Antibody–drug conjugates (ADCs) are reshaping the treatment landscape of breast cancer at an unprecedented pace. From HER2 to Trop-2, and from late-line metastatic settings to early-stage neoadjuvant therapy, ADC indications continue to expand while efficacy breakthroughs accumulate. Oncology Frontier invited Professor Jian Zhang from Fudan University Shanghai Cancer Center and Professor Songqing Ye from Fujian Provincial Hospital to engage in an in-depth discussion on the evolution of ADCs, recent clinical advances, toxicity management, and future trends. Drawing on cutting-edge clinical data and real-world experience, the two experts offer valuable insights into efficacy optimization, toxicity management, frontline integration, combination strategies, and drug diversification.Evolution of ADCs: a microcosm of breast cancer therapeutic progress
Professor Jian Zhang: ADCs have become a cornerstone of precision therapy in breast cancer and represent one of the most dynamic areas of current research. A growing number of ADCs targeting HER2, Trop-2, HER3, Nectin-4, and EGFR are emerging.
Mechanistically, ADCs bind to cell surface antigens, undergo internalization, and release cytotoxic payloads through lysosomal degradation. Some agents also exhibit a “bystander effect,” allowing payload diffusion into the tumor microenvironment and enhancing efficacy in heterogeneous tumors.
Historically, trastuzumab emtansine (T-DM1) was the first ADC widely used in HER2-positive breast cancer, followed by trastuzumab deruxtecan (T-DXd), which demonstrated not only strong activity in HER2-positive disease but also efficacy in HER2-low tumors—expanding its clinical applicability.
While T-DM1 remains important in later-line and post–non-pCR adjuvant settings, T-DXd has rapidly advanced across multiple treatment stages, including first-line metastatic therapy, adjuvant, and neoadjuvant settings. Notably, its activity in HER2-low and ultra-low populations represents a paradigm shift.
Beyond HER2, Trop-2–targeted ADCs such as sacituzumab govitecan have transformed treatment in triple-negative breast cancer (TNBC) and expanded into HR+/HER2– disease. Emerging agents such as Dato-DXd and SKB264 further reinforce this therapeutic class.
In essence, the evolution of ADCs mirrors the broader trajectory of breast cancer therapy—moving toward greater precision, broader applicability, and deeper biological targeting.
Key clinical advances: a breakthrough year for ADCs
Professor Songqing Ye: There is no doubt that ADCs have become one of the brightest innovations in oncology, and 2025 marked a breakthrough year for their development in breast cancer.
In early HER2-positive disease, the DESTINY-Breast11 and DESTINY-Breast05 studies were particularly impactful. DESTINY-Breast11 demonstrated a pCR rate of 67.3% with T-DXd-based neoadjuvant therapy, despite a high-risk population. DESTINY-Breast05 further showed that T-DXd significantly improved invasive disease–free survival compared with T-DM1 in patients with residual disease, establishing a new standard for non-pCR populations.
Notably, domestic ADCs have also delivered impressive results. Agents such as SHR-A1811 and TQB2102 have demonstrated strong efficacy, highlighting the rapid progress of Chinese drug development.
In the metastatic setting, DESTINY-Breast09 showed remarkable first-line results, with T-DXd plus pertuzumab achieving a median PFS of 40.7 months. However, questions remain regarding patient selection, treatment duration, and maintenance strategies, emphasizing the need for individualized approaches.
For TNBC, ADCs have fundamentally changed the treatment paradigm. Studies such as ASCENT-03 and TB-02 confirmed the efficacy of Trop-2–targeted ADCs, while combination strategies with immunotherapy are showing promising synergy.
In HR+/HER2– disease, ADCs such as T-DXd and SKB264 have demonstrated consistent efficacy across molecular subgroups, further expanding treatment options in later lines.
Overall, ADCs are rapidly reshaping both early- and late-stage breast cancer management, with several agents already influencing clinical practice.
Clinical research landscape: expanding targets and technologies
Professor Jian Zhang: A wide range of ADCs are currently under investigation. Novel Trop-2 ADCs with optimized linker technologies are being developed to reduce adverse events such as mucositis.
In the HER2 field, next-generation agents—including dual-epitope ADCs such as JSKN003—are showing promising activity in both HER2-positive and HER2-low populations.
Beyond HER2 and Trop-2, ADCs targeting HER3 and Nectin-4 are gaining traction. For example, HER3-targeted bispecific ADCs and Nectin-4 ADCs have demonstrated encouraging results, particularly in patients who have progressed on prior ADC therapies.
Additionally, the emergence of bispecific ADCs and dual-payload ADCs represents an exciting frontier. Ultimately, head-to-head trials will be essential to define the relative clinical value of these agents.
Toxicity: not necessarily “safer” than chemotherapy
Professor Songqing Ye: There is a common misconception that ADCs are less toxic than traditional chemotherapy, but this is not necessarily the case.
ADC toxicity consists of three components: antibody-related toxicity, payload-related toxicity, and ADC-specific adverse effects. These may include cardiotoxicity, interstitial lung disease, thrombocytopenia, and ocular toxicity, in addition to conventional chemotherapy-related effects.
Therefore, toxicity management must be individualized and proactive. Clinicians must carefully balance efficacy with safety and prioritize patient quality of life.
Future directions: toward more effective and precise therapy
Professor Jian Zhang: The future of ADCs lies in improving both efficacy and safety. Addressing resistance mechanisms, particularly in low-antigen–expression tumors, will be critical to translating PFS benefits into OS gains.
Technological advancements aimed at reducing on-target and off-target toxicity will also play a key role in optimizing patient outcomes.
Professor Songqing Ye: I fully agree. Looking ahead, ADC development will follow four major trends:
First, frontline integration—moving from late-stage disease into neoadjuvant and adjuvant settings for high-risk patients.
Second, combination strategies—including combinations with chemotherapy, immunotherapy, targeted therapies, radiotherapy, and even dual-ADC approaches.
Third, diversification—with multiple targets and payloads enabling more rational sequencing strategies.
Fourth, precision medicine—driven by biomarker discovery and resistance mechanism research, allowing truly individualized treatment.
Conclusion ADC therapy has entered a phase of rapid expansion and transformation. While significant progress has already been achieved, continued innovation in drug design, patient selection, and combination strategies will be essential to fully realize its potential. The ultimate goal remains clear: to deliver more effective, safer, and truly personalized treatment for patients with breast cancer.
Expert profiles
Jian Zhang, MD Fudan University Shanghai Cancer Center
Songqing Ye, MD Chief Physician, Department of Breast Surgery
Fujian Provincial Hospital
