyond systemic disease control, including the potential to reduce the incidence of CNS metastases. Yuan explained that although encouraging signals are emerging regarding CNS activity, the underlying mechanisms remain poorly understood. She noted ongoing uncertainty regarding how large antibody-drug conjugate (ADC) molecules such as T-DXd penetrate the blood-brain barrier and exert therapeutic activity within the CNS. Yuan emphasized that the field continues to explore these pharmacologic and biologic principles as more ADCs enter clinical practice.

As the oncology community advances into a new era of targeted therapies, Yuan highlighted the need for focused translational research to characterize how ADCs interact with the tumor microenvironment, particularly within the CNS. She stated that the DESTINY-Breast09 results represent a promising example of the evolving role of these agents and support continued investigation into optimizing upfront treatment strategies for HER2-positive metastatic disease.