Antibody-drug conjugates in breast oncology: new standards,emerging challenges,and future directions

Introduction

Antibody-drug conjugates (ADCs) are novel targeted therapies that link a monoclonal antibody to a cytotoxic payload, allowing for effective targeted delivery of anticancer molecules to cancer cells. ADCs combine precision with potency; their efficacy has been evident in prior studies in breast cancer. ¹ Ado-trastuzumab emtansine (T-DM1) was the first ADC approved for the management of metastatic HER2-positive breast cancer. ² The subsequent success of trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd) in the metastatic setting expanded the scope of ADCs to include all breast cancer subtypes.^3–7 This special collection brings together leading experts to explore the rapidly evolving role of ADCs in breast cancer, including their mechanisms of action, real-world applicability, and the utility of moving these agents into early-stage settings.

T-DXd has rapidly emerged as a highly effective therapy for patients with advanced HER2-positive breast cancer. It has also shown improvement in overall survival (OS) and progression-free survival (PFS) in heavily pretreated patients with HER2-low and HER2-ultralow disease, respectively.^3,8 Sang et al. ⁹ conducted an observational, multicenter, real-world analysis of T-DXd in 61 patients in China with advanced or metastatic HER2-positive and HER2-low expressing breast cancer. This study demonstrated a median PFS of 10.51 and 10.18 months in HER2-low and HER2-positive disease, respectively. ⁹ Approximately 77% of patients received T-DXd in the third-line setting or beyond, with prior exposure to other HER2-targeted agents, including trastuzumab and pertuzumab, among those with HER2-positive breast cancer, and prior CDK4/6 inhibitors among those with HER2-low breast cancer. The objective response rates (ORR) were 38% for HER2-low and 62.5% for HER2-positive cancers. Time to response to therapy was 1.3 months in both cohorts. This study confirmed the efficacy of T-DXd in a small real-world cohort of patients from China, regardless of their HER2 status, ensuring that advances in cancer care translate to patients in diverse settings.

There has been increasing interest in evaluating the role of other ADCs in HER2-low metastatic breast cancer, including the use of SG and novel agents like MRG002 (HER2-targeted ADC with a monomethyl auristatin E (MMAE) payload) and RC48-ADC (HER2-targeted ADC with MMAE payload). Michelon et al. ¹⁰ evaluated the efficacy of ADCs among patients with metastatic HER2-low breast cancer in a meta-analysis of 14 studies (five real-world studies and nine clinical trials) encompassing 2883 patients receiving various ADCs, including T-DXd, SG, MRG002, and RC48-ADC. ADCs demonstrated a consistent improvement in PFS and OS compared to the physicians’ choice of treatment (typically chemotherapy), with a 50% reduction in the risk of progression (n = 1828, hazard ratio (HR) 0.50, 95% confidence interval (CI), 0.36–0.68, I ²  = 82%, p < 0.001) and a 30% reduction in the risk of death (n = 1546, HR 0.70, 95% CI, 0.57–0.86, I ²  = 43%, p < 0.001), respectively. Furthermore, T-DXd achieved the highest ORR, disease control rate, and clinical benefit rate among all the ADC studies. This study underscores the need for researching the role of ADCs in earlier lines of treatment in metastatic HER2-low breast cancer. Yet the optimal sequencing of ADCs in HR-positive metastatic breast cancer remains unclear. McLaughlin et al. ¹¹ review the retrospective data on ADC sequencing and provide a framework for an optimal approach to sequencing.

ADCs such as SG and Dato-DXd, directed against TROP-2, have also made their way to treating metastatic triple-negative breast cancer (TNBC) that expresses programmed death-ligand (PDL-1). There is a paucity of prognostic biomarkers for patients receiving this therapy. In a Polish study, no body mass index category or weight change was predictive of disease progression or mortality despite the known association between obesity and breast cancer. ¹²

Given the median OS of less than 2 years with first-line chemoimmunotherapy in metastatic TNBC, there was an unmet need to improve patient outcomes, as some patients never make it to the second-line setting. ASCENT-04 demonstrated improvement in PFS with the use of SG with pembrolizumab in first line setting. ¹³ In this special collection, Schmid et al. ¹⁴ report the study design of the TROPION-Breast05 study, a pivotal phase III trial evaluating the efficacy and safety of Dato-DXd, a TROP-2 directed ADC with a topoisomerase I inhibitor payload in combination with the immune checkpoint inhibitor durvalumab for first-line treatment in metastatic PDL-1-positive TNBC. ¹⁴ The frontline implementation of ADCs will likely enable a large percentage of patients to access this highly effective treatment modality, compared with waiting for second- or third-line treatment, where a large percentage of patients may be lost to follow-up or die.

Despite these advances, breast cancer is one of the leading causes of brain metastases, which has historically rendered a poor prognosis. Pan et al. ¹⁵ reviewed the emerging role of ADCs in treating breast cancer-related brain metastasis, highlighting the compelling evidence of the intracranial activity of T-DXd and limited but promising data for SG and T-DM1. A major barrier has been the exclusion of patients with active brain metastases from pivotal ADC trials, underscoring the need for central nervous system-inclusive studies.

Most patients receiving ADCs eventually progress, despite treatment. This may be attributable to resistance to treatment, which can be acquired or de novo. Medhus et al. ¹⁶ demonstrated that the cytotoxic activity of HER2-targeted ADCs, specifically T-DM1 and T-DXd, is critically dependent on RAB GTPases, which regulate the endocytic trafficking and lysosomal delivery of the ADC-antigen complex. These small GTP-binding proteins orchestrate vesicular transport within cells. T-DM1 efficacy correlated with the level of HER2 and RAB5A expression, whereas T-DXd did not show a correlation with the HER2 expression level but did correlate with RAB5A levels, albeit less strongly than T-DM1. Knockdown or overexpression of RAB5 altered the cytotoxicity of both ADCs—more so for TDM1—highlighting the importance of early endosomal trafficking. Profiling RAB GTPase expression could predict which patients respond better to T-DM1 than to T-DXd, enabling better patient selection and a biomarker-driven approach to treatment.

The role of ADCs in the early-stage setting has been limited, with T-DM1 being the only approved ADC for several years for HER2-positive breast cancer. Recently, T-DXd has shown efficacy in the adjuvant setting for patients with high-risk residual disease with HER2-positive breast cancer. ¹⁷ There is also interest in bringing ADCs to early stage TNBC. In our special collection, McArthur et al. ¹⁸ report on the study design of the TROPION-Breast04 study, which evaluates the role of neoadjuvant Dato-DXd, another ADC, and durvalumab for resectable TNBC compared with pembrolizumab and chemotherapy. ¹⁸

Qiu et al. ¹⁹ describe the newer ADCs in the pipeline for managing all subtypes of breast cancer. Furthermore, they review the currently ongoing preclinical studies and clinical trials evaluating these therapies.

Izzo et al. ²⁰ highlight how ADCs have evolved beyond delivering traditional chemotherapy payloads. Their review centers on emerging non-chemotherapy payloads, including immune-stimulating agents, natural toxins, PROTACs, and radionuclides, and examines how these novel designs may expand ADC potential and utility in oncology. Intriguingly, they also discuss the “magic shield” concept, where ADCs could guard healthy tissues against the side effects of concurrent systemic therapies by delivering protective or antidotal agents—flipping the conventional paradigm of ADCs as purely cytotoxic.

While ADCs represent an exciting therapeutic strategy for breast cancer, they are not without toxicities. Kang and Kim ²¹ summarize the common toxicities with ADCs utilized in breast cancer and stress the need to proactively prevent and mitigate the side effects of treatment. They also highlight the importance of appropriate dose reductions, treatment delays, discontinuations, and collaborations with subspecialists for optimal management of ADC-related toxicities.

Conclusion

The articles in this special collection highlight the breadth of scientific progress—from payload innovations to resistance mechanisms that could suggest potential biomarker discovery—and the depth of clinical impact, with ADCs now firmly established across all breast cancer subtypes. They also highlight the challenges we face, including optimizing sequencing and combinations, managing toxicities, and ensuring equitable global access to these therapies.

While the story is far from complete, it is clear that ADCs have reshaped the paradigm of breast cancer treatment. With the power of translational science, collaborative clinical investigation, and precision therapeutics, breast cancer will likely remain at the forefront of ADC development in medical oncology.