Antibody-drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment

Abstract

Antibody-drug conjugates (ADCs) are a class of antineoplastic agents whose structure is composed of three main components: a monoclonal antibody (mAB) targeting a specific target antigen, a cytotoxic payload, and a linker binding the antibody to the payload. By combining the specificity of mABs with the high potency of the payloads, ADCs constitute a smart drug delivery system with improved therapeutic index. After recognition and binding of the mAB to its target surface antigen, ADCs are internalized by endocytosis by the tumor cell, releasing the payloads into the cytoplasm, where they exert their cytotoxic activity, eventually leading to cell death. The composition of some of the new ADCs confers additional functional properties that allow expanding their activity to neighboring cells not expressing the target antigen, constituting a valuable strategy to overcome tumor heterogeneity. Some of these 'off-target effects', such as the bystander effect, are possibly the mechanism underlying the antitumor activity demonstrated in patients with low expression of the target antigens, which represents an important paradigm shift in anticancer targeted therapy. Three ADCs are currently approved for the treatment of breast cancer (BC); two anti-HER2 (human epidermal growth factor receptor 2) ADCs (trastuzumab emtansine and trastuzumab deruxtecan); and one Trop-2-targeted ADC (sacituzumab govitecan). Based on the unprecedented efficacy data demonstrated by these agents, ADCs have been incorporated as part of standard regimens for all subtypes of advanced BC, as well as for high-risk early HER2-positive BC. Despite the remarkable advances, several hurdles still remain to overcome, including the development of reliable biomarkers for patient selection, prevention, and management of potentially severe toxicities, ADC resistance mechanisms, post-ADC resistance patterns, and optimal treatment sequencing and combinations. In this review, we will summarize the currently available evidence related to the use of these agents, as well as explore the current landscape of ADC development for BC treatment.

Keywords: antibody–drug conjugates; breast cancer; targeted therapy.

Figure 1.

ADCs currently approved by the US FDA and EMA for the treatment of breast cancer. EMA, European medicines agency.

Figure 2.

Incidence of adverse events associated with T-DXd, T-DM1, and SG in DESTINY-Breast03 and ASCENT trials. The rates of adverse events are based on the data reported from the DESTINY-Breast03 and ASCENT trials.^, The incidence of adverse events for the same ADC may vary between different trials. ^aIncidence of ILD in DESTINY-Breast03. ^bAspartate aminotransferase increased. ILD, interstitial lung disease; SG, sacituzumab govitecan, T-DM1, trastuzumab emtansine, T-DXd: trastuzumab deruxtecan. Created with BioRender.com.

Figure 3.

Incorporation of ADCs into the management of metastatic breast cancer. ^aThe treatment options presented for each line are not exhaustive and should not necessarily be administered in the order in which they are listed. More than one regimen listed for each line can be administered before moving on to subsequent line options. The proposed order may vary according to drug availability, clinical conditions and patients’ preferences. ^bThere is no direct evidence supporting an optimal treatment sequence after progression on CDK4/6 inhibitors in hormone receptor-positive/HER2-negative aBC, and after T-DXd in HER2-positive disease. ^cET + CDK4/6 inhibitors may be considered in selected patients with visceral crisis based on the results of the RIGHT Choice trial. ^dEndocrine therapy combined with HER2-targeted agent may be considered in selected patients. AI, aromatase inhibitor; ET, endocrine therapy; gBRCA, germline BRCA mutation; ICI, immune checkpoint inhibitor; HER2-Low, HER2 IHC 1+ or IHC 2 + and ISH-negative; TNBC, triple negative breast cancer.