**1. Introduction**

Antibody drug conjugates (ADCs) continue to change the treatment paradigm of breast cancer and recent regulatory approvals of next generation ADCs are shifting how breast cancer is classified and treated. ADCs combine precision targeting with traditional cytotoxic treatment allowing for the delivery of highly potent chemotherapy to malignant cells. There are three U.S. Food and Drug Administration (FDA) approved ADCs in breast cancer including ado-trastuzumab emtansine (T-DM1), fam trastuzumab deruxtecan (T-Dxd), and sacituzumab govitecan (SG). The 3 approved ADCs in breast cancer are summarized in **Table 1**. T-DM1 is approved for the treatment of human epidermal growth factor receptor 2 positive (HER2+) early breast cancer (EBC) and advanced, recurrent or metastatic breast cancer (MBC). T-Dxd is approved for the treatment of HER2+ MBC and hormone receptor positive (HR+), HER2 low MBC. HER2 overexpression or HER2+ is defined as having immunohistochemistry (IHC) 3+ or IHC 2+ with positive HER2 gene amplification measured by in situ hybridization (ISH) [1]. Approximately, 15–20% of breast tumors are HER2+ [2]. HER2 low is defined as IHC 1+ or IHC 2+ and ISH negative [1]. Approximately, 50–55% of HR+, HER2 negative breast cancer is HER2-low [3]. HER2-low breast tumors do not respond to trastuzumab or T-DM1 [4, 5].

SG is approved for the treatment of metastatic triple negative breast cancer (TNBC) and HR+ MBC after progressing on prior lines of chemotherapy. Both SG and T-Dxd have a topoisomerase I inhibitor cytotoxic payload, which presents a clinical challenge in terms of how to best sequence these two agents when used for the treatment of HR+ MBC. In this chapter, we will describe ADCs pharmacology,


*Abbreviations: ADCs, antibody drug conjugates; DAR, Drug-to-antibody ratio; FDA, U.S. Food and Drug Administration; HER2, human epidermal growth factor receptor 2; IgG, immunoglobulin G; mAb, monoclonal antibody; MMC, maleimidomethyl cyclohexane-1-carboxylate; SG, sacituzumab govitecan; T-DM1, ado-trastuzumab emtansine; T-Dxd, fam-trastuzumab deruxtecan.*

#### **Table 1.**

*Approved ADCs in breast cancer [14–16].*

pharmacokinetic and pharmacodynamic properties, pharmacogenomic implications, clinical outcomes and place in breast cancer therapy, safety and monitoring.
