Next-generation antibody–drug conjugates revolutionize the precise classification and treatment of HER2-expressing breast cancer

Abstract

The concept of antibody–drug conjugations (ADCs) can be tracked back to the early 20th century when the renowned immunologist, Paul Ehrlich, proposed the idea of a “magic bullet”, which utilizes ADCs for targeted destruction of microorganisms and tumor cells1. After nearly one century of development, ADCs have emerged as a rather promising approach in the treatment of cancer, especially breast cancer, which is the most common malignant tumor in women2. Human epidermal growth factor receptor 2 (HER2), also known as Erb-B2 receptor tyrosine kinase 2 (ERBB2), is a crucial molecular classifier for breast cancer. The HER2 status is determined using immunohistochemistry (IHC) and in situ hybridization (ISH) in pathology laboratories. Approximately 15% of breast cancer patients exhibit HER2 overexpression and are thus defined as HER2-positive breast cancers. HER2 was a pivotal driver and therapeutic target in these patients3. HER2 is not considered to be a driving factor and is conventionally not targetable for breast cancers that display low-to-moderate HER2 expression (usually referred to as HER2-low breast cancers)4. The emergence of next-generation ADCs, represented by trastuzumab deruxtecan [T-DXd (also called DS-8201)], has revolutionized the precise classification and treatment of HER2-expressing breast cancer, including both HER2-overexpressing HER2-positive breast cancers and HER2-moderately expressed HER2-low breast cancers. By summarizing the unique mechanism of next-generation ADCs and their application in HER2-expressing breast cancers, we hope to examine the great impact of next-generation ADCs on clinicians and researchers, and to stimulate more emphasis on adapting to the era of next-generation ADCs.