Antibody-Drug Conjugates for the Treatment of Breast Cancer

Abstract

Metastatic breast cancer (BC) is currently an incurable disease. Besides endocrine therapy and targeted agents, chemotherapy is often used in the treatment of this disease. However, lack of tumor specificity and toxicity associated with dose exposure limit the manageability of cytotoxic agents. Antibody-drug conjugates (ADCs) are a relatively new class of anticancer drugs. By merging the selectivity of monoclonal antibodies with the cytotoxic properties of chemotherapy, they improve the therapeutic index of antineoplastic agents. Three core components characterize ADCs: the antibody, directed to a target antigen; the payload, typically a cytotoxic agent; a linker, connecting the antibody to the payload. The most studied target antigen is HER2 with some agents, such as trastuzumab deruxtecan, showing activity not only in HER2-positive, but also in HER2-low BC patients, possibly due to a bystander effect. This property to provide a cytotoxic impact also against off-target cancer cells may overcome the intratumoral heterogeneity of some target antigens. Other cancer-associated antigens represent a strategy for the development of ADCs against triple-negative BC, as shown by the recent approval of sacituzumab govitecan. In this review, we discuss the current landscape of ADC development for the treatment of BC, as well as the possible limitations of this treatment.

Keywords: ADCs; antibody; antibody–drug conjugates; breast cancer; target therapy.

Figure 4

Toxicity profiles of the antibody–drug conjugates currently approved or in late stages of development. Abbreviations: WBC, white blood count; T-DM1, trastuzumab emtansine; T-Dxd, trastuzumab deruxtecan; neutr, neutrophil [7,25,42,56].

Figure 1

Temporal milestones of antibody–drug conjugates currently approved for the treatment of BC. Abbreviations: HER2, human epidermal growth factor receptor 2; T-DM1, trastuzumab emtansine; T-Dxd, trastuzumab deruxtecan; EMA, European Medicines Agency; FDA, Food and Drug Administration; 1MBC, metastatic breast cancer; 2EBC, early breast cancer; 3ABC, advanced breast cancer; mTNBC, metastatic triple-negative breast cancer.

Figure 2

Main features of ADCs currently FDA-approved for the treatment of BC. Abbreviations: T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan; SG, Sacituzumab govitecan; HER2, human epidermal growth factor receptor 2; mAb, monoclonal antibody; DAR, drug-to-antibody ratio; DM1, emtansine; DxD, deruxtecan; TROP2, Trophoblast cell surface antigen 2; TNBC, triple-negative breast cancer. Created with Biorender.com (accessed on 15 March 2021).

Figure 3

Spectrum of toxicity observed in clinical trials investigating novel ADCs. Abbreviations: ILD, interstitial lung disease; FcγR, Fragment crystallizable-gamma receptor; T-DXd, trastuzumab deruxtecan; MMAE, Monomethyl auristatin E; MMAF, Monomethyl auristatin F; DM1, mertansine/emtansine; DM4, ravtansine/soravtansine; seco-DUBA, seco-duocarmycin-hydroxybenzamide-azaindole; LVEF, Left Ventricular Ejection Fraction; Abs, antibodies. Created with Biorender.com (accessed on 15 March 2021).