Introduction
Breast cancer is the most common cancer among women worldwide, with approximately 20% of cases being HER2-positive. These patients have a high recurrence rate and poor prognosis. The advent of HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab has improved the prognosis for patients with HER2-positive advanced breast cancer. In recent years, antibody-drug conjugates (ADCs) have been changing the treatment landscape for HER2-positive advanced breast cancer. Trastuzumab emtansine (T-DM1) is the first ADC approved for the treatment of HER2-positive advanced breast cancer. Subsequently, the DESTINY-Breast 03 (DB03) study showed that trastuzumab deruxtecan (T-DXd) was more effective than T-DM1 as a second-line treatment for HER2-positive advanced breast cancer. However, the efficacy of ADCs is limited by acquired resistance. A review published in the journal Cancer Drug Resist elaborates on the structure, mechanisms of action, and resistance mechanisms of ADCs and discusses potential strategies to overcome ADC resistance.
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Structure, Mechanism of Action, and Clinical Activity of ADCs
ADCs consist of a humanized monoclonal antibody linked to a cytotoxic drug payload via cleavable or non-cleavable linkers. Currently, T-DM1 and T-DXd have been approved for the treatment of HER2-positive advanced breast cancer.
T-DM1 is composed of trastuzumab and a derivative of maytansine (DM1) linked by a non-cleavable linker, with a drug-to-antibody ratio (DAR) of 3.5. T-DM1 selectively releases DM1 into HER2-positive tumor cells, inhibiting the HER2 signaling pathway and promoting the shedding of the HER2 extracellular domain. Additionally, similar to trastuzumab, T-DM1 can also exert its effects through antibody-dependent cell-mediated cytotoxicity (ADCC). The EMILIA study showed that T-DM1 significantly prolonged the median progression-free survival (PFS) (9.6 months vs 6.4 months, P<0.001) and median overall survival (OS) (30.9 months vs 25.1 months, P<0.001) compared to the capecitabine plus lapatinib regimen in HER2-positive advanced breast cancer patients.
T-DXd is a novel ADC drug composed of trastuzumab linked to a potent topoisomerase I inhibitor (DXd) via a cleavable linker, with a DAR of 8, a short systemic half-life, and a bystander effect. In the DESTINY-Breast 01 study, T-DXd demonstrated significant clinical activity in HER2-positive advanced breast cancer patients, with an objective response rate (ORR) of 61% and a median PFS of 19.4 months. The subsequent DESTINY-Breast 02 (DB02) study further confirmed that in HER2-positive advanced breast cancer patients who had failed T-DM1 treatment, the median PFS in the T-DXd group was significantly better than in the control group (17.8 months vs 6.9 months, P<0.0001). The DB03 study directly compared the efficacy of T-DXd and T-DM1 in HER2-positive advanced breast cancer patients who had previously received taxane and trastuzumab treatment, showing that the median PFS in the T-DXd group was significantly extended compared to the T-DM1 group (28.8 months vs 6.8 months, P<0.0001).
Resistance Mechanisms of ADCs
Due to the structure and mechanisms of action of ADCs involving multiple steps, resistance may occur at any stage. This may be related to factors such as antigen expression and recognition, drug internalization and degradation, effective payload release, and regulation of apoptosis.
Regarding antigens, prolonged ADC treatment may lead to decreased HER2 receptor expression or structural changes, affecting ADC efficacy. Additionally, tumor heterogeneity can impact antigen expression and ADC efficacy. The presence of truncated forms of HER2 in the extracellular domain is also considered a potential resistance mechanism, although this mechanism has not yet been confirmed in ADC treatment. Furthermore, neuregulin (NRG) regulates ADC sensitivity by stimulating the formation of heterodimers between HER2 and HER3, HER4, and overexpression of HER3 has been confirmed to be associated with resistance to ADCs (such as T-DM1).
In HER2-positive tumor cells, the inability of HER2 to internalize through endocytosis is one of the main mechanisms of ADC resistance. Studies have shown that overexpression of caveolin-1 (CAV-1) is associated with reduced sensitivity of tumor cells to T-DM1. After ADC binds to its target molecule and enters tumor cells via endocytosis, it is transported to lysosomes, where the cytotoxic drug is released through chemical and enzymatic actions. Impaired lysosomal function may lead to ADC resistance. Additionally, defects in the lysosomal release of cytotoxic drugs or barriers to drug transport to the cytoplasm may also be related to ADC resistance. For example, in vitro models have shown that silencing or deletion of the SLC46A3 gene leads to the accumulation of metabolites in lysosomes, resulting in T-DM1 resistance. The DAISY study indicated that deletion of the SLX4 gene leads to resistance to T-DXd treatment in cancer cells.
Regarding effective payloads, studies have shown that increased efflux of the payload DM1 is a significant cause of T-DM1 resistance.
Moreover, drug efflux pumps are also an important mechanism of ADC resistance, mediating ADC treatment resistance by accelerating the expulsion of drugs from tumor cells, which may lead to a multidrug-resistant phenotype in cancer.
Activation of signaling pathways is also a potential mechanism leading to ADC resistance, including activation of the PI3K/AKT/mTOR pathway and the Wnt/β-catenin signaling pathway. Additionally, overexpression of trophoblast cell surface antigen 2 (TROP-2) may also be a potential resistance mechanism.
Strategies to Overcome ADC Resistance
To address the issue of resistance to HER2 ADC treatment and enhance its clinical efficacy in advanced breast cancer, various strategies are being explored. These strategies include the development of novel ADC drugs or the combination of ADCs with tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and DNA-damaging agents.
Novel ADC Drugs
The DB02 study confirmed that the novel ADC drug T-DXd can overcome tumor resistance to T-DM1 treatment. Additionally, novel HER2 ADC drugs such as SYD985, SHR-A1811, and ARX788 have shown some efficacy in HER2-positive advanced breast cancer patients who have previously received T-DM1 treatment.
ZW49 is a bispecific ADC that can target two non-overlapping HER2 antigens simultaneously. In a phase I dose-escalation trial, the disease control rate (DCR) for HER2-positive advanced breast cancer patients treated with 2.5 mg/kg ZW49 was 50%. BIO-201 is another bispecific ADC that can target both TROP-2 and HER2 antigens. A preclinical study indicated that BIO-201 is effective against various cancers that co-express TROP-2 and HER2, only express TROP-2, or only express HER2.
In the U31402-A-J101 study, patritumab deruxtecan (HER3-DXd) demonstrated good clinical activity in HER2-positive breast cancer patients, with an ORR of 42.9%, a DCR of 92.9%, and a median PFS of 11.0 months.
Furthermore, another strategy to overcome ADC resistance is to develop non-internalizing ADCs that target the tumor microenvironment (TME). The TME plays a crucial role in tumor cell growth, neovascularization, and metabolic waste clearance. Novel ADCs targeting TME antigens such as CD74, CCR7, and CD276 are currently in clinical development and evaluation for hematological malignancies and solid tumors.
ADC Combination Therapy
ADC+TKI
The HER2CLIMB-02 study aimed to compare tucatinib combined with T-DM1 versus T-DM1 alone in HER2-positive advanced breast cancer patients who had previously received taxane combined with trastuzumab treatment. The results showed that the median PFS in the combination therapy group was significantly better than in the T-DM1 monotherapy group (9.5 months vs 7.4 months, HR=0.74). However, this study did not directly compare the current second-line standard treatment regimen T-DXd, so the clinical positioning of this combination regimen remains unclear.
ADC+ICI
The KATE2 study evaluated the efficacy of T-DM1 combined with the PD-L1 inhibitor atezolizumab in previously treated HER2-positive advanced breast cancer patients. The results indicated that adding atezolizumab to T-DM1 did not significantly improve the median PFS of patients (8.2 months vs 6.8 months; P=0.33). The KATE3 study aims to compare T-DM1 combined with atezolizumab versus T-DM1 monotherapy in previously treated HER2-positive, PD-L1-positive advanced breast cancer patients; the ASTEFANIA study aims to evaluate the efficacy of T-DM1 combined with atezolizumab or placebo as adjuvant therapy in high-risk HER2-positive breast cancer patients after neoadjuvant chemotherapy. Both trials are ongoing.
Conclusion
The issue of resistance to ADC drugs has become a key challenge in the current clinical practice of HER2-positive advanced breast cancer. Strategies to address this challenge include the development of next-generation ADC drugs and ADC combination therapies. Therefore, the development of next-generation ADC drugs is urgent, requiring in-depth exploration of their pharmacological mechanisms, resistance pathways, and precise application scenarios. Based on the existing encouraging research data, combination therapy strategies may become a key pathway to overcome resistance challenges, bringing new treatment hope to patients!
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Valid until: 2026/10/27
References
1. Saleh K, Khoury R, Khalife N, et al. Mechanisms of action and resistance to anti-HER2 antibody-drug conjugates in breast cancer. Cancer Drug Resist. 2024;7:22. Published 2024 Jun 3.
Editor: ICEY
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