Toxicities and management strategies of emerging antibody-drug conjugates in breast cancer

Abstract

Antibody-drug conjugates (ADCs) offer a promising therapeutic approach for various cancers, enhancing the therapeutic window while mitigating systemic adverse effects on healthy tissues. ADCs have achieved remarkable clinical success, particularly in treating breast cancer, becoming a standard therapy across all subtypes, including hormone receptor-positive, human epidermal growth factor receptor 2-positive, and triple-negative breast cancer. Although designed to selectively target antigens via monoclonal antibodies, ADCs can exhibit toxicity in normal tissues, often due to off-target effects of their cytotoxic payloads. Understanding and managing these toxicities according to established guidelines are crucial for enhancing ADC clinical efficacy, minimizing adverse events, and ultimately improving patient outcomes. This review comprehensively examines the toxicities of ADCs employed in breast cancer treatment and explores their management strategies. Furthermore, we investigate novel ADCs beyond trastuzumab deruxtecan and sacituzumab govitecan, evaluating their potential efficacy and corresponding safety profiles.

Keywords: adverse events; antibody–drug conjugates; breast cancer; trastuzumab deruxtecan.

Graphical abstract

Figure 1.

Structure of ADC and brief mechanisms of ADC toxicity. (a) Schematic diagram of an ADC comprising a monoclonal antibody, a cytotoxic payload, and a linker. (b) Schematic diagram illustrating on-target, off-tumor toxicity. ADCs could bind the target antigens expressed in healthy normal tissues, and, through target-mediated endocytosis, result in target-dependent toxicities. (c) Schematic diagram of off-target, off-tumor toxicity. ADCs could affect healthy non-target tissues, causing target-independent toxicity. ADCs utilizing cleavable linkers frequently release payloads prematurely in plasma, and these released (free) payloads may be internalized by normal cells through passive diffusion or specific transporters. Furthermore, intact ADCs can be internalized into normal cells through receptor-mediated (Fcγ receptors, neonatal Fc receptor, or C-type lectin receptors) or nonspecific endocytosis. Source: Created with BioRender.com ADC, antibody–drug conjugates; FcγRs, Fcγ receptors; FcRn, neonatal Fc receptor.

Figure 2.

Incidences of common toxicities associated with ADCs in breast cancer treatment. AE incidences are based on the data reported from the EMILIA,^, meta-analysis of T-DM1 associated with cardiotoxicity, DESTINY-Breast03, ASCENT, TULIP, ICARUS-BREAST01, and TROPION-Breast01 trials. The reported incidence of AEs for the same ADC can vary across different trials. ADC, antibody–drug conjugates; AE, adverse event; ANC, neutropenia; AST/ALT, increased transaminase levels; Dato-DXd, datopotamab deruxtecan; HER3-DXd, patritumab deruxtecan; ILD, interstitial lung disease/pneumonitis; PLT, thrombocytopenia; PN, peripheral neuropathy; SG, sacituzumab govitecan; T-DM1, ado-trastuzumab emtansine; T-duo, trastuzumab duocarmazine; T-DXd, trastuzumab deruxtecan.